Advanced Organic Chemistry by David Lewis

Advanced
Organic Chemistry
David E. Lewis
University of Wisconsin–Eau Claire
New York Oxford
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contents
Preface ix
chapter one
The Fundamentals Revisited: Structure, Bonding, and Reactivity
1.1 Organic Structure: A Brief History 1
1.2 Proton Transfers Revisited: Acids and Bases 7
1.3 Reactions and Reaction Mechanisms: “Electron Pushing” 13
1.4 Resonance 24
1.5 Spectroscopy and Chromatography 30
Chapter Summary 31
Key Terms 32
Additional Problems 33
chapter two
Stereochemistry
2.1 Stereoisomers and Chirality 37
2.2 Absolute Configuration 46
2.3 Optical Purity and Configuration 57
2.4 Conformation 63
2.5 An Introduction to Asymmetric Synthesis: Asymmetric Induction 67
2.6 How Well Did It Go? Measuring Enantiomer Ratios 77
2.7 Chirality at Atoms Other Than Carbon: Inversion of Pyramidal Centers 78
Chapter Summary 80
Key Terms 81
chapter three
Organic Shorthand: Acronyms and Name Reactions
3.1 Organic Synthesis: A Brief Introduction 87
3.2 Name Reactions: A Historical Overview 87
3.3 Acronyms and Abbreviations 91
chapter four
Orbitals and Reactivity
4.1 Introduction 105
4.2 Atomic Orbitals: The History of the Modern Atomic Model 106
4.3 Covalent Bonding and Molecular Orbitals 111
Chapter Summary 125
Key Terms 126
iii
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iv contents
chapter five
Frontier Orbitals and Chemical Reactions
5.1 Chemical Reactions: Frontier Orbitals 129
5.2 Using Frontier Molecular Orbitals to Categorize Reactions and Reagents 137
5.3 Categorizing Reactions Using Frontier Molecular Orbital Pairings 142
5.4 Stereoelectronic Effects 156
5.5 Radical Reactions 159
Chapter Summary 160
Key Terms 160
chapter six
Organic Reactions I: Pericyclic Reactions and the Conservation
of Orbital Symmetry
6.2 π Molecular Orbitals of Conjugated Systems and Orbital Symmetry 165
6.3 Frontier Orbital Analysis: Stereochemical Consequences 167
6.4 Sigmatropic Rearrangements: More Details 170
6.5 Cycloaddition Reactions: More Details 180
6.6 Ene, Retro-Ene, and Similar Reactions 201
6.7 Orbital Correlation Diagrams 206
6.8 Combining Pericyclic Reactions in Sequence 209
Chapter Summary 214
Key Terms 215
chapter seven
Aromaticity: The 150-Year Riddle
7.1 Benzene: The Beginning 221
7.2 Aromaticity and Antiaromaticity: The Hückel Molecular Orbital
Model of Cyclic Polyenes 222
7.3 How Does One Measure Aromaticity? Criteria for Aromaticity
and Its Quantification 233
7.4 Möbius Aromaticity 243
7.5 Homoaromaticity 246
7.6 The Rest of the Story: The History and Mythology of Benzene 250
Chapter Summary 254
Key Terms 254
chapter eight
Physical Organic Chemistry and Reaction Mechanisms
8.2 Solvents and Solubility 262
8.3 Reaction Kinetics 270
8.4 Activation Parameters from Kinetic Studies 279
8.5 Correlating Reaction Rates: Linear Free Energy Relationships 280
8.6 Isotope and Element Effects 291
8.7 Trapping and Crossover Experiments 299
8.8 The Variable Transition State and the Concept of the Mechanistic
Spectrum 301
8.9 Using Regiochemistry and Stereochemistry 307
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contents v
8.10 The Reactivity-Selectivity Principle 308

Chapter Summary 309
Key Terms 309
chapter nine
Reactive Intermediates I: Carbocations
9.1 Carbocations 317
9.2 Rearrangements 327
9.3 Neighboring Group Participation 332
9.4 Nonclassical Carbocations 335
9.5 Methods for Generating Carbocations 339
Chapter Summary 342
Key Terms 343
chapter ten
Organic Reactions II: Synthesis Using Carbocations to Form C—C Bonds
10.2 The Friedel-Crafts Reactions 348
10.3 Formylation 364
10.4 Addition of Stabilized Carbocations: The Prins, Mannich,
and Mukaiyama Reactions 370
Chapter Summary 386
Key Terms 386
chapter eleven
Reactive Intermediates II: Carbanions and Their Reactivity
11.1 Carbanions: Introduction and Overview 391
11.2 Metal Alkyls 397
11.3 Carbanions Stabilized by Heteroatoms 411
11.4 Formation of Enolate Anions 420
11.5 Rearrangements of Carbanions 430
Chapter Summary 434
Key Terms 434
chapter twelve
Organic Reactions III: Synthetic Reactions of Carbon Nucleophiles:
Substitution and Addition
12.1 Carbon-Carbon Bond Formation: Carbon Nucleophiles and Electrophiles 439
12.2 Substitution and Addition with Metal Alkyl Reagents Having
C—M σ Bonds 439
12.3 Metal Enolates: Versatile Carbon Nucleophiles 458
12.4 The Aldol Addition Reaction 466
12.5 Conjugate Addition of Enolates and Similar Compounds 481
12.6 Azaenol Derivatives: Imines, Hydrazones, and Enamines 486
Chapter Summary 492
Key Terms 493
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vi contents
chapter thirteen
Reactive Intermediates III: Free Radicals, Carbenes, Arynes, and Nitrenes
13.1 Free Radicals 497
13.2 Carbenes 505
13.3 Nitrenes 516
13.4 Arynes 518
Chapter Summary 528
Key Terms 528
chapter fourteen
Organic Reactions IV: Applications of Free Radical Chemistry in Synthesis
14.1 Methods for Site-Specific Generation of Free Radicals 533
14.2 Reactions of Free Radicals 542
14.3 Reactions of Free Radicals Useful for Synthesis 548
14.4 Additions and Cyclizations of Free Radicals 557
14.5 Diradicals: Formation and Uses in Synthesis 567
Chapter Summary 569
Key Terms 570
chapter fifteen
Organic Synthesis: Retrosynthetic Analysis, Protecting
Groups, and the Strategy of Organic Synthesis
15.1 What Is Organic Synthesis? 577
15.2 Organic Reactions: Tools of the Synthetic Chemist 583
15.3 Retrosynthetic Analysis: An Introduction to the Vocabulary
and Strategy of Organic Synthesis 591
15.4 Applying RetrosyntheticAnalysis to a Real Example 605
15.5 Selectivity Revisited 610
15.6 Protection of Alcohols 614
15.7 Protection of Aldehydes, Ketones, and Carboxylic Acids 624
15.8 Protection of Amines 631
15.9 Protecting Groups for Hydrocarbons 635
Chapter Summary 638
Key Terms 638
chapter sixteen
Organic Reactions V: Condensations and Cascade Reactions
of Carbon Nucleophiles
16.1 Addition, Condensation, Cascade Reactions: Definitions 647
16.2 The Aldol Condensation and Related Reactions 647
16.3 Condensations Where the Initial Adduct Is Intercepted 650
16.4 The Claisen Condensation and Related Reactions 656
16.5 The Wittig, Horner-Wadsworth-Emmons, and Related Reactions 661
16.6 Cascade Reactions Initiated by Carbon Nucleophiles 677
Chapter Summary 682
Key Terms 682
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contents vii
chapter seventeen
Organic Reactions VI: Metal-Catalyzed Reactions for C—C Bond Formation
17.1 Catalysis and “Green” Chemistry 689
17.2 Bonding in Organometallic Complexes 690
17.3 Basic Organometallic Reactions I: Reactions at the Metal 697
17.4 Basic Organometallic Reactions II: Reactions at the Ligand 704
17.5 Hydrometalation: Making the Organometallic Reagents by Addition 716
17.6 Palladium-Catalyzed Substitution: Tsuji-Trost and Buchwald-Hartwig
Reactions 730
17.7 Cross-Coupling Reactions to Form C—C Bonds 737
Chapter Summary 752
Key Terms 753
chapter eighteen
Redox Reactions I: Oxidation
18.2 Overview of Oxidation 765
18.3 Oxidation of Alcohols to Aldehydes and Ketones with Stoichiometric
Metal-Based Reagents 766
18.4 Oxidation of Alcohols Using Non-Metal-Based Reagents 775
18.5 Oxidations to Carboxylic Acids 784
18.6 Oxidation of Ethers and Amines 789
18.7 Oxidative Rearrangements 792
18.8 Oxidation of Unsaturated Hydrocarbons 801
18.9 Oxidative Cleavage of Carbon-Carbon Bonds 815
18.10 Oxidative Substitution of Carbon-Hydrogen σ Bonds 821
18.11 Oxidation of Alkanes 834
18.12 A Catalogue of Oxidation Reactions: Oxidation at a Glance 838
Chapter Summary 842
Key Terms 842
chapter nineteen
Redox Reactions II: Reduction with Molecular Hydrogen or Its Equivalent
19.1 Overview of Reduction 855
19.2 Catalytic Hydrogenation 855
19.3 Hydrogenolysis 877
Chapter Summary 883
Key Terms 883
chapter twenty
Redox III: Reduction with Complex Metal Hydrides and Active Metals
20.1 Reductions with Metal Hydrides 891
20.2 Reduction by Hydrogen Transfer from Carbon 905
20.3 Stereochemistry and Stereoselectivity in Hydride Reductions 910
20.4 Reduction Using Metals 912
20.5 Reduction of Carbonyl Compounds to Hydrocarbons 924
20.6 A Catalog of Reduction Reactions: Reduction at a Glance 932
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viii contents
Chapter Summary 935

Key Terms 935
chapter twenty-one
Asymmetric Oxidation and Reduction
21.1 Asymmetric Redox Reactions: An Overview 943
21.2 Sharpless Asymmetric Epoxidation of Allylic Alcohols 944
21.3 Asymmetric Epoxidation of Unfunctionalized Alkenes 950
21.4 Oxidation with Chiral Three-membered Heterocycles 955
21.5 Asymmetric Dihydroxylation 965
21.6 Kinetic Resolution of Alcohols 967
21.7 Enantioselective Insertion into C—C and C—H Bonds 972
21.8 Asymmetric Hydrogenation 973
21.9 Asymmetric Reductions with Metal Hydrides and Metal Alkyls 980
21.10 Enzymes: Biocatalysis of Redox Reactions 983
Chapter Summary 985
Key Terms 986
chapter twenty-two
The Organic Compounds of Silicon, Phosphorus,
Sulfur, Selenium, and Tin
22.2 Silanes and Stannanes as Directing Groups: Carbocation Chemistry 999
22.3 Heteroatom-Centered Nucleophiles: Silyllithiums, Stannyllithiums,
Sulfides and Selenides 1008
22.4 Reactions of Organophosphorus, Organosulfur and Organoselenium
Compounds 1010
Chapter Summary 1021
Key Terms 1022
chapter twenty-three
Modern Asymmetric Synthesis
23.1 Controlling Absolute Stereochemistry 1027
23.2 Asymmetric Synthesis with Chiral Auxiliaries: Additions 1038
23.3 Asymmetric Substitution at Carbon: Alkylation of Enolates and
Related Nucleophiles 1051
23.4 Catalytic Asymmetric Synthesis 1055
23.5 Representative Asymmetric Syntheses 1066
Chapter Summary 1086
Key Terms 1086
Appendix 1: Named Reactions, Named Reagents, and Named Rules 1095

Appendix 2: Glossary of Key Terms 1119
Appendix 3: Selected Physical Constants 1133
Index 1137
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Preface
Over the past three decades of my career, I have seen introductory organic chemistry
change from a foundation course for chemists and chemical professionals, to a service
course for students planning on careers in the medical field. This change in emphasis has
been accompanied, in my opinion, by an erosion of the level of the course material, so that
students who do go on to graduate school in chemistry are no longer well prepared for the
introductory courses in organic chemistry at the graduate level. At the same time, the
amount and level of material that confronts new graduate students in organic chemistry
has become more demanding, and this has further widened the gap between the introduc-
tory courses at the undergraduate and graduate levels.
This book specifically targets advanced undergraduate students and entering graduate
students, and is an attempt to bridge that gap—to provide upper-level undergraduate stu-
dents with an advanced textbook that addresses a number of important topics in more
depth than now occurs in most introductory textbooks, while providing both a useful
review, and then a much more substantial discussion of these topics for beginning gradu-
ate students.
Organization
This book has been written explicitly as a textbook, and its organization reflects this. The
book is divided loosely into four sections: 1) introductory materials and general concepts
of bonding and stereochemistry; 2) physical organic chemistry, reactive intermediates,
and their reactions; 3) redox reactions; and 4) modern asymmetric reactions and synthe-
sis. This last section also contains a chapter on the chemistry of the elements in the lower
periods of the main groups, as well as a chapter on modern catalytic reactions for the
formation of carbon–carbon bonds.
Each chapter concludes with a list of key terms introduced in the chapter. In chapters
where new organic reactions are introduced, there are Reaction Synopses that contain the
general reaction and typical reagents and reaction conditions to effect the reaction. I also
feel that the humanity of our science is often overlooked in an effort to impart the most
factual information possible. To counter this, I have included footnotes where biographi-
cal information about the chemists who developed the science can be found. For the most
part, these footnotes contain references to longer biographical works or obituaries, but on
a few occasions, these biographies are somewhat more expansive because additional infor-
mation is so scarce.
Among the introductory chapters are discussions of stereochemistry and molecular
orbital theory, including frontier orbital theory and the question of aromaticity. This sec-
tion also contains a chapter (Chapter 3) containing the most frequently used acronyms in
organic chemistry. In many books, the acronyms list is relegated to an appendix, but their
use has become so widespread in modern synthetic organic chemistry that I have chosen
to include them explicitly in the body of the book.
ix
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x Preface
Traditionally, there have been three core courses in organic chemistry: 1) physical or-
ganic chemistry, which encompasses the study of the structure and properties of reactive
intermediates; 2) organic reactions, in which the individual reactions and reaction types
are taught; and 3) organic synthesis, where the design of syntheses—the art of combining
organic reactions in sequence—is the focal point. In most cases, these three courses are
sufficiently different that they can be taught separately, but this does lose the benefits that
accrue to the student when new concepts are applied immediately after they are learned.
In this book, I have deliberately chosen to follow each chapter introducing a new reactive
intermediate with a chapter discussing reactions that involve those intermediates, so the
student can see immediately just how these reactions can be used in the construction of
complex molecules. For example, the chapter on modern molecular orbital theory and
frontier orbital theory is followed immediately by a chapter on pericyclic reactions, where
the application of these concepts in synthesis is illustrated.
Chapter 1 is essentially a review of concepts of structure and bonding from the intro-
ductory course in organic chemistry, with an emphasis on arrow-pushing and resonance
theory. It is my belief that this will constitute a useful review for upper-level undergradu-
ate students, especially, but in my experience it may not be completely unnecessary for
entering graduate-level students. In my own upper-level undergraduate organic chemistry
course, Modern Organic Chemistry, I have covered this material explicitly in class, and I
have also set this as advanced reading, rather than explicitly including it in the lecture
material.
Chapter 2 focuses on stereochemistry, and introduces students to both axial and
planar chirality, and the Cahn-Ingold-Prelog method for assigning configurations to
chiral molecules and to geometric isomers is introduced. The conformations of open-
chain and cyclic molecules is discussed. The measurement of optical purity and the deter-
mination of enantiomeric excess (e.e.) or enantiomer ratio (e.r.) are discussed in the light
of methods to achieve asymmetric synthesis. The Cram and Felkin-Anh models for pre-
dicting the stereochemistry of additions to chiral aldehydes and ketones are introduced.
Chapter 3 contains a list (already far from exhaustive) of acronyms used in modern
synthetic organic chemistry.
Chapter 4 introduces the modern orbital model of atoms and molecules, including the
LCAO method for obtaining molecular orbitals. Hybridization theory is extended to in-
clude variable hybridization, and the modeling of π-bonding systems by Hückel molecu-
lar orbital theory is introduced. Much of this forms the basis for the subsequent discussion
of frontier orbital theory in Chapter 5. In Chapter 5, frontier orbital theory is introduced
as an organizing principle for organic reactions, and as a basis for interpreting regiochem-
istry and stereochemistry in organic reactions, as well as stereoelectronic effects such as
the anomeric effect in organic molecules. Chapter 6 introduces pericyclic reactions. These
reactions are now often a "special topic" in introductory texts, so this chapter is focused on
how these reactions are used in modern synthesis to build complex molecules and transfer
chirality from one part of a molecule to another. The chapter concludes with a discussion
of "click" chemistry, and tandem and domino reactions.
Chapter 7 explores questions of aromaticity and antiaromaticity, and discusses the
various criteria that have been developed to measure aromatic character, including reso-
nance stabilization energy, and the related REPE, REPB and DRE parameters, HOMA,
and NICS. The complementary Hückel and Möbius criteria for aromaticity are introduced,
as is the Clar model of aromatic compounds, and its use in predicting reactivity in polycy-
clic aromatic systems.
Chapter 8 introduces physical organic chemistry. Reaction kinetics and the kinetic
order of reactions are discussed, and the use of the rate law in making deductions about
reaction mechanism is explored. The role of trapping and crossover experiments in deduc-
ing a mechanism is discussed. The Arrhenius equation and the activation parameters of a
reaction are discussed, as is the Hammett equation and the various parameters arising
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Preface xi
from the original σ and ρ constants. The Grunwald-Winstein relationship for solvent
effects on reactions, the Brønsted catalysis law, the salt effect, and element and isotope ef-
fects are introduced. The distinction made between primary and secondary isotope effects
is pointed out, and the discussion is extended to include the concepts of the variable tran-
sition state and a mechanistic spectrum. The chapter concludes with a short discussion of
the reactivity-selectivity principle.
Chapters 9–14 are all involved in the properties and chemistry of reactive intermedi-
ates. Chapter 9 introduces the discussion of carbocations and their stabilization, includ-
ing the topics of hyperconjugation, the Baker-Nathan effect, resonance and σ-bridging to
give non-classical carbocations. Anchimeric assistance in reactions involving carboca-
tions, and Wagner-Meerwein rearrangements of carbocations are also discussed. Chap-
ter 10 continues the discussion of carbocations, but now the focus shifts to synthetic
reactions in which carbocations are key intermediates. These include Friedel-Crafts reac-
tions and related formylations. Reactions involving carbocations stabilized by an adjacent
lone pair-bearing heteroatom such as the Prins, aza-Prins, and Mannich reactions, as well
as the Mukaiyama alkylation and aldol reactions, are introduced in this chapter, also.
Chapter 11 introduces the structure and reactivity of carbanions, and the related metal
alkyls. The stabilization of carbanions by adjacent π bonded functional groups (e.g. car-
bonyl and cyano) is discussed, as is the generation of enolate anions by deprotonation.
This discussion addresses questions of enolate regiochemistry and stereochemistry, and
kinetic versus thermodynamic enolate generation. The stabilization of carbanions by
third- and higher-row main group elements is introduced, as is the concept of umpolung.
Anionic rearrangements (Wittig, Stevens, and Sommelet-Hauser) are discussed. The dis-
cussion of carbanion chemistry continues in Chapter 12, where the focus is now the use of
carbanion nucleophiles in synthesis. This discussion includes some of the most important
modern synthetic reactions, including the aldol addition and its congeners, and the Mi-
chael addition. The stereochemistry of these reactions is discussed at some length. The
alkylation of organometallic nucleophiles, especially organocuprates, with halides and
epoxides is discussed, and enamines and sulfinylimine anions are introduced as enolate
anion surrogates.
Chapter 13 introduces free radicals, and important electrophilic reactive intermedi-
ates: carbenes, arynes and nitrenes. The structures of these species are discussed, and the
reactions of carbenes, arynes and nitrenes are discussed in some detail. The involvement
of metallocarbenoids in synthetic reactions is introduced. The synthetically useful reac-
tions of free radicals are discussed in Chapter 14. This discussion includes site-specific
methods for the generation of free radicals, and important radical reactions, such as radi-
cal cyclization reactions.
Students are introduced to the terminology and practice of modern synthesis in Chap-
ter 15. This introduction includes discussions of selectivity in organic synthesis, retrosyn-
thetic analysis, and the Evans-Lapworth consonant and dissonant difunctional
relationship analysis. Also in this chapter, the use of protecting groups in synthesis is in-
troduced, and the concept of orthogonal protection is discussed. The most widely used
protecting groups for a number of the most common functional groups are introduced.
Important condensation and cascade reactions are the topic of Chapter 16. In this
chapter, the Claisen condensation and its congeners (including the Robinson annelation),
the Wittig reaction, and its analogues (including reactions involving sulfur ylides), the
Ramberg-Bäcklund olefination and its analogues, and the Seyferth-Gilbert acetylene syn-
thesis are all discussed. Thus, this chapter includes some of the most important methods
for the synthesis of products containing C=C π bonds.
Chapter 17 concentrates on an area of synthetic organic chemistry that has undergone
explosive growth in the last three decades: the use of transition metal-catalyzed reactions
in synthesis. After a brief introduction to some basic organometallic chemistry, the chapter
moves to discuss such important reactions as transition metal-catalyzed cross-coupling
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xii Preface
reactions such as the Stille, Heck, Negishi, and Suzuki couplings, olefin metathesis using
transition metal carbene complexes, and the Tsuji-Trost and similar reactions of allylic
substrates. The chapter also discusses catalyzed hydrometallation reactions, as well as car-
bometallation reactions.
The next four chapters are substantial, and are focused on redox reactions. Chapter 18
is the largest single chapter in this book, and it covers oxidation reactions. Chapter 19 is
focused on reductions with molecular hydrogen or its surrogates (e.g. formic acid), and
Chapter 20 continues with a discussion of reduction with complex metal hydrides and
active metals. The final chapter of this quartet, Chapter 21, is devoted to modern asym-
metric redox reactions, with major emphasis on asymmetric oxidation reactions, inclu-
diong the Sharpless asymmetric epoxidation and dihydroxylation reactions, the Katsuki
and Shi oxidations, and asymmetric hydroxylation of ketone enolates with chiral oxaziri-
dines. The formation of chiral products by the desymmetrization of meso compounds is
also addressed, as is the asymmetric hydrogenation of alkenes, and the reduction of car-
bonyl compounds and imines with chiral hydride transfer reagents.
Chapter 22 is devoted to a discussion of the organic chemistry of compounds of sili-
con, phosphorus, sulfur, selenium, and tin. Key discussions of the organic chemistry of
compounds of these elements focus on the stabilization of carbocationic and carbanionic
intermediates by the heteroatom, and on the control of regiochemistry exerted by the he-
teroatomin on many reactions. Reactions such as the Hosomi-Sakurai reaction, the Mis-
low-Evans, Pummerer, and Arbuzov rearrangements are also discussed.
Chapter 23 is, in many ways, the capstone chapter in organic synthesis because it fo-
cuses on asymmetric organic synthesis. Among the topics discussed are chiral auxiliary,
chiral reagent, and chiral catalyst approaches in asymmetric synthesis, and the concepts
of simple and double diastereoselection, along with the concepts of matched and mis-
matched reacting pairs of stereoisomers.
The chapters discussing the reactive intermediates are autonomous enough that they
can be used as support for a course in physical organic chemistry (Chapters 1, 2, 4, 5, 7–9,
11 and 13 are primarily concerned with topics in physical organic chemistry, and I have
used them to cover physical organic chemistry in our Modern Organic Chemistry course).
Likewise, the chapters that describe modern organic reactions are also autonomous
enough that they, too, can be used to support a stand-alone Organic Reactions course
(Chapters 6, 10, 12, 14, and 16–22 are primarily concerned with organic reactions, and I
have used them to support Modern Organic Chemistry when I have taught it with an or-
ganic reactions focus during the development of this book). For much the same reason, I
have incorporated the references as footnotes on the page where they occur. While this has
meant a small amount of duplication of literature citations, I feel that it helps the student
to have the reference immediately available, rather than having to flip back through the
previous pages to find it.
In many ways, modern organic synthesis has evolved much faster than other sub-dis-
ciplines of the science, and the tools available to the modern synthetic chemist are now
truly staggering. From a beginning where problems of regioselectivity and chemoselectiv-
ity limited what chemists could accomplish, organic synthesis has become a truly asym-
metric science. The chapters on synthesis (Chapters 15 and 23) have been written with this
modern focus on the control over the absolute configuration of chiral products in mind.
The chapter on modern catalysis (Chapter 17) and the final chapter on redox reactions
(Chapter 21) have a strong focus on modern asymmetric synthesis.
There are three areas where I have made the decision, in the interests of keeping the
size of this volume within reasonable bounds, to leave the discussion to more specialized
texts: polymer chemistry, heterocyclic chemistry, and bioorganic chemistry. In all three
areas, there are a number of excellent specialist books that will serve as resources. The first
two have been the most difficult, especially given the importance of heterocycles in
modern medicinal chemistry, and the ubiquitous nature of polymers in modern life, and
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Preface xiii
it may be that they will be incorporated into a later edition of this book, depending on
demand. I have also taken the difficult choice not to include spectroscopy in this book
because, once again, there are excellent specialist books available for students at this level.
Every chapter of the book (except Chapter 3, for obvious reasons) has a number of
worked problems. There are also copious end-of-chapter problems that should test the
student, and for many it will be necessary to consult the original literature to obtain the
complete picture—it was certainly necessary for the author!
Acknowledgments
This has been a huge undertaking, and I could not have accomplished it without the sup-
port of my family. My wife, Debbie, has had to cope with a preoccupied husband for years,
and my children (Graeme and Veronica) have also had to cope with less than complete
attention from their father. My students at UW-Eau Claire have been willing and effective
guinea pigs during the development of the manuscript over the past several years, and
many of their insights have found their way into the final book. Another individual whom
I must thank is my friend and Mentor, Angas Professor Emeritus John H. Bowie of the
University of Adelaide, Australia, who has mentored me throughout my career. The edito-
rial staff at Oxford University Press assembled an impressive group of reviewers whose
contribution to the final product cannot be overemphasized. Their reviews have been
cogent and extremely useful, and I would be remiss without thanking them for their intel-
lectual contribution to this book. Finally, I must thank the editorial staff at Oxford Uni-
versity Press who have been involved with this project over its lifetime: Jason Noe (Senior
Editor), Andrew Heaton (Assistant Editor, Life Sciences and Chemistry), and Melissa
Rubes (Editorial Assistant, Life Sciences and Chemistry).
Ancillary materials available include an extensive Solutions Manual, where the
worked answers to every problem in the book are contained. An Instructor's Resource CD
contains all the numbered Figures from the text in electronic format, as well as most other
graphics from the chapters. It also contains the solutions in editable Word format.
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00-Lewis-FM.indd 14 14/08/15 10:48 AM
chapter one
The Fundamentals Revisited

Structure, Bonding, and Reactivity
1.1 Organic Structure: A Brief History
The origins of organic chemistry as a separate science are popularly traced to the synthesis
of urea by Friedrich Wöhler1 in 1828,2 but this is actually an oversimplification of the prog-
ress of the science. Several authors have held the view that Wöhler’s synthesis of urea was the
seminal point in the overthrow of vital force theory.3 Others believe that this was not the
case. However, it was not until later (usually attributed to Kolbe’s unambiguous synthesis of
acetic acid from its elements4) that vital force theory was finally abandoned.5
The rapid development of organic chemistry during the second half of the 19th century
can be traced to the development of the concept of chemical structure.6 Prior to the devel-
opment of the structural theory of organic chemistry, chemists struggled to find common
threads between different compounds and different reaction types. Then, in 1858, two
papers appeared within 2 months of each other, one by a German chemist, Friedrich
August Kekulé,7 and the other by a young Scotsman, Archibald Scott Couper,8 who was
working in Paris in the laboratory of Charles Adolphe Wurtz.9 These pioneering papers
laid the groundwork for the spectacular advances to be made later. Of course, any new
1. Friedrich Wöhler (1800-1892) received his MD from Heidelberg, and after positions at the polytechnic
schools at Berlin and Kassel, he became Professor at Göttingen, where he spent the remainder of his career. For
a relatively modern, more complete biography, see: Kauffman, G.B.; Chooljian, S.H. (2001). The Chemical Edu-
cator 2001 6, 121.
2. (a) Wöhler, F. Ann. Physik [2] 1828, 12, 253. (b) Wöhler, F. Ann. Chim. 1828, 37, 330.
3. (a) Hofmann, A.W. Ber. Deut. chem. Ges. 1882, 15, 3127, 3152. (b) Armstrong, H.E. Introduction to the Study
of Organic Chemistry (Longmans: London, 1884), p. 1. (c) Warren, W.H. J. Chem. Educ. 1928, 5, 1539. (d) Cam-
paigne, E. J. Chem. Educ. 1955, 32, 403.
4. Kolbe, H. Ann. Chem. Pharm. 1845 54, 145.
5. (a) McKie, D. Nature 1944, 153, 608. (b) Hartmann, L. J. Chem. Educ. 1957, 34, 141.
This view, with supporting references, is given in several advanced organic chemistry textbooks, for example:
(b) Wheland, G.W. Advanced Organic Chemistry, 3rd, Ed. (John Wiley & Sons: New York, 1960), p. 3-5, and
references therein.
6. Lewis, D.E. In Giunta, C.J., Ed. Atoms in Chemistry: From Dalton’s Predecessors to Complex Atoms and
Beyond. ACS Symp. Ser. 2010, 1044, 35.
7. Friedrich August Kekulé von Stradonitz (1829-1896) was educated at Giessen and Paris, and held faculty
positions at Heidelberg, Ghent and Bonn. At Ghent, he proposed the tetravalent carbon atom and the structure
of benzene. “Kekulé’s dream”, a source of controversy since the 19th century, has even been the subject of a
lawsuit! For a more complete biography, see: Alyea, H. In Halsey, W.D.; Friedman, E. Eds., Collier’s Encyclope-
dia, (Macmillan: New York, NY, 1985), Vol. 14, p. 15.
8. Archibald Scott Couper (1831-1892) was born and educated in Scotland before moving to Paris to study
with Wurtz. Independently of Kekulé, he proposed a theory of organic structure, but the delay in publication
of his paper meant loss of priority for this theory. He suffered a nervous breakdown and returned to Scotland a
broken man. For more complete biographies, see: (a) Dobbin, L. J. Chem. Educ. 1934, 11, 331. (b) Anschütz, R.
Proc. Roy. Soc. Edinburgh 1909, 29, 193.
9. Charles Adolphe Wurtz (1817-1884) was born in Strasbourg and educated, in part, in Justus Liebig’s
Giessen laboratory. He became a major figure in the development of French organic chemistry, and his Paris
laboratory became an important center for research in Europe. See: Rocke, A.J. Nationalizing Science. Adolphe
Wurtz and the Battle for French Chemistry (MIT Press: Cambride, MA, 2001).
01-Lewis-Chap01.indd 1 14/08/15 8:05 AM

2 Advanced Organic Chemistry | chapter one
theory must have its advocates, and the most ardent advocate for structural theory was
neither Couper nor Kekulé but a young Russian chemist by the name of Aleksandr
Mikhailovich Butlerov,10 who saw and articulated more clearly than Kekulé, at least, the
true potential of this new theory.11 Butlerov had met Kekulé and Wurtz and had been
struck by the ability of the new theory to reconcile many of the apparent contradictions
still prevalent in organic chemistry. His textbook, the first based entirely on structural
theory, was published first in Russian and then in German.12 It set the trend for all subse-
quent textbooks in organic chemistry.
Lewis Structures
The modern classification of compounds as ionic or covalent is usually attributed to
American chemist G. N. Lewis,13 who in 1916 proposed a simple theory to account for the
bonding in practically every type of compound known. At the same time, a similar theory
was developed independently by German physicist Walther Kossel.14 Both theories derive
ultimately from the 1904 principle proposed by German chemist Richard Abegg15 that
each element possesses a positive and a negative valency whose sum is eight. Lewis ex-
panded this principle and noted, in particular, that the noble gases were all characterized
by having eight electrons in their valence shell.16 In addition, he noted that the stable ions
formed by atoms such as sodium and chlorine were characterized by having either lost
enough electrons to lay bare an inner shell containing eight electrons (thus giving the ion
a valence shell containing a complete octet) or by having gained enough electrons to com-
plete the valence shell octet. From these observations, Lewis deduced that a valence shell
containing eight electrons is associated with extraordinary chemical stability. Stated in its
simplest terms, the Lewis theory is as follows:
Whenever atoms react to form molecules or ions, they do so in such a way as to ensure that
every non-hydrogen atom possesses a complete octet of electrons in the valence shell.
10. Aleksandr Mikhailovich Butlerov (1828-1886) was a Russian organic chemist who was educated at
Kazan, where he became a faculty member after 3 years in western Europe, including a year with Liebig. In 1869
he became Professor at the Medical-Surgical Academy of St. Petersburg. For more details, see Lewis, D.E. Early
Russian Organic Chemists and Their Legacy (Springer: Heidelberg, 2012), pp. 32, 47.
11. Some seminal early papers by the major players on the structural theory of organic chemistry: (a) Kekulé,
F. Liebigs Ann. Chem. Pharm. 1858, 106, 129. (b) Couper, A.S. Compt. rend. 1858, 46, 1157. (c) Butlerow, A.M.
Ann. Chem. Pharm. 1859, 111, 5146; Z. Chem. 1861, 4, 549. (d) Boutlerow, A. Bull. Soc. Chim. Paris, Nouv. Sér.
1864, 1, 100.
12. Butlerov, A.M. Introduction to the Study of Organic Chemistry (Kazan, 1864) [in Russian]; Lehrbuch der
organischen Chemie zur Einführung in das specielle Studien derselben (Leipzig, 1867).
13. Gilbert Newton Lewis (1875-1946) was educated at Harvard, Leipzig, and Göttingen, then after a brief
period at the Massachusetts Institute of Technology, he moved to Berkeley. Here he became one of the giants of
physical chemistry of the 20th century, and yet he never won the Nobel Prize. For more details, see: Coffey, P.
Cathedrals of Science (Oxford: New York, 2008).
14. Walther Ludwig Julius Paschen Heinrich Kossel (1888-1956), the son of Albrecht Kossel, was educated
at Heidelberg. His first positions were in Munich and Kiel, and he then moved to Danzig (Gdansk); he fled to
Tübingen ahead of the Russians in 1945. For a more complete biography, see: Andrade, E.N.da C. Nature, 1956,
178, 4533.
15. Richard Wilhelm Heinrich Abegg (1869-1910) was educated at Berlin and served as assistant to both
Nernst and Arrhenius after graduation. He became Professor at the Wrocław University of Technology in 1900,
but he was killed in a ballooning accident a decade later. For more complete biographies, see: (a) Hills, W. J.
Chem. Soc., Trans. 1911, 99, 599. (b) Nernst, W. Ber. dtsch. chem. Ges. 1913, 46, 619.
16. Seminal early papers on the development of the covalent and ionic bonding models:
(a) Lewis, G.N. J. Am. Chem. Soc. 1916, 38, 762. (b) Lewis, G.N. Valence and the Structure of Atoms and
Molecules (The Chemical Catalog Co.: New York, 1923); reprinted by Dover Press in 1966 with a foreword by
Kenneth Pitzer. (c) Kossel, W. Ann. Physik 1916, 49, 229. (d) Abegg, R. Z. Anorg. Chem. 1904, 39, 330-380.
These structural theories were consolidated, refined and extended by Irving Langmuir:
Langmuir, I. J. Am. Chem. Soc. 1919, 41, 868; J. Am. Chem. Soc. 1920, 42, 274.

The Fundamentals Revisited 3
This principle is called the Lewis octet rule. It is one of the most useful concepts available
to the organic chemist for rationalizing the structures and reactivity of organic com-
pounds and the course of organic reactions.
The Lewis electron-pair covalent bond was the first truly effective generalization
about chemical bonding used by organic chemists. Indeed, Lewis theory has formed the
basis for numerous other theories used in organic chemistry, so that it occupies a central
position in modern organic chemistry. It is applied throughout modern organic chem-
istry, and many, if not all, reactions are rationalized on the basis of the Lewis structures
of the molecules involved. In addition, it is a testimonial to its durability that it remains
one of the cornerstone theories of modern organic chemistry, despite the advances in
atomic and molecular theory that have been made since it was first proposed in 1916.
Because organic chemistry is intimately concerned with the fates of chemical bonds in
molecules, it is critical that one have mastered an understanding of the Lewis structures
of organic molecules.
The simple Lewis covalent bond model involves (in the formal sense, at least) the
contribution of one electron to the bonding electron pair from each partner. Although
this simple model does go a long way in explaining the bonding in the vast majority of
covalent compounds, there are compounds known whose bonding is not completely ex-
plained by the simple Lewis covalent model. This is particularly the case for metal com-
plexes, but this problem also occasionally arises in organic chemistry. In such cases,
Lewis proposed that one of the two partners in the bond formally contributes both elec-
trons to the bond. This bond, which was called a dative bond, a semipolar bond, or a
coordinate covalent bond, is frequently designated in older (especially British) books by
an arrow from the donor atom to the acceptor atom, but this practice is now largely ob-
solete. Instead, modern applications of Lewis theory use the concept of formal charge to
indicate that both electrons in a covalent bond formally originate on only one of the two
atoms. The concept of formal charge is often more useful than the dative bond model—
many coordinate covalent bonds exhibit properties normally associated with ionic bonds,
so the formal charge model allows the chemist to make predictions of properties that are
closer to the experimental values.
Determining the formal charge on any atom in a Lewis structure is actually fairly
simple. Electrons in a molecule fall into two major types: (1) nonbonding lone pairs, which
are under the formal control of a single nucleus, and (2) electrons in a covalent bond,
which are under the formally equal control of two nuclei—one electron from each cova-
lent bond is formally under the control of each nucleus. The total number of electrons in a
molecule formally controlled by each nucleus, therefore, is equal to the sum of the number
of electrons in lone pairs and half the number of electrons in covalent bonds.
Formal charge = (number of valence electrons in the neutral atom)

– (number of covalent bonds)
– (number of electrons in lone pairs)
Drawing the Lewis structures of polyatomic molecules and ions is relatively simple
provided that one remembers two simple rules:
1. Electrons in a molecule have no memory. One cannot assign an electron in a molecule

as originating on any particular component atom, even if it may be convenient to
adopt such a view for understanding the course of a reaction.
2. The valence shell of the elements of the second period of the periodic table has a max-
imum capacity of eight electrons. This restriction does not apply to elements in the
third or lower periods of the periodic table (the capacity of the third electron shell
is 18 electrons). These elements can, and do, expand their outer-shell octets when
necessary.

The process of drawing the Lewis structure of a molecule involves five fairly straight-
forward steps:
1. Determine the total number of valence electrons.

2. Establish the connectivity of the atoms.
3. Connect the atoms using single covalent bonds so that every atom is connected to at
least one other by a covalent bond.
4. Distribute the remaining electrons (if any).
5. Assign formal charges to atoms as required.
Worked Problem
1-1 Complete the Lewis structures of each of the following compounds by distribut-
ing the electrons appropriately among the atoms, which are arranged as shown.
Note that in some cases, there may be more than one valid Lewis structure that
can be written. In those cases, draw all the valid Lewis structures.
H
H O O
(a) H C H (b) H C H (c) H N C O
C C N N
H C H H H
H H
§Answer below.
Representing Organic Compounds: Structural Formulas

Because of the complexity of the structure of many organic compounds, as well as the
importance of structure in organic chemistry, the development of shorthand methods for
representing the structures of organic compounds has been almost mandatory to allow
the drawing of structures in a reasonable amount of space and time. By way of reviewing
§ Answers for Worked Problem:
H
H O O O O O O
(a) H C C C H (b) H N C N H H
N
C
N
H H
N
C
N
H H
N
C
N
H H
N
C
N
H
H C H H H H H H H H H H H
H H
(i) (ii) (iii) (iv) (v)
(c) H N C O H N C O H N C O H N C O H N C O
(i) (ii) (iii) (iv) (v)
(a) In this example, there are 4(4) + 1(6) + 8(1) = 30 valence electrons to distribute. When we place a pair of
electrons between each adjacent pair of atoms, all the valence shells have complete octets, and there are no
electrons left over.
(b) In this example, there are 1(4) + 2(5) + 4(1) + 1(6) = 24 valence electrons to distribute. After placing one
pair of electrons between each adjacent pair of atoms (i), there are 14 valence electrons used and 10 left. To
simple fill the octets of the remaining atoms with lone pairs will take 12 valence electrons, so we must first place
a double bond between two of the electron-deficient atoms. This gives us either a C=O bond (ii) or a C=N bond
(iii). Now we have exactly enough electrons left to satisfy all the octets, and we can distribute them. Structure
(iv) has no charged atoms, but when we test the nitrogen and oxygen atoms of structure (v), we find that the
doubly bonded nitrogen atom has a formal positive charge, and the oxygen atom has a formal negative charge.
(c) This problem is identical in all respects to that posed by (b), except that we now need to add two double
bonds (or one triple bond) to the structure to complete the octets of all. Again, the structures must be tested for
the presence of charged atoms.

H [CH3(CH2)3]3COH
H H H H O H H H H
or
H C C C C C C C C C H
H H H H H H H H (CH3CH2CH2CH2)3COH
H C H
or
H C H
H C H OH
H C H H3CH2CH2CH2C C CH2CH2CH2CH3
H CH2CH2CH2CH3
(a) (b)
H
O
C C C C C C C C C OH
C
C
C
C
(c) (d)
Figure 1.1 The different representations of tributylcarbinol found in organic chemistry are
the complete structural formula (a), the condensed structural formula (b), the connectivity
formula (c), and the line formula (d). Of these, the line formula has found the most widespread
use in modern organic chemistry.
the conventions for drawing organic structures, let us use tributylcarbinol (5-butyl-5-
nonanol, Figure 1.1) as an example.
The molecular formula of this compound is C13H28O, and its full structure is shown in
Figure 1.1 as (a). Even this structure is a simplification over what we saw in Worked Prob-
lem 1-1; now the bonding electron pairs are represented by lines instead of pairs of dots,
and the lone pairs are omitted. This particular representation, in which every atom of the
molecule is explicitly drawn, is often referred to as a complete structural formula. It is
essentially the same as the formula first proposed by Crum Brown17 in 1861 and published
in 1864.18
Even in a molecule as small as tributylcarbinol, however, it takes considerable space to
draw this structure. The first simplification, therefore, is to condense the various groups of
atoms about each carbon to a simple molecular formula for each carbon atom. This gives
rise to formula (b) in Figure 1.1, which is usually referred to as a condensed structural
formula, or simply a condensed formula. Such formulas are most frequently encountered
in printed works because they are very amenable to typesetting, although they convey
little or no information about molecular shapes. An alternative simplification of formula
(a) can be made by omitting the hydrogen atoms. Although such formulas (c) are very
good for showing connectivity, they are very poor at showing molecular shape. By omit-
ting the symbols for the carbon atoms, one can simplify the formula (c) even further to
give (d), which is known as a line formula, or, if a ring of atoms is involved, a polygon
formula.
In a line formula, the end of each line, as well as each vertex, is occupied by a carbon
atom bearing sufficient hydrogen atoms to complete its octet (unless it is charged). Where
17. Alexander Crum Brown (1838-1922) was educated at Edinburgh (MA, 1858; MD,1861) and London (DSc,
1862). His MD thesis contained the first truly modern line formulas. After postdoctoral study with Bunsen and
Kolbe, he returned to Edinburgh, where he remained, a much-loved teacher, until his retirement in 1908. For a
more complete biography, see: J. Chem. Soc., Trans. 1923, 3422.
18. Crum Brown, A. MD Thesis, University of Edinburgh, 1861; Trans. Roy. Soc. Edin. 1864, 23, 707-719; Proc.
Roy. Soc. (Edinburgh) 1866-1867, 6 (#73), 89.

fewer than four lines meet at a vertex, the remainder of the four valencies of the carbon
atom are assumed to be occupied by hydrogen atoms. Atoms that are neither carbon nor
hydrogen are called heteroatoms, and all heteroatoms are explicitly shown in line formu-
las. In general, only non-hydrogen and noncarbon atoms are explicitly indicated in a line
formula, although hydrogen atoms bonded to heteroatoms are frequently shown, as shown
in Figure 1.1 (d). In modern usage, lone pairs on heteroatoms are often omitted unless
specifying their presence makes an important point for the chemist.
Worked Problem
1-2 Draw the structures of the compounds in Worked Problem 1-1 using lines to represent
covalent bonds and condensed formulas for parts of the molecule as appropriate.
§Answer below.
Problems
1-1 One compound, with the molecular formula C5H8, is the hydrocarbon isoprene,
which is the basis of the “isoprene rule” for terpenoid natural products. Draw the
complete Lewis dot structures for all the compounds with the molecular formula
C5H8 and the complete Lewis structures with lines for each covalent bond, as well
as the line or polygon formula for each.
1-2 What is the molecular formula of each of the two compounds below?
HO OMe
MeO OH
(a) H (b) N OH
H H HO OMe
OH
HO
§ Answers for Worked Problems:
H H H
O H H
H O H O O O OH
(a) H C H CH H H C
C C H2C CH2 C C
H C H C H H C
H H H2 H H
(i) (ii) (iii) (iv) (v) (vi)
O O O O O O
(b) H H H H
N N H2N NH2 H2N NH2 N N H2N NH2 H2N NH2
H H H H
(i) (ii) (iii) (iv) (v) (vi)
(c) H N C O H N C O H N C O H N C O
(i) (i) (iii) (iv)
(a) The structures, from left to right, are the complete structural formula (i), a condensed structural formula
(ii), a simplified complete structural formula (iii), the connectivity formula (iv), the polygon formula with the
OH group explicitly drawn (v), and the polygon formula as it is usually used (vi). Note how, in these
representations, the lone pairs have been omitted, as is often done for clarity.
(b) The formulas, from left to right, are the complete structural formula (i, note how the double bond is so
much more easily spotted by even this simplification relative to the Lewis dot structure), the line formula with
condensed groups (ii), and the line formula with the lone pairs omitted (the usual structure). The next three
structures represent the same representations for the form of the molecule with atoms carrying formal charges.
(c) The four structures in this case are the same as the corresponding structures in (b).

1.2 Proton Transfers Revisited: Acids and Bases
The concepts of acid and base are central to chemistry as a whole. A vast majority of organic
reactions are either promoted by acids or bases or involve the participation of acids or bases at
some stage of the reaction pathway. Moreover, the application of acid-base chemistry in or-
ganic chemistry is wide reaching; unlike the other subdisciplines of chemistry, an over-
whelming majority of organic reactions are carried out in media other than water. This means
that the concepts of acids and bases must be applied to a much broader range of conditions
than those that applied when most of us learned about acids and bases for the first time. How-
ever, let us begin by reviewing the definitions of acids and bases in aqueous solution.
Arrhenius Acids and Bases

The earliest operational definitions of acids and bases were related to the neutralization of
acids by bases given by the relatively simple equation that follows:
Acid + Base → Salt + Water (Eq. 1.1)
This simple equation defines neutralization: the destruction of an acid by an equivalent

amount of base to give a salt. The formation of the water itself comes from the neutralization
process, a situation first recognized by the great Swedish chemist, Svante Arrhenius. As part
of his dissociation theory of electrolytes (that when ionic compounds dissolve in water the
ions dissociate and become free to move within the solution), Arrhenius looked at electrolytes
that were originally nonconductors and proposed the first definition of an acid.
An acid is a substance that functions as a source of hydrogen ions in aqueous solution.
Once acids had been defined in this manner, the extension of this definition to bases
was relatively straightforward. The Arrhenius definition of a base is stated below.
A base is a substance that functions as a source of hydroxide ions in aqueous solution.
The strength of an acid is related to the ease with which it functions as a hydrogen ion
(or, more accurately, hydronium ion) source in aqueous solution. The functional defini-
tions of strong and weak acids are still based largely on the Arrhenius definition. Strong
acids ionize (dissociate) completely in aqueous solution. Many are familiar to most stu-
dents in chemistry; sulfuric acid (H2SO4), nitric acid (HNO3), hydrochloric acid (HCl),
hydrobromic acid (HBr), hydriodic acid (HI), and perchloric acid (HClO4) are among the
more familiar strong acids. All these acids are covalent when pure but dissolve in water to
give a strongly conducting solution containing hydronium (H3O+) ions. The pH of 1 M
solutions of these acids is typically quite low—close to zero. Weak acids, on the other
hand, do not dissolve to give complete dissociation. Instead, much of a weak acid remains
unionized in aqueous solution. Typical weak acids are compounds such as acetic acid
(CH3COOH), which ionizes only to the extent of a few percent in a 1 M solution. The pH
of a 1 M solution of a weak acid is much more likely to be close to 2 or 3, indicating a
hydronium ion concentration only a few percent of that of a strong acid.
In a similar vein, the strength of a base is related to the ease with which it functions as
a source of hydroxide ions in aqueous solution; strong bases are good sources of hydroxide
ions in aqueous solution and weak bases are not. Most of the strong bases commonly used
in aqueous solution are ionic hydroxides that already have the hydroxide ion present, and
so need only dissolve to dissociate and liberate their hydroxide ion. The ionic hydroxides
of the Group IA and heavier Group IIA metals, especially those of the Group IA metals,
dissolve freely in water to give solutions containing high concentrations of hydroxide ions.

The substances LiOH, NaOH, and KOH are all widely used as strong bases. Ammonia, on
the other hand, dissolves extremely well in water, but it does so without extensive ioniza-
tion. Ammonia solutions, often labeled as “ammonium hydroxide,” are actually best de-
scribed as ammonia molecules dissolved in water, with only a few percent being converted
to ammonium and hydroxide ions. Like the aqueous solutions of weak acids, aqueous
solutions of weak bases such as ammonia are relatively poor electrolytes.
There are two structural features that one can use to predict the probable strength of an
acid: the atom to which the acidic hydrogen is bonded and the number of multiple bonds
between the central atom and oxygen in oxyacids. In general, as the electronegativity of the
element bonded to the acidic hydrogen atom increases, acid strength increases. For exam-
ple, O–H hydrogens are more acidic than N–H hydrogens, which are in turn more acidic
than C–H hydrogens. Acid strength also increases dramatically as the element to which the
hydrogen is bonded becomes larger. Although hydrogen fluoride is a relatively weak acid
(pKa ≈ 2), hydrogen iodide is the strongest binary (two-element) acid known. In addition,
the effects of multiple bonds between the central atom and oxygen atoms appear to be cu-
mulative. For example, hypochlorous acid (HClO), which has no chlorine-oxygen double
bonds, is a very weak acid, and perchloric acid (HClO4), which has three oxygen atoms
doubly bonded to the central chlorine atom, is one of the strongest acids known.
Lowry-Brønsted Acids and Bases

Not all chemistry is carried out in aqueous solution, and not all acid-base reactions result
in the formation of water. There are, in fact, many cases where an acid-base reaction has
obviously occurred but where no water is formed. For example, hydrogen chloride gas
reacts with ammonia gas to form ammonium chloride, a salt. Because hydroxide ion is
never involved in this reaction, it does not fit well with the Arrhenius definition of an
acid-base reaction. And yet this reaction clearly leads to the neutralization of the hydrogen
chloride, the acid, and the ammonia, the base, leading to the formation of the salt. A more
widely applicable definition of acids and bases is that due to Lowry19 and Brønsted,20 who
extended the Arrhenius definition of acids and bases to cover just such situations.
In the Lowry-Brønsted formalism, an acid is a hydrogen ion donor; a base is a hydrogen ion
acceptor.
A simple example of an acid-base reaction by the Lowry-Brønsted definition is the

Figure 1.2 The transfer of a
protonation of the methanol molecule by hydrogen chloride to give the methyloxonium
proton to a proton acceptor
is an acid-base reaction ion (Figure 1.2). The oxygen atom of the methanol molecule is functioning as the proton
under the Lowry-Brønsted
conjugate
definition. Here, the proton base acid
is transferred from a mole-
O
cule of hydrogen chloride to H3C H O
H3C H
a molecule of methanol to H Cl
generate its conjugate acid, H Cl
conjugate
acid base
methyloxonium ion.
19. Thomas Martin Lowry (1874-1936) took his DSc under H. E. Armstrong in 1899, and he remained with
him until 1913. His career took him through positions at Westminster Training College and Guy’s Hospital
Medical School, to the inaugural Chair in Physical Chemistry at Cambridge. Lowry, who wrote several books,
was elected a Fellow of the Royal Society in 1914. For more biographical information, see: Pope, W.J. Obit. No-
tices Fellows Roy. Soc. 1938, 2, 287.
20. Johannes Nicholaus Brønsted (1879-1947) was educated at Copenhagen (PhD, 1908), where he remained
as Professor of Physical and Inorganic Chemistry. His principal research was in thermodynamics, especially
the strengths and catalytic properties of acids and bases. Throughout World War II, he firmly opposed the
Nazis, a stand that won him election to the Danish Parliament in 1947. Unfortunately, by the time of his
election, he was too ill to take his seat.

acceptor, and is therefore the base. The hydrogen chloride molecule is the proton donor,
and is therefore the acid. When a proton is removed from an acid, HA, the anion formed,
A–, is termed the conjugate base of the acid. When a proton is added to a base, the prod-
uct of the reaction is termed the conjugate acid of the base. Thus, during the course of
the reaction in Figure 1.2, the acid (hydrogen chloride) is converted to its conjugate base
(chloride ion), while the base (methanol) is converted to its conjugate acid (methyloxo-
nium ion).
Because of the frequency and importance of proton-transfer reactions in organic
chemistry, some familiarity with the acidity constant, Ka, is required. The acidity constant
of a Lowry-Brønsted acid was originally defined in terms of its ability to form hydronium
ion, H3O+, from water and is given in Equation 1.3:
HA + H2O → H3O+ + A– (Eq. 1.2)
[H3O1 ][A2 ]
Ka 5 (Eq. 1.3)
[HA]
However, with the extension of acid-base chemistry into nonaqueous reaction sol-
vents, this definition is rather too narrow, and we are now in a position where Equation 1.1
is too limiting. Nevertheless, we have retained the concept of the acidity constant, Ka, and
its negative log10, the pKa, as useful measures of the relative acid strength of a species in
solution. Many of these values for organic compounds, however, have been measured
indirectly—by competition reactions in a nonaqueous solvent, for example.
As the acid (or base) becomes stronger, its conjugate base (or acid) becomes weaker.
Thus, for a strong acid such as hydrogen chloride (or hydrochloric acid), the conjugate
base (chloride anion) is weak, whereas for a weak acid, such as water, the conjugate base
(hydroxide anion) is strong. All acid-base reactions proceed to give the weaker of the two
conjugate acids and the weaker of the two conjugate bases as the products of the
reaction.
Let us examine the case of a simple proton-transfer reaction between an acid, HA, and
a base, B –:
HA + B– → HB + A– (Eq. 1.4)
The equilibrium constant for this reaction is given by Equation 1.5.
[HB][A2 ]
K eq 5 (Eq. 1.5)
[HA][B2 ]

By multiplying both the numerator and the denominator of this expression by [H3O+],
Equation 1.6 is obtained.
[HB][A2 ][H3O1 ] (Eq. 1.6)

K eq 5
[HA][B2 ][H3O1 ]
Reorganization of Equation 1.6 gives the particularly useful Equation 1.7.
[H3O1 ][A2 ] [HB] K aHA (Eq. 1.7)

K eq 5 • =
[HA] [H3O1 ][B2 ] K aHB

What Equation 1.7 tells us is (1) that if HA is a stronger acid than HB (i.e., if the K a of
HA is greater than the Ka of HB), then the equilibrium for the reaction of HA with B –
will lie to the right, and (2) that the equilibrium constant for the reaction will be given
by the ratios of the Ka values for the two acids. The other measure of acidity, the pKa,
which was defined earlier as –log10(Ka), is a much more commonly used measure of acid
strength. Stronger acids have an algebraically smaller value of the pKa than weaker
acids. Using pKa values for the two acids, Equation 1.7 can be rewritten as the useful
Equations 1.8 and 1.9:
log( K eq ) 5 pK aHB 2 pK aHA (Eq. 1.8)

HB
2 pK aHA ) (Eq. 1.9)
K eq 5 10(pKa

As pointed out earlier, acid the strength of a covalent compound varies with the ele-
ment to which the acidic hydrogen is bonded. As the covalent radius of that element in-
creases, the acid strength increases, and as the electronegativity of the element bonded to
the acidic hydrogen increases, acid strength increases. This allows us to observe that
Se—H bonds are more acidic than S—H bonds; that S—H bonds are, in turn, more acidic
than O—H bonds; and that O—H bonds are more acidic than N—H bonds, which are, in
turn, more acidic than C—H bonds. One consequence of this is that we can expand our
view of acids and, more particularly, bases. Bases such as amide anion, NH2–, the conju-
gate base of ammonia (NH3, pKa ≈ 35) and methyllithium, CH3Li, the conjugate base of
methane (CH4, pKa ≈ 45–60), are much stronger bases than hydroxide ion, the conjugate
base of water. It is worth repeating here that although the pKa scale was originally defined
for Lowry-Brønsted acids in aqueous solution, we will use it for a wide variety of acids and
bases which are much too strong to exist in aqueous solution without reacting with the
water. Some typical pKa ranges are given in Table 1.1.
Let us now examine some examples of acid-base reactions in organic chemistry and
see just how to approach the problems associated with proton transfer chemistry.
Example 1. CH3Li + H2O →
In this reaction, as in all potential acid-base reactions, we must first identify the acid
and the base. While doing so, we must keep in mind that there is one acid and one base on
each side of the arrow. In this example, the two species reacting are methyllithium, CH3Li,
Table 1.1 Typical Ranges of pKa Values for Representative Acids
Conjugate pKa
Functional Group Acidic Bond Acid Examples Base Examples Range
Alcohol O–H RO–H (CH3)3C–OH, H2O RO – (CH3)3C–O – , OH– 15–19
Carboxylic acid COO–H RCOO–H HCO–OH, CH3CO–OH RCO–O – HCO–O – , CH3CO–O – 4–6
– – –
Amine N–H R 2N–H (CH3)2CH–NH2, NH3 R 2N NH , (CH3)2CH–NH
2
33–38
Amide CON–H RCONR–H CH3CO–NH2 RCONR– CH3CO–NH– 15–17
– – –
Alkane C–H R–H CH4, (CH2)6 R CH , [(CH2)5CH]
3
45–60
Alkyne C≡C–H RC≡C–H CH3–C≡C–H RC≡C – CH3–C≡C – 25–30
Aldehyde, ketone COC–H RCOCR 2–H CH3COCH3 RCOCR 2– CH3COCH2– 25–30

and water, H2O. The methyllithium is a compound that contains a Group IA Table 1.2 Reacting Species
metal, lithium, and we are usually safe in considering that such compounds
Reacting Species Conjugate
will react as ionic compounds containing Li+ cations. This means that meth-
yllithium also contains the CH3– anion. This ion is capable of accepting a Acid H 2O OH–
proton to become the neutral molecule, methane, CH3—H (or CH4); it is the Base CH3– CH4
conjugate base of methane. More importantly, it is highly unlikely that CH3–
will readily lose a proton to become CH22–. Therefore, the water is almost certain to be the
source of protons in this reaction. At this point, we can fill out the table of reacting species
in Table 1.2.
This now allows us to write the balanced equation for this reaction:
CH3– + Li + H2O → CH4 + Li+ OH–
From the data in Table 1.1, we find that the pKa of H2O is in the of 15 to 18 and that the
pKa of CH4 is in the range of 45 to 60. On substituting these values in Equation 1.9, we
obtain:
K eq 5 10(45 2 18) 5 1027 and K eq 5 10(60 2 15) 5 1045

as the minimum and maximum values for the equilibrium constant for this reaction.
These are both huge numbers, so we expect that methyllithium will react completely with
water to give methane gas and lithium hydroxide. It does—methyllithium is rapidly (ex-
plosively!) and quantitatively destroyed by water.
Example 2. LiN(CH3)2 + (CH2)5 →
In this reaction, the first step is also to identify the acid and the base. In this example,
the two species reacting are lithium dimethylamide, LiN(CH3)2, and cyclopentane, (CH2)5.
Again, we may consider that the lithium dimethylamide will react as an ionic lithium
compound, which means that it contains the (CH3)2N– anion. This ion is capable of accept-
ing a proton to become the neutral molecule, dimethylamine, (CH3)2N—H; it is the conju-
gate base of dimethylamine. So the cyclopentane, which cannot accept a proton, is forced
to be the source of protons in this reaction. At this point, we can fill out the table of react-
ing species (Table 1.3).
This now allows us to write the balanced equation for this reaction:
H3C H3C
N Li + H Li + N H
H3C H3C
From the data in Table 1.1, we find that the pKa of (CH2)5 is in the range of 45 to 60 and
the pKa of (CH3)2NH is in the range of 33 to 38. On substituting these values in Equation
1.9, we obtain:
K eq 5 10(45 2 38) 5 1025 and K eq 5 10(60 2 33) 5 10227

as the maximum and minimum values for the equilibrium constant for this Table 1.3 Reacting Species
reaction. These are both very small numbers, so we expect that lithium dime-
thylamide will not react with cyclopentane. In fact, these numbers suggest Reacting Species Conjugate
that the reverse reaction (between cyclopentyllithium and dimethylamine to Acid (CH2)5 [(CH2)4CH]–
give cyclopentane and lithium dimethylamide) should be the one that actually Base (CH3)2N– (CH3)2NH
occurs, and this is observed.

Worked Problem
1-3 Complete the following equations using the approximate pKa values given in
Table 1.1. If no reaction should occur, write “N/R” and give the reason.
(a) CH3CH2CH2CH2Li + CH3OH →
(b) NaNH2 + HCºCCH2CH3 →
(c) LiN(CH3)2 + (CH3)4C →
§Answer below.
Leveling Effect
There is one very important consequence of Equations 1.6 and 1.7, and this is known as the
leveling effect. Simply stated, the leveling effect states that one cannot use an acid or base in
a solvent that has a stronger conjugate base or acid than the acid one is trying to use. In
other words, the solvent limits both the strongest acid you can use (the conjugate acid of the
solvent) and the strongest base (the conjugate base of the solvent). In water, for example,
this means that any attempt to use an acid stronger than hydronium ion, H3O+, is doomed
to failure, as is any attempt to use a base stronger than hydroxide ion, OH–, because the
stronger acid will simply react with the water to give hydronium ion, and the stronger base
will, likewise, react with the water to give hydroxide ion. As an illustration, because meth-
ane (CH4) has a pKa of 45 to 60, one cannot use its conjugate base, methyllithium (CH3Li)
in any solvent with a smaller pKa. Using the equation of Worked Problem 1-3 (a) above, we
see that if one tries to use methyllithium in water, the solvent reacts with the base to give
lithium hydroxide (the conjugate base of water) and methane. For similar reasons, one
cannot use concentrated sulfuric acid (pKa ≈ –7) in aqueous solution, because it reacts with
the water to give the conjugate acid of water, hydronium ion, H3O+. Beginning students at-
tempting to use H3O+ and OH– in the same solution frequently commit this error (usually
when answering a mechanism question). Of course, these two react to give water. Similar
errors are frequently made using other incompatible acid-base combinations.
Problem
1-3 The reactant, product, and intermediate in the two-step reaction below are all
correct, but the mechanism as written is wrong. What is the error in the mecha-
nism as written? What changes are required to correct it (assume that the reac-
tion occurs in D2SO4/D2O)?
D D D
OD
OD
§ Answers for Worked Problems:
(a) CH3CH2CH2CH2Li + CH3OH → CH3CH2CH2CH3 + Li+OCH3–

(b) NaNH2 + HC≡CCH2CH3 → Na+ –C≡CCH2CH3 + NH3
Note that in this reaction, only the hydrogen directly attached to the triple bond is attacked. Its pKa from
Table 1.1 is approximately 25 to 30, making it a stronger acid than ammonia; the approximate pKa values of the
other hydrogens are predicted to be in the 45 to 60 range.
(c) LiN(CH2CH3)2 + (CH3)4C → N/R
The conjugate acid of LiN(CH2CH3)2 is H–N(CH2CH3)2, which is a stronger acid than (CH3)4C. Using Equa-
tion 1.9 and the pKa values in Table 1.1, we can calculate that the equilibrium constant in favor of products will be
less than 10–5, corresponding to no reaction; the equilibrium strongly favors the weaker acid and the weaker base.

1.3 Reactions and Reaction Mechanisms: “Electron Pushing”
Every organic reaction occurs by an ordered series of steps that convert the reactants into
products. The detailed step-by-step description of this process is known as the reaction
mechanism, and the purpose of a mechanism—as written by organic chemists—is to
show in a clear manner how the electron reorganization between reactants and products
may be rationalized. In the process, the mechanism provides a framework for discussing
the reaction and for proposing modifications to a reaction.
Writing Mechanisms
All reactions involve, at their core, the breaking and making of chemical (usually cova-
lent) bonds. When we are dealing with a covalent bond, there are only two ways in which
this may be accomplished. In the first, the bond may break in such a fashion that both
atoms retain one unpaired electron, a process known as homolysis. Alternatively, the bond
may break in such a fashion that one of the two atoms retains both electrons of the bond-
ing pair, a process known as heterolysis.
A B A• + •B
homolysis
A B A + B
heterolysis
In writing modern mechanisms for organic reactions, the focus is on the movement of
electrons, although this emphasis arose only slowly during the middle decades of the 20th
century, due largely to the work of Sir Robert Robinson21 and Sir Christopher Ingold.22
Today, arrows are used to specify the relocation of electrons during a reaction step.23 When
the movement of an unpaired electron is shown, the arrowhead has a single “barb” (this
type of arrow is often called a “fish-hook”); when the movement of a pair of electrons is
shown, the arrowhead has both “barbs.” This modern differentiation between the two
types of arrows did not become commonplace until the 1960s. Prior to that time, the
double-headed arrow was used to designate the movement of electrons without regard to
the number of electrons.24 In either case, the arrow shows the movement of the electrons
from their initial location to their final location during that particular reaction step.
21. Sir Robert Robinson (1886-1975) was educated at Manchester (BSc, 1906; DSc, 1910) and in 1912 became
the first Professor of Pure and Applied Organic Chemistry at Sydney. After time in industry following his
return to Britain in 1915, eventually becoming Waynflete Professor of Chemistry at Oxford University. He
received the Nobel Prize in 1947; for a more complete biography see: Todd, Lord; Cornforth, J.W. Biogr. Mem.
Fellows Roy. Soc. 1976, 22, 414.
22. Sir Christopher Kelk Ingold (1893-1970) was educated at Southampton and London, where he also spent
the major part of his career. Ingold was a pioneer of physical organic chemistry with his student and collaborator,
E. D. Hughes. For a more complete biography, see: Shoppee, C.W. Biogr. Mem. Fellows Roy. Soc. 1972, 18, 348.
23. Early papers on use of “curly arrows” to rationalize reactivity used the arrows to designate movement of
one or two electrons at a time: (a) Kermack, W.O.; Robinson, R. J. Chem. Soc. 1922, 121, 427. (b) Robinson, R. J.
Soc. Chem. Ind. 1924, 43, 1297. (c) Allan, J.; Oxford, A.E.; Robinson, R.; Smith, J.C. J. Chem. Soc. 1926, 401.
The use of the two-barbed arrow to indicate movement of an electron pair was proposed by Lowry and
expanded on by Ingold: (d) Lowry, T.M. J. Chem. Soc. 1923, 123, 822, 1886. (e) Lowry, T.M. Nature 1925, 114, 376.
(f) Ingold, C.K.; Ingold, E.H. J. Chem. Soc. 1926, 1310.
24. Ingold and Robinson entered into a lifelong dispute over priority claims for this useful concept; although
history shows that Robinson first used the “curly arrows,” it was Lowry and Ingold who gave the concept its modern
usage. The differentiation between arrow types did not appear in advanced textbooks in organic chemistry until
after 1962; until then, the movement of one or two electrons was commonly shown by the same type of arrow.

Homolysis
O O
Br + (1.1)
O O Br
Me Me
Me N Br Me N (1.2)
+ Br
H
O OH CH2
(1.3)
R H R H
N N CH2 (1.4)
R R
O O
Me
CH2 (1.5)
Me
During a homolysis, the two electrons of the rupturing (or forming) bond are distrib-
uted equally—basically the same situation as in the intact bond. Therefore, the formal
charges on both atoms of the bond being cleaved remain the same, because the two atoms
formally control one electron of the pair when bonded, and each has one electron when
the bond is broken.
The simplest case of a homolysis reaction is the homolytic cleavage of one bond, as
shown in Examples 1.1 and 1.2. In Example 1.1, the atoms at both ends of the reacting bond
are uncharged in the starting compound, so they remain uncharged in the final free radi-
cals. In Example 1.2, the nitrogen carries a formal positive charge in the starting ion, and
it retains that formal charge in the product.
The same situation—that the charge on the atoms involved does not change during the
course of the reaction step—holds true when an atom is transferred from one site in a radical
to another, or when a radical fragments. In Example 1.3, which is taken from photochemis-
try, the hydrogen atom is transferred from carbon to oxygen; none of the atoms involved is
charged in the starting species, and no atom is charged in the final product. In the hydrogen
atom transfer reaction shown as Example 1.4, the nitrogen atom carries a formal positive
charge in the starting radical, and it retains that formal positive charge in the product. In the
radical fragmentation reaction shown as Example 1.5, the same principles obtain.
Problem
1-4 Write mechanisms to account for each of the following homolysis reactions.
(a)
O ∆ hν
(b) O
(c) N
H2C
N
O

Heterolysis
In contrast to the homolysis case, heterolysis of a covalent bond leads to a change in the
formal charge of both participating atoms, with the atom retaining the two electrons from
the bond gaining a unit of formal negative charge and the atom losing the two electrons of
the bond gaining a unit of formal positive charge.
H
H
O O
O O
+
(1.6)
S Br S + Br (1.7)
In the first simple heterolysis shown as Example 1.6, the carbon-oxygen bond is broken.
The carbon atom, which is at the origin of the arrow, gains one unit of formal positive
charge to become a carbocation. The oxygen atom, which is at the terminus of the arrow,
gains a full unit of formal negative charge to become an anion.
Me Me
CO2H HCl CO2H Figure 1.3 Potential initial
H2O protonation sites of the start-
OMe O ing compound.
C8H10O3 C8H10O3
Me Me
OH
A CO2H D
OH
OMe OMe
Me Me Me
B CO2H CO2H CO2H E
OMe OMe OMe

H
Me Me
CO2H CO2H F
C
OMe OMe
In Example 1.7, two bonds—one being formed, and one being broken—are involved at
the same time. The negatively charged sulfur, which is at the origin of one arrow, loses one
unit of formal negative charge, and the bromine, which is at the terminus of gains one unit
of formal negative charge, becoming a bromide ion. The formal charge on the carbon atom,
which is at the origin of one arrow and at the terminus of another, remains unchanged.
R R
O OH
+
H
N N
H N H N
(1.8)
O
O
The same situation applies in more complex mechanistic steps where electrons around
carbon reorganize (e.g., in the fragmentation reaction shown in Example 1.8, the negative

E (i) (ii) (iii)

Me Me Me Me Me
CO2H CO2H CO2H CO2H CO2H
H
OMe OMe O
H MeO O H Me O O H Me O O H
H H H
H
H
Me Me Me Me
CO2H CO2H CO2H CO2H
H
O O OH OH
H
(vi) (v) (iv)
Figure 1.4 The complete mechanism.
charge on the alkoxide oxygen eventually ends up on the other oxygen atom; because the
nitrogen and carbon atoms are at the origin of one arrow and the terminus of another,
none of these atoms undergoes a change of formal charge).
Let us now look at how one approaches writing mechanisms for reactions, by using
the reaction highlighted in Figure 1.3. A quick examination of the molecular formulas of
the reactant and the product shows us that CH2 is lost—the methyl group of the ether is
now gone. Checking the molecular formulas this way is often very helpful in determining
what might have happened during a reaction (the author of this book has used the tech-
nique more than once the past year in reading papers in catalytic synthesis). The remain-
ing parts of the molecule show that the substituents have not moved (with the exception
of the double bond in the ring), so we do not have skeletal rearrangements to contend
with. There are six sites where the proton from the HCl may attack the ring, and the re-
sults of these attacks are shown in Figure 1.3, but only one of them has the effect of chang-
ing the structure adjacent to the OCH3 group that is going to be lost and that is
intermediate E, which places a new positive charge adjacent to the group that is going to
be lost. If that cation reacts with water (not hydroxide anion, which is totally incompatible
with the hydrochloric acid), we get the reaction in Figure 1.4 to give intermediate cation
(i). This cation now has relatively few options for reaction, and the simplest is to lose a
proton to give the hemiacetal (ii). Reprotonation of this hemiacetal can occur on either
the OH or the OMe oxygens; protonation of the OH is nonproductive, so we protonate on
the other one to give the new oxonium ion (iii). This now allows us to lose the methyl
group as methanol by heterolysis of the C–O bond, giving us the new cation (iv). If this
cation loses a proton from carbon, as in the second step of the E1 mechanism), we get a
diene (v). Protonation of the diene at the terminal carbon gives an allyl cation (vi) that
can now lose a proton to give the final product. Note how in every heterolysis of a bond
during this mechanism, one of the atoms gains a unit of formal positive charge relative to
its charge in the reactant state, and the other gains a unit of formal negative charge rela-
tive to its charge in the reactant state.
Worked Problem
1-4 Write a mechanism that accounts for the formation of the product below. (Hint:
CF3CO2H behaves like a strong acid with a non-nucleophilic anion.)
O
1) CF3CO2H/∆
O 2) H2O
HO

§Answer on next page.

Problems
1-5 Write mechanisms for each of the transformations shown below:

O O CN
(a) + CN
OH2
H2O
(b)
N
(c) C N + H2O
OH2
OH O
H
(d)
(cat.)
CH3 CH3
OH H O
(e) OH + H2O
O (cat.) O
CCl3
•CCl3
(f) + CCl4
Cl
S S
(g) + S RS•
S
N
(h) O +
O
OH O
H H
(i) C C H + H2O
cat. cat.
H2N HN
N N
(j) + OH + H 2O

(continues)

O
CF3
O
H O HO HO HO
H2O H H
OCOCF3 O O
COCF3 O OCOCF3 O OCOCF3
H
H
HO HO HO
HO HO
Although the trifluoroacetate anion is generally considered a non-nucleophilic anion, it traps the vinyl
cation as a vinyl trifluoroacetate because the vinyl cation is such a high-energy cation.

Problems (continued)
1-6 Write a mechanism that accounts for the formation of each of the products in the
reactions below:
Ts
H HN
(a) N H
KOCMe3
(e) O
O
Me3COH
H H
H
(b) H2O OH
hν I
Me CHO
O Me (f)
(c) H2SO4 O
O
OI
Me
HO OH
(d) O
H2SO4 H
O (g)
O
CO2H
O
Kinetic Order, Molecularity, and Mechanistic Type

Much of the experimental evidence for the mechanism of an organic reaction is deduced
from kinetics. Kinetics is the study of the relationship between the rate of a chemical
reaction and two experimental parameters that the chemist can vary: the concentra-
tions of the reactants and the reaction temperature. Kinetic measurements give the
chemist a rate law, which relates the rate of the reaction to reactant concentrations. Rate
laws are all of the form
Rate = k[A]m[B]n . . . (Eq. 1.10)
where [A], [B], and so on, are the concentrations of the reactants and m, n, and so on, are
mathematical exponents. Only those reactants that participate in the reaction before or
during the rate-determining step appear in the rate law.
In 1889, the great Swedish chemist, Svante Arrhenius,25 studied the mutarotation of
glucose in aqueous solution, and from his studies, he derived what is now known as the
Arrhenius rate equation:
k = A•exp(–Ea/RT) (Eq. 1.11)
where k is the rate constant, A is the “pre-exponential” factor and is related to entropy, Ea
is the activation energy of the reaction, and T is the Kelvin temperature. Inherent in this
equation is the observation that all reactions have to surmount an activation energy in
order to occur.26
One way to visualize the processes occurring in a reaction is to use a reaction coordi-
nate diagram or reaction energy profile.
25. Svante August Arrhenius (1859-1927) was educated at Uppsala (PhD, 1884, but with the lowest possible
passing grade). After being appointed to the physics faculty at Uppsala, he studied with Ostwald, van’t Hoff,
and Boltzmann. In 1903, he received the Nobel Prize in Chemistry. A more complete biography is available at
the Nobel website, and at: Snelders, H.A.M. Dictionary of Scientific Biography (Charles Scribner’s and Sons:
New York, 1970); vol. 1, p. 296.
26. Arrhenius, S. Z. physik. Chem. 1889, 4, 226.

transition state 1
‡
transition state transition state 2
‡ ‡
intermediate
Energy
Energy
reactants
reactants
rate
determining fast
products step step products
Extent of Bonding Change Extent of Bonding Change

(Reaction Coortdinate) (Reaction Coordinate)
CONCERTED STEPWISE
Figure 1.5 Reaction coordinate diagrams for concerted and stepwise reactions. The concerted reaction
occurs in a single step through a single activated complex. In the stepwise reaction, more than one acti-
vated complex is involved, and at least one intermediate is formed. In this example, the first step is rate
determining because the energy of transition state 1 is higher than the energy of transition state 2.
This diagram has its ultimate origin in the Arrhenius equation and followed from the
construction of reaction potential energy surfaces27 by American chemist, Henry Eyring,28
in the early 1930s. In these diagrams, the pathway between reactants and products lay
along a trench or “valley” in the surface, with the high-energy point being a saddle point.
The simplification that is made to give the modern reaction coordinate diagram was to use
the path along the bottom of the valley as the x-axis and energy as the y-axis of the dia-
gram. In this way, the “reaction coordinate” now corresponds to the progress of each mol-
ecule individually through the bonding changes needed to be converted to products.29
The high-energy point on the diagram is unusual, in that it represents a structure that
is inherently unstable, as well as the highest energy point of the reaction pathway. Eyring
called this the activated complex,30 a name that emphasizes its structure, whereas Evans
and Polanyi called it the transition state,31 which emphasizes its ephemeral existence.
Reactions can be divided into two broad categories based on the timing of the bonding
changes involved. Reactions that occur in a single step—in which all the bonding changes
occur simultaneously—are called concerted reactions. They proceed through a single ac-
tivated complex, and there is only one transition state in the reaction coordinate diagram.
In contrast to a concerted reaction, a stepwise reaction proceeds through two activated
complexes, and an intermediate is formed during the reaction. In stepwise reactions, only
those species involved prior to the highest energy step, known as the rate-determining
step, appear in the rate law of the reaction. The reaction coordinate diagrams for a typical
concerted and stepwise reaction are compared in Figure 1.5.
27. (a) Eyring, H.; Polanyi, M. Z. physik. Chem. 1931, B12, 279. (b) Eyring, H. J. Am. Chem. Soc. 1931, 53, 2537;
1932, 54, 3191. (c) Eyring, H. Chem. Rev. 1932, 10, 103.
28. Henry Eyring (1901-1981) was born in Juarez, Mexico, and educated at Arizona and Berkeley (PhD, 1927).
After graduating, he worked at Wisconsin, Berlin, and the University of California at Berkeley before moving to
Princeton in 1931. In 1946 he moved to Utah, where he spent the rest of his career. For a more complete biography,
see: Kauzmann, W. Biogr. Mem. Nat. Acad. Sci. (National Academies Press: Washington, D.C., 1996), 47.
29. One of the first appearances of the reaction coordinate diagram in the modern form in a textbook is in
Glasstone, S.; Laidler, K.J.; Eyring, H. The Theory of Rate Processes (McGraw-Hill: New York, 1941), pp. 97-100.
30. The activated complex was first proposed by Eyring, who applied statistical methods to the calculation of
reaction rates: (a) Eyring, H. J. Chem. Phys. 1935, 3, 107. (b) Eyring, H. Chem. Rev. 1935, 17, 65. (c) Eyring, H.
Trans. Faraday Soc. 1938, 34, 41.
31. (a) Evans, M.G.; Polanyi, M. Trans. Faraday Soc. 1935, 31, 875; 1937, 33, 448. (b) Polanyi, M. J. Chem. Soc. 1937, 629.

Two particularly important parameters used to describe a reaction are its kinetic
order and its molecularity. It is important to distinguish between these two. The kinetic
order of a reaction is the sum of the exponents in the rate law. It is an experimental quan-
tity that is directly related to the algebraic form of the rate law, it can be determined by
appropriate kinetic measurements, and it relates the rate of the reaction to the concentra-
tions of the reactants. The molecularity, on the other hand, is a theoretical concept that is
used to describe the relationship of the activated complex to the reactants. Reactions
where the activated complex is derived from a single distinct chemical species are unimo-
lecular, those where two distinct chemical species combine to form the activated com-
plex are bimolecular, those where three distinct chemical species form the activated
complex are termed termolecular, and so on. Unlike kinetic order, molecularity depends
on the assumed mechanism of the reaction. In some ways, this gives molecularity an
advantage compared to the kinetic order of a reaction, and it is constant for all reactions
of a given mechanism type. However, one must remember the caveat that, unlike the ki-
netic order of the reaction, molecularity may be subject to reinterpretation as the pro-
posed mechanism changes.32
Most of the time, the kinetic order and the molecularity of a reaction correspond, but
this is not universally the case, as the acid-catalyzed reaction between tert-butyl alcohol
and bromide ion shows. As shown in Figure 1.6, the reaction mechanism involves the
formation of two reactive intermediates—the oxonium ion, which carries the actual leav-
ing group that is replaced, and the carbocation, which reacts with the nucleophile. Of
these two, the carbocation is the higher-energy intermediate, so its formation is more
endothermic.
In this reaction, the slow step is the heterolysis of the carbon-oxygen bond of the oxo-
nium ion, and only the oxonium ion is involved in the slow step. This makes this reaction
unimolecular because only one particle is involved in the rate-determining step. However,
‡
δ δ
OH2 δ ‡
δ
Br
Hδ ‡
H
Energy
Oδ
H
carbocation OH OH2
OH2
OH oxonium ion Br
Br Br
Extent of Bonding Change

(Reaction Coordinate)
Figure 1.6 The reaction between tert-butyl alcohol and bromide ion in the presence of a strong
acid catalyst. Note how the oxonium ion is formed in a rapid pre-equilibrium step.
32. Molecularity: Hughes, E.D.; Ingold, C.K.; Patel, C.S. J. Chem. Soc. 1933, 526. For discussions of
molecularity and kinetic order, see Ingold, C.K. Structure and Mechanism in Organic Chemistry (Cornell
University Press: Ithaca, N.Y., 1953), pp. 308-316; Gould, E.S. Mechanism and Structure in Organic Chemistry
(Holt, Rinehart and Winston: New York, 1959), p. 164.

‡
δ δ
Br R OH2
Hδ ‡
R Oδ
H
Energy
H
OH OH2 R OH2
R OH oxonium ion
Br
Br
R Br

(Reaction Coordinate)
Figure 1.7 The acid-catalyzed reaction between 1-butanol and bromide ion.
because two reactants are required to make the species that participates in the rate deter-
mining step, the rate law for the reaction is:
Rate = k[ROH][H+] (Eq. 1.12)
This makes the reaction second-order. Here we see the effects of a pre-equilibrium,
where the initial starting compound is first converted in a rapid equilibrium step to the
actual substrate for the reaction, which then participates in the slow step of the reaction.
By comparison, the acid-catalyzed reaction between 1-butanol and bromide anion
(Figure 1.7) proceeds by the SN2 mechanism. It is a bimolecular reaction between the oxo-
nium ion and bromide ion, with third-order kinetics, and a rate law:
Rate = k[ROH][H+][Br–] (Eq. 1.13)
The Arrhenius equation permits the effects of temperature on a reaction to be pre-

dicted, but it is often more useful to be able to predict the effects of small changes in the
reacting species on relative reaction rates. One important tool used by organic chemists to
predict the relative rates of closely related reactions was proposed in 195533 by American
chemist George S. Hammond.34 His proposal, which has become known as the Hammond
postulate, states that:
If two states, as for example a transition state and an unstable intermediate, occur consec-
utively during a reaction process and have nearly the same energy content, their intercon-
version will involve only a small reorganization of molecular structure.
Thus, we expect that in reactions where the activation energy is low (usually exother-
mic reactions), the activated complex and the reactant are separated by only a small energy
33. Hammond, G.S. J. Am. Chem. Soc., 1955, 77, 334.

34. George Simms Hammond (1921-2005) was educated at Bates College and Harvard University (PhD,
1947). He held faculty positions at Iowa State University, the California Institute of Technology, and the
University of California at Santa Cruz, and he served as Foreign Secretary of the National Academy of Sciences.
For a more detailed biography, see: Wamser, C.C. J. Phys. Chem. A 2003, 107, 3149.

Energy
Reactants
Products
Extent of bonding change and/or atom reorganization
Figure 1.8 The change in transition state structure with the enthalpy of the reaction.
gap, and it will therefore require only a small reorganization of the atomic positions to
convert the reactants to the activated complex. In a highly endothermic reaction, with a
large activation energy, the energy gap between reactants and activated complex is large,
but that between the activated complex and the product is small; in these cases, we expect
that the conversion of product to activated complex, and vice versa, will involve only a
small reorganization of the atomic positions. This can be stated in a generalized form
(shown schematically in Figure 1.8).
The more endothermic a reaction, the higher its activation energy, and the more closely the
structure of the activated complex resembles the structure of the product (or intermediate).
The more exothermic a reaction, the lower its activation energy, and the more closely the
structure of its activated complex resembles the structure of the reactants.
A more recent theoretical basis for the Hammond postulate arises as an extension of
the Marcus theory35 for outer-sphere electron transfer reactions.36 To apply this extension
of Marcus theory, the potential energy surface of the reactant and product are represented
by parabolas that are separated along the reaction coordinate. The positions are labeled in
Figure 1.9 as being at the reactant geometry and the product geometry. The fact that these
outer-sphere electron transfer reactions are not accompanied by structural changes greatly
simplifies the geometric picture and allows the effects of energy to be isolated—only the
parameter along the z axis changes.
In an endothermic reaction, the product parabola is located at a higher Gibbs free
energy than that of the reactant (i.e., higher up the vertical axis). In a thermoneutral reac-
tion, the two parabolas are at the same energy (i.e., the same height up the axis. In an
exothermic reaction, the product parabola occurs at a lower Gibbs free energy than the
reactant. The points where the reactant and product parabolas cross (the black dots in
Figure 1.9) correspond to the transition state energy and geometry. As is evident from
Figure 1.9, the predictions of the Marcus theory and the Hammond postulate correlate
well when the reaction is not highly exothermic.
35. (a) Marcus, R.A. J. Chem. Phys. 1956, 24, 966, 979; 1965, 41, 2654; 43, 679. (b) Siders, P; Marcus, R.A. J.
Am. Chem. Soc. 1981, 103, 741, 748.
36. Rudolph Arthur Marcus (1923-) was educated at McGill University in Montreal, and after postdoctoral
work in North Carolina, he joined the Polytechnic Institute of Brooklyn in 1951. In 1964 he moved to the
University of Illinois at Urbana-Champaign, and in 1978 he joined the California Institute of Technology. He
received the Nobel Prize in 1992 for his theoretical work in electron transfer reactions and unimolecular
reactions. For more biographical information, see the Nobel Foundation web site.

Gibbs Free Energy Figure 1.9 Marcus theory

approach to the prediction of
transition state energy and
endothermic
structure.
thermoneutral
exothermic
‡ extremely exothermic
‡ ‡
‡ Reaction Coordinate
product geometry
reactant geometry
Worked Problem
1-5 The electrophilic substitution of benzene by bromine in the presence of ferric bro-
mide and the sulfonation of benzene by sulfur trioxide in concentrated sulfuric acid
follow a common mechanism. The first step is addition of the electrophile to the
benzene π-bond system, and the second step is loss of a proton from the benzeno-
nium ion intermediate. However, bromination is irreversible, whereas sulfonation is
reversible (i.e., it comes to an equilibrium). Draw appropriate reaction coordinate
diagrams to explain this observation. The mechanism is drawn below:
FeBr3 FeBr3
Br Br O
Br S
O O O O O
O O
H Br Br H S O S
§Answer below.

The first step of the reaction is the same in both, so any difference in the outcome most likely comes in the
second step of the reaction. In bromination, the activation energy leading from the intermediate cation to the
product must be lower than the activation energy leading back to reactant, whereas in sulfonation, the activa-
tion energy leading from the intermediate cation to the product must be comparable to the activation energy
for the reaction leading back to the reactant. In sulfonation, also, the relative energies of the reactant and prod-
uct are probably comparable, thus permitting the reaction rates converting reactant to product and product
back to reactant to be similar.
bromination sulfonation

Problems
1-7 The ring opening of three-membered rings by strong, non-nucleophilic bases is

a method for the formation of allylic compounds. The reaction occurs in
a single step.
base
X
X
Arrange the compounds with X = N, X = O, and X = S in the expected order of

the rate of this reaction under comparable conditions. Draw appropriate reaction
coordinate diagrams to support your answer. You may find the following pKa
values useful: H2O, 15.74; NH3, 33; H2S, 7.00.
1-8 Arrange the compounds with values of n from 1 to 3 in order of the ease of their
ring opening reactions by hydrogen sulfide in the presence of strong acid. Draw
appropriate reaction coordinate diagrams for the reaction.
H H
S H
HS SH
(CH2)n (CH2)n (CH2)n (CH2)n
O O O OH
H H
H
1.4 Resonance
Occasionally, the known facts about the structure of a molecule or ion cannot be accom-
modated by a single Lewis structure. These compounds are best described in terms of
resonance theory,37 first developed by the American chemist Linus Pauling.38 In a
resonance-stabilized system, there are at least two valid Lewis structures that can be
drawn for the molecule or ion, and these are related by having a different arrangement of
the electrons between the nuclei. The compliant structures that can be drawn using the
Lewis rules are known as resonance contributors, limiting structures, or canonical forms,
and the correct structure is a resonance hybrid of these three. In order not to confuse
resonance with equilibrium, canonical forms (which have no independent existence) are
linked by a double-headed arrow39 rather than by the double arrows used to designate
equilibria (which link structures that do exist).
Writing structures of canonical forms and predicting the structure and reactivity of
resonance hybrids follows the set of general precepts below. Of course, these generaliza-
tions are like most generalizations—they work in most cases, but it is always possible to
find exceptions to the rule.
37. Early papers describing resonance: (a) Pauling, L.; Wheland, G.W. J. Chem. Phys. 1933, 1, 362-374. (b)
Pauling, L.; Sherman, J. J. Chem. Phys. 1933, 1, 606-617.
The subject is dealt with at length in Wheland, G.W. Resonance in Organic Chemistry (John Wiley & Sons:
New York, 1955).
38. Linus Carl Pauling (1901-1994) was educated at the California Institute of Technology (PhD, 1925) and
then studied in Europe with Sommerfeld, Bohr, Schrödinger, and Bragg before returning to “Caltech” in 1927
as a member of the faculty. Pauling made numerous contributions to physical and theoretical chemistry. He
received the Nobel Prize twice (Chemistry, 1954; Peace, 1962). For more complete biographies, see the Nobel
Foundation web site, and the Linus Pauling Institute web site (http://lpi.oregonstate.edu/lpbio/lpbio2.html,
accessed November 21, 2012).
39. (a) Bury, C.R. J. Am. Chem. Soc. 1935, 57, 2115. (b) Eistert, B. Angew. Chem. 1936, 49, 33.

1. Resonance stabilization always requires delocalized electrons in a molecule. It must be

possible to write at least two different, valid Lewis structure for the molecule.
2. The number of atoms carrying formal positive or negative charges is minimized (i.e.,
the number of contributors in which there is charge separation is minimized).
3. Nuclei may not move during the interconversion of canonical forms—only electrons
may move.
4. Maximum resonance stabilization occurs when the number of equivalent canonical
forms is maximized.
5. The structure of the resonance hybrid will most strongly resemble the average of the
structures predicted for the major canonical forms.
6. The reactivity of the resonance hybrid will most often resemble the reactivity predicted
for the minor canonical form.
H
H N H
N
H N H
H
(1.9)
H H
H N H H N H
N N
H N H H N H
H H
H 1/3
H N H
1/3 N (1.10)
H N H
H 1/3
We can illustrate the principles of resonance using the guanidinium cation, shown in
Example 1.9. This ion is known to have three equivalent nitrogen atoms. Using the rules for
writing correct Lewis structures, one cannot, however, write a compliant structure in which
more than two nitrogen atoms are equivalent. The third nitrogen is always different; one is
double-bonded and carries a formal positive charge, whereas the two are single-bonded and
neutral. It is possible to write two other structures for this ion by simply rearranging the way
that the electrons in lone pairs and π bonds are distributed, so one obtains three different
structures containing the same set of nitrogen atoms. However, because each of these com-
pliant structures has one unique nitrogen atom, none can be the correct structure of the
guanidinium cation. The true structure must lie somewhere between these three struc-
tures—it must be a hybrid structure of the three with elements of all. A more accurate rep-
resentation of the structure of the guanidinium cation is shown as Example 1.10.
It is important to remember that canonical forms are simply useful representations of
limiting Lewis structures for a compound and do not exist in the real world.40 Nevertheless,
resonance theory has the important ability to be used to predict both structure and reac-
tivity of reactive intermediates in organic chemistry. The structure of a resonance-
stabilized species may be described in terms of equivalent or nonequivalent canonical
forms. The guanidinium cation above is an example of a species whose canonical forms
are equivalent, as are the carboxylate anion, and the nitro group, each of which has two
equivalent canonical forms (Figure 1.10).
Many resonance-stabilized systems have canonical forms that are not equivalent (i.e.,
do not contribute equally to the resonance hybrid); the structure of such systems looks
more like a weighted average of the contributors. To predict the structure and reactivity of
40. The analogy that is widely used for describing resonance—that a rhinoceros (a real animal) is the resonance
hybrid of a unicorn (a fictional creature) and a dragon (another fictional creature)—is due to J. D. Roberts [cited
in Wheland, G.W. Advanced Organic Chemistry, 3rd. Ed. (John Wiley & Sons: New York, 1960), p. 91].

R R
C C
O O O O
R R
N N
O O O O
Figure 1.10 The two equivalent canonical forms of the structure of the carboxylate anion (upper)
and the nitro group (lower) have the same set of bonds and electron pairs. No nuclei move during
the conversion of one canonical form to the other.
such species, one needs to be able to predict the relative importance of the canonical
forms. This can be done on the basis of a few simple rules:
1. Canonical forms where all non-hydrogen atoms have a complete octet are more im-
portant than canonical forms where one atom lacks a complete octet.
2. Canonical forms with the maximum number of covalent bonds tend to be most important.
3. When two or more resonance structures are possible, the major contributors to the
overall resonance hybrid will be those in which all non-hydrogen atoms possess a com-
plete outer-shell octet of electrons.
4. In anions, the canonical forms with the negative charge on an electronegative atom are
preferred.
5. In cations where the charged atom must have only six electrons, canonical forms with
a positive charge on an atom of low electronegativity are preferred.
6. In cations for which one can draw canonical forms where every non-hydrogen atom
has a complete octet, these canonical forms are more important even if this requires
placement of the positive charge on an electronegative atom.
Unequally contributing canonical forms can be used to predict the chemical reactiv-
ity, structure, and stability of the resonance-stabilized species.
In general, the chemical reactivity of a resonance-stabilized molecule or ion most often resem-
bles the reactivity that one would predict for the canonical form making the minor contribution
to the resonance hybrid (minor resonance contributor). In contrast, the molecular structure of
a resonance-stabilized molecule most often resembles the structure that one would predict for
the canonical form making the major contribution to the resonance hybrid (major resonance
contributor). It is also observed that the chemical stability of a resonance-stabilized molecule or
ion is best predicted by the structure of the major resonance contributor.
Two good examples of resonance-stabilized charged systems are the enolate anions,
R 2C=CRO–, and acylium cations, RCO+. There are two reasonable canonical forms of the
structure of the enolate anion (Figure 1.11), and the acylium ion (Figure 1.12).
O O
R C R C
C R C R
R R
major minor
canonical canonical
form form
(structure) (reactivity)
Figure 1.11 The enolate anion is an example of an anion in which the two resonance contributors are
no longer equivalent. The major contributor to the structure of this ion is the one on the left, where
the negative charge is on the more electronegative oxygen atom; the minor contributor (which fre-
quently dictates the normal chemical reactivity) has the negative charge on the carbon atom.

R C O R C O
minor major
(reactivity) (structure)
Figure 1.12 In the acylium cation, only the contributor on the right has a complete outer-shell
octet on every non-hydrogen atom. Therefore, even though it requires that the more electronega-
tive oxygen atom carry a formal positive charge, it is still the major contributor to the resonance
hybrid.
In the left-hand canonical form in Figure 1.11, there is a carbon-carbon double bond,
and the negative charge is on the oxygen atom. In the right-hand canonical form, there is
a carbon-oxygen double bond, and the negative charge is on the carbon atom. Based on
the arguments above, one would predict that the contributor on the left would be the more
thermodynamically stable because the negative charge is on the most electronegative
atom. Accordingly, we would expect that this should contribute to the overall structure of
the anion to a greater extent than the contributor with the negative charge on carbon.
Indeed, the structures of several metal enolates chemically similar to this have been deter-
mined, and in every case the carbon-carbon bond is a double bond, and the length of the
carbon-oxygen bond is exactly that expected for a carbon-oxygen single bond.
The two most important canonical forms of the structure of an acylium ion are shown
in Figure 1.12. The major difference between the two canonical forms is that the positively
charged carbon atom in the left-hand contributor has only six valence electrons, whereas
all the non-hydrogen atoms in the right-hand contributor have complete valence shell
octets. The major contributor is the right-hand structure, in spite of the fact that it requires
that a positive charge be placed on the most electronegative atom (the oxygen atom).
The canonical forms of the acylium ion emphasize another important precept of reso-
nance theory—when two or more canonical forms can be drawn for a structure, the major
contributor(s) to the resonance hybrid will be the one(s) in which every non-hydrogen
atom possesses a complete valence shell octet of electrons.
All arguments about structure based on resonance arguments must be prefaced with
one important restriction. These arguments apply only if one is dealing with reasonable
resonance contributors. In other words, all resonance contributors must obey the rules for
writing Lewis structures (the number of atoms with complete outer-shell octets must be
maximized, the number of atoms with incomplete outer-shell octets must be minimized).
It is always possible to write resonance contributors for the structure of any molecule or
ion, but most of these will be patently unreasonable. They will contain several (i.e., more
than two) atoms without complete outer-shell octets, they will contain several atoms
carrying opposite charges that could be neutralized by simply moving electrons, and they
will contain several atoms with unpaired electrons.
Although resonance contributors in which there is charge separation are occasionally
used in discussions of the reactivity of organic compounds, such contributors are invari-
ably minor contributors to the overall resonance hybrid. By far the most common versions
of this situation involve polar covalent bonds, which may be viewed as the resonance
hybrid of a nonpolar contributor and an ionic contributor. The formaldehyde and forma-
mide molecules provide good examples of this situation (Figure 1.13). In both of these
molecules, one can write at least one resonance contributor to the structure in which two
atoms bear opposite formal charges. In the formaldehyde molecule, this is done by choos-
ing to leave the carbon atom with six electrons, and placing three lone pairs around the

O O O
O O C H C H C H
C C H N H N H N
H H H H H H H
major minor major very minor minor
formaldehyde formamide
Figure 1.13 Resonance in formaldehyde and formamide molecules illustrates charge separation in
generating the minor contributing structures. In both cases, the structures carrying formal
charges are minor contributors, but the reactivity of the molecules may be best rationalized in
terms of the minor contributors.
oxygen atom; in formamide, one can write a similar canonical form, and one where no
non-hydrogen atom lacks a complete outer-shell octet, but the oxygen is again negatively
charged, and the nitrogen atom carries a formal positive charge. This process, where one
generates a minor canonical form carrying two atoms with opposite charges, is known as
charge separation. Canonical forms where there is charge separation are always minor
contributors to the resonance hybrid.
Problems
1-9 Which of the following molecules and ions is/are resonance-stabilized? Draw the
resonance contributors for those that are. Of those that are resonance stabilized,
for which ions are there two or more equivalent resonance contributors? For
those resonance-stabilized species where the contributors are not equivalent, in-
dicate the major and minor contributors.
N
(a) Me
(b) N
(c)
N Me
O OH O
N N NH
(d) (e) N
Me Me
N N H3CO O OCH3
(f) (g)
N N
Me Me
Me
O
N N N
(h) (i) NC CHO
(j)
N N O
Me
N
(k) N (l) O NO2 (m)
N O O
1-10 The diazomethane molecule, H2CN2, and the azide ion, N3–, are both linear, and
both contain the N–N group. Draw the reasonable canonical forms of these two
species and indicate which make the major contributions to the resonance hybrid
of each. The diazomethane molecule reacts with acid to give a resonance-stabilized
ion with the molecular formula CH3N2+. Draw the reasonable canonical forms of
this ion, and designate the major and minor contributors to the resonance hybrid.

1-11 Benzoic acid, C6H5CO2H, dissolves in concentrated sulfuric acid to give a cation
with the formula C6H5CO2H+2 , where an oxygen atom has been protonated. There
are two possible oxygen atoms for protonation in this molecule, but the experi-
mental evidence suggests that only one protonated species is formed in measur-
able amounts. What is the structure of the ion formed, and why is it the only
major product of the reaction?
1-12 Dicyclohexylcarbodiimide, whose structure is given below, is not strongly

resonance-stabilized despite having two nitrogen atoms and two π bonds.
Why not?
N
C
N
1-13 The compounds below are weak bases that react with strong acid to give cat-
ions in which the nitrogen atoms are not protonated. Suggest a structure for
the protonated species and suggest why the protonation does not occur at
nitrogen.
O
N
N N
1-14 The sydnones are an interesting class of compounds known as “mesoionic” com-
pounds. A typical sydnone is shown below. Draw the structures of all reasonable
canonical forms contributing to the resonance hybrid of this compound, and
show the electron movement that interconverts them. Can you draw a structure
without any formally charged atoms?
O
H
O
N N
H3C
1-15 The cations below are strongly resonance stabilized. Draw all the possible reason-
able resonance contributing forms for each ion and show the electron movement
that interconverts them.
F
N N
HO NH2
1-16 The classes of compounds below have the approximate pKa values shown. How
can these values be rationalized? (Remember the Hammond postulate; you might
also want to consider resonance.)
O O O
R C pKa 4-6 R C pKa 15-16 R C pKa 25-27
OH NH2 CH3

1-17 Suggest a rationalization for the relative rates of nitration of the series of substi-
tuted benzene derivatives, C6H5R, below, based on an analysis of the possible
benzenonium ion intermediates involved.
H
NO2
Isomer R: H CH3 CO2Et Cl Br CH2CO2Et CH2Cl

ortho 1 42 0.0026 0.030 0.037 4.62 0.200
meta 1 2.5 0.0079 0.00 0.00 1.16 0.140
para 1 58 0.0009 0.139 0.106 10.4 0.951

1-18 The protonation of an epoxide leads to the resonance-stabilized carbocation
shown below.
O O O
H H H
The equilibria below would also delocalize the positive charge to the same carbon
atoms.
HO O
H OH
How does the equilibrium model differ from the resonance model?
1.5 Spectroscopy and Chromatography
Nothing changed organic chemistry during the 20th century so much as the development
of spectroscopy and chromatography. With the availability of techniques such as hplc
(high performance liquid chromatography), we are able to separate mixtures that were
once considered impossible to separate. With the advent of modern techniques of NMR
(nuclear magnetic resonance) spectroscopy and mass spectrometry, we are now able to
deduce structural details in molecules that just a decade ago would have been viewed as
hopelessly complex.
This book will not explicitly treat modern spectroscopy except superficially. To obtain
a better grasp of the subject, you should consult introductory books in organic chemistry
and specialized books in spectroscopy. That being said, some form of review is still appro-
priate here.
Infrared (IR) spectroscopy (or, more properly, spectrophotometry) records the ab-
sorption of IR radiation by the sample. The absorption of radiation occurs by exciting
molecular vibrations of the molecule, and it is useful because many functional groups in
organic compounds absorb IR radiation within a narrow, characteristic range of frequen-
cies. These characteristic functional group frequencies occur in the range from 4000 to
500 cm–1, with the most useful vibrations occurring above 1500 cm–1. A correlation chart
for IR frequencies is given as Figure 1.14.
The 20th century was certainly the decade of NMR spectroscopy, and it saw the rise of 1H
NMR and 13C NMR spectroscopy as routine methods for examining the structures of organic
compounds. The proton spectrum covers a fairly narrow range, with most resonances ap-
pearing between –2 and 12 ppm. As with the IR spectrum, the 1H NMR spectrum can be
subdivided into ranges where one can make structural inferences about the resonances. The

Frequency (cm–1)
3000 2500 2000 1500 1000 500
X—H (str.) X—H (str.) X≡Y (str.) X=Y (str.) fingerprint out-of-plane
X=O, N X=S, etc. X=Y=Z (str.)
OH OH C≡N C=O
alcohols acids 2260-2150 aldehydes
3400-3200 3200-2500 C≡C 1720-1740
acids O=C—H 2250-2100 ketones
3200-2500 aldehydes 1705-1725
NH 2720 carboxylic acid
amines 2820 1700-1725
3300-3100 SH esters skeletal NMR
amides 2550 1730-1750 vibrations spectroscopy
3300-3100 amides does this
CH 1660-1690 complex better
alkynes anhydrides
3300 1810, 1760
alkenes acid chlorides
3100-3000 1800
arenes arenes
3150-3050 3150-3050
C=C
alkenes
1600-1660
arenes
1600, 1500
Figure 1.14 Correlation chart for infrared spectra. Note how the fingerprint region is left blank
(this region contains skeletal vibrations that complicate interpretation), and the out-of-plane
region is also omitted (this is are better served by NMR spectroscopy).
chemical shift range of 13C resonances is wider, and again, one can subdivide the spectrum
into ranges that contain the resonances of particular kinds of carbon atoms.
NMR spectroscopy has the added bonus that the nuclear spins of the NMR active
nuclei allow them to couple, and this spin-spin coupling allows one to derive both stereo-
chemical and regiochemical information by the application of an increasingly useful array
of techniques. Today, one can literally trace atomic connectivity through the backbone of
a molecule and so derive the complete structure by NMR. A chemical shift correlation
chart for 1H NMR spectra is given in Figure 1.15.
A chemical shift correlation chart for 13C NMR spectra is given in Figure 1.16.
Chapter Summary
This chapter has discussed chemical bonding—from (1) ionic bonding, where there is
complete transfer of an electron from one reactant to the other; to (2) nonpolar covalent
bonding, where the electron pair is shared essentially equally; to (3) polar covalent bond-
ing, which lies between the two extremes. Lewis structures of organic compounds have
been considered, with the concepts of formal charge and the dative (coordinate covalent)
bond. The Arrhenius and Lowry-Brønsted theories of acids and bases have been intro-
duced as a prelude to later discussions of proton transfer reactions. The general classes of
organic reactions (homolysis and heterolysis) have also been discussed, along with writing
mechanisms for them. Kinetics of reactions, including rate laws and the Arrhenius equa-
tion, have been introduced, and the relationship between mechanism and kinetics has
been briefly discussed. The concept of resonance and the significance of major and minor
canonical forms of resonance-stabilized species, have also been introduced.

Chemical Shift (ppm)

12 10 8.5 6.5 4.5 2 0
H
R
X O R H R H
X R
R R H
OH H R
R R R H R
carboxylic aromatics alkynes alkanes

aldehydes alkenes
acids 6.5-8.0 4.5-6.5 1.7-2.7 0.7-1.7
9.0-10.0
10-12 X=OH, OR
3.2-3.8 allylic
enols X=OCOR 1.6-2.4
12-15 3.5-4.5
X=F benzylic
4.2-4.8 2.3-2.7
X=Cl
3.0-3.5 α to C=O
X=Br 2.1-2.5
2.7-3.2
X=I
2.0-2.5
X=NR2
2.2-2.9
O—H: 0-5 (alcohols); 4-8 (phenols). N—H: 0-4 (amines); 3-5 (anilines); 5-9 (amides).
H—CR2SiR3 0; cyclopropane H 0.5- -2.
Figure 1.15 Correlation chart for 1H NMR spectroscopy. The chemical shift ranges are such that
methyl protons tend to occur at the high-field end of the range and methine protons at the low end
of the range, with methylene protons in the middle. CH resonances typically occur ≈ 0.4 ppm
downfield from the CH2 resonances, which in turn resonate ≈ 0.4 ppm downfield from the CH3
resonances.
Chemical Shift (ppm)

220 200 180 160 130 100 50 0
O R X R R
C C C
O R O R R R R X R
R R
R C C C C
O R X R R
R R R
C C X C R
R
Figure 1.16 Correlation chart for 13C nuclear magnetic resonance chemical shifts. The ranges are
approximate.
Key Terms
acid dative bond minor contributor

Arrhenius rate equation formal charge molecular formula
base Hammond postulate molecularity
canonical forms heterolysis polygon formula
complete structural hemolysis rate law
formula ionic bond reaction coordinate
condensed structural kinetic order diagram
formula kinetics reaction energy profile
connectivity formula line formula resonance
coordinate covalent bond major contributor resonance contributors
covalent bond mechanism resonance hybrid

Additional Problems
1-19 The addition of Br2 to 1,3-butadiene in carbon tetrachloride solution gives

3,4-dibromo-1-butene as the major product of the reaction at 0°C, and
1,4-dibromo-2-butene when the reaction is carried out at 77°C. Provide an
explanation for this observation.
1-20 Write an acceptable mechanism for the reaction below.
Me
NH2 H2CO/HCl N
EtOH/H2O N
Me Me
2 C7H9N + 3 CH2O C17H18N2 + 3 H2O
1-21 Why does the anion below decompose rapidly to give the products shown, even at
low temperature?
O CH2
+ CO
1-22 The Sharpless asymmetric epoxidation of geraniol at 25°C gives the two enantio-
meric products in a ratio of 39:1. What is the difference in the activation energies
of the two competing reactions (in kcal mol–1) if the Arrhenius pre-exponential
(A) factor is assumed to be the same for both reactions?
[R = 1.98717 cal mol–1 K–1]
1-23 (a) The amine in the figure is a considerably stronger acid (pKa ≈ 15) than one
would expect. Using resonance arguments to support your answer, provide a
reasonable rationalization of this observation. You should consider both the
amine and its conjugate base in your answer.
NH2 NH
O N O O N O
Me Me
(b) Draw a reaction coordinate diagram that rationalizes the effects of resonance
on this reaction.
1-24 Suggest reasonable mechanisms for the transformations below:
Cl O
H H
HClO4/H2O
(a)
HCO2H
H H H H
H H H
O O H
H O ∆ O O
(b) + O
H H
O H OH O
O O
O H H

H CO2Me
MeO2C MeCN H H
(c) N ∆
N
H
N2
O OMe O O
(d) O CF3CO2H/CH2Cl2/–20°C O
Cl3C Cl3C
O O
Me
O OEt O N Ph
(e) PhCH2NHMe/85°C
CO2Et CO2Et
O
O H
O
0.5 M HCl
(f) O O O OH
O H H O
R O
SiR3 R H OR'
OR'
CO2Me
CO2Me
OH HCl (trace) O
(g) O CHCl3 O
O
HO
1-25 The mechanism of the reaction in the figure was used as a worked example
earlier in this chapter (Worked Problem 1-4). Based on the mechanism given
in that Worked Problem 1-4, draw a labeled reaction coordinate diagram for
this reaction.
O
1) CF3CO2H/∆
O 2) H2O
HO
1-26 The addition of bromine to an alkene in the presence of other nucleophiles leads
to products that have bromine and another group. Explain how this reaction
might be used to develop a scale of nucleophilic power.
Br
Br2/X or
Br2/HX: X
1-27 Mononitration (HNO3–AcOH or HNO3–CF3CO2H) of the citrus flavonoid pig-

ment diosmetin (shown in the figure) occurs only to give the two mononitro
products shown, where nitration has occurred in the phenyl ring, and none of the
product of nitration in the other aromatic ring despite it being highly activated.
Suggest a reason why this should be so. [Tetrahedron Lett. 2010, 51, 1145].
R OMe
OMe
HO O
HNO3 OH
HO O
OH AcOH R'
OH O
OH O
R=H; R'=NO2
R=NO2; R'=H

1-28 Each of the species below is a 1,3-dipole that will react with an alkene to give a
five-membered heterocyclic product. Each of the 1,3-dipoles is stabilized by reso-
nance. Draw the contributors to the resonance hybrid of each 1,3-dipole and write
a reasonable one-step mechanism for each reaction given below, using the reso-
nance contributor shown.
N O
(a) C N O
O O
(b)
N Me N Me
SiMe3
Me3Si N
(c) N N N N
N
O
O
(d) O
O O O
(e) O O
N N

Chapter two
Stereochemistry
2.1 Stereoisomers and Chirality1
The three-dimensional shape of a molecule can be a critical factor in its reactivity. The
stereochemistry of compounds is usually considered under two major categories: confor-
mation and configuration. The conformations of a molecule are dynamic—they are con-
stantly interconverted by rotation about σ bonds. Thus, the term preferred conformation of
a molecule refers to the weighted average conformation of a population, not a single confor-
mation of a single molecule. Configurations, on the other hand, cannot be interconverted
without cleaving and reforming covalent bonds. Stereoisomers with differing configura-
tions are further defined as enantiomers, which are chiral molecules that are nonsuper-
imposable mirror images, and diastereoisomers, which are not mirror images. The term
stereoisomers is usually reserved for compounds differing in configuration—conformers
are not commonly designated as stereoisomers.2
Representing Stereochemistry
A molecule is a three-dimensional object, but we almost always have to represent it in two
dimensions. As with any three-dimensional object, how it will appear depends on the
perspective from which we view it. There are several different conventions that organic
chemists use to represent molecules in two dimensions, and all of them are derived at
some point from the same kinds of approaches that an artist might adopt to paint a
three-dimensional object. Those most commonly used by modern organic chemists are
shown in Figure 2.1.
Reduced to their simplest principles, each of the conventions shown in Figure 2.1
requires that we first take up a position in space at some point from which we can see
the whole molecule and that we then draw the molecule in perspective from that point.
From this kind of approach, we obtain representations known as projection formulas,
such as the line formula (A); the bow-tie projection (B); and its analog, the Fischer
projection, 3 named for Emil Fischer4 (C); and the Newman projection 5 (D), named for
1. The definitive book on this subject is Eliel, E.L.; Wilen, S.H.; Mander, L.N. Stereochemistry of Organic
Compounds (Wiley-Interscience: New York, 1994). This book is encyclopedic in coverage and should be the first
reference work consulted for more details than can be provided in this chapter.
2. (a) McCasland, G.E. A New General System for the Naming of Stereoisomers. (Chemical Abstracts Service:
Columbus, OH, 1950), 2. (b) Mislow, K.; Siegel, J. J. Am. Chem. Soc. 1984, 106, 3319. (c) Eliel, E.L. Chirality, 1997,
9, 48.
3. Fischer, E. Ber. Deut. chem. Ges. 1891, 24, 2683.
4. Emil Fischer (1852-1919) studied at Bonn, then Strasbourg (PhD, 1874). After 8 years as assistant to Baeyer,
he became professor of chemistry at Berlin. His pioneering work in synthetic chemistry and stereochemistry
won him the Nobel Prize in 1902. A more complete biography may be found in: Nobel Lectures, Chemistry, 1901-
1921 (Elsevier Publishing Company, Amsterdam, 1966)
5. Newman, M.S. J. Chem. Educ. 1955, 32, 344.
37

38 Advanced Organic Chemistry | Chapter two
Figure 2.1 Conventions for

drawing representations of
the stereochemistry of or-
ganic molecules and the per-
spectives that give rise to
each representation
Melvin S. Newman.6 These projection formulas are, of course, stylized representations

of what the viewer actually sees. The convention of omitting the symbol for the carbon
atoms is common (just as in drawing line or polygon formulas) and can often lead to a
dramatic simplification of the diagram—one that actually draws the reader's attention
to the shape of the molecule.
The convention in the line formula (A) and the bow-tie projection (B) is that all bonds
drawn as simple straight lines are assumed to lie in the plane of the page, whereas atoms
at the thick end of the wedges are projecting out of the plane of the page toward the reader
and those at the end of the hatched lines project away from the viewer behind the plane of
the page. Thus, in the line formula B for ethane, there are four atoms in the plane of the
page (the two carbon atoms and two of the six hydrogens).
In the Fischer projection (C), there are no wedges or hatched lines to indicate the loca-
tion of the four groups about each carbon atom, but a Fischer projection corresponds to a
strictly defined orientation of the molecule where the horizontal bonds project out toward
the viewer, and the vertical bonds project away from the viewer, as shown in the bow-tie
projection (B). Although this is a useful convention in the right circumstances, it does
have some rather unfortunate consequences because simple rotations of the Fischer pro-
jection do not correspond to simple rotations of the molecule unless the rotation is through
a multiple of 180°. Rotations of a Fischer projection through odd multiples of 90° invert the
absolute configuration of the molecule being represented.
The Newman projection (D) is possibly the best representation for illustrating the ori-
entation of groups about σ bonds, but it suffers from the fact that one is restricted to look-
ing at pairs of atoms instead of the molecule as a whole. Like the other projections, the
Newman projection is stylized—the central carbon atoms are omitted and the electron
density of the σ bond is represented by a circle. Because the electron density of the σ bond
6. Melvin S. Newman (1908-1993) was educated at Yale (PhD, 1932). He joined the Ohio State University,
where he spent the remainder of his professional career, in 1935. He is best remembered for his development of
the Newman projection formulas for illustrating conformations of organic compounds. For more detail, see:
Paquette, L.A.; Orchin, M. Biogr. Mem. Nat. Acad. Sci. 1998, 73, 334.

Stereochemistry 39
should obscure part of each bond to the back carbon atom, only the bonds to the front
carbon are visible for their entire length.
Problem
2-1 Draw the structure of each of the following molecules using projection formulas
(A) to (D) from Figure 2.1. Is there more than one way to represent each
molecule?
F F F F
(a) F3C CCl3 (b) Cl2HC CHCl2 (c) Cl Cl (d) H3C Cl (e) F2HC Cl
Br Br Br Br
Symmetry Elements in Organic Compounds
The symmetry of an organic molecule determines, among other things, whether the mol-
ecule will be chiral. For this reason, we need to be well acquainted with the most common
symmetry elements found in organic molecules and with their effects on the stereochem-
ical properties of the molecule.
The simplest symmetry element in an organic compound is a proper axis of symmetry,
designated Cn, where n is the order of the symmetry axis. The effect of this symmetry op-
eration is to rotate the molecule through 360/n degrees. In molecules that possess this
symmetry element, the rotation converts the molecule into a totally equivalent represen-
tation. Example 2.1a has a C2 axis of symmetry through the midpoints of the three bonds
indicated by heavy dots on the axis, and Example 2.1b has a C3 axis of symmetry perpen-
dicular to the page in the polygon representation.
Problem
2-2 Locate all axes of symmetry in the following molecules: (a) terephthalonitrile; (b)
1,1-dichlorocyclobutane; (c) 1,3,5-tribromo-2,4,6-trichlorobenzene; and (d) mel-
litic anhydride.
O O O
N Cl Br
C Cl
Cl O O
(a) (b) (c) Br Cl (d)
C O O
N Cl Br
O O

Another common symmetry element in an organic molecule is the mirror plane of

symmetry, σ. The effect of this symmetry operation is to reflect one half of the molecule
through the mirror. In molecules that possess this symmetry element, one half of the mol-
ecule reflects exactly onto the other half. In the molecule in Example 2.2, for example,
every atom in the left half of the molecule is reflected through the mirror plane onto a
corresponding atom in the right half of the molecule.
Problems
2-3 Locate all the mirror planes of symmetry in the molecules in Problem 2-2.
2-4 Draw the Newman projections of the compounds in Problem 2-1 to show how
they may have a mirror plane of symmetry. Are there any compounds for which
no mirror plane of symmetry can be drawn?
The third symmetry element that can be present in an organic molecule is an inversion
center of symmetry, i. The effect of this symmetry operation is to reflect each atom of a
molecule through a single point (the center of symmetry). This symmetry element is
common in inorganic compounds but much less common in organic compounds than the
proper axes and mirror planes of symmetry. But it is still common enough to remember it.
In the molecule in Example 2.3, for instance, there is a center of inversion designated by
the dot right in the middle of the six-membered ring. Every atom in this molecule has a
corresponding atom of the same type at the same distance from the inversion center on
the opposite side of the center.
Problem
2-5 Draw the Newman projections of the compounds in Problem 2-1 to show how
they may have an inversion center of symmetry. Are there any compounds for
which no inversion center of symmetry can be drawn?

Stereochemistry 41
S6
F
FF FF
F
(2.4)
A fourth symmetry element that is occasionally found in organic molecules is an im-

proper axis of rotation, Sn, where n is an even number. The operation of this symmetry
element is more complex than the simple symmetry elements described above because it
involves the sequential application of an n-fold axis of rotation and a mirror plane of sym-
metry perpendicular to it. This symmetry operation is always accompanied by a proper
axis of rotation of half the order of the improper axis. In the molecule in Example 2.4, for
instance, there is a threefold axis through the center of the ring. Rotation of the molecule
by 60° (360 ÷ 6) around this axis and reflection in the plane perpendicular to the axis
restores the original appearance. This molecule has a sixfold improper axis of rotation (S6).
Worked Problem
2-1 Identify the symmetry elements present in the molecule below. Is the compound
chiral? Give reasons for your answer.
Cl Cl
Cl Cl
§Answer below
Problems
2-6 Identify the symmetry elements present in each of the following molecules (you
will find molecular models helpful).
F
O O
(a) O (b) (c) (d)
F
(continued)
§ Answer for Worked Problem:

Cl Cl Cl Cl
C2 S4
Cl Cl Cl Cl
This molecule has a twofold axis of symmetry (C2) and a fourfold improper axis of symmetry (S4). The S4
operation is detailed below:
Cl Cl Cl Cl
rotate 90° about two-
fold axis of symmetry
Cl Cl Cl Cl
reflect through mirror

perpendicular to two-
fold axis of symmetry
Although the molecule possesses neither a mirror plane of symmetry nor an inversion center of symmetry,
it does possess an improper axis of rotation (S4), so it cannot be chiral.

H
(e) (f) (g) (h)
H
H H
F O
(i) (j) (k) (l)
F O H H
O
2-7 Are the compounds below chiral? Give reasons for your answer.
O OH OH OH
H H H H
(a) O (b) O (c) O (d) O
H H H H
O O OH OH
O OH OH
H H H H H H
(e) O O (f) O O (g) O O
H H H H H H
O O OH
OH OH OH
H H H H H H
(h) O O (i) (j)
H H H H H H
OH OH OH
H H H H H H
S S S
(k) N (l) O O (m) O O (n) O O
H
Protocenters of Stereochemistry
For a molecule to exist as stereoisomers, it must have at least four groups that can be ar-
ranged in two or more configurationally stable, nonequivalent ways. Stereochemistry is
most simply discussed in terms of protocenters of stereochemistry, which we will define
as a single atom or group within a molecule, bonded to two different substituent groups in a
nonlinear fashion.7 The bisector of the bond angle at the protocenter defines the axis of the
protocenter, and the three atoms define the plane of the protocenter. Representative exam-
ples of protocenters are shown in Figure 2.2.
Figure 2.2 Representative a
a
types of protocenters a a a
C M N
b b b
b b
7. Lewis, D.E. J. Chem. Educ. 2010, 87, 604.

Stereochemistry 43
It requires two protocenters in a molecule to give rise to Table 2.1 Combinations of Two Coaxial Protocenters That Can
stereoisomers. Protocenters may be centered on the same Give Rise to Stereoisomers in a Molecule
axis (coaxial) or on different axes. By far the most θ b
a b
common situation in organic compounds involves coax- a
ial protocenters, and the discussion that follows will θ Protocenters r=0 r>0
focus on that. There are two parameters that define the a b
relationship between two coaxial protocenters: the dis- 0 Achiral Achiral
(E/Z) (E/Z)
tance between them, r, and the angle between the two b a
planes, θ. Protocenters may be coincident (r = 0), in ≠ 0 a a
a r b r Achiral Chiral
which case they share a common atom, or noncoincident b
b
a
b
(r > 0). They may also be coplanar (θ = 0) or noncopla- a a
≠0 a r c r Achiral Chiral
nar (θ ≠ 0). When the two protocenters are coplanar, the c a
molecule cannot be chiral, but E/Z isomerism may result. b b
When the two protocenters are not coplanar, the mole- ≠ 0 c r

a
d
a Chiral Chiral
r
cule may or may not be chiral, depending on the separa- d
b
c
b
tion between them.
The possible stereochemical outcomes arising from
a pair of coaxial protocenters are summarized in Table 2.1. When the two protocenters
are not coincident (r > 0) and not coplanar (θ ≠ 0), the molecule will be chiral with-
out restriction on the identities of the groups bonded to the protocenters, meaning
that as few as two different groups are sufficient to give rise to chirality in the mole-
cule. The situation becomes more restrictive when the two protocenters are coinci-
dent. In this case, both protocenters must carry different substituents in order for the
molecule to be chiral. Under these circumstances, the result is a center of chirality.
When the two protocenters are coplanar, the molecule is not chiral but exists as geo-
metric (E/Z or cis/trans) isomers (e.g., coincident, coplanar protocenters correspond
to the situation in a square planar compound.
The minimum requirement for a molecule to be able to exist as enantiomers is that it

lack reflection or inversion symmetry. A mirror plane of symmetry or an inversion center
is not permitted in a chiral molecule. All the symmetry requirements for chirality can be
met by a single criterion—for a molecule to be chiral, it may not have an improper axis of
rotation. This does not mean that a chiral molecule must lack any symmetry; proper axes
of rotation are not only permitted, but quite common in chiral molecules. A good example
of this is tartaric acid, which has a twofold axis of symmetry but which is still chiral. In
fact, the existence of a twofold axis of symmetry in the molecule is often a key feature of
chiral molecules used in the synthesis of chiral catalysts (e.g., BINAP,8 the binaphthyl
shown next page).
8. Reviews: (a) Noyori, R. Science, 1990, 248, 1194. (b) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23 345.

(R)-BINAP
Ph2P PPh2
In 1815, the French chemist Jean-Baptiste Biot9 observed that solutions of certain or-
ganic compounds rotate the plane of plane-polarized light.10 Forty-five years later,11 Louis
Pasteur12 suggested that molecules of the same substance with opposite rotations might be
related to each other as object to mirror image, much like a right- and left-handed helix.
The importance of configuration was reinforced by the work of Johannes Wislicenus,13
who suggested in 1873 that the differing properties of stereoisomers could be traced to
differing three-dimensional arrangements of their atoms.14 This was a radical proposal at
the time, because few chemists believed that it was possible to deduce the physical loca-
tions of atoms within a molecule. This proposal was taken further the next year, when
Jacobus Henricus van't Hoff 15 and Joseph-Achille Le Bel16 independently proposed the
concept of the tetrahedral carbon.17,18,19 Interestingly, although these two chemists had
worked together in Wurtz's laboratory in Paris during the year before their publications,
9. Jean Baptiste Biot (1774-1862) studied at the École Polytechnique under Lagrange and Berthollet and
taught at the Collège de France. His study of the properties of light included plane-polarized light. He was made
chevalier (1814), and later commander (1849), of the Legion of Honour. For further biographical details, see
Crosland, M.P. Jean Baptiste Biot. In Dictionary of Scientific Biography (Charles Scribner's Sons: New York,
1970), vol. 2, p. 133.
10. Biot, J.B. Bull. soc. philomath. Paris 1815, 190; 1816, 125; Mém. acad. roy. sci. inst. France 1817, 2, 41, 114.
11. See: (a) Pasteur, L. Researches on the Molecular Asymmetry of Natural Organic Products Alembic Club
Reprints (University of Chicago Press, Chicago, 1902). (b) Oevres de Pasteur (Masson et Cie.: Paris, 1922), vol.
1, p. 315, 329.
12. Louis Pasteur (1822-1895) studied chemistry under Dumas and Balard, and his resolution of tartaric acid
still stands as one of the seminal events in the history of organic chemistry. His later work in microbiology
made him one of the greatest scientists of his generation. Biographies of Pasteur abound, such as Debré, P. Louis
Pasteur; E. Forster, transl. (Johns Hopkins University Press: Baltimore, 1998).
13. Johannes Wislicenus (1835-1902) was educated at Halle but was forced to flee Germany to avoid arrest
for his religious activism. After 2 years in the United States, he moved to Zürich; in 1857 he returned to Halle,
as a private assistant. During his career, he worked at the ETH, Würzburg, and Leipzig. For a more complete
biography, see: Beckmann, E. Ber. dtsch. Chem. Ges. 1905, 37, 4861.
14. Wislicenus, J. Liebigs Ann. Chem. 1873, 167, 302.
15. Jacobus Henricus van't Hoff (1852-1911) was educated at Delft, Leiden, Bonn, Paris, and finally at Utrecht
(PhD, 1874). His contributions to thermodynamics helped to found the discipline of physical chemistry and
won him the first Nobel Prize in Chemistry. After initial positions at Utrecht and Amsterdam, he became Pro-
fessor at Berlin. More biographical details are available at the Nobel Prize web site.
16. Joseph-Achille Le Bel (1847-1930) was born in Péchelbronn, France, and he was educated at the
École Polytechnique in Paris. He inherited the family's petroleum works, making him independently
wealthy. He proposed the tetrahedral carbon and predicted, correctly, that optical activity could arise in
compounds of elements other than carbon. For more biographical details, see: Leicester, H.M. (1973). Le
Bel, Joseph Achille. In Gillispie, C.M., Ed. Dictionary of Scientific Biography, Vol. 8, (New York: Scribners:
New York, 1973)
17. (a) van't Hoff, J.A. Voorstel tot Uitbreiding der tegenwoordig in de scheikunde gebruitke Structuur-Formules
in die ruimte; benevens een daarmeê samenhangende opmerkung omtrent het verband tusschen optisch actief
Vermogen en Chemische Constitutie van Organsiche Verbindingen (Utrecht, 1874); Arch. Néerland. Sci. Exactes
Natur. 1874, 9, 445; Bull. soc. Chim. Paris 1875, [2] 23, 295; La chimie dans l'espace (Bazendijk: Rotterdam, 1875);
Die Lagerung der Atome im Raume, Hermann, F., trans. (Vieweg: Braunschweig, 1877).
18. Le Bel, J.A. Bull. soc. chim. Paris 1874, [2] 22, 337.
19. For an interesting history of the development of stereochemistry, see Ramberg, P.J. Chemical Structure,
Spatial Arrangement. The Early History of Stereochemistry 1874-1914. (Ashgate Publishing Company: Aldershot,
U.K., 2003).

Stereochemistry 45
it appears that they developed their ideas independently and did not even discuss them
with each other.20
The initial reception of the concept—or the idea that it was even possible to estab-
lish the positions of atoms in space—was lukewarm, and Hermann Kolbe, editor and
founder of the Journal für praktische Chemie, and a highly respected (and conserva-
tive) chemist, sought to prevent its circulation by an infamous diatribe21 against
the idea.
Chirality in simple molecules can be in the form of a center of chirality, an axis of
chirality, or a plane of chirality. A center of chirality is a position in a molecule with more
than three different substituents arranged in three dimensions. The concept is most com-
monly seen in tetrahedral species, but the transition state for an SN2 reaction of a chiral
secondary halide, which is a trigonal bipyramid, also possesses a chiral center. Some ex-
amples of chiral centers in a molecule are gathered in Figure 2.3.
20. Walker, J. J. Chem. Soc. 1913, 103, 1127.

21. Kolbe, H. J. Prakt. Chem. [2] 1877, 15, 473.
In a recently published paper with the same title [Signs of the Times], I pointed out that one of the causes of
the present-day retrogression of chemical research in Germany is the lack of general and, at the same time,
fundamental chemical knowledge; under this lack no small number of our professors of chemistry are laboring,
with great harm to the science. A consequence of this is the spread of the weed of the apparently scholarly and
clever, but actually trivial and stupid natural philosophy, which was displaced fifty years ago by exact natural
science, but which is now brought forth again, out of the storeroom harboring the errors of the human mind,
by pseudoscientists who try to smuggle it, like a fashionably dressed and freshly rouged prostitute, into good
society, where it does not belong.
Anyone to whom this concern seems exaggerated may read, if he is able to, the book by Messrs. van't Hoff
and Herrmann on The Arrangement of Atoms in Space, which has recently appeared and which overflows with
fantastic foolishness. I would ignore this book, as [I have] many others, if a reputable chemist had not taken it
under his wing and warmly recommended it as an excellent accomplishment.
A Dr. J.H. van't Hoff, of the Veterinary School at Utrecht, has no liking, it seems, for exact chemical investi-
gation. He has considered it more convenient to mount Pegasus (apparently borrowed from the Veterinary
School) and to proclaim in his La chimie dans l'espace how the atoms appear to him to be arranged in space,
when he is on the chemical Mount Parnassus which he has reached by bold flight.
The prosaic chemical world had little liking for these hallucinations. Therefore, Dr. F. Herrmann, Assistant
at the Agricultural Institute at Heidelberg, undertook to give them wider vogue by means of a German edi-
tion. This carries the title, “The Arrangement of Atoms in Space, by Dr. J.H. van’t Hoff; translated into German
from the author’s monograph La chimie dans l’espace by Dr. F. Herrmann, Assistant at the Agricultural Insti-
tute at Heidelberg; with a foreword by Dr. Johannes Wislicenus, Professor of Chemistry at the University of
Würzburg . . .”
It is not possible to criticize this work even half-way thoroughly because the play of fantasy therein dispenses
completely and entirely with factual basis and is absolutely unintelligible to the sober scientist.
It is indicative of the present day, in which critics are few and hated, that two practically unknown chem-
ists, one from a veterinary school and the other from an agricultural institute, judge with such assurance
the most important problems of chemistry, which may well never be solved—in particular, the question of
the spatial arrangement of atoms—and undertake their answer with such courage as to astonish real
scientists.
As I have said, I would have taken no notice of that work if Wislicenus had not inconceivably written a fore-
word for it and, not jokingly but in complete seriousness, warmly recommended it as a worthwhile
contribution—whereby many young inexperienced chemists might be misled into assigning some value to
these shallow speculations . . .
It is a sign of the times that the modern chemists feel themselves qualified and able to give an explanation for
everything, and, when the results of experience are not sufficient, they seize upon supernatural explanations.
Such treatment of scientific questions, which is not far removed from the belief in witches and from ghost-
rapping, even Wislicenus considers to be admissible . . .
Wislicenus thereby makes it clear that he has left the ranks of exact scientists and has gone over to the camp
of the natural philosophers of ominous memory, who are only by a narrow “medium” separated from the
spiritualists.
[Translation taken from Wheland, G.W. Advanced Organic Chemistry, 3rd, ed. (John Wiley & Sons: New
York, 1960), pp. 197-198]

A A δ Br ‡
Br E
e.g. e.g. Me
X B X H
B D Me D δ C
H
C C N
Figure 2.3 Typical centers of chirality. The atom X is usually carbon in organic chemistry, but it
may be any element (including nonmetals such as sulfur and phosphorus, or metals).
b b
a a b
b
a b
b a
a a
a a
b b
b b
a
a b a
a b
Figure 2.4 Typical compounds that have an axis of chirality but no chiral centers. Note how each
molecule and its mirror image are not superimposable.
NO2
Me O2 N
H
(2.5)
Et O
H OH
O
HO
An axis of chirality occurs in a molecule with two noncoplanar protocenters located at

opposite ends of the axis; it occurs in alkylidenecycloalkanes or substituted allenes where two
mutually perpendicular protocenters are separated by two double bonds or a ring (Figure 2.4).
In a molecule with an axis of chirality, it is not necessary to have a chiral center for the mole-
cule to be able to exist as enantiomers. A third kind of molecule with an axis of chirality where
the two protocenters are not necessarily orthogonal is exemplified by biphenyls carrying bulky
ortho substituents that prevent free rotation about the σ bond between the two aromatic rings.
These isomers are also called atropisomers. The two structures in Example 2.5 are examples of
an allene22 and a b iphenyl23 that have been prepared in optically active form.
2.2 Absolute Configuration
The absolute configuration of a chiral molecule is a description of the three-dimen-

sional arrangement of its atoms such that the two enantiomers are distinguished. The
configuration of a chiral molecule is designated using one of three conventions. In the
22. (a) Walbrich, J.M.; Wilson, J.W.; Jones, W.M. J. Am. Chem. Soc. 1968, 90, 2895. (b) Borden, W.T.; Corey,
E.J. Tetrahedron Lett. 1969, 6741.
23. Christie, G.H.; Kenner, J. J. Chem. Soc. 1922, 121, 614. (b) Newman, P.; Rutkin, P.; Mislow, K. J. Am. Chem.
Soc. 1958, 80, 465.

Stereochemistry 47
oldest of these conventions, the configuration of the molecule is related to its optical
rotation. If the specific rotation is right-handed, or clockwise, it is the d (Latin dextro,
to the right) or (+) isomer, and if the specific rotation is left-handed, or counterclock-
wise, it is the l (Latin laevo, to the left) or (–) isomer. Racemates are designated as dl or
(±) under this system, and this part of the system has persisted; racemic compounds
are still referred to as dl or (±) forms or modifications of the compound. It is important
to recognize that the dl system is empirical and that there is no simple relationship
between the rotation of a molecule and its absolute configuration (indeed, lactic acid
and ethyl lactate with the same absolute configuration actually have specific rotations
of opposite sign).
CHO CHO
H OH H OH
HO H H OH
H OH HO H CO2H CO2H
H OH HO H H2N H H NH2
CH2OH CH2OH CH2SH CH3
D-glucose L-mannose L-cysteine D-alanine
In biochemistry, as well as in the related fields of carbohydrate chemistry and pep-

tide chemistry, the absolute configurations of molecules are assigned based on the
arrangement of groups about a single (defining) chiral center of the molecule in one
specific Fischer projection (the standard orientation). For carbohydrates, the mole-
cule is written vertically with the carbonyl closer to the top of the representation. In
this orientation, the configuration is d when the hydroxyl group on the lowest chiral
center is to the right and l when it is to the left. Note that this configuration is speci-
fied using small capital letters to distinguish it from the rotation, which uses lower
case letters. Amino acids are written with the carboxyl group at the top and the alkyl
group at the bottom; the amino acid is l when the amino group is to the left and d
when it is to the right.
The most widely used method for specifying the absolute configuration of a chiral
molecule today is the R/S convention developed by Cahn, 24 Ingold, 25 and Prelog 26
based on the application of sequence rules.27 These sequence rules were developed to
24. Robert Sidney Cahn (1899-1981) was Editor of the Journal of the Chemical Society, but biographical de-
tails about him are hard to obtain, so this brief biography is longer than most in this book. Cahn began his
graduate education at Manchester, where he studied the chemistry of the morphine alkaloids under Robert
Robinson. Following his MA, conferred by Cambridge, he moved to Cairo, where he spent 4 years on the fac-
ulty of the Egyptian University studying the constituents of cannabis (he had developed an allergy to morphine
derivatives that stopped his research into these compounds). In 1928, he received the PhD from Frankfurt. In
1930, he moved to University College of North Wales at Bangor. He remained there until 1936, when he joined
Cooper, McDougall & Robertson as a member of the Cooper Technical Bureau, working with insecticides of
natural origin. In 1949, he joined the Chemical Society (now the Royal Society of Chemistry) as Editor of the
Journal of the Chemical Society. In this capacity he was a prime moving force in the development of organic
nomenclature. He remained in this position until 1963, when he retired, although he continued working as a
consultant for the Society.
25. Sir Christopher Kelk Ingold (1893-1970): see Chapter 1.
26. Vladimir Prelog (1906-1997) was educated at the Czech Institute of Technology in Prague (doctorate,
1929). He taught at Zagreb until 1942, when he moved to the ETH, in Zürich, where he became Professor in 1950
and Head of the Laboratory of Organic Chemistry in 1957. For a more complete biography see the Nobel Prize
web site.
27. (a) Cahn, R.S.; Ingold, C.K. J. Chem. Soc. 1951, 612. (b) Cahn, R.S.; Ingold, C.K.; Prelog, V. Experientia
1956, 12, 81; Angew. Chem. Int. Ed. Engl. 1966, 5, 385. (d) Cahn, R.S. J. Chem. Educ. 1964, 41, 116. (e) Fernelius,
W.C.; Loening, K.; Adams, R.M. J. Chem. Educ. 1974, 51, 735. (f) Prelog, V.; Helmchen, G. Angew. Chem. Int. Ed.
Engl. 1982, 21, 567.

allow the specification of absolute configuration unambiguously by text alone, so they

do not necessarily correlate with other nomenclature rules (e.g., International Union
of Pure and Applied Chemistry [IUPAC] rules). The sequence rules for chiral centers
follow:
1. Atoms directly attached to the chiral center are ranked in increasing order of their
atomic numbers (e.g., H < C < N < O ...).
2. If two or more atoms directly attached to the chiral center have the same atomic
number, these atoms are ranked in increasing order of their mass numbers (e.g., 1H <
2
H < 3H).
3. If the application of these two sequence rules does not result in a differentiation
between all four groups attached to the chirality center, rules 1 and 2 are applied in
sequence to all atoms one bond further removed from the chirality center in those
groups that have not yet been differentiated. This process is repeated until either all
four groups are differentiated or until it is determined that the center in question is
not chiral.
4. Once the four groups attached to the chiral center are ranked, the molecule is ori-
ented with the lowest ranked group oriented away from the viewer (the standard
orientation).
5. If the rankings of the three higher ranked groups in this orientation decrease in a
clockwise direction, the configuration is R. if the rankings of the three higher ranked
groups decrease in a counter-clockwise direction, the configuration is S.
When one or more of the groups attached to the chiral center has multiple bonds, the
rules are modified slightly. The two bond types in the multiple bond—σ and π—are
counted individually, but only the σ bonds are used if the rules must be applied to atoms
further from the chiral center; the atoms at the ends of the π bonds are terminal “phantom
atoms.”
C
H H 4
C
HH C
H C H
C
C(σ) H C H
C N C(π) C (π)N
C(σ)
C(π) C C C N(π) 2
HS
H N(σ)
3 H C
(2.6) (π)C C(σ) H C
H
S
1
Figure 2.5 Applying the sequence rules to determine the absolute configuration of a chiral mole-
cule. Note how all four atoms directly attached to the chiral center are carbon, so we must move
one bond further out to begin to apply the rules. The single sulfur atom at the next level has the
highest atomic number, followed by nitrogen, so these elements are ranked 1 and 2, respectively.
To distinguish between the remainder, we need to move another two levels out before a difference
is found.
There are numerous papers describing mnemonics to aid in determining the absolute configurations of
complex molecules: (f) Mandal, D.K. J. Chem. Educ. 2007, 82, 274; J. Chem. Educ. 2000, 77, 866. (g) Wade, L.G.,
Jr. J. Chem. Educ. 2006, 83, 1793. (ch Gawley, R.E. J. Chem. Educ. 2005, 82, 1009. (i) Lloyd-Williams, P.; Giralt,
E. J. Chem. Educ. 2005, 82, 1031; J. Chem. Educ. 2003, 80, 1178. (j) Hart, H. J. Chem. Educ. 2001, 78, 1632. (k)
Luján-Upton, H. J. Chem. Educ. 2001, 78, 475. (l) Siloac, E. J. Chem. Educ. 1999, 76, 798. (m) Neeland, E.G. J.
Chem. Educ. 1998, 75, 1573. (n) Baker, R.W.; George, A.V.; Harding, M.M. J. Chem. Educ. 1998, 75, 853.

Stereochemistry 49
Me
H
Figure 2.6 Determining the
Br absolute configuration of a
H
chiral allene
1 3
Me Me
4 H Br 3 1 Br H 2
H H
2 4
Using Example 2.6, we can illustrate the application of these rules to a simple chiral
compound. All four groups are bonded to the chiral center through carbon, so we need to
move outward one bond to attempt to rank them. The results of this are summarized in
Figure 2.5. In the right diagram, we see that the two smallest groups, physically, are
actually the two highest ranked due to the application of rule number 1. Note also that the
rules apply to atoms individually: One simply looks for the single atom with the highest
atomic number; the aggregate total atomic number of atoms does not affect the outcome,
so three nitrogen atoms do not outrank one sulfur atom. Based on this analysis, the
configuration of the compound is R.
To apply these rules to compounds with an axis of chirality, two modifications are
made to the rules: (1) in the standard orientation, these compounds are viewed in terms
of the Newman projection along the chiral axis; and (2) groups on the protocenter at the
near end of the axis are ranked higher than groups on the protocenter at the far end of
the axis.
The direction in which the rankings of the top three ranked groups decrease in the
standard orientation still decides the configuration: clockwise is R, and counterclockwise
is S. Applying these rules to the simple allene shown in Figure 2.6 gives the name,
S-1-bromo-1,2-butadiene.
Planar Chirality28
P
H H a
c b
H H
(2.7)
O OP
O O a
b
X c X
Molecules such as trans-cyclooctene or the p-cyclophane shown in Example 2.7 are

chiral because they do not superimpose on their mirror images. However, these mole-
cules possess neither a chiral center nor a chiral axis. In these cases, the molecules are
dissymmetric with respect to a plane, and they are said to exhibit planar chirality. As-
signing the configuration to a molecule of this type requires that we first define the
chiral plane. In the case of trans-cyclooctene, this will be the plane of the double bond,
28. For a discussion of assigning the configuration to molecules with planar chirality, see Eliel, E.L.; Wilen,
S.H.; Mander, L.N. Stereochemistry of Organic Compounds (Wiley-Interscience: New York, 1994), ch. 14-1, p.1119.

and in the case of the cyclophane, this will be the plane of the substituted (higher prior-
ity) aromatic ring. In each molecule, an atom known as the pilot atom is now chosen.
This atom is not in the chiral plane but it lies closest to it; if more than one atom is in
the same location relative to the plane, the one with the higher priority according to the
sequence rules is chosen (in the cyclophane, for example, the oxygen is chosen over the
carbon). The pilot atom is labeled P in the structures. To assign the configuration of
the molecule, one starts at the pilot atom and moves one bond at a time into the chiral
plane through the first three atoms (labeled a, b, and c). If there is a choice for any of
these atoms, the one with the higher priority according to the sequence rules is chosen
(i.e., the carbon over the hydrogen in cyclooctene and the C–X carbon over the C—H
carbon in the cyclophane). When one now views the atoms a, b, and c from the position
of the pilot atom (P), the isomer is designated as P (for Plus; originally, this was R, but it
has been replaced) if a-b-c describes a clockwise direction; if a-b-c describes a
counter-clockwise direction, the enantiomer is M (for Minus; originally S). Thus, in the
examples we have been using, the trans-cyclooctene has the P configuration and the cy-
clophane has the M configuration.
Diastereoisomers
H H
(2.8)
H H
trans-4-nonene cis-decalin
Stereoisomers not related to each other as enantiomers are diastereoisomers. There are two
categories of diastereoisomers with which you should already be acquainted. The first of
these has the special name geometric isomers. These diastereoisomers differ from each
other in the arrangement of protocenters about a rigid framework such as a ring or a double
bond (e.g., Example 2.8). These stereoisomers are named according to the Cahn-Ingold-
Prelog E/Z system or according to the older cis/trans system. The older system is now gen-
erally restricted to alkenes where both protocenters carry a hydrogen atom (e.g.,
trans-4-nonene) or cyclic hydrocarbons (e.g., cis-decalin, for which the E/Z system has not
been approved by IUPAC).
In the Cahn-Ingold-Prelog E/Z system, the protocenters are treated one at a time. The
groups attached to each protocenter are ranked using the sequence rules, and the location
of the two higher-ranked groups is compared. If the two higher ranked groups are on the
same side of the double bond, the configuration is Z; if they are on opposite sides, the
isomer is E.
OH OH OH
OH OH OH
(1R, 2R) (1S, 2S) (1S, 2R), or (1R, 2S),
or meso
(2.9)
When a molecule contains an even number of chiral centers, with pairs of chiral cen-
ters carrying the same four groups, whether or not the molecule as a whole is chiral de-
pends on the absolute configuration of the individual chiral centers. This is illustrated by

Stereochemistry 51
the three isomeric 1,2-diphenylethane-1,2-diols shown in Example 2.9. In the two struc-
tures on the left, the two chiral centers of the molecule have the same absolute configura-
tion, so the molecules are chiral, and enantiomers of each other. In the right structure,
however, the two chiral centers have opposite absolute configurations, which means (1)
that the left half of the molecule is the mirror image of the right half, and (2) that the mol-
ecule may be numbered from either end, giving two different correct names once the ste-
reochemistry is included. The molecule is no longer chiral, despite the fact that it has two
chiral centers. This is a meso compound.
OH
* * (2.10)
OH
Me Me Me Me
HO H H OH HO H H OH
HO H H OH H OH HO H
Et Et Et Et
erythro threo
Another type of chiral compound is represented by 2,3-pentanediol (Example

2.10). The chiral centers at C-2 and C-3 in this molecule have the same pair of substit-
uents (H, OH), with the third substituent at each carbon (Me, Et) being similar, but
different. In compounds of this type it is least ambiguous to specify the absolute con-
figuration of this compound by specifying the absolute configuration of each chiral
center individually. However, it is sometimes useful to specify the relative configura-
tions of the chiral centers of the molecule (e.g., as in a racemate). The configuration of
a racemate can be specified using the R*/S* terminology, where the asterisk indicates
that we are dealing with relative configurations rather than absolute configurations
(i.e., we do not specify which enantiomer of the chiral compound we are dealing with).
In the case of 2,3-pentanediol, however, there is also a system of nomenclature where
one can specify the relative configuration based on the presence or absence of a plane
approximating a plane of symmetry. When the molecule is drawn in a conformation
that shows eclipsing of the maximum number of identical groups attached to the
chiral centers, the isomer with the greater number of eclipsing interactions of identi-
cal groups (the isomer more closely mimicking a meso compound) is the erythro
isomer, and the other isomer is the threo isomer. There are two enantiomers of each
diastereoisomer.
OH O OH O OH O OH O
R R' R R' R R' R R'

Me Me Me Me
syn isomers anti isomers
(2.11)
Work directed toward the synthesis of the macrolide antibiotics led to the need for a
simple, general method for designating the relative stereochemistry of straight-chain
polyhydroxycarboxylic acid derivatives in a way that allows the direct comparison of sim-
ilar compounds. In such systems (e.g., Example 2.11), the stereochemistry of the com-
pounds (and, by extension, the reactions producing them) is designated using the syn/anti

nomenclature system.29 With the compound drawn with the straight-chain backbone in
the extended (“zig-zag”) conformation, the isomer is syn if the substituent groups are
pointed in the same direction relative to the chain and anti if they are pointed in opposite
directions.
α,β Nomenclature
17
13
9
H 14
10 8
H H (2.12)
3
HO
Another convention that is still in widespread use occurs in the semisystematic or trivial
names of steroids and related natural products. Under this convention, the steroid (or
other) ring system is written as the plane projection, which places each of the substituents
either above (β) or below (α) the plane of the paper. In this system, the hydroxyl group at
position 3 in the cholesterol molecule (Example 2.12) is β, as are the methyl groups at
positions 10 and 13, and the hydrogens at positions 9 and 14 are in the α position.
Epimers
CHO CHO
H OH HO H
HO H HO H
H OH H OH
H OH H OH
CH2OH CH2OH
D-glucose D-mannose
(2.13)
O OH O OH
HO HO
HO OH HO OH
OH OH
α-D-glucose β-D-glucose
(2.14)
A special situation arises when two compounds with multiple chiral centers have the
same absolute configuration of all but one of them. Examples of this are especially
common in carbohydrates—the Fischer projections of the open-chain forms of
d-g lucose and d-mannose, for example (shown as Example 2.13), have three of the
four chiral centers in common. Diastereoisomers that differ only by a single chiral
center are referred to as epimers. Epimers can also arise when a single chiral com-
pound reacts to generate a new chiral center, as occurs in the cyclization of d-glucose
to give the two isomeric hemiacetals (Example 2.14). In these molecules, the newly
generated hydroxyl group may be above the plane of the ring, or below it. This is
a nother place where the α,β system for naming stereoisomers is widely used. Epimers of
29. Masamune, S.; Kaiho, T.; Garvey, D.S. J. Am. Chem. Soc. 1982, 104, 5521.

Stereochemistry 53
this type, based on acetals or ketals or similar compounds are also known as anomers, so
one speaks of the α-anomer of d-glucose, for example. The equilibrium between anomers
is subject to a stereoelectronic effect referred to as the anomeric effect, which we will dis-
cuss further in Chapter 4.
Pseudochiral Centers
(s) (r)
O O O O
(R) (S) (R) (S)
(2.15)
A special case arises when a meso compound has an odd number of protocenters, as illus-
trated by the two acetals in Example 2.15. Both these compounds have a mirror plane of
symmetry, with the acetal carbon being a stereochemical center but not a chiral center.
This type of stereochemical center is referred to as a center of pseudochirality. There is a OH
subrule of the Cahn-Ingold-Prelog sequence rules that allows one to assign a configura-
tion to this type of pseudochiral center. In a molecule of type CabR RR S , where R R and RS Me
are two alkyl substituents with the same groups, differing only in absolute configuration,
addition to Re face
R R (with the R configuration) takes precedence over R S , and the configuration of the pseu-
dochiral center is designated r or s, applying the rules—with this subrule—as usual.30 The
two compounds are, therefore, (2s,4S,6R)-2,4,6-trimethyl-1,3-dioxane (left) and (2r,4S,6S)-
2,4,6-trimethyl-1,3-dioxane (right).
O
Prochiral Centers H
The carbonyl group of an aldehyde is not chiral (it is planar and lacks the three-dimensional top face: Si
bottom face: Re
character necessary for chirality), but the addition of a Grignard reagent to the aldehyde can
convert it into a new chiral center (as in Example 2.16). This makes the aldehyde group a
prochiral center—one that has the potential to be converted into a chiral center by an addi-
tion reaction. The absolute configuration of the product will depend on which of the two faces
OH
of the carbonyl group participates in the reaction. We designate the two faces of a prochiral
center using the same Cahn-Ingold-Prelog sequence rules as for chiral centers. In this case,
Me
there will be only three groups attached to the prochiral center, so we do not need to worry
about a standard orientation. If the rankings of the groups decrease in the clockwise direction addition to Si face
as one looks at the prochiral center, it is the Re face, if counterclockwise, it is the Si face. (2.16)
Stereotopism
H Me
H H Me
H
H H C6H5 Me
H C6H5
Me C6H5
homotopic diastereotopic
enantiotopic
(2.17) (2.18) (2.19)
Identical groups attached to a common atom may still have different stereochemical
properties (often evident when, for example, their nuclear magnetic resonance (NMR)
30. (a) Cahn, R.S.; Ingold, C.K.; Prelog, V. Angew. Chem. Int. Ed. Engl. 1966, 5, 385. (b) Goldberg, S.I.; Bailey,
W.D. J. Am. Chem. Soc. 1971, 93, 1046. (c) Nourse, J.G. J. Am. Chem. Soc. 1975, 93, 4594. (d) IUPAC 1974 Recom-
mendations for Section E, “Fundametal Stereochemistry” Pure Appl. Chem. 1976, 45, 13.

spectra are recorded). This type of stereochemistry is known as stereotopism. Groups

are homotopic when the replacement of any leads to exactly the same product; the sim-
plest examples are the three hydrogens of a methyl group (e.g., Example 2.17), or the
methylene hydrogens of a simple cycloalkane. Homotopic groups are equivalent under
all conditions. Enantiotopic groups are groups attached to the same atom where re-
placement of one gives the enantiomer of the compound obtained when the other is
replaced; an example of enantiotopic groups are the phenyl groups and the methylene
hydrogens of 2,2-diphenylbutane (Example 2.18). Enantiotopic groups are different
only in a chiral environment (e.g., enantiotopic hydrogens have the same chemical
shifts in the NMR spectrum and the same reaction rate in proton abstraction reactions
by achiral bases). Diastereotopic groups are groups attached to the same atom where
the replacement of one gives rise to a diastereoisomer of the compound obtained by
replacement of the other. For groups to be diastereotopic, the molecule must already
have a chiral center; an example is the methylene hydrogens of 2-phenylbutane
(Example 2.19). Diastereotopic groups are not chemically equivalent; they have differ-
ent chemical shifts in the NMR spectrum, and they react at different rates with the
same reagent.
Geometric Isomers
Compounds need not have a chiral center to exist as stereoisomers, a fact that was known
by the time that van't Hoff and Le Bel published their pioneering work. Much of the work
with these compounds was carried out by German chemist, Johannes Wislicenus. He
found that oximes existed in two forms, and first used the term, geometric isomers, to
describe them. Geometric isomers occur in alkenes, oximes, and cycloalkanes. Today,
geometric isomers in alkenes and oximes and similar compounds are designated using the
Cahn-Ingold-Prelog E/Z system.
OH
(2E,6E)-3,7,11-dodeca-2,6,10-trien-1-ol
(farnesol)
H
CO2H
H
Z-octadec-9-enoic acid
(oleic acid)
(2.20)
OH
trans, trans-farnesol
(2.21)
The E/Z system gives an unambiguous designation of stereochemistry for alkenes (and
it would for cycloalkanes, except that IUPAC does not permit the use of this system for
cycloalkanes at this time). In systems where both protocenters carry a hydrogen atom, it is
still common to find the older cis/trans nomenclature used (e.g., oleic acid is also

Stereochemistry 55
cis-9-octadecenoic acid, Example 2.20), but this is gradually being replaced even in these
cases by the newer system. There are also compounds (e.g., trans,trans-farnesol, Example
2.21) where the stereochemical designation a trisubstituted double bond by the cis/trans
system is fixed by long-standing convention.
(2.22)
OH
1-cis-4-dimethylcyclohexan-r-1-ol
With substituted cycloalkanes, the use of the R/S system gives the most unambiguous
nomenclature, but this cannot be applied to cyclic systems that do not contain chiral cen-
ters. Although the application of the E/Z nomenclature system to such cyclic compounds
would provide the simplest solution to this problem in nomenclature (e.g., compound 2.22
would be Z-1,4-dimethylcyclohexanol), this is not approved by IUPAC. At this time, one
selects one substituent on the ring (usually the highest ranked substituent) as the reference
substituent and designates this by the descriptor, r. One then specifies the locations of the
other substituents relative to this. Under this system, compound 2.22 becomes
1,cis-4-dimethyl-cyclohexan-1-r-ol.
exo (2.23)
endo
In bridged-ring systems, another system of nomenclature is widely established by

common usage. This is the exo/endo system of stereochemical designation, which is
especially important in bicyclic compounds. In these compounds, substituents that are
cis to the shortest bridge of the bicyclic system are designates as exo substituents,
whereas substituents that are trans to the shortest bridge are endo substituents, as
shown in Example 2.23.
Problems
2-8 How many ways can one select the two protocenters that combine to generate a
chiral center? Illustrate your answer using bromochlorofluoromethane as an
example.
2-9 Draw the 24 possible Fischer projections of CHClBrF and assign each an absolute
configuration in the R/S system. How does this number correlate with the answer
to Problem 2-8?
2-10 Does either of the following two molecules possess an improper axis of rotation?
Give your reasoning.
Me Me Me Me
Me Me
Me Me
2-11 Identify all the sets of homotopic, enantiotopic, and diastereotopic atoms or
groups in tert-butylcyclohexane.
(continues)

(Problems continued)
2-12 What is the type of chirality (center, axis, plane) and the absolute configuration
of each chiral element in each of the following compounds? If the molecule as a
whole is not chiral, why not?
Me
CN HO OH
F Me OMe O
H
(a) (b) NC Me
(c) (d) N
H F
OMe HO OH
Cl Me
F
OMe
(e) Me (f) F (g) HN O (h)
F S N
CO2H F NH2
O
OH F
HO
OH HO OH O OH
(i) (j) (k) (l) Cl
HO HO OH
HO
OH
Stereochemistry in Reactions: Defining Terms

Many organic reactions occur with stereochemical consequences, and this means that we
need to define some terms to allow the discussion of reaction stereochemistry that comes
later in this book. Reactions may be stereospecific, stereoselective, or stereorandom. A
stereospecific reaction is one in which a single stereoisomer of the reactant is constrained
by the mechanism of the reaction to give a single stereoisomer in the product, and in
which changing the stereochemistry of the reactant changes the stereochemistry of the prod-
uct. In other words, one can reliably predict the stereochemistry of the reaction product,
knowing the stereochemistry of the reactant and vice versa. A stereoselective reaction is
one where more than one stereoisomer of the product may be formed. By convention, the
use of this term is reserved for reactions where one stereoisomer of the product predomi-
nates by a large amount over the other possible stereoiosmers. Unlike a stereospecific re-
action, the stereochemistry of the major product is not necessarily determined by the
stereochemistry of the starting material. A stereorandom process is one in which both
stereoisomers are produced in approximately equal amounts.
Stereospecific reactions abound in organic chemistry: the SN2 reaction occurs with
inversion of configuration at the carbon bearing the leaving group, and Baeyer-Villiger
rearrangements (e.g., Example 2.24 31) occur with retention of configuration at the mi-
grating carbon. Where there are two reacting centers in a molecule, the reaction may
also occur with defined stereochemistry: in catalytic hydrogenation, the two hydrogen
atoms are delivered to the same face of the reacting π bond, a situation similar to
the hydroboration and hydroxylation reactions (e.g., Example 2.2532); the addition of
halogens and halogen-like electrophiles to alkenes proceeds to give the product where
one part of the reagent adds to one face of the π bond, and the remainder of the reagent
31. Turner, R.B. J. Am. Chem. Soc. 1950, 72, 878.

32. Suzuki, T.; Ghozati, K.; Katoh, T.; Sasai, H. Org. Lett. 2009, 11, 4286.

Stereochemistry 57
adds to the other face. In the E2 elimination, the hydrogen and the leaving group must
adopt an anti conformation in order for the reaction to proceed. Addition reactions in
which both parts of the reagent add to the same face of the π bond are known as suprafacial
or syn additions, and reactions such as catalytic hydrogenation or osmium tetroxide
hydroxylations belong to this class. Addition reactions where the two parts of the reagent
add to opposite faces of the π bond are known as antarafacial or anti additions, and
reactions such as the addition of bromine to alkenes belong to this class.
O
OAc
PhCO3H
(66%)
O (2.24)
OAc
PhCO3H
(64%)
Br OsO4 (3 mol %) Br OH
OH
NMMO (1.5 eq)
H H
O THF/0°C—r.t O OH
(73%)
H H OH
(2.25)
2.3 Optical Purity and Configuration
A sample of a compound in which all the molecules are of the same enantiomer is now
“optically pure,” although the terms “enantiopure” and “homochiral” are still encoun-
tered.33 A sample of a compound containing more of one enantiomer than the other is now
“enantiomerically enriched.” It is still most usual to describe such compounds in terms of
the enantiomeric excess, ee, although a case has now been made for “enantiomer ratio,”
er, in its place.34 This is gaining in popularity. The enantiomeric excess of a compound is
defined as the ratio of the specific rotation of the sample to the maximum specific rotation
of the same compound, where the specific rotation is
α α
for solids, [α ]λ 5
T
[α ]Tλ 5 and for liquids,
cl lρ
where α is the observed rotation, is the path length in dm, c is the concentration of the
solute in g mL–1, and ρ is the density of a pure liquid in g mL–1. Because the behavior or the
specific rotation is not necessarily linear with concentration, it is important to note the
concentration of the sample. This corresponds to the difference between the fractions of
the two enantiomers in the sample or to the amount of one enantiomer present in excess
of the racemate:
Optical purity = { [α ]Tλ (obs)/ [α ]Tλ (max)} × 100% = {(% major enantiomer) –
(% enantiomer)} = major enantiomer in total – % racemate in total
33. (a) Review: Raban, M.; Mislow, K. Top. Stereochem. 1967, 2, 199. (b) For a discussion of the use and abuse
of stereochemical terms, see Eliel, E.E. Chirality 1997, 9, 428.
34. Gawley, R.E. J. Org. Chem. 2006 71, 2411.

left right nL > nR

polarization polarization
Figure 2.7 Differential refraction of waves of circularly polarized light leads to observed rotation
of the plane of plane-polarized light.
For example, optically pure (+) glyceraldehyde has a specific rotation of +14°. Thus, a
sample of glyceraldehyde with a specific rotation of +7.0° is (7.0/14) 100 = 50% optically
pure. It may be viewed as consisting of a mixture of 50% (+) glyceraldehyde and 50% (±)
glyceraldehyde, or 75% (+) glyceraldehyde and 25% (–) glyceraldehyde.35 The optical purity
of a compound can be measured by a variety of methods, of which NMR spectroscopy36
and chromatography on a chiral stationary phase37 have become the most widely used. The
use of these techniques, which provide the ratio of the enantiomers (or diastereoisomers)
directly, prompted a reevaluation of the use of the terms enantiomeric excess (e.e.) and
diastereoisomeric excess (d.e.)38 as well as the suggestion that the e.e. be replaced by the
enantiomer ratio (e.r.) as a more useful measure of the composition of a mixture of
enantiomers.
Before we proceed further, we need to discuss the nature of plane-polarized light,
which is responsive to chirality, in more detail. In plane-polarized light, the electric
vector of the radiation oscillates in a single plane, but its chiral nature may be viewed as
arising from the superimposition of two waves of circularly polarized light, one left-
handed, and one right-handed (Figure 2.7). In circularly polarized light, the electric
vector describes a helix along the direction of propagation of the wave. If the two circu-
larly polarized waves are passed through an achiral medium, they emerge unchanged at
the end, and the plane of polarization remains unchanged. If the same plane-polarized
wave is passed through a chiral medium, however, the two circularly polarized waves will
interact differently with the medium. If the medium has different refractive indices for
right and left circularly polarized light, for example, the wave emerging from the medium
will again be plane polarized, but the plane of polarization will have been rotated by an
amount proportional to the difference between the two refractive indices. The angle of
rotation per unit path length is α 5 (nL 2 nR )π , where nL and nR are the refractive indices for
λ
the left and right circularly polarized light, respectively, and λ is the wavelength of the
light.39 Just as the refractive indices of right circularly and left circularly polarized light
35. This method does require that be independent of concentration: Horeau, A. Tetrahedron Lett. 1969, 3121.
36. (a) Raban, M.; Mislow, K. Tetrahedron Lett. 1965, 4249; 1966, 3961. (b) Jacobus, J.; Raban, M. J. Chem.
Educ. 1969, 46, 351. (c) Tokles, M.; Snyder, J.K. Tetrahedron Lett. 1988, 29, 6063. (z) Review: Parker, D. Chem.
Rev. 1991, 91, 1441.
37. Gas chromatography: (a) Halpern, B.; Westley, J.W. Chem. Commun. 1965, 246. (b) Vitt, S.V.; Sapor-
ovskaya, M.B.; Gudkova, I.P.; Belikov, V.M. Tetrahedron Lett. 1965, 2575. (c) Guett, J.; Horeau, A. Tetrahedron
Lett. 1965, 3049. (d) Westley, J.W.; Halpern, B. J. Org. Chem. 1968, 33, 3978.
High-performance liquid chromatography: Pirkle, W.H.; Finn, J. In Morrison, J.D., Ed. Asymmetric Synthe-
sis, Vol. 1 (Academic Press: New York, 1983), p. 87.
38. (a) Selke, R.; Facklam, C.; Foken, H.; Heller, D. Tetrahedron: Asymmetry 1993, 4, 369. (b) Seebach, D.;
Beck, A.K.; Schmidt, B.; Wang, Y.M. Tetrahedron 1994, 50, 4363. (c) Gallagher, D.; Du, H.; Long, S.A.; Beak, P.
J. Am. Chem. Soc. 1996, 118, 11391.
39. Fresnel, A. Ann. chim. phys. [2] 1825, 28, 147.

Stereochemistry 59
Figure 2.8 Circular dichro-

ism spectrum of camphor-
sulfonic acid (1 mg mL–1).
The vertical scale is specified
as millidegrees, which is a
reasonable approximation
for small values of θ because
tan θ ≈ θ when θ is small.
are different in a chiral medium, so, too, are their extinction coefficients for absorption.
This results in plane-polarized light becoming elliptically polarized on passing through
a chiral medium. The measurement of differential absorption of right and left circularly
polarized light is the basis of the technique of circular dichroism (CD). CD is expressed
in terms of the molar ellipticity, θ, which is related to the difference in absorbance (∆A)
for right and left circularly polarized light by θ = 3238(∆A). The tangent of the ellipticity,
tan θ, is related directly to ∆A. CD is especially important in biochemistry, where it is
used to probe the conformations of biological molecules such as nucleic acids and
proteins. The CD spectrum of (1R)-camphor-10-sulfonic acid (1 mg/mL in water) is shown
in Figure 2.8.
The specific rotation of a substance depends both on the temperature and wave-
length at which the measurement is made. Most measurements are made using the
sodium D line (589.0 nm). This sharp, bright line in the sodium atomic spectrum has
long been easy to obtain. The measurement of the specific rotation over the range of
wavelengths from the visible to the ultraviolet (UV) gives a spectrum known as the
optical rotatory dispersion (ORD) curve. ORD spectra of a group of four steroids 40
are shown in Figure 2.9.
In a plain ORD curve, the specific rotation changes monotonically with wavelength.
In ORD curves with an anomalous Cotton effect, the magnitude of the rotation initially
increases as the wavelength becomes shorter, and it then changes sign, passing through
another maximum (or minimum).41 Typical examples of the anomalous Cotton effect are
provided by the ORD spectra shown in Figure 2.9. Enantiomers exhibit mirror image
ORD curves (i.e., if the ORD curve of one enantiomer exhibits a positive Cotton effect, the
ORD curve of other will exhibit a negative Cotton effect).
The use of ORD curves in studying the chiroptical properties of chiral ketones led to
the development of the octant rule.42 This empirical rule, which was originally devel-
oped to allow the prediction of the sign of the Cotton effect from a known absolute
configuration, can also be applied in the corollary sense, to determine absolute
40. Djerassi, C.; Closson, W.; Lippman, A.E. J. Am. Chem. Soc. 1956, 78, 3163.
41. (a) Cotton, A. Ann chim. phys. [7] 1896, 8. 347. (b) Mitchell, S. The Cotton Effect (G. Bell & Sons)
42. (a) Moffitt, W.; Woodward, R.B.; Moscowitz, A.; Klyne, W.; Djerassi, C. J. Am. Chem. Soc. 1961, 83, 4013.
(b) Mislow, K.; Glass, M.A.W.; Moscowitz, A.; Djerassi, C. J. Am. Chem. Soc. 1961, 83, 2771.

Figure 2.9 Optical rotatory (a)

dispersion spectra of a series
of steroidal ketones
H H
H H H H
O AcO
H H
O O
(V) (VI)
H H O
H H O H H
HO
H H
(VIII) (IX)
(b)
IX
+3000
+2000
VIII
+1000
Specific Rotation
VII
VI
-1000
IX
-2000
-3000
300 400 500
Wavelength (nm)
configuration of a known structure from the sign of the Cotton effect. To apply the rule,
the carbonyl group of the ketone is oriented as if to draw the Newman projection with
the carbonyl oxygen atom toward the observer (Figure 2.10). The middle of the C = O
bond is the origin, with the plane of the sp2 orbitals and the plane perpendicular to it
and containing the C = O bond (the two lines in Figure 2.10) as the first two planes. The
plane perpendicular to the C = O bond is the third plane. These three planes divide the

Stereochemistry 61
Figure 2.10 Octant rule for

cyclohexanone derivatives
region about the C = O group into eight octants: four rear octants and four front octants.
The four rear octants make positive (lower right and upper left) and negative (lower left
and upper right) contributions to the observed Cotton effect, with the corresponding
front octants making the opposite contributions. However, because groups in the front
octants must necessarily project forward beyond the carbonyl oxygen, they are seldom
involved.43
When one examines the cyclohexanone ring using these rules, one can make some
fairly straightforward predictions. Thus, by numbering the carbonyl carbon 1 and
then proceeding in clockwise order around the cyclohexane ring (so that the α carbon
to the left becomes position 2, and the α carbon to the right becomes position 6), one
predicts that:
1. Substituents at position 3 make a positive contribution to the Cotton effect and that
substituents at position 5 make a negative contribution
2. Substituents at position 4 make a minimal contribution to the Cotton effect
3. Equatorial substituents at positions 2 and 6 make a minimal contribution to the Cotton
effect
4. Axial substituents at position 2 make a negative contribution to the Cotton effect, and
axial substituents at position 6 make a positive contribution
Exciton Chirality and Absolute Configuration

In the early 1980s, a method known as exciton chirality method was developed for deter-
mining the absolute configuration of cyclic 1,2-diols where the two OH groups are gauche
to each other. It involves measuring the CD spectra of derivatives that have a groups that
can absorb UV-visible light (a chromophore).44 The derivatives are defined to have positive
or negative chirality based on the dihedral angle between the two chromophores, as illus-
trated by structures 2.26 and 2.27 in Figure 2.11. When the dihedral angle from front to
back is clockwise, the chirality is defined as positive. The technique can be used on very
small scale (micro to nanomolar). The diol is esterified with an achiral aromatic acid
(p-aminobenzoate esters have been especially popular), and the CD spectrum of the
resulting diester (which need not even be purified) is then measured. The spectrum shows
two Cotton effects near the maximum absorbance of the ester, one positive and one
43. Review of chiroptical spectroscopy: Kirk, D.N. Tetrahedron, 1986, 42, 777.
44 Monograph: Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy. Exciton Coupling in Organic Ste-
reochemistry (University Science Books: Mill Valley, CA, 1983).

Figure 2.11 Defining positive NMe2 NMe2

and negative chirality
Me2N NMe2
O OO OO O
O O
counterclockwise: negative clockwise: positive

(2.26) (2.27)
Figure 2.12 Predicted Cotton

effects in chirality exciton positive chirality
method
negative chirality
A
λ
egative. For molecules with “positive chirality,” the longer wavelength Cotton effect is
n
positive, and the shorter wavelength Cotton effect is negative. The reverse is true for
molecules with negative chirality (Figure 2.12).
Problems
2-13 What is the relationship (enantiomers, diastereoisomers, constitutional isomers)

between the two molecules in each of the following pairs of compounds?
Et Et Et Et
Et Me
Me H Me H Me H Me H
(a) Me H Pr Et (b) Me H H Me
(c) Me H H Me
Pr H
Me Me Et Et
Et H Et Me
Et Me
H Me Me Et Me H H Et
(d) Me H H Et (e) Me H H Et
(f) Me H Et H
Et Me Et Me
2-14 What is the relationship (enantiomers, diastereoisomers, epimers, anomers, con-

stitutional isomers) between the two molecules in the following pairs of
compounds?
OH
H
HO HO
OH
(a) (b) OH
HO Cl Cl
H

Stereochemistry 63
Me Br Br Me
HO HO
O OH O OH
(c) (d)
HO OH HO OH
OH OH
Me Br Br Me
O O
O O OH N
O OH Me
(e) (f) HO O
Me
N HO
CHO
CHO
2-15 Define the sign of the chirality of each of the following 1,2-diols as needed to pre-
dict the Cotton effects in the CD spectra of their bis-p-dimethylaminobenzoate
derivatives. Note that a single OH group distant from the diol has little effect on
the Cotton effects.
OH OH OH OH
(a) (b) (c) HO (d) OH
OH OH
H H
O O O
H H H
HO HO HO
(e) H H (f) H H (g) H H
HO HO HO
H H H
O OH O OH
HO
H H H OH
(h) H H (i) H H (j) H H

HO OH HO HO
H H H
OH
2.4 Conformation
The field of conformational analysis was founded by British chemist D. H. R. (later Sir
Derek) Barton45 and Norwegian chemist Odd Hassell46 who shared the Nobel Prize in 1969
for the development. Conformations of open-chain saturated compounds are intercon-
verted by rotation about the σ bonds. The rotation is not free, but every σ bond has a barrier
to rotation that increases with both the number and size of groups at the two ends of the
bond, except in extreme circumstances. All σ bonds pass through two extreme conforma-
tions during rotation: the eclipsed conformation and the staggered conformation. For σ
45. Sir Derek Harold Richard Barton (1918-1997) was educated at Imperial College (PhD, 1942). His career
spanned more than four decades on two continents, beginning at Imperial College in London as an assistant
lecturer in 1945. He shared the Nobel Prize in 1969, and was knighted in 1972. In 1978, Barton moved to the
Institut pour la Récherche des Substances Naturelles in Gif-sur-Yvette, outside Paris. He moved to Texas A&M
University in 1986. For more information, see: Ley, S.V.; Myers, R.M. Biogr. Mem. Fellows Roy. Soc. 2002, 48, 1,
and the Nobel Foundation web site
46. Odd Hassell (1897-1981) was educated in Oslo, Munich and Berlin. He returned to the University of Oslo in
1925, where he spent the remainder of his professional career. From 1943 to 1945, he was imprisoned by the Nazis.
He shared the 1969 Nobel Prize in Chemistry. For more biographical details, see the Nobel Foundation web site.

Figure 2.13 Conformations
R
about nonterminal C–C
H H
bonds in straight-chain
alkanes
H H
R
H R H R
antiperiplanar
H anticlinal anticlinal R
H H H H
R H
R R
R H gauche gauche H R
H H H H
synperiplanar
H H
R R
H
H H
H
bonds in an alkane, every staggered conformation is lower in energy than any eclipsed
conformation.
Bonds in the middle of a chain (e.g., the 2,3 bond of butane) have conformations avail-
able to them beyond the simple eclipsed and staggered conformations.
When we examine the internal C—C bonds of n-alkanes, we can see that there are six
different extreme conformations, three eclipsed, and three staggered, that can be de-
scribed in terms of the dihedral angles (θ) between the methylene groups. In the eclipsed
conformations, the dihedral angles in degrees fit the equation θ = 120n, where n is an in-
teger, and in the staggered conformations, the dihedral angles fit the equation θ = 120n +
60. The conformation where θ = 0° is known as the synperiplanar (sp, also called the cis
or syn) conformation, and those where θ = 120° or 240° are known as anticlinal confor-
mations. The conformation where θ = 180° is known as the anti (a) conformation, and
those where θ = 60° or 300° are known as gauche conformations. In 1974, IUPAC recom-
mended the names synclinal for the gauche conformation, and antiperiplanar for the anti
conformation; neither has yet come into widespread use. These conformations are shown
in Figure 2.13.
The conformational energy of a series of saturated open-chain compounds is summa-
rized in Figure 2.14.47 Calculations show that the barrier to rotation in the series methanol
(one eclipsing H-H interaction in the highest energy conformation), methylamine (two
H-H interactions), and ethane (three H-H interactions) increases by approximately 0.9
kcal mol–1 per H-H eclipsing interaction. In alkanes, the barrier to rotation has a mini-
mum value in ethane and increases as the number of alkyl groups eclipsed increases to a
maximum in neopentane. The barrier to rotation increases by approximately 0.6 kcal
mol–1 as one moves from ethane to propane to isobutane to neopentane, which corre-
sponds to a CH3-H eclipsing energy of approximately 0.6 kcal mol–1 greater than the H-H
eclipsing energy.
The anti conformation is the lowest energy conformation of the butane molecule.
The synperiplanar conformation is the highest energy conformation—some 20 kJ
47. All calculations in this section were performed by the author at the HF/6-31G* level of theory, using
Spartan 08 for the Mac.

Stereochemistry 65
Figure 2.14 Conformational
energy of open-chain
compounds
sp g ac a ac g sp

mol–1 (4.8 kcal mol–1) higher in energy than the anti conformation. The other eclipsed
conformation, the anticlinal conformation, is approximately 14 kJ mol–1 (3.0 kcal mol–1)
higher in energy than the anti conformation. The energy difference between the
gauche and anti conformations of butane is only 3.6 kJ mol–1 (0.87 kcal mol–1), and this
is sufficiently small that a sample of butane at room temperature should contain
significant numbers of molecules close to both conformations, with those near the
anti conformation predominating by a factor of slightly more than five. Neither
eclipsed conformation contributes significantly to the conformer population at room
temperature.
In saturated compounds, the lowest energy conformations are all staggered, as the
top two diagrams in Figure 2.14 show. However, the angular dependence of conforma-
tional energy in unsaturated hydrocarbons (and carbonyl compounds) is markedly
different from that of these saturated systems. In the case of all nonconjugated alkenes,
as well as the structurally similar carbonyl compounds, the lowest energy conforma-
tion is, in fact, one in which the allylic or α-hydrogen eclipses the double bond. In
conjugated compounds, on the other hand, the anti conformation once again has the
lowest energy.
Although they have fewer conformations available than their open-chain counter-
parts, cyclic compounds still have some flexibility, although the levels of flexibility vary.
For example, the chair conformation of the six-membered ring, is much less conforma-
tionally flexible that similar five-membered rings. In the chair conformation, each ring
atom has one bond parallel to the ring's threefold axis of symmetry (the axial bonds) and
one bond disposed generally in the plane of the ring (the equatorial bonds). The alterna-
tive relatively low-energy conformation of the six-membered ring is the skew-boat, or
skew conformation. This conformation, which is flexible, is some 4 to 5 kcal mol–1 higher
energy than the chair.
The cyclohexane chair can undergo conformational inversion, known as “ring flip-
ping,” through a high-energy transition state known as a half-chair (Figure 2.15). In the
process of this inversion, all equatorial bonds become axial, and all axial bonds become
equatorial. Thus, in simple monosubstituted cyclohexanes, the substituent may occupy
both an axial and an equatorial position, with the two in equilibrium. Equatorial substit-
uents are lower energy than axial substituents, so a substituent will occupy the equatorial
position preferentially; the energy difference between the two chair conformers is known
Figure 2.15 Conformations half-chair half-chair

of the cyclohexane chair
Energy
44 kJ/mol
10.5 kcal/mol
20-25 kJ/mol
skew 5-6 kcal/mol
chair chair

Stereochemistry 67
as the conformational preference of the substituent. Table 2.2 Conformational Preference of Cyclohexane Substituents
Values for a number of common substituents are gathered H
in Table 2.2. R H
In 1980, Corey and Feiner48 developed a program for R
analyzing the conformation of polysubstituted cyclohex- Conformational Conformational
anes. They defined a destabilization energy, ED, which is Preference Preference
composed of three components: an AR value for R–H X (kcal mol–1) X (kcal mol–1)
1,3-diaxial interactions, a UR value for R–R' 1,3-diaxial in- CH3 1.7 OH 0.7
teractions, and a GR value for R–R' 1,2-diequatorial gauche
C2H 5 1.8 OCH3 0.7
interactions. Values for a series of common substituent
fragments are collected in Table 2.3. CHMe2 2.1 Cl 0.4
CMe3 5 Br 0.5
CH2CMe3 2.0 I 0.4
Problem C 6H 5 3.1 NH2 1.8
2-16 Calculate the destabilization energy of the two Cyclohexyl 2.15 NMe2 2.1
conformations of 1,1,2-t rimethylcyclohexane COOH 1.2 CN 0.2
given below using the Corey-Feiner constants.
The measured conformational preference in this
compound differs from that of methylcyclohex-
ane by approximately 0.2 kcal mol–1. How does
this compare with the predicted value?
2.5 An Introduction to Asymmetric Table 2.3 AR, UR and GR Values for Cyclohexane Derivatives (kcal mol–1)
Synthesis: Asymmetric Induction H R H R' E =U +U +
H R D R R'
ED=AR
0.5(AR+AR') RR' ED=GR+GR'
Creating New Chiral Centers in a Reaction
R or R' AR UR GR R or R' AR UR GR
An achiral reagent may add to either face of a
prochiral center to generate a product with a F 0.2 0 0 Aryl 3.0 1.1 1.2
new chiral center. An example of such a reaction Cl 0.4 0.4 0.5 C≡ 0.2 1.2 0
is the reaction between the prochiral 2-butyl
Br 0.4 0.4 0.8 CO2H, CO2R 1.2 1.2 0.5
cation, and chloride ion (Figure 2.16). The two
possible activated complexes for this reaction I 0.4 0.4 1.0 CHO 0.8 0.8 0.3
are enantiomers; outside a chiral environment, OH, OR 0.9 0.9 0.2 CH3, CH2R 1.8 1.8 0.4
the energy of enantiomers does not depend on
their absolute configurations, so they must be of NHR 1.3 1.3 0.3 CHR 2 2.1 2.1 0.8
equal energy. Therefore, the reaction leading to NR 2 2.1 2.1 0.5 CR 3 6.0 6.0 2.5
the R enantiomer of the product must proceed
C= 1.3 0.9 0.2
at exactly the same rate as the reaction leading
to the S enantiomer, and an equal number of
molecules of the R and S enantiomers will be
formed. This is an important observation.
If the reaction between a prochiral compound and an achiral reagent generates a new chiral
center, the product will be obtained as the racemate.
48. Corey, E.J.; Feiner, N.F. J. Org. Chem. 1980, 45, 765.

Figure 2.16 Generating a new Cl

chiral center from an achiral H3CH2C CH3 H3CH2C CH3
C + Cl C
precursor
H H
‡ ‡
H δ− δ− δ+
H
H3CH2C δ+ Cl Cl CH2CH3
H3C CH3
Figure 2.17 Generating a new CH3 CH3

chiral center in the presence
H CH2CH3 H CH3
of another C + Cl C
H3CH2C H3CH2C Cl
CH3 H
H3C δ− ‡ H3CH2C δ− ‡
δ+ δ+
H3CH2C Cl H3C Cl
H3C H3C
H CH2CH3 H CH2CH3
In other words, one cannot form an optically active product from the reaction of two
achiral starting compounds alone, but one will always obtain the racemic mixture.
If there is a chiral center already present in the starting molecule, however, the situa-
tion is different because one is generating the new chiral center in the chiral environment
generated by the presence of the first chiral center. For example, if one carries out the same
kind of reaction as in the example above but now uses a chiral cation as the electrophilic
reagent, the two products formed are no longer enantiomers but diastereoisomers. In
these circumstances, the activated complexes for the competing reactions are diastereo-
isomers (Figure 2.17); they are not mirror images, they have different enthalpies, and the
activation energies of the competing reactions are not equal. Consequently, the two prod-
ucts will be formed at different rates, and they will be formed in unequal amounts. In
practically all reactions of this type, the two products are formed in different amounts;
one isomer almost always predominates—sometimes to the almost complete exclusion of
the other.
If a reaction of a chiral compound leads to the generation of a new chiral center, the product
will almost always be an unequal mixture of the possible diastereoisomeric products.
The application of these two principles to the direct synthesis of enantiomerically

enriched chiral compounds has led to the field of asymmetric synthesis.49 From its
49. The topic of asymmetric synthesis is the subject of several multivolume monographs, books, and reviews:
(a) Morrison, J.D., Ed. Asymmetric Synthesis, 5 vols. (Academic Press: New York, 1983-1985). (b) Morrison, J.D.;
Mosher, H.S. Asymmetric Organic Reactions (Prentice-Hall: New York, 1971). (c) Eliel, E.L.; Otsuka, S. Asym-
metric Reactions and Processes in Chemistry, ACS Symposium Series 185 (American Chemical Society: Wash-
ington, D.C., 1982). (d) Aitken, R.A.; Kilényi, S.N., Eds. Asymmetric Synthesis (Blackie Academic & Professional:
Glasgow, 1992). (e) Gawley, R.E.; Aubé, J. Principles of Asymmetric Synthesis (Pergamon:: Oxford, 1996). (f)
Procter, G. Asymmetric Synthesis (Oxford University Press: Oxford, 1996). (g) Ward, R.S. Chem. Soc. Rev. 1990,
19, 1. (h) Whitesell, J.K. Chem. Rev. 1989, 89, 1581. (i) Oppolzer, W. Tetrahedron 1987, 43, 1969. (j) Quinkert, G.;

Stereochemistry 69
beginnings in the last three decades of the 20th century, asymmetric synthesis has
now grown to be a major theme of organic synthesis, and a huge amount of effort has
gone into developing methods for making enantiomerically enriched chiral com-
pounds. This, in turn, briefly led to a whole new vocabulary of stereochemistry, al-
though many of the terms are now no longer in use, with a gradual reversion to the
earlier terminology.
Asymmetric synthesis is the synthesis of a single enantiomer of a chiral product from
achiral precursors. A reaction where an achiral substrate is converted into an unequal
mixture or enantiomeric products is an enantioselective reaction, and the process in-
volved is known as asymmetric induction. The synthesis of a new chiral center with high
levels of asymmetric induction requires that it be formed in a chiral environment so that
the two transition states are not enantiomeric but diastereomeric. Two main strategies
have been adopted by organic chemists for accomplishing this: covalent modification of
one of the achiral substrates (the reactant or the reagent) before the formation of the new
chiral center and carrying out the reaction in a chiral environment without covalently
modifying either substrate (using a chiral catalyst).
What factors affect the addition of nucleophiles to a chiral aldehyde or ketone may be
among the most intensely studied questions in organic chemistry, with two major models
for predicting the stereochemical outcome emerging during the last half of the 20th cen-
tury. These major models take into account the influences of steric and electronic factors
on the stereochemical course of the addition reaction, with the balance between the two
determining, to a degree, the prediction.
The first empirical rule for predicting the stereochemistry of addition reactions to
carbonyl groups was proposed by American chemist, Donald J. Cram in 1952.50 Cram's
rule (Figure 2.18) assigns the control of asymmetric induction in the addition of nucle-
ophiles to chiral aldehydes and ketones to steric factors. The model is based on a reac-
tive conformation in which the carbonyl oxygen is oriented anti to the largest group,
which eclipses the hydrogen in aldehydes, and the alkyl group in ketones. The complex-
ation of the metal of an organometallic reagent to the carbonyl oxygen was expected to
O OH OH Figure 2.18 The Cram rule

M S M S M S for addition to chiral ketones
Nu
R Nu Nu R
RL Nu L L
"Cram" product "anti-Cram" product
O OH
1) EtLi
2) H3O+
O OH
1) MeLi
2) H3O+
Stark, H. Angew. Chem.Int. Ed. Engl. 1983, 22, 637. (k) Mosher, H.S.; Morrison, J.D. Science 1983, 221, 1013. (l)
Tramontini, M. Synthesis 1982, 605. (m) Kagan, H.; Fiaud, J.C. Top. Stereochem. 1978, 10, 175.
50. (a) Cram, D.J.; Abd Elhafez, F.A. J. Am. Chem. Soc. 1952, 74, 5828. (b) Cram, D.J.; Knight, J.D. J. Am.
Chem. Soc. 1952, 74, 5835. (c) Curtin, D.Y.; Harris, E.E.; Meislich, E.K. J. Am. Chem. Soc. 1952, 74, 2901. (d)
Leitereg, T.J.; Cram, D.J. J. Am. Chem. Soc. 1968, 90, 4019.

Figure 2.19 The Felkin-Anh O OH

rule for addition to chiral L M L M
aldehydes
R R Nu
Nu
S S
"Felkin-Anh" product
O OH
L M L M
Nu
Nu R
S R S
"anti-Felkin-Anh" product
Figure 2.20 Chelation con- M M

trol in addition to chiral
X O X O
aldehydes
s s Nu
L R L R
MeO O MeO OH
1) MeLi Me
Me Me
2) H3O+
increase the effective size of the carbonyl oxygen and make this conformation most
favorable. The major diastereoisomer of the product is then predicted to be that where
the nucleophile adds to the carbonyl group from the same side as the small group at the
α carbon.
A similar rule, known as the Felkin-Anh rule, was proposed in 1968. In the Felkin-Anh
model (Figure 2.19), the addition is presumed to occur through a reactant-like transition
state where the conformation has the carbonyl oxygen between the medium and large
groups, and, in carbonyl compounds with electronegative α substituents, as far from the
substituent as possible. This model is actually a combination of two different models, one
of which (the Felkin model51) has steric interactions predominating, and the other (the
Anh model52) has stereoelectronic effects dominating.
When the α carbon carries a group capable of coordinating the metal of an organome-
tallic reagent (Figure 2.20), the addition is proposed to occur by chelation control,53 where
the metal is chelated by the carbonyl oxygen and the substituent, and the nucleophile
again attacks from the same side as the small α substituent.
Chiral Auxiliaries
The first approach for obtaining asymmetric induction in the formation of a new chiral
center that we will discuss involves modification of the reactant by a chiral molecule
called a chiral auxiliary.54 The chiral auxiliary converts the previously achiral substrate
51. Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199.
52. Anh, N.T.; Eisenstein, O. Nouv. J. Chem. 1977, 1, 61.
53. (a) Cram, D.J.; Kopecky, K.R. J. Am. Chem. Soc. 1959, 81, 2748. (b) Frye, S.V.; Eliel, E.L. J. Am. Chem. Soc.
1988, 110, 484. (c) Chen, X.; Hortelano, E.R.; Eliel, E.L.; Frye, S.V. J. Am. Chem. Soc. 1992, 114, 1778. (d) Reetz,
M.T. Acc. Chem. Res. 1993, 26, 462.
54. Seyden-Penne, J. Chiral Auxiliaries andLigands in Asymmetric Synthesis (John Wiley & Sons: NewYork,
1995).

Stereochemistry 71
DIASTEREOISOMERIC
TRANSITION STATES
E
A A ‡ A ‡
W W
A F H
G W
D E D E D and/ E D
add chiral form new or
B
auxiliary F H chiral center F H F H
G G G
A A
remove chiral W W remove chiral
A auxiliary auxiliary A
W E D E D W
B D B D
F H F H
G G
Figure 2.21 The chiral auxiliary approach to asymmetric induction
into a chiral compound, so that generating a new chiral center now involves the forma-
tion of diastereoisomers rather than enantiomers. Using the chiral auxiliary approach,
organic chemists have been able to carry out important reactions with d.e.'s above 99.9%
(d.r.'s > 1999:1) in favorable cases. After the new chiral center has been generated, the
chiral auxiliary is then removed to leave the product, enriched in one enantiomer
(Figure 2.21).
One of the oldest and most striking examples of asymmetric induction in a reaction
involving the use of a chiral auxiliary is the Evans asymmetric aldol addition55 between an
aldehyde and an enol borinate, where the two new chiral centers generated during the
course of the reaction are both generated with e.e.'s at or above 99.8% (e.r.'s ≥ 999:1), as il-
lustrated below. This reaction, and its stereochemical nuances, will be discussed in much
more detail later in this book, when we discuss the aldol addition reaction as a method for
stereoselective synthesis.
Chiral Reagents
O O
O
1) NaH O N 1) R2BX/base
O NH
2)(CH3)2CHCHO
2) CH3CH2COCl
O O OH O O OH O O OH O O OH
O N O N O N O N
99.8 0.2 0.0 0.0

(2.29)
H
B OH
BH3•THF 1) Z-2-butene (2.29)
2) H2O2/NaOH/H2O
74% e.e (R)
(+)-α-pinene (–)-diisopinocamphenylborane
"(–)-Ipc2BH"
55. Evans, D.A.; Bartroli, J.; Shih, T.L. J. Am. Chem. Soc., 1981, 103, 2127.

Figure 2.22 Chiral reagent DIASTEREOISOMERIC TRANSITION STATES

approach to asymmetric
induction
E ‡ B ‡
E G A D
A G F
W and/or
W F W
D G
chiral reagent
B A D F
B E
W B
A D
A D
B W
The same success in terms of asymmetric induction might have been anticipated by
moving the chiral auxiliary to the reagent species rather than the reactant species
(Figure 2.22). Here, however, the levels of asymmetric induction have been less spectacular
than with the chirally modified substrates. This relatively lower level of success may be
traced to the fact that when the chiral group is part of the reagent instead of the substrate,
it tends to be further from the developing chiral center. This means that it exerts less influ-
ence over the geometry and transition state energy (and, therefore, the activation energy
of the reaction).
To achieve high levels of asymmetric induction with a chiral reagent, it is important to
use a reagent that will form the shortest possible bonds between the reacting species during
the reaction. For this reason, many of the successful methods of using chiral reagents have
been based to date on boron reagents. B–C, B–N, and B–O bonds are quite short, and this
brings the two reacting species much closer together than with reagents based on other ele-
ments (e.g., lithium). For example, chiral borane reagents (diisopinocampheyl-borane, in
particular) have been used successfully for the hydroboration of cis alkenes, as shown in
Example 2.29.56
Chiral Catalysts57
The second major strategy for constructing a new chiral center enriched in one enantio-
mer is to form it in a chiral environment that strongly favors one of the diastereoisomeric
activated complexes. The simplest way to accomplish this without using at least one chiral
reagent is by means of a chiral catalyst (Figure 2.23). This approach has been successfully
applied by living systems to the construction of chiral molecules for countless millennia;
it is used by every living cell to form chiral molecules from achiral precursors. In a living
cell, the key to this is the enzyme—a catalyst that is formed from chiral α-amino acids.
In almost every enzyme-catalyzed reaction, at least one of the reacting species is bound
to the enzyme so that the new chiral center cannot be formed in one of the two enantio-
meric forms.
Me3CO—OH/Ti(OCHMe2)4
OH OH (2.30)
diethyl L-(+)-tartrate
O
77% 95% e.e.
56. (a) Brown, H.C.; Zweifel, G.; J. Am. Chem. Soc. 1961, 83, 486. (b) Brown, H.C.; Yoon, N.M. Isr. J. Chem.
1977, 15, 12. (c) Brown, H.C.; Desai, M.C.; Jadhav, P.K. J. Org. Chem. 1982, 47, 5065. (d) Srebnik, M.; R
amachandran,
P.V. Aldrichim. Acta 1987, 20, 9.
57. (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis, 3nd. ed. (Wiley-VCH: New York, 2010) and earlier edi-
tions. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis (Wiley-Interscience: New York, 1994).

Stereochemistry 73
DIASTEREOISOMERIC TRANSITION STATES
E B
E G ‡ A D ‡
A G H F
D + W H F W and/or W
B chiral catalyst
H F
A D G
B E
W B
A D
A D W
B
Figure 2.23 Chiral catalyst approach to asymmetric induction
CO2H H2/Rh CO2H

(2.31)
NHCOCH3 NHCOCH3
PPh2
PPh2
100% e.e.
Until the 1980s, organic chemists had been less successful in adapting organic reac-
tions to asymmetric synthesis by the use of chiral catalysts, but there were two spectacular
successes: the Sharpless asymmetric epoxidation reaction, in which an achiral allylic
a lcohol is oxidized to an epoxide,58,59 and the emergence of asymmetric homogeneous
hydrogenation catalysts60 developed by Noyori and Knowles.61 In many cases, the Sharp-
less asymmetric epoxidation gives e.e's of 95% or higher (e.r's ≥ 39:1), and in especially fa-
vorable cases its performance is even better. In similar vein, the asymmetric hydrogenation
of α-aminocinammates is now the method of choice for the preparation of chiral phenyl-
alanine derivatives. The development of chiral catalysts is now a major emphasis of syn-
thetic organic chemistry.
58. Reviews: (a) Rossiter, B.E. In Morrison, J.D., Ed. Asymmetric Synthesis, Vol. 5 (Academic Press: Orlando,
1985), 194. (b) Finn, M.G.; Sharpless, K.B. In Morrison, J.D., Ed. Asymmetric Synthesis, Vol. 5 (Academic Press:
c, 1982), 247. (c) Johnson, R.A.; Sharpless, K.B. In Ojima, I., Ed. Catalytic Asymmetric Synthesis, 2nd. ed.
(Wiley-VCH: New York, 2000), p. 231.
59. K. Barry Sharpless (1940-) was educated at Dartmouth (BS, 1963) and Stanford (PhD, 1968). He joined
the Massachusetts Institute of Technology (MIT) in 1970, moved to Stanford in 1977, and returned to MIT in
1980. In 1986 he moved to the Scripps Institute in La Jolla. Sharpless shared the 2001 Nobel Prize for his work.
For a more detailed biography, see the Nobel Foundation web site
60. Reviews: (a) Okhuma, T.; Kitamara, M.; Noyori, R. In Ojima, I., Ed. Catalytic Asymmetric Synthesis, 2nd.
ed. (Wiley-VCH: In Morrison, J.D., Ed. Asymmetric Synthesis, Vol. 5 (Academic Press: New York, 1982), 247,
2000), p.1. (b) Halpern, J. In Morrison, J.D., Ed. Asymmetric Synthesis, Vol. 5 (Academic Press: In Morrison,
J.D., Ed. Asymmetric Synthesis, Vol. 5 (Academic Press: New York, 1982), 247, 1982), 41. (c) Koenig, K.E. In Mor-
rison, J.D., Ed. Asymmetric Synthesis, Vol. 5 (Academic Press: New York, 1982), 71.
61. Ryoji Noyori (1938-) was educated at Kyoto University (D Eng, 1967). From 1963 to 1968, he was an in-
structor at Kyoto University. In 1968, he took the Chair in Organic Chemistry at Nagoya. He served as Dean of
the Graduate School of Science at Nagoya from 1997 to 1999 and is currently Director of the Research center for
Materials Science. Noyori shared of the 2001 Nobel Prize in Chemistry. For a more detailed biography, see the
Nobel Foundation web site.
William Standish Knowles (1917-) was educated at Harvard (B.A. 1939) and Columbia (PhD, 1942). Knowles
joined the Thomas and Hochwalt Laboratories, shortly after their acquisition by Monsanto. He spent his entire
career at Monsanto, except for nine months with R. B. Woodward in 1959. He shared the Nobel Prize in Chem-
istry for 2001. For a more detailed biography, see the Nobel Foundation web site.

Worked Problem
2-2 Predict the major organic product of each of the following addition reactions.
1) MeMgBr/Et2O O 1) MeMgBr/Et2O
(a) (b)
2) HCl/H2O 2) HCl/H2O
CHO CHO
§Answer on below
Problem
2-17 What will be the major organic product of each of the following reactions?
CHO 1) MeMgBr/Et2O CHO 1) MeMgBr/Et2O

(a) (b)
CHO CHO
1) MeMgBr/Et2O 1) MeMgBr/Et2O
(c) (d) O
1) MeMgBr/Et2O 1) MeMgBr/Et2O
(e) H CHO (f)
NMe CHO

(a) This compound has a chiral center adjacent to the carbonyl group. The groups attached to that chiral
center, in terms of increasing size, are H, Me, and C6H5 (Ph). The Cram and Felkin-Anh models for predicting
the outcome the reaction are:
O OH O OH
Me H Me H Ph Me Ph Me
Cram Felkin-Anh
H Me H Me
MeMgBr MeMgBr
H Ph Ph HH H
Both models predict that the major product of the reaction should be:
OH
(b) This compound has a chiral center adjacent to the carbonyl group. The groups attached to that chiral
center, in terms of increasing size, are H, Me, and furyl(C 4H3O). The oxygen atom in the furan ring means that
this reaction should be under chelation control:
Mg
OH
O
H O H C4H3O
MeMgBr
Me H
H Me
Me
This makes the predicted major product of the reaction:
OH

Stereochemistry 75
Using Conformational Analysis in Synthesis

Conformational analysis of reactive intermediates and activated complexes has become an
integral part of analyzing an organic reaction, particularly when one is looking to control
stereochemistry. This has been especially the case when the transition state for the reac-
tion involves a six-membered cyclic structure, where one can use the conformational pref-
erences of the substituent groups to help make predictions about preferred conformations
and stereochemistry.
R ‡
R OLi O H Li O OH
+ O (2.32)
Ra H Rt O R Ra
Rt Rc Ra Rc
Rt
Rc
A good example of this type of analysis is provided by the aldol addition of preformed
lithium enolates to aldehydes. The stereochemistry of this reaction is commonly analyzed in
terms of the preferred conformation of the transition state. The first such model that has
been widely used for this reaction is known as the Zimmerman-Traxler transition state
(Example 2.32),62 which is a chairlike six-membered transition state. In the Zimmerman-
Traxler transition state for the aldol addition of enolate anions to aldehydes, the largest
groups are in the equatorial position.
In the Evans asymmetric aldol addition,63 this type of analysis allows one to predict the
absolute configuration of the major product. The enol borinate intermediate is formed as
the Z isomer under the reaction conditions. What Evans and his coworkers found is that
the absolute configuration of the chiral center adjacent to the nitrogen in the heterocyclic
ring totally controls the face-selectivity of the reaction, rendering moot the differences
leading to Cram selectivity. They rationalized this finding in terms of the Zimmerman-Traxler
transition state model shown in Figure 2.24, where the conformation of the ring of the
chiral auxiliary places the isopropyl group over the (smaller) oxygen atom.
Bu Bu ‡
O O BBu2
O O B
O O
O N Bu2B—OTf Me2CHCHO
O N
EtN(i-Pr)2 N H
O Me H
O
‡
Me
R
O H Bu Bu
Bu O B
B H O OH O O
O
Bu N H2O
N N H
O Me O Me H
O
O O
Figure 2.24 Predicting the stereochemistry of the Evans asymmetric aldol addition reaction using
a Zimmerman-Traxler transition state model
62. Zimmerman, H.; Traxler, M. J. Am. Chem. Soc. 1957, 79, 1920.
63. Review: Evans, D.A. Aldrichimica Acta 1982, 15, 23.

One of the especially useful consequences of cyclic transition states having a preferred
conformation that can be predicted on the basis of conformational analysis of similar
stable species occurs in reactions leading to chirality transfer. In these reactions, a chiral
center at one site in the reacting molecule is lost, while its stereochemistry is transferred
to a prochiral center elsewhere in the molecule.64
(Z)
(S) (S) H
H2
HO HO OEt
optical Lindlar Pd O (2.33)
resolution (S)
∆
HO
Na/NH3
HO HO
(R)
(R)
(E)
We will discuss this type of reaction in more detail when we discuss pericyclic reac-
tions (e.g., the Cope and Claisen rearrangements), but a simple example of the strategy will
serve here. In the synthesis of the side chain of α-tocopherol, Saucy and coworkers used an
especially elegant method to obtain a single isomer of the product from the racemic start-
ing alcohol by using the stereochemistry of the intermediate compounds.65 In their proce-
dure (Example 2.33), the acetylenic alcohol was resolved, and the different enantiomers
were reduced to give different geometric isomers of the double bond.
Me Ph
Me Ph Me
Si Si
Me O
HO BuLi (cat)
(2.34)
H
(R)-(–) (R)-(+)
A cyclic transition state is not always necessary for good levels of chirality transfer, as is
illustrated by the reaction shown as Example 2.34.66 In this reaction, the original chiral
center is the carbinol carbon of the silyl alcohol. When this alcohol is treated with a cata-
lytic (5 mol %) amount of strong base, the oxygen is deprotonated, and there is a migration
of the silicon from carbon to oxygen. This is accompanied by transfer of a proton from
another molecule of the alcohol, to give the chiral allene. This is, therefore, an example of a
center of chirality in the reactant being converted into an axis of chirality in the product.
Worked Problem
2-3 The Claisen rearrangement shown in Example 2.33 predicts the stereochemistry
of the reaction based on a chairlike transition state. How would he prediction
change if the reaction were to proceed through a boatlike transition state?
§Answer on next page
64. Review: Hill, R.K. In Morrison, J.D., Ed. Asymmetric Synthesis (Academic: New York, 1984), vol. 3, ch. 8,
p. 503.
65. Chan, K.K.; Cohen, N.; DeNoble, J.P.; Specian, A.C., Jr.; Saucy, G. J. Org. Chem. 1976, 41, 3497.
66. Reynolds, T.E.; Bharadwaj, A.R.; Scheidt, K.A. J. Am. Chem. Soc. 2006, 128, 15382.

Stereochemistry 77
Problems
2-18 Account for the appearance of the conformational energy profile of isopentane
(CH2CH2CHMe2), which is given in Figure 2.18.
2-19 Cis-1,4-di-tert-butylcyclohexane should have one axial and one equatorial
tert-butyl group. Conformational analysis of the compound suggests that in the
preferred conformation, it does not. How does this occur, and why?
2-20 The Cope rearrangement is similar to the Claisen rearrangement, with the exception
that there is now one more alkene π bond, with its accompanying stereochemistry.
Use the same analysis of stereochemistry and conformation used in Sample Problem
2-3 to predict the stereochemistry of the product in the Cope rearrangement, and the
effects of changing the conformation of the transition from chairlike to boatlike.
2-21 Predict the major organic product expected in each of the following organic
reactions:
Br Cl Br Cl Br
∆ ∆
∆
(a) (b) (c) Cl
Br Cl Br Cl Br
Cl
2.6 How Well Did It Go? Measuring Enantiomer Ratios
The final measure of the success of an asymmetric synthesis is the enantiomer ratio (or
enantiomeric excess) of the products of the reaction. When the e.r. is small, one can use
the optical rotation to see how well the reaction has worked. However, as one attains the
kind of e.r. now expected in an asymmetric synthesis, this method is much less reliable

The reaction above proceeds through a chairlike transition state.
R1 ‡ R1
1 R7 6 R7 R6 R7 R6
R R R2
R2 R2
O R5 O
O R5 R4 R5
R3 R8 4 R3
R3 8 R R8
R R4
In the reactant model for this reaction, we see that R 1 is trans to R 3 and that R6 is trans to R8. In the chairlike
transition state model, we see that R 1 and R8 adopt pseudoaxial positions in the chair, with the result that they
become anti to each other in the product as drawn. In the model as drawn, R4 is axial and R 5 is equatorial, which
leads to the new double bond geometry with R4 trans to R6.
In the boatlike transition state, the two alkene π bonds have the same geometry as above. In the transition
state model, the atoms whose hybridization remains unchanged at sp2 are the most likely atoms to occupy the
positions shown below, because this removes any flagpole-flagpole interactions.
geometric isomerism here- - - - - - - - - - -becomes - - - - - - - - - - - - -chirality here
R3 R3
R3 R1 ‡
R1 R7 R6 R1
R7 R6 R7 R6
R2 O 5
R O4
O R5 R2 R5
R2 R8 4 R
R R8
R8 R4
chirality here- - - - - - - - - - - - -becomes - - - - - - - - - - - - - -geometric isomerism here
In this model, the conformation of the final product places R 2 anti to R7, with R4 trans to R6. This is the same
stereochemistry as predicted by the chairlike transition state model.

unless the final product has a very large specific rotation. Under these conditions, other
techniques must be used to give a measure of the e.r. of the product.
This has been accomplished by two major approaches: NMR spectroscopy, and chiral
high-performance liquid chromatography (HPLC). Beginning in the late 1970s with the
work of Pirkle,67 chiral HPLC has become the method of choice for separating mixtures of
enantiomers as both an analytical and a preparative technique. The basis for the separa-
tion is, as one might expect, the formation of diastereoisomeric species as the enantiomers
interact with the chiral column material.
MeO CF3
CO2H
Mosher's acid
The other way to analyze mixtures of enantiomers involves the formation of a deriva-
tive of the mixture with a single enantiomer of a chiral derivatizing reagent and then
observing the formation of diastereoisomeric products by looking at the NMR spectrum.
One especially useful chiral derivatizing agent is known as Mosher's acid.68 This reagent
has the added advantage that it contains a trifluoromethyl group, which allows 19F NMR
spectroscopy to be used to measure the enantiomer ratio (a considerable simplification
because the protons of the molecules do not interfere with the analysis).
2.7 Chirality at Atoms Other Than Carbon:

Inversion of Pyramidal Centers
The heteroatoms of silanes, quaternary ammonium and phosphonium salts, and amine-N-
oxides and phosphine oxides are tetrahedral; therefore, they are structurally analogous to
the carbon-based chiral centers of the type that we have been discussing in this chapter. As
such, these compounds should be resolvable into configurationally stable enantiomeric
forms, and they are.69 One particularly simple method for resolving quaternary ammonium
salts is by means of their (S)-BINOL complexes (Example 2.35) if these can be crystallized.70
This involves simply partitioning the precipitated complex between dichloromethane and
water separates the quaternary salt from the resolving agent.
OH
HO OH HO
CO2But CO2But
OH
N N
CH2Cl2 OH
Me Ar Me Ar
X X
(2.35)
67. (a) Pirkle, W.H.; House, D.W. J. Org. Chem. 1979, 44, 1957. (b) Pirkle, W.H.; House, D.W. Finn, J.M. J.
Chromatogr. 1980, 192, 143. (c) Pirkle, W.H.; Finn, J.M. J. Org. Chem. 1981, 46, 2935. (d) Pirkle, W.H.; Schreiner,
J.L. J. Org. Chem. 1981, 46, 4988.
68. (a) Dale, J.A.; Dull, D.L.; Mosher, H.S. J. Org. Chem. 1969, 34, 2543. (b) Dale, J.A.; Mosher, H.S. J. Am.
Chem. Soc. 1973, 95, 512.
69. (a) Barbachyn, M.R.; Johnson, C.R. In Morrison, J.D.; Scott, J.W., Eds. Asymmetric Synthesis (Academic:
New York, 1984), Ch. 2, p. 227. (b) Valentine, D., Jr.; In Morrison, J.D.; Scott, J.W., Eds. Asymmetric Synthesis
(Academic: New York, 1984), Ch. 3, p. 263. (c) Davis, F.A.; Jenkins, R.H., Jr. In Morrison, J.D.; Scott, J.W., Eds.
Asymmetric Synthesis (Academic: New York, 1984), Ch. 4, p. 313. (d) Maryanoff, C.A.; Maryanoff, B.E.; In
Morrison, J.D.; Scott, J.W., Eds. Asymmetric Synthesis (Academic: New York, 1984), Ch. 2, p. 355.
70. Tayama, E.; Otoyama, S.; Tanaka, H. Tetrahedron: Asymmetry 2009, 20, 2600.

Stereochemistry 79
Like the heteroatoms in chiral ammonium and phosphonium salts, the heteroatoms
in amines, phosphines, sulfoxides, and sulfonium salts may also be chiral. In these cases,
the fourth group about the chiral center is the lone pair on the heteroatom. Potentially, X sp3
1 R2
therefore, such compounds ought to be resolvable into the two enantiomers. There is a R chiral
R3
mechanism for inversion of configuration available to these compounds that is not avail-
able to chiral centers lacking a lone pair. In the absence of lone pairs, the inversion of
configuration of the chiral center requires the cleavage and reformation of a covalent
bond. In the case of a heteroatom carrying a lone pair, however, the inversion may occur R2 sp2
by means of a rehybridization of the heteroatom from sp3 (chiral) to sp2 (not chiral) and R1 X
R3 not chiral
back again (Example 2.36). This is the same hybridization change that occurs at carbon
during the SN2 reaction, but the process generally has a lower activation energy than the
SN2 process.
The barrier to inversion of open-chain amines is small71 (as measured by dynamic R3 sp3
R1 2
NMR,72 it is typically 5–7 kcal mol–1). This makes this inversion an especially facile pro- X R chiral
cess, because a barrier to inversion of at least 23 kcal mol–1 is needed for enantiomers to
be configurationally stable at room temperature.73 Acyclic amines rapidly racemize at
room temperature. The barrier to inversion of amine nitrogen atoms is raised substan-
tially by (1) incorporating the nitrogen atom into a small ring (e.g., an aziridine, where (2.36)
attaining the sp2 hybridization results in increasing the already large angle strain in the
three-membered ring) and by (2) attaching an electronegative substituent to the nitro-
gen. Thus, although simple N-alkylaziridines themselves are not configurationally
stable at room temperature, N-chloro-2,2-diphenylaziridine (Example 2.37) has
been prepared in optically active form.74 Its barrier to inversion of 24.4 kcal mol–1 is
modest, so it still racemizes completely in 4 days at 0°C. The effects of small ring size
and electron-withdrawing substituents are even more pronounced in rings such as the
oxaziridine ring system, which can fairly readily give stereochemically stable enantio-
meric compounds.
Ph Cl Ph
N N (2.37)
Ph Ph Cl
∆G‡ = 24.4 kcal mol–1
Unlike tricoordinate nitrogen, the barrier to inversion of tricoordinate sulfur and

phosphorus is large enough that chiral sulfoxides and phosphines are configurationally
stable at room temperature and may be resolved and used. The barriers to inversion in
simple diaryl sulfoxides and aryl methyl sulfoxides are typically in the range of 35 to 42
kcal mol–1, which means that the racemization of these compounds typically has a half-
life of 6 hours at 200°C.75 The activation parameters of this inversion are consistent
with its being the “umbrella” inversion at sulfur, rather than some other mechanism.
The corresponding barrier to inversion of phosphines is dependent on the substituents
on phosphorus. For simple trialkylphosphines not bearing electronegative substituents
or having the phosphorus in a small ring, the barrier to inversion is typically in the
71. Reviews: (a) Rauk, A.; Allen, L.C.; Mislow, K. Angew. Chem. Int. Ed. Engl. 1970, 9, 400. (b) Lambert, J.B.
Top. Stereochem. 1971, 6, 19. (c) Jennings, W.B.; Boyd, D.R. In lambert, J.B.; Takechi, Y., Eds. Cyclic Organoni-
trogen Stereodynamics (VCH: Cambridge, 1992), 105.
72. (a) Stevenson, P.E.; Burkey, D.L. J. Am. Chem. Soc. 1974, 96, 3061. (b) Bushweller, C.H.; Anderson, W.G.;
Stevenson, P.E.; Burkey, D.L.; O’Neil, J.W. J. Am. Chem. Soc. 1974, 96, 3892. (c) Bushweller, C.H.; Lourandos,
M.Z.; Brunelle, J.A. J. Am. Chem. Soc. 1974, 96, 1591.
73. Kessler, H. Angew. Chem. Int. Ed. Engl. 1970, 9, 219.
74. Annunziata, R.; Fornasier, R.; Montanari, F. J. Chem. Soc., Chem. Commun. 1972, 1133.
75. Rayner, D.R.; Gordon, A.J.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4854.

range of 29 to 36 kcal mol–1.76 The incorporation of an electronegative substituent on

phosphorus raises the barriers to inversion significantly (as happens with the corre-
sponding amines).77
Me Me
MgBr
MeO (2.38)
O O
S S
MeO
O O
N O (2.39)
S
Chiral sulfoxides are readily available by the reaction between optically active men-
thyl p-toluenesulfinate with alkyllithium nucleophiles; the reaction occurs with inver-
sion at sulfur. Indeed, chiral sulfoxides have been used as chiral directing groups in a
variety of reactions, including conjugate addition (e.g., Example 2.38)78 and reduction.79
In both these reactions, chelation by a metal ion involving the sulfoxide oxygen restricts
the conformation of the reactant and thus facilitates chirality transfer from sulfur to
carbon. Nitrogen bound to sulfur makes these sulfur derivatives especially configura-
tionally stable. For this reason, chiral sulfinylamines such as the tert-butylsulfinylimine
(Example 2.39), which carries a chiral sulfur atom, have become widely used chiral
auxiliaries in asymmetric synthesis.
Chapter Summary
This chapter has considered organic stereochemistry—the shape of molecules in three

dimensions. The discussion has ranged from enantiomers (molecules that are non-
superimposable mirror images) to diastereoisomers (molecules that are stereoisomers
but not enantiomers), including considerations of geometric isomers and meso com-
pounds. The symmetry requirements compatible with chirality (axes of symmetry) and
those incompatible with chirality (mirror plane, inversion center, improper axis of ro-
tation) have been discussed. The protocenter model for the basis of stereoisomerism
has been introduced. The difference between configuration and conformation has been
discussed, and the Cahn-Ingold-Prelog method for assigning configurations to chiral
molecules and to geometric isomers has been introduced. The conformations of open-
chain and cyclic molecules have been discussed. The measurement of optical purity
and the determination of enantiomeric excess (e.e.) or enantiomer ratio (e.r.) have been
discussed in the light of methods to achieve asymmetric synthesis. The three concep-
tually different methods for obtaining asymmetric induction in a reaction (chiral
auxiliaries, chiral reagents, and chiral catalysts) have been introduced. The Cram and
Felkin-Anh models for predicting the stereochemistry of additions to chiral aldehydes
76. Baechler, R.D.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 3090.
77. Baechler, R.D.; Andose, J.D.; Stackhouse, J.; Mislow, K. J. Am. Chem. Soc. 1972, 94, 8060.
78. Posner, G.H. Acc. Chem. Res. 1987, 20, 72.
79. Bode, M.L.; Gates, P.J.; Gebretnsae, S.Y.; Vleggaar, R. Tetrahedron 2010, 66, 2026.

Stereochemistry 81
and ketones have been introduced. Chirality at atoms other than carbon has been
briefly discussed, and the configurational stability of chiral compounds carrying a lone
pair on the chiral atom has been briefly addressed. The concepts of topism and prochi-
rality have been discussed.
Key Terms
absolute configuration chiral auxiliary improper axis of rotation

anomers chirality meso isomers
anti, gauche circular dichroism mirror plane of symmetry
asymm etric induction conformation Newman projection
atropisomers Cram's rule optical activity
axial, equatorial diastereoisomers optical rotatory dispersion
axis of chirality eclipsed, staggered plane of chirality
boat, chair conformational preference prochiral center
Cahn-Ingold-Prelog enantiomeric excess proper axis of rotation
systems enantiomers protocenters of
center of chirality epimers stereochemistry
center of inversion Felkin-Anh rule racemate
center of pseudochirality geometric isomers topism
Additional Problems
2-22 Draw the Newman projection of the most stable conformation about the indi-
cated bond of each of the following compounds.
(a) meso-3,4-dimethylhexane (the 3–4 bond)
(b) (3R,4R)-3-chloro-4-methylheptane (the 3–4 bond)
(c) S-1,2-dicyclopentylpropane (the 1–2 bond)
(d) meso-2,3-dicyclohexylbutane (the 2-3 bond)
(e) (1S,2S)-1,2-dichlorocyclohexane (the 1-2 bond)
(f) meso-1,2-divinylcyclopropane (the 1–2 bond)
2-23 Each of the following reactions gives a product in which at least one new chiral
center has been formed. The stereochemistry of the final product has not been given
explicitly in any of these reactions, but it can be deduced from the reactants and the
reagents used. Draw all the products in each of the reactions (including pairs of en-
antiomers, if appropriate). Are the products formed in equal amounts? Draw the
lowest energy and highest energy conformations about the bond to the new chiral
center in each product (use the Newman projection for acyclic compounds).
H EtMgBr
(a)
CHO OH
H
H2/PtO2
(b)
Me2CuLi
(c)
O O
HBr/ROOR Br
(d)


O OH
NaBH4/EtOH
(e)
CN CN
Me3SiCN/Zn(CN)2
(f) OSiMe3
CHO
NC
2-24 What is the major product of each of the following reactions?

CHO
CH3MgBr/Et2O CH3MgBr/Et2O
(a) (b)
CHO
CHO
CH3MgBr/Et2O CH3MgBr/Et2O
(c) (d)
O CHO
OCH3
CHO
CHO
C6H5C≡CLi C6H5C≡CLi
(e) (f)
O
CHO O O BBu2
1) THF
(g) + O N
2) H2O
CHO O O Li
1) THF
(h) + O N
O 2) H2O
CHO O O BBu2
1) THF
(i) + O N
O 2) H2O
CHO O O BBu2
1) THF
(j) + O N
2) H2O
2-25 Using dynamic NMR spectroscopy to study the inversion of aziridines, it has
been shown that the inversion of the aziridine nitrogen in the upper compound at
left (a 1,4-benzoquinone) is more than 50 times as fast as the inversion of its re-
duction product (a 1,4-hydroquinone derivative, shown as the lower example).
Provide a rationalization of these observations. Based on your answer, how could
you slow down the inversion of the quinone?
O
Ph H O fast Ph H
N N
H H O
Ph Ph
O
OH
Ph H OH slow Ph H
N N
H H HO
Ph Ph
HO

Stereochemistry 83
2-26 In carbon tetrachloride solution, cis-cyclohexane-1,3-diol exists mainly in the

conformer with two axial OH groups, but in methanol solution, the major con-
former has both OH groups equatorial. Why?
2-27 Calculate the populations of the two chair conformers of each of the following
cyclohexane derivatives using the Corey-Feiner parameters.
N
HO C
(a) (b) (c) (d)
OH

2-28 The diketone in the figure is a meso compound, with a plane of symmetry
through the molecule, and therefore it cannot be resolved into two enantio-
mers. Reduction of the diketone with a metal hydride reducing agent leads to
the formation of two diastereoisomeric diol products. The diol in the figure
has a mirror plane of symmetry like the starting diketone, and is therefore a
meso compound incapable of optical resolution. The diastereoisomeric diol
shown does not have a mirror plane of symmetry (nor, in fact, does it have a
simple axis of rotation). Can it be resolved into enantiomers? Give your
reasons.
H H H H H H
O O HO OH + HO OH
H H H H H H

2-29 The following synthesis of acetate anion with a chiral methyl group was com-
pleted by the research group of Sir John Cornforth in 1969. Analyze the stereo-
chemistry of each step of the sequence. Then deduce both the regiochemistry and
the stereochemistry of each reaction used in the sequence.
H T
H Br H T Ph O H LiAlD4/Et2O
1) BuLi/THF/-78°C PhCO3H/CHCl3
Ph H 2) T2O Ph H H T
Ph O H
O
H T H T O T
1) 1) H2CrO4
HO D O HO D D
Ph H Ph H 2) CF3CO3H O H
O 3) KOH/H2O
2) brucine; crystallize
H T 3) KOH/H2O H T 1) H2CrO4 O T
HO D HO D D
Ph H Ph H 2) CF3CO3H O H
3) KOH/H2O
2-30 The barrier to inversion at sulfur in benzylic sulfoxides is much less than for sim-
ilar simple dialkyl or diaryl sulfoxides. In addition, sulfoxides such as the one at
right, which is chiral at both sulfur and carbon, racemize at both carbon at
sulfur. Suggest a mechanism for the racemization that is consistent with these
observations.
2-31 Tröger's base is a fascinating molecule that has a rigid skeleton containing two
chiral nitrogen atoms. In dilute acid, Tröger's base racemizes. Two mechanisms,
shown below as mechanisms A and B, have been proposed for this reaction.

Mechanism A
H
N N N N H H2C N NH N N H N N
Mechanism B
H
N N N N H N N N N H N N
H
Where bonds are broken, the racemization involves inversion of configuration as

the bonds are reformed. Consider the racemization of the Tröger's base derivative
at left and suggest the outcome of its racemization by both mechanisms. (As part
of your answer, it may be useful to analyze the topism of the various groups on
the Tröger's base molecule.)
2-32 The polynactins are a class of ionophore antibiotics based on the same ring
system. They differ in the substitution pattern on the ring. Analyze each of the
five polynactins below for their symmetry elements. Which is (are) the most sym-
metrical (i.e., has [have] the highest order symmetry element)?
R1 R 2 R 3 R4
R4 O
Nonactin Me Me Me Me
Monactin Et Me Me Me O O O
O H H H H R3
Dinactin Et Me Et Me O O
R1 H H H H O
Trinactin Et Et Et Me
O O O
Tetranactin Et Et Et Et O R2
Does this give any hints about how the synthesis of any of these compounds
might be approached?
2-33 All the l-amino acids have the same general structure and the same Fischer
rojection. What is the absolute configuration of each of the amino acids shown
p
in the R/S system?
CO2H
H2N H
R
Trp Ser Cys Phe Val Ala

H2C
R = R = HO CH2 R = HS CH2 R = CH2 R = R = Me

N
H
Does this suggest any caveats when using the R/S protocol in biochemical
systems?

Stereochemistry 85
2-34 The synthesis of 8-phenylmenthol (or phenmenthol) from pulegone is carried out
using the sequence of reactions shown.
1) PhMgBr/CuBr Ph OH
+
O 2) HCl/H2O
3) Na/EtOH HO Ph

Analyze the stereochemistry of the reactions that give these two products. What
fixes the stereochemistry of the carbinol carbon? The minor product of the reac-
tion is epi-ent-phenmenthol. Which of the two structures above is most likely to
be this minor product? Why?
2-35 Deduce the stereochemical course of each of the following reactions. Where more
than one organic reactant is involved, deduce the reaction stereochemistry with
respect to each reactant.
OH
AgOAc/I2/H2O/HOAc
(a)
HO
OH
NBS/H2O/MeCN
(b)
H Br
O OMe O OMe
∆
(c) +
OMe OMe
H
O O
O O
1) Me3SiN3/CCl4
(d) 2) H2O
N
H
I2/KOH/H2O
(e) CO2H O O
H
I
2-36 Why is the 400 MHz 1H NMR signal from the methylene group indicated in the
compound shown much more complex than the simple quartet that would be
expected by splitting by the three protons of the adjacent methyl group?
Me
H
H
O
O
MeO


Chapter three
Organic Shorthand: Acronyms

and Name Reactions
3.1 Organic Synthesis: A Brief Introduction
In this author’s opinion, organic synthesis is at the heart of organic chemistry, because
everything that we do as organic chemists ultimately requires the synthesis of organic
compounds. Compounds are synthesized for a variety of reasons: to confirm structures
assigned on the basis of spectroscopic studies or chemical degradation, to elucidate the
stereochemistry of a compound whose stereochemistry cannot be established by other
means, to modify an existing natural compound to make it more active, or to develop
methods for the preparation of important medicinal compounds that may be in short
supply from natural sources. Synthesis has been used to explore the limits of structure and
bonding. For example, the synthesis of cyclobutadiene1 was an important target for testing
theories of aromaticity. Also, the synthesis of prismane2 provided insights into the synthe-
sis of highly strained molecules and also showed that this fully saturated isomer of ben-
zene could, in fact, exist.
In this book, we will be looking at a wide range of organic reactions—how they work
and how they can be assembled into sequences to achieve the synthesis of complex organic
compounds. As organic chemistry has grown, so have the number of reactions and re-
agents available to the synthetic chemist to accomplish the tasks at hand. The increasing
complexity of modern synthetic reactions has resulted in a need for a shorthand method
for discussing or representing reagents and/or reactions.
3.2 Name Reactions: A Historical Overview
The first type of such shorthand to become widely used by organic chemists is the name
reaction. At first, name reactions were used sparingly and almost always in reference to
reactions that were already widely used and well known. In this way, a name reaction
was more widely viewed as a tribute to the discoverer of a highly useful reaction. For
example, within the dozen years after its first appearance in the literature, Victor Gri-
gnard’s synthesis of alcohols by the reaction between an alkyl- or arylmagnesium halide
and a carbonyl compound had become so widely used that almost all chemists knew
what was meant by the term, “Grignard’s synthesis.” Within the same time period, the
Grignard reaction had so completely displaced the previous methods—also name reac-
tions using organozinc reagents—that it was the reaction of first choice for the synthesis
of alcohols.
This general principle—that a reaction on which the discoverer’s name was conferred
should be both widely known and widely used—stood for much of the 20th century, and
1. Review: Pettit, R. Pure Appl. Chem. 1968, 17, 253.

2 Katz T.J.; Acton N. J. Am. Chem. Soc. 1973, 95, 2738.
87

88 Advanced Organic Chemistry | Chapter three
conferring a name on a reaction was thus sparingly done. Toward the end of that century,
however, the proliferation of variations on a theme and the need for using a specific varia-
tion of a particular reaction meant that the use of name reactions and named reagents
began to be used more as a shorthand to describe the explicit version of the base reaction
being used rather than as a tribute to the discoverer of the generic reaction. This trend still
continues.
Unfortunately, this very proliferation of named reactions and reagents has made a
chapter like this increasingly necessary in modern organic synthesis—few people can
keep the full set of named reactions and reagents clear in their minds (and that includes
this author!).3 Over the course of this book, we will discuss many name reactions. Some of
the oldest named reactions—all from before World War I—are gathered (in alphabetical
order) in Table 3.1. The list is not exhaustive, and it has expanded by a large amount in the
century that followed.
When you examine the list, you will find many reactions that you have already
learned in your introductory course in organic chemistry; it is worthwhile taking some
time to review them. Unless you have been asked for a superhuman effort, you will not
have studied all the reactions in Table 3.1, so do not be discouraged if you find reactions
that you are not familiar with. When you examine Table 3.1, you will find two rather
obvious omissions from the list—Markovnikov’s rule4 for addition and Zaitsev’s rule5
for elimination. Likewise, substituent effects on regiochemistry in aromatic substitution
are not in the table.
Table 3.1 Long-standing Name Reactions
Reaction Name Reaction Year Ref.
O O
R'CO3H
Baeyer-Villiger oxidation R R 1899 6
R' O R'
R' R R'
PCl5
Beckmann rearrangement N NH 1886 7
R OH O
R R R
1) Zn, R'CN R'
Blaise reaction R CO2R CO2R 1901 8
Br 2) HCl/H2O
O
O
Borodin-Hunsdiecker Br2
R R Br 1861 9
reaction OAg
3. There are several books and monographs devoted to name reactions that have appeared in recent years: (a)
Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis (Academic Press: New York,
2005). (b) Li, J.J. Name Reactions. A Collection of Detailed Mechanisms and Synthetic Applications, 4th ed.
(Springer-Verlag: Berlin, 2009). (c) Mundy, B.P.; Ellerd, M.G.; Favaloro, F.G. Name Reactions and Reagents in
Organic Synthesis, 2nd ed. (Wiley-Interscience: New York, 2005).
4. (a) Markownikoff, W. Ann. Chem. Pharm. 1870, 133, 228. (b) Markovnikov, V. Compt. Rend. 1875, 82, 668,
728, 776.
5. Saytzeff, A. Justus Liebigs Ann. Chem. 1875, 179, 296.
6. Baeyer, A.; Villiger, V. Ber. dtsch. chem. Ges. 1899, 32, 3625; 1900, 33, 858.
7. Beckmann, E. Ber. dtsch. chem. Ges. 1886, 19, 988.
8. Blaise, E.E. Compt. rend. 1901, 132, 478.
9. Borodine, A. Ann. Chem. Pharm. 1861, 119, 121; Z. Chem. 1861, 4, 5; 1869, 12, 342; Ann. Chem. Pharm. 1869,
121, 119.

Organic Shorthand: Acronyms and Name Reactions 89
R CO2R' Na
Bouveault-Blanc reduction R'OH R OH 1903 10
NaOEt O CO2Et
Claisen condensation R CO2Et 1881 11
R R
O OH
Claisen rearrangement ∆ 1912 12
O Zn(Hg), HCl, ∆ H H
Clemmensen reduction 1913 13
R R R R
R R"2C=O O
Darzens condensation CO2R' R" CO2R' 1904 14
X base R" R
HONO
Demyanov rearrangement NH2 OH + CH2OH 1903 15
O
CO2Et NaOEt
Dieckmann condensation CO2Et
1894 16
CO2Et
Diels-Alder reaction + 1929 17
Étard oxidation CrO2Cl2 1880 18

Ph Me Ph CHO
X AlCl3 X
Friedel-Crafts acylation 1877 19
Cl R Ar-H Ar R
OCOR OH
AlCl3
Fries rearrangement 1908 20
COR
HCN, HCl
Gattermann-Koch reaction Ar H Ar CHO 1897 21
AlCl3
Glaser coupling CuCl, O2 1869 22

R H R R
(continues)
10. Bouvealt, L.; Blanc, G. Compt. Rend. 1903, 136, 1676; Bull. Soc. Chim. France [3], 1904, 31, 666.
11. Claisen, L.; Claparède, A. Ber. dtsch. chem. Ges. 1881, 14, 2460.
12. Claisen, L. Ber. dtsch. chem. Ges. 1912, 45, 3157.
13. Clemmensen, E. Ber. dtsch. chjem Ges. 1913, 46, 1837; 1914, 47, 51, 681.
14. Darzens, G. Compt. rend. 1904, 139, 1214; 1905, 141, 766; 1906, 142, 214.
15. (a) Demyanov, N.Ya. Zh. Russ. Fiz.-Khim. O-va. 1903, 35, 26; 1904, 36, 186. (b) Demjanov, N. Chem. Zentr.
1903, I, 828; 1904, I, 1214; Ber. dtsch. chem. Ges. 1907, 40, 4393, 4961; 1908, 41, 43.
16. Dieckmann, W. Ber. dtsch. chem. Ges. 1894, 27, 102, 965; 1900, 33, 595, 2670; Ann. Chem. Pharm. 1901, 317, 51, 93.
17. Diels, O.; Alder K. Justus Liegigs Ann. Chem. 1929, 460, 98.
18. Étard, A.L. Compt. rend. 1880, 90, 534; Ann. Chim. Phys. [5] 1881, 22, 218.
19. Friedel, C.; Crafts, J.M. Compt. rend. 1877, 84, 1392, 1450.
20. (a) Fries, , K.; Fink, G. Ber. dtsch. chem. Ges. 1908, 41, 4271. (b) Fries, K.; Pfaffendorf, W. Ber. dtsch. chem.
Ges. 1910, 43, 212.
21. Gattermann, L. Ber. dtsch. chem. Ges. 1898, 31, 1149; Ann. Chem. Pharm. 1907, 357, 313.
22. Glaser, C. Ber. dtsch. chem. Ges. 1869, 2, 422; Ann. Chem. Pharm. 1870, 154, 159.

(Table 3.1 continued)
R
1) Mg, Et2O
Grignard reaction R X R' OH 1900 23
2) R'2C=O R'
R'
R EtO2C CO2Et
R' CHO
Hantzsch pyridine synthesis 2 1882 24
O CO2Et NH3
R N R
H
R O Br2, P R O
Hell-Volhard-Zelinskii
1881 25
reaction OH Br OH
O
KOH, Br2
Hofmann rearrangement R R NH2 1881 26
NH2
O
Hofmann, Curtius, Lossen X
N C O
R
1874–1894 27
rearrangements R N
H
Kishner cyclopropane R1 R2 1) N2H4 R2

2)KOH, Pt-kaolin, ∆ R1 1911 28
synthesis O R3 R3
ONa OH
CO2, Na2CO3
Kolbe carbonation 1860 29
∆, pressure
CO2Na
CO2R CH2(CO2Et)2 EtO2C CO2R

Michael addition Ar NaOEt 1887 30
EtO2C Ar
Ac2O Ph
Perkin condensation Ph CHO CO2H 1868 31
AcONa, ∆
R R RCO2OH O
Prilezhaev reaction R R 1909 32
R R R R
23. (a) Barbier, P. Compt. rend. 1899, 128, 110. (b) Grignard, V. Compt. rend. 1900, 130, 1322; 1901, 133, 336, 558;
1902, 134, 849; Chem. Zentr. 1901, II, 622; Ann. Chim. Phys. 1901, 24 [vii], 433. (c) Grignard, V.; Tissier, L. Compt.
rend. 1901, 133, 835; 1902, 134, 107.
24. (a) Hantzsch, A. Ann. Chem. Pharm. 1882, 215, 1, 72; Ber. dtsch. chem. Ges. 1885, 18, 1744; 1886, 19, 289.
25. (a) Hell, C. Ber. dtsch. chem. Ges. 1881, 14, 891. (b) Volhard, J. Ann. Chem. Pharm. 1887, 242, 141.
(c) Zelinskii, N. Ber. dtsch. Chem. Ges. 1887, 20, 2026.
26. Hofmann, A.W. Ber. dtsch. chem. Ges. 1881, 14, 2725.
27. (a) Curtius, T. J. prakt. Chem. [2] 1894, 50, 275. (b) Lossen, W. Ann. Chem. Pharm. 1874, 161, 347; 1875, 175,
271, 313.
28. (a) Kizhner, N.; Zavadovskii, A. Zh. Russ. Fiz.-Khim. O-va. 1911, 43, 1132. (b) Kizhner, N. Zh. Russ. Fiz.-
Khim. O-va. 1912, 434, 1132165, 849; 1913, 45, 949, 957, 987; 1915, 47, 1102.
29. (a) Kolbe, H. Ann. Chem. Pharm. 1860, 113, 125. (b) Schmitt, R. J. prakt. Chem. [2] 1885, 31, 397.
30. Michael, A. J. prakt. Chem. [2] 1887, 35, 349.
31. Perkin, W.H. J. Chem. Soc. 1868, 21, 53, 181; J. Chem. Soc. 1877, 31, 388.
32. Prileschajew, N. Ber. dtsch. chem. Ges. 1909, 42, 4811.

R R R R
Zn, R'2CO
Reformatskii reaction HO 1887 33
Br CO2R CO2R
R' R'
OH OH
CHCl3
Reimer-Tiemann reaction 1876 34
KOH
CHO
CO2Et CO2Et
EtO2C
Stobbe condensation CHO 1893 35
Ar
NaOEt, EtOH, ∆ Ar CO2H
1) HCN, NH3 CO2H

Strecker amino acid R CHO R 1850 36
synthesis 2) HCl, H2O, ∆ NH2
Ag(NH3)2OH
Tollens oxidation R CHO R CO2H 1882 37
R I
Ullmann Coupling Ar Br Ar R 1881 38
Na
Wagner-Meerwein HCl
+ 1899 39
rearrangement Cl Cl
O N2H4, KOH, ∆ H H
Wolff-Kishner reduction 1911 40
R R R R
Wurtz coupling Na 1855 41

R X R R
3.3 Acronyms and Abbreviations
The dramatic growth in the number and complexity of reagents in modern organic chem-
istry has led to an equally dramatic increase in the use of acronyms for reagents, so that
since the last third of the 20th century or so, the use of acronyms in organic chemistry has
blossomed. There are now acronyms for parts of a molecule, such as alkyl and acyl groups,
functional groups (especially protecting groups), solvents, and an increasing number of
common reagents. These are summarized in Tables 3.2 through 3.6. The entries in the
tables are organized in alphabetical order.
33. (a) Reformatsky, S. Ber. dtsch. chem. Ges. 1887, 20, 2110; 1895, 28, 2838, 2842, 3262. (b) Reformatsky, S.;
Plesconossoff, B. Ber. dtsch. chem. Ges., 1895, 28, 2838.
34. Reimer, K.; Tiemann, F. Ber. dtsch. chem. Ges. 1876, 9, 824, 1268, 1285.
35. Stobbe, H. Ber. dtsch. chem. Ges. 1893, 26, 2312; Ann. Chem. Pharm. 1894, 282, 280.
36. Strecker, A. Ann. Chem. Pharm. 1850, 75, 27; Ann. Chem. Pharm. 1854, 91, 349.
37. Tollens, B. Ber. dtsch. chem. Ges. 1882, 15, 1635.
38. (a) Tollens, B.; Fittig, R. Ann. Chem. Pharm. 1864, 131, 301. (b) Fittig, R.; König, J. Ann. Chem. Pharm.
1867, 144, 277.
39. (a) Vagner, E.E. Zh. Russ. Fiz.-Khim. O-va. 1899, 31, 690. (b) Wagner, G. Ber. dtsch. chem. Ges. 1899, 32,
2302; 1900, 33, 2121. (c) Meerwein, H. Liebigs Ann. Chem. 1914, 405, 129.
40. (a) Kizhner, N.M. Zh. Russ. Fiz.-Khim. O-va. 1911, 43, 582. (b) Wolff, L. Ann. Chem. Pharm. 1912, 394, 86.
41. Wurtz, C.A. Ann. Chim. Phys. [3] 1855, 44, 275; Ann. Chem. Pharm. 1855, 96, 364.

Table 3.2 Acronyms for Alkyl, Acyl, and Substituent Groups, Including Protecting Groups for
Alcohols and Amines
Acronym Name/Structure Acronym Name/Structure
Ac acetyl, CH3CO– Ar aryl
O
Ad Adoc
O
1-adamantyl
1-adamantyloxycarbonyl
O O
Alloc O Boc O
allyloxycarbonyl tert-butoxycarbonyl
O
O O
Br S
Bom Bs
benzyloxymethyl p-bromobenzenesulfonyl,
brosyl
O
N
N
Bt N Btc
N
N
N
benzotriazol-1-yl
benzotriazolylcarbonyl
Bu or n-Bu n-butyl, –(CH2)3CH3 i-Bu, or Bui isobutyl, –CH2CH(CH3)2
s-Bu, or Bu s
sec-butyl, CH(CH3)CH2CH3 t-Bu or Bu t
tert-butyl, –C(CH3)3
Bz or PhCO benzoyl, C6H5CO– Bzl benzyl, C6H5CH2–
Me Me
Cp Cp* Me Me
Me
η -cyclopentadienyl
5
η5-pentamethylcyclopentadienyl
O
Cy or Chx dimsyl S
Me
cyclohexyl methylsulfinylmethyl
O2 N NO2 OEt
DNP EE
Me
2,4-dinitrophenyl 1-ethoxyethyl
–C2H5 –CH3
Et Me
ethyl methyl
O
O
Fm Fmoc
9-fluorenylmethyl 9-fluorenylmethyloxycarbonyl

Me
O
OMe Me
MEM Mes
(2-methoxyethoxy)-methyl Me
mesityl
O
OMe
MOM Ms S
Me O
methoxymethyl
methanesulfonyl, mesyl
O
S O2 N S O
Nf C4F9 O Ns
O
nonaflyl, or
perfluorobutanesulfonyl p-nitrobenzenesulfonyl, nosyl
F F
O O
n
F
PEG OH Pfp
polyethylene glycol or F F
polyethylene glycol substituent pentafluorophenyl
O
–C6H5 N
Ph Pht, PhthN
phenyl
O
phthalimidoyl
MeO MeO
PMB PMP
p-methoxybenzyl p-methoxyphenyl
O2N –(CH2)2CH3
Pnb Pr
O n-propyl
p-nitrobenzoyl
O
–CH(CH3)2
i-Pr or Pri SEM SiMe3
isopropyl
(2-trimethylsilyl-ethoxy)methyl
SiMe3 Ph Me
Si SiMe3 Si Me
sisyl TBDPS
SiMe3 Ph Me
tris(trimethylsilyl)silyl tert-butyldiphenylsilyl
Me Me O
TBS or Si Me SiMe3
Teoc O
TBDMS Me Me
2-(triemthylsilyl)
tert-butyldimethylsilyl ethoxycarbonyl
(continues)

Et O O
Si Et S
TES Tf F3C
Et trifluoromethanesulfonyl,
triethylsilyl or triflate
CF3CO–
TFA Th
trifluoroacetyl
tert-hexyl, or thexyl
O
S O
Tibs , Tris,
THP
O trisyl
tetrahydropyranyl
2,4,6-triisopropyl-
benzenesulfonyl
Me
Si Me –CPh3
TMS Tr
Me trityl, or triphenylmethyl
trimethylsilyl
O
Troc, Tce,
Tcec Cl3C O
2,2,2-trichloroethoxycarbonyl
O
Me S O O
Ts, Tos Z or Cbz
O
p-toluenesulfonyl
benzyloxycarbonyl
Table 3.3 Acronyms for Solvents

Cl
An, ACN
MeCN
bmimCl Bu N N Me
acetonitrile N-butyl-N'-methyl-
imidazolium chloride
ClCH2CH2Cl
CH2Cl2
DCE ethylene dichloride, or DCM
dichloromethane
1,2-dichloroethane
O MeCONMe2
DEG HO OH DMA
dimethylacetamide
diethylene glycol

Me N N Me
MeOCH2CH2OMe
DME DMEU O
1,2-dimethoxyethane
N,N'-dimethylethyleneurea
N,N'-dimethylimidazolidin-2-
one
HCONMe2
DMF DMI see DMEU
dimethylformamide
MeN NMe Me2SO

DMPU DMSO
dimethyl sulfoxide
N,N'-dimethylpropylene urea
Cl
EDC See DCE emimCl Et N N Me
N-ethyl-N'-methylimidazolium
chloride
Me O BF4
EtOAc hmim BF4 C6H13 N N Me
O
N-hexyl-N'-methylimidaz-
ethyl acetate olium tetrafluoroborate
(Me2N)P 5 O
HMPA hexamethylphosphoric
MBE, Me
MTBE O
triamide
methyl tert-butyl ether
O
MeCOEt
MEK methyl ethyl ketone, or MIBK
2-butanone methyl isobutyl ketone, or
4-methyl-2-pentanone
MTBE See MBE NMP N O

Me
N-methylpyrrolidone
N
py THF O
pyridine tetrahydrofuran
Table 3.4 Acronyms for Oxidizing Reagents
OAc
H
I N
BAIB, DAIB, OAc Cr2O72
BIDC N
PIDA diacetoxyiodobenzene, or H 2
iodosobenzene diacetate, or
phenyliodonium diacetate benzimidazolium dichromate
(continues)

OCOCF3
O I
Cr OCOCF3
N HN O O BTI, BTIB,
BPCC Cl bis-(trifluoroacetoxy)-
PIFA
2,2'-bipyridinium iodobenzene, or
chlorochromate phenyliodonium
bis-(trifluoroacetate)
O
Cl CN
(NH4)2Ce(NO3)6
CAN DDQ Cl CN
ceric ammonium nitrate
O
2,3-dichloro-5,6-dicyano-1,4-
benzoquinone
AcO OAc
Me Me I OAc
DMD, O
O O DMP
DMDO
dimethyldioxirane O
Dess-Martin periodinane
O OH
OTs
I I
O
HTIB OH IBX
Koser’s reagent, O
hydroxy(tosyloxy)iodobenzene
iodoxybenzoic acid
HN NH ClCrO3 HN NH FCrO3
ICC IFC
imidazolium chlorochromate imidazolium fluorochromate
O
Cl OH
lead tetraacetate MCPBA O
LTA
Pb(OAc)4 m-CPBA
m-chloroperbenzoic acid
CO2 H
N ClCrO3
Mg Me
MMPP MPCC
CO3H N-methylpiperidinium
2
chlorochromate
magnesium monoperphthalate
Br Cl
O N O O N O
NBS NCS
N-bromosuccinimide N-chlorosuccinimide
I
O
O N O NMO, O N
NIS Me
NMMO
N-iodosuccinimide N-methylmorpholine N-oxide
NH Cr2O72
NH ClCrO3
PCC PDC
2
pyridinium chlorochromate
pyridinium dichromate

NH FCrO3
PFC PIDA see DAIB
pyridinium fluorochromate
Cr2O72
PIFA see BTI QDC N 2
H
quinolinium dichromate
Bu4N ClCrO3 Me4N ClCrO3
TBACC tetrabutylammonium TMACC tetramethylammonium
chlorochromate chlorochromate
Me O
TMNO, N
TMANO Me Me
trimethylamino N-oxide
Table 3.5 Acronyms for Reducing Reagents

BH
Alpineborane
® B 9-BBN
B-isopinocampheyl 9-BBN 9-borabicyclo[3.3.1]nonane
Me2S•BH3 Al
BMS DIBAL-H H
borane-dimethyl sulfide
diisobutylaluminum hydride
Ipc-BH2 BH2 Ipc2BH B

H
isopinocampheylborane diisopinocampheylborane
H B K H B Li
K-Selectride L-Selectride
potassium lithium
tri-sec-butylborohydride tri-sec-butylborohydride
O
O H2Al OMe
Na
PBH, pinBH O
BH Red-Al ® O
OMe
sodium bis-(2-methoxy-
pinacolylborane
ethoxy)aluminum hydride
B BH2
Sia 2BH H ThBH2
disiamylborane thexylborane

Table 3.6 Acronyms for Ligands, Acids, Bases, Catalysts, and Other Substances
NC N
O O
ABCN, N CN
acac
ACN Me Me
azo-bis(cyclohexane-
Acetylacetonato
carbonitrile)
OH
CN
N
AIBN N BHT
NC
azo-bis(isobutyronitrile)
butylated hydroxytoluene
PPh2
OH
PPh2
BINAP BINOL OH
2,2'-bis(diphenylphosphino)-
1,1'-binaphthol
1,1'-binaphthyl
P P
Bipy, bpy N N bpe
2,2'-bipyridyl 1,2-bis(phospholano)ethane
O O Ph2P
Fe
BPO (–)-BPPFA Ph2P
O O Me
benzoyl peroxide
NMe2
PPh2 O
BPPM BTC Cl3C CCl3
O O
Ph2P N Boc
bis(trichloromethyl) carbonate
NEt3 Br
Cl CF3
BTEA(B,C,F) F BTF
(trifluoromethyl)benzene, or
benzyltriethylammonium benzotrifluoride
(bromide, chloride, fluoride)
O
O O O
O
O O
12-C-4 O 18-C-6
O O
12-crown-4, or 18-crown-6, or
1,4,7,10-tetraoxacyclodecane 1,4,7,10,13,16-hexaoxa-
cyclooctadecane
H Ph Ph
O
O
N B N N
CBS catalyst CDI N N
R
(S)-alkyl-Corey-Bakshi-Shibata carbonyl bis(imidazole)
catalyst

Me PPh2
Chiraphos Ph2P Me cod

(S,S)-2,3-
1,5-cyclooctadiene
bis(diphenylphosphino)-butane
cot CSA
HO3S
O
cyclooctatetraene
camphorsulfonic acid
O NMe3 X
O
Cl S
CSI N C O
CTA(B,C)
chlorosulfonyl isocyanate cetyltrimethylammonium
(bromide, chloride)
PCy2
N
DABCO N DavePhos
Me2N
1,4-diazabicyclo[2.2.2]-octane
2-dimethylamino-2'-
diphenylphosphinobiphenyl
N
O
dba DBN N
Ph Ph
1,5-diaza-bicyclo[4.3.0]-non-
dibenzylideneacetone
5-ene
N
Cy
N N C N
DBU DCC Cy
1,6-diaza-bicyclo[5.4.0]-
dicyclohexylcarbodiimide
undec-6-ene
ClCH2CH2Cl Et 2AlCl
DCE, EDC DEAC
1,2-dichloroethane diethylaluminum chloride
EtO2C N H
N CO2Et N
DEAD DETA, dien H2N NH2
diethyl azodicarboxylate diethylenetriamine
PriO2C N
DHP DIAD N CO2Pri
O
diisopropyl azodicarboxylate
dihydropyran
N DIEA,
DIC, DICI, C N
N DIPEA, EDA,
DIPCDI
diisopropylcarbodiimide Hünig’s base
diisopropylethylamine
(continues)

Ph2P O
Ph2P O
H
(–) N
DIOP DIPA
Ph2P O
diisopropylamine
Ph2P O
(+)
MeO OH O
(R,R)- (2)-DIPT O
P O
DIPAMP P
O OH
OMe S,S-(−)-diisopropyl tartrate
OH O
Me
O N N
O DMAP
(+)-DIPT Me
O OH
R,R-(+)-diisopropyl tartrate 4-dimethylaminopyridine
O2 N NO2
Me2S
DMS DNPH
dimethyl sulfide NHNH2
2,4-dinitrophenyl-hydrazine
PPh2
Ph2P
dppe, or PPh2
dpbp diphos 1,2-bis(diphenyl-phosphino)
Ph2P
ethane
2,2'-bis(diphenyl-phosphino)
biphenyl
PPh2
Fe N C N
PPh2 NMe2 Et
dppf EDCI, EDC
1,1'-bis-(diphenylphosphino)- N'-(3-dimethylaminopropyl)-
ferrocene N-ethylcarbodiimide
CO2H
HO2C N Cy3P Cl
N CO2H Ru
EDTA HO2C Grubbs-I
Cl PCy3
ethylenediaminetetraacetic
acid
Me Me
N N Cy3P Cl
Cl Ru
Me Me Me Grubbs-
Grubbs-II Me Ru
Hoveyda Cl O
Cl PCy3

Ph Ph
N N
H
N
H2TPP N N N
H
HBT, HOBt
TPP OH
N
Ph Ph 1-hydroxybenzotriazole
tetraphenylporphyrin
OH H
HFIP HMDS N
F3C CF3 Me3Si SiMe3
hexafluoroisopropyl alcohol hexamethyldisilazane
Cy N N Cy
Hünigs base see DIEA ICy
1,3-dicyclohexylimidazol-2-
ylidene
H2N NH K
IMes Mes N N Mes
KAPA
potassium
1,3-dimesitylimidazol-2-ylidene 3-aminopropylamide
K Li
KHMDS, N N
Me3Si SiMe3 LDA
KHDS
potassium
lithium diisopropylamide
hexamethyldisilazide
Li
Li N
LHMDS, N
Me3Si SiMe3 LICA
LHDS
lithium hexamethyldisilazide lithium
isopropylcyclohexylamide
Li
N Me-BPE, P P
LTMP, (R,R-Me-
LiTMP BPE, (R,R)
lithium S,S-MeBPE) 1,2-bis(2,5-dimethyl-
2,2,6-6-tetramethylpiperidide
phospholano)ethane
O O
N N
HO OH
(+)-MIB (–)-MIB
(1S,3S)-(+)-3-(morpholino) (1R,3R)-(–)3-(morpholino)
isoborneol isoborneol
F3C
MoOPH, MTPA, Ph CO2H
Vedejs’ MoO5•py•HMPA Mosher’s MeO
reagent acid α-methoxy-α-(trifluoromethyl)-
phenylacetic acid
(continues)

OH
O
N
MVK NHS, HOSu O O
methyl vinyl ketone

N-hydroxysuccinimide
O N Me H2N CO2H
NMM PABA, PAB
N-methylmorpholine p-aminobenzoic acid
OMe
Me
polycyclic aromatic P
PAH PAMP
hydrocarbon Ph
phenyl(o-anisyl)-
methylphosphine
PET photoelectron transfer phen

N N
1,8-phenanthroline
H H H OH OH OH
Si Si Si P P P
PMHS O O O O PPA O O O O
Me Me Me O O O
poly(methylsiloxane) polyphosphoric acid
NH O3 S Me
PPTS PTC phase transfer catalyst
pyridinium p-toluenesulfonate
OMe
O O RAMP N
pybox N NH2
N N R-2-methoxymethyl-1-
2,6-bis(oxazolin-2-yl)pyridine aminopyrrolidine
ring opening metathesis
ROM ring opening methathesis ROMP
polymerization
OMe Ph
N
N
SAMP NH2 Schrock Mo
O CF3
S-2-methoxymethyl-1- O CF3
aminopyrrolidine F3C CF3
O O
C12H25 S Na
O O
SDS SET single electron transfer
sodium dodecyl sulfate
(sodium lauryl sulfate)
NMe2
S Bu4N Br (Cl, F)
Me2N NMe2 Me3SiF2
TASF TBAB (C, F) tetra-n-butylammonium
tris(dimethylamino)sulfonium bromide (chloride, fluoride)
difluorotrimethylsilicate

O O
CF3CO2H
TFA TFAA F3C O CF3
trifluoroacetic acid
trifluoroacetic anhydride
tetramethylammonium
Ti(O-i-Pr)4
TIP TMAB(C, F) bromide (chloride, fluoride)
titanium tetra-isopropoxide
Me4N Br (Cl, F)
Me4N OH
Me2NCH2CH2NMe2
TMAH tetramethylammonium TMEDA
tetramethylethylenediamine
hydroxide
Me2N
N C
NH
Me S O
TMG Me2N TosMIC O
N,N,N',N'- p-toluenesulfonylmethyl-
tetramethylguanidine isocyanide
Ph3P tetraphenylporphyrin, see
TPP TPP
triphenylphosphine H2TPP
Ph3P 5 O
TPPO
triphenylphosphine oxide
The lists in the tables are not exhaustive by any means, and the number of acronyms in
general use will almost certainly have grown by the time you are reading this. Still, the use
of this type of shorthand to refer to reagents and reactions is now the norm in modern
synthesis, so one needs to know what the latest acronyms are. There are four reasonably
good web sites to find the acronym or name reaction you are seeking:
• www.cheminform.com/acronyms/
• www.chem.wisc.edu/areas/reich
• orgchem.chem.uconn.edu/namereact/named.html
• www.organic-chemistry.org/reactions.htm
The Cheminform web site is maintained by Wiley-VCH and Fiz Chemie Berlin
(Fachinformationszentrum Berlin GmbH). Limited to reagent acronyms, it has been quite
reliable since being posted to the web, but one should be careful to visit it regularly—the
URL changed during 2014.The Reich web site at the University of Wisconsin is also a reli-
able resource, especially for name reactions, but also for acronyms of important reagents.
The University of Connecticut web site, maintained by Michael B. Smith, is focused on
name reactions, as is the fourth web site, which is part of the Organic Chemistry Portal
maintained, in part, by Douglass Taber, of the University of Delaware.
Remember, however, the lifetimes of web sites are limited by a number of factors
beyond the user’s control, and they are not always maintained as well later on as they are
when they are new.

Chapter four
Orbitals and Reactivity
4.1 Introduction
Until the mid-1920s, the Lewis theory of bonding1 was the only truly general rationalization
of how bond formation occurs in chemical compounds. Now, a century later, it still pro-
vides a good qualitative description of bonding in organic compounds, and for that reason
it is still in use. However, Lewis bonding theory does have its limitations, not the least of
which is its failure to accurately predict the structures, bonding, and chemistry of certain
types of compounds (e.g., nitromethane and the allyl cation). Many of these limitations
were alleviated by expanding Lewis theory to include the theory of resonance,2 but what
was really required was a new theory that would account for the observed chemical and
physical properties of compounds without requiring such empirical approaches as reso-
nance. This theory, developed over the decades of the 1920s and 1930s, was quantum me-
chanics, which was applied to problems in chemistry in the form of valence bond theory;3
molecular orbital theory;4 and, in the last two decades of the 20th century, d ensity func-
tional theory.5
1. Lewis, G.N. J. Am. Chem. Soc. 1916, 38I, 762.

2. (a) Pauling, L.; Wheland, G.W. J. Chem. Phys. 1933, 1, 362. (b) Pauling, L.; Sherman, J. J. Chem. Phys. 1933,
1, 606-617. (c) Wheland, G.W. Resonance in Organic Chemistry (John Wiley & Sons: New York, 1955).
3. (a) Heitler, W.; London, F. Z. Phys. 1927, 44, 455. (b) Segiura, Y. Z. Phys. 1927, 45, 484. (c) Wang, S.C. Phys.
Rev. 1928, 31, 579. (d) Rosen, N. Phys. Rev. 1931, 38, 2099. (e) Weinbaum, S. J. Chem. Phys. 1933, 1, 593. (f) James,
H.M.; Coolidge, A.S. J. Chem. Phys. 1933, 1, 825.
For an extended discussion: Coulson, C.A. Valence, 2nd ed. (Oxford University Press: Oxford, 1961),
ch. 5, ch. 6.
4. For leading references, see: (a) Hund, F. Z. Phys. 1931, 73, 1, 565. (b) Mulliken, R.S. J. Chem. Phys. 1933, 1,
492. (c) Lennard-Jones, J.E. Trans. Faraday Soc. 1929, 25, 6668. (d) Hückel, E. Z. Phys. 1931, 72, 310; 1932, 76, 628;
1933, 83, 632. (e) Hückel, E. Trans. Faraday Soc. 1934, 30, 40.
Textbooks: (f) Pauling, L.; Wilson, E.B., Jr. Introduction to Quantum Mechanics with Applications to Chemistry
(McGraw-Hill: London, 1935); reprinted by Dover Books, New York, 1985. (g) Coulson, C.A. Valence, (Oxford/
Clarendon Press: London, 1952), ch. 4, ch. 6, ch. 7. (h) Liberles, A. Introduction to Molecular Orbital Calculations
(Holt, Rinehart and Winston: New York, 1966). (i) Roberts, J.D. Noptes of Molecular Orbital Theory (W.A.
Benjamin: New York, 1962). (j) Streitwieser, A., Jr. Molecular Orbital Theory for Organic Chemists (Wiley-
Interscience: New York, 1961). (k) Dewar, M.J.S. The Molecular Orbital Theory of Organic Chemistry (McGraw-Hill:
New York, 1969). (l) Dewar, M.J.S.; Dougherty, R.C. The PMO Theory of Organic Chemistry (Plenum: New York,
1975). (m) Z immerman, H.E. Quantum mechanics for Organic chemists (Academic Press: New York, 1975). (n)
Richards, W.G.; Horsley, J.A. Ab Initio Molecular Orbital Calculations for Chemists (Oxford University Press
(Clarendon Press): New York, 1970). (o) Pople, J.A.; Beveridge, D.L. Approximate Molecular Orbital Theory
(McGraw-Hill: New York, 1970). (p) Jorgensen, W.L.; Salem, L. The Organic Chemist’s Book of Orbitals (Academic
Press: New York, 1973).
5. (a) Parr, R.G.; Yang, W. Density Functional theory of Atoms and molecules (Oxford University Press:
Oxford, 1989). (b) Hohenberg, P.; Kohn, W. Phys. Rev. A 1964, 136, 864. (c) Becke, A.D. Phys. Rev. A 1988, 38,
3098. (d) Becke, A.D. J. Chem. Phys. 1992, 96, 2155; 1992, 97, 9173; 1993, 98, 5648.
105

106 Advanced Organic Chemistry | Chapter four
4.2 Atomic Orbitals: The History of the Modern Atomic Model
The equation for determining the energy of a photon is due to Max Planck,6 who first in-
troduced the idea that light was transmitted in the form of small energy packets, which he
called quanta. The energy could be straightforwardly related to the frequency of the radi-
ation.7 Planck’s equation, E 5 hν, has become one of the cornerstones of modern atomic
physics and modern chemistry.
The idea that energy in an atom is quantized was a revolutionary one, reinforced when
the Danish physicist Niels Bohr8 proposed a model of the nuclear atom in which the quan-
tization of energy levels was an integral part of the model.9 From Bohr’s work first emerged
the concept of quantum numbers, which have become so important in more recent theo-
ries of atomic structure and bonding.
The electron had been discovered in the late 19th century, and its behavior had marked
it as a particle (e.g., it possesses both mass and momentum). However, electron beams can
be diffracted—behavior restricted to waves—so that electrons also exhibit some charac-
teristics of a wave. This initial radical departure from the principles of classical m
echanics—
that particles could exhibit wave behavior and that waves could exhibit particle-type
behavior—was first suggested in 1924 by Louis de Broglie,10 who proposed the term
wave-particle duality 11 to describe the equivalence of matter and energy at the atomic and
subatomic level.
The dual nature of the electron solved some problems in atomic physics, but more
problems were added by the work of Werner Heisenberg,12 who pointed out that many of
the ideas of classical physics could not be applied at the atomic level. In his uncertainty
principle,13 he stated that the position and momentum of a particle cannot be known
simultaneously to such precision that the product of the uncertainty in each quantity is
less than h/2π. Equation 4.1, due to Kennard14 and Weyl,15 uses the standard deviations of
position (σx) and momentum (σp):
σ x • σ p ≥ h 2π (4.1)

6. Max Karl Ernst Ludwig Planck (1858-1947) was educated at Munich and Berlin. In 1889, he joined the
faculty of Physics at Berlin; he received the 1918 Nobel Prize in Physics. After the war, Planck resumed the pres-
idency of the Kaiser Wilhelm Society, which was renamed the Max Planck Society in his honor. For more bi-
ographical details, see the web site of the Nobel Foundation.
7. Planck, M. Ann. Phys. 1901, 4, 553.
8. Niels Hendrik David Bohr (1885-1962) was educated in Copenhagen and Cambridge. He returned to
Copenhagen in 1916 as professor of physics. Bohr escaped the Nazi occupation of Denmark and eventually
became an important contributor to the Manhattan Project. Bohr returned to Copenhagen in 1945 and devoted
the rest of his life to finding peaceful uses for atomic energy. There are numerous biographies of Bohr available,
including Blaedel, N. Harmony and Unity: The Life of Niels Bohr (Science Tech.: Madison, Wisconsin, 1988).
9. Bohr, N. Phil. Mag, 1913, 26, 1; 1914, 27, 506.
10. Louis Victor Pierre Raymond, 7th duc de Broglie (1892-1987) took his PhD in theoretical physics at the
Sorbonne in 1924. De Broglie was professor of physics at the Université de Paris from 1928 until his retirement
in 1962. He received the Nobel Prize in Physics in 1929. In 1960, he succeeded his brother as duc de Broglie. For
more biographical information, see: Abraham, A. Biogr. Mem. Fellows Roy. Soc. 1988, 32, 22.
11. De Broglie, L. Thesis, Université de Paris (Sorbonne), 1924; Ann. phys. (10) 1925, 3, 22.
12. Werner Karl Heisenberg (1901-1975) was educated at Munich. He became professor of theoretical phys-
ics at Leipzig in 1928 and was Professor in Berlin and Director of the Kaiser Wilhelm Institute during World
War II. Heisenberg was awarded the 1932 Nobel Prize in Physics. His work on the Nazi atomic bomb is still a
source of controversy. For more biographical details, see: Rechenberg, H.; Wiemers, G. Werner Heisenberg
(1901–1976), Schritte in die neue Physik (Sax-Verlag Beucha, 2001).
13. Heisenberg, W. Z. Phys. 1927, 43, 172.
14. Kennard, E.H. Z. Phys. 1927, 44, 326.
15. Weyl, H. Gruppentheorie und Quantenmechanik (Hirzel: Leipzig, 1928).

Orbitals and Reactivity 107
The insight of genius required to consolidate the theories of atomic structure and
bonding was supplied by the Austrian physicist Erwin Schrödinger,16 who combined a
number of principles and theories extant in the mid-1920s and unified them into what we
now term wave mechanics, or quantum mechanics.17 The English physicist P. A. M. Dirac18
combined the work of de Broglie, Heisenberg, and Schrödinger into one unified theory.19
In simple terms, Schrödinger took the approach that electrons about an atomic nucleus
will behave exactly like a standing wave in three dimensions. However, he also incorpo-
rated into his theory the Heisenberg uncertainty principle, so that instead of addressing
the positions and energies of electrons in atoms in classical terms, he addressed the prob-
lem in terms of probability. Because the spectra of atoms can be measured in very high
precision, the energy levels of the electrons in atoms can be determined with a very small
uncertainty. Accordingly, the position of the electron must be highly uncertain. Although
it had been shown that quantization of the energy levels of the atom led to a model that
could be used to predict atomic properties, one of the major questions which Bohr’s theory
of the atom had left unaddressed was why the energy levels of atoms should be quantized.
Wave mechanics answered this question.
Standing Waves and Atomic Orbitals

At the heart of quantum mechanics is the premise that one can reasonably treat the elec-
trons of an atom or molecule as a standing wave in three dimensions.
The simplest standing wave is the standing wave in one dimension, exemplified by a
vibrating string. The displacement, r, of any part of a vibrating string at time t can be cal-
culated by using the standard equation for a simple harmonic oscillator if one knows two
fundamental properties of the vibration: the amplitude of the vibration, A, which is de-
fined as the maximum displacement of the string from its equilibrium position, and its
frequency, v
r = A sin (2nπωt) (4.2)
Equation 4.2 is the wave function for a standing wave in one dimension and is simply
an algebraic expression that one can use to describe a vibrating string. The variable n in
this equation is an integer that tells if one is dealing with the fundamental vibration
(n = 1), or an overtone or harmonic (n = 2, 3, 4, . . .). This number is strictly analogous
to the quantum numbers of atomic physics. The wave functions for the fundamental and
first three harmonic vibrations of a standing wave in one dimension are plotted in
Figure 4.1.
In Figure 4.1, there are several important points marked as nodes. A node is defined as a
point within the standing wave where the displacement from the equilibrium position is always
zero. A standing wave in one dimension must have a minimum of two nodes, one at each
16. Erwin Schrödinger (1887-1961) was educated in Vienna and remained there until 1920. In 1921, he went
to Zürich, and in 1927, he joined the faculty at Berlin but left Germany in 1933 over the Nazi treatment of the
Jews. From 1940 to 1956, he taught at Dublin before returning to Vienna. He shared the 1933 Nobel Prize in
Physics. For more detail, see: Moore, W.J. A Life of Erwin Schrödinger (Canto ed.) (Cambridge University Press:
Cambridge, 2003).
17. Schrödinger, E. Ann. Phys. 1926, 79, 361, 489, 734; 1926, 80, 437; 1926, 81, 109.
18. Paul Adrien Maurice Dirac (1902-1984) was educated at Bristol and Cambridge, where he was appointed
Lucasian Professor of Mathematics at the age of 30; he was Lucasian Professor until 1969. Dirac shared the 1933
Nobel Prize in Physics with Heisenberg. Following his retirement from Cambridge, Dirac became Professor of
Physics at Florida State University, a post he held until his death. For more biographical detail, see: Dalitz, R.H.;
Peierls, R. Biogr. Mem. Fellows Roy. Soc. 1986, 32, 138.
19. Dirac, P.A.M. Proc. Roy. Soc. A 1927, 113, 621; 1927, 114, 243; 1928, 117, 610.

node node node node node
amplitude
n=1 n=2
n=3 n=4
node node node node node node node node node

Figure 4.1 A vibrating string provides an example of a standing wave in one dimension
end of the wave. For convenience, we shall call these nodes terminal nodes. For the funda-
mental vibration, these are the only nodes; for the harmonics, however (n = 2, 3, 4, . . . in
Equation 1.6), there are (n – 1) internal nodes in addition to the two terminal nodes. In a
one-dimensional standing wave, all nodes are point nodes, or nodal points.
The wave equation of a standing wave in two dimensions is more complex than the
wave equation for a vibrating string because the vibration is occurring in more dimen-
sions. When reduced to its simplest form, the wave equation for a standing wave in two
dimensions requires two, rather than one, “quantum number”—one for each dimension—
to describe the vibration completely.
The best analogy for a standing wave in two dimensions is probably a vibrating drum-
head. Some typical vibrations of a drumhead are illustrated in Figure 4.2. In two dimen-
sions, the nodes are no longer nodal points, but are, instead, nodal lines; there are two
major types of nodes in two dimensions—circular nodes and linear nodes—which divide
the vibrations into two classes (symmetrical vibrations and antisymmetrical vibrations).
The symmetrical vibrations of a drumhead have only circular nodes; they are shown as the
top line of drumhead vibrations. The antisymmetrical vibrations of a drumhead have at
least one linear node, so that half of the drumhead is above the average plane, while half
of the drumhead is below it. The antisymmetrical vibrations are the lower ones in Figure
4.2. Exactly what type of vibration one is examining will be determined by the values of
the two “quantum numbers” in the wave equation.
Because of the additional dimension, the picture in three dimensions becomes even
more complex, although the same rules apply. In three dimensions, the nodes now
become surfaces, rather than lines or points, and three “quantum numbers,” rather than
two, are required to describe the vibration. Just as there were two types of nodal lines in
standing waves in two dimensions (a vibrating drumhead), there are two types of nodal
surfaces in three dimensions: spherical nodes, which are analogous to the circular nodes
in two dimensions, and planar nodes, which are analogous to the linear nodes in two
dimensions.
Schrödinger’s equation for the energy of an electron in an atom is a second-order
differential equation for a standing wave in three dimensions. As with the string and
the drumhead, the fact that this equation describes a standing wave means that only
certain solutions are allowed (there may not be a nonintegral number of waves within
the atom). The energy of the atom can have only certain values—it must be quantized.
Here, for the first time, the origin of the quantization of atomic energy levels was
explained.

Figure 4.2 Standing waves in two dimensions. The dark areas and light areas are moving in oppo-
site directions with respect to the viewer. Standing waves in two dimensions have nodal lines (cir-
cles or straight lines) rather than nodal points. The displacement of the drumhead with respect to
the dashed lines drawn on each diagram is shown above the diagram for the top set of vibrations
and below the diagram for the lower set of vibrations.
Each of the solutions to the Schrödinger equation is in the form of an algebraic

f unction—the wave function in three dimensions. Each of these wave functions (usually
designated by the Greek letter c for atomic orbitals, and by the Greek letter f for molecular
orbitals) is properly called the probability amplitude of an electron of a given energy in any
region of space around the nucleus of the atom. The square of the wave function (f2 or c2)
gives the probability of finding an electron within a given volume around the nucleus of the
atom. One of the important things to note about wave functions is that the sum of the
squares of all the orbital wave functions in a given subshell is the equation of a sphere.
Because this is the simplest set of solutions, we usually describe the atom in terms of
orbitals that are mathematically orthogonal (i.e., the product of the wave functions of any
pair of orbitals is zero). The individual orbitals of an atom are described in terms of three
integer quantum numbers. These quantum numbers are the principal quantum number,
n, which defines the electron shell in which the orbital occurs and specifies the total
number of nodes in that orbital; the azimuthal quantum number, l, which defines the
subshell to which the orbital belongs and specifies the type of orbital by specifying the
number of planar nodes (there are l – 1); and the magnetic quantum number, ml, which
defines the orientation of that particular orbital in space. There are a total of n2 orbitals in
an energy level for which the principal quantum number has the value n.
We can describe the shapes of orbitals by specifying their symmetry. This is a useful
way of describing orbitals because it allows us to identify a directional component of the
atomic orbital that is important in the formation of molecular orbitals. The electron prob-
abilities for a 2p and a 4s orbital are given in Figure 4.3.

orbital axis
nodal plane nodal plane nodal surfaces

Figure 4.3 Projections of the electron probability distributions for 2p (left), 3p (center), and 4s
(right) orbitals. Note that the 4s orbital has only spherical nodal surfaces, that the 2p and 3p orbit-
als have a single planar nodal surface, and that there are additional nodes in the 3p.
All s orbitals are spherically symmetrical; they have no directional characteristics. In

contrast, p orbitals have a unique axis perpendicular to a single planar node passing
through the nucleus, so unlike s orbitals, p orbitals have a directional character. When a p
orbital is viewed from a perspective perpendicular to the nodal plane (i.e., along the axis),
it always appears circular in cross-section—it is cylindrically symmetrical.¶
The fourth quantum number for electrons is the spin quantum number, ms, which
takes one of only two permitted values, ± 1/2. Because of this restriction on the possible
values for the spin quantum number of an electron, the capacity of an orbital is restricted
to two electrons. The origins of this restriction on the electron capacity of an orbital were
first set forth in 1925 by Austrian-born physicist Wolfgang Pauli,20 in the form of the prin-
ciple that bears his name, the Pauli Exclusion principle. This principle states that no two
electrons in any atom may simultaneously have the same values for all four quantum
numbers.21 In other words, because the electrons in any single orbital must have the same
values of n, l, and ml, they must differ in the value of ms. Because there are only two possi-
ble values of m2, the orbital can hold only two electrons. The Pauli Exclusion principle ap-
plies not only to electrons in the orbitals of isolated atoms but also to electrons in the orbitals
of molecules. Two electrons occupying the same orbital are said to be paired.
¶. Spatial Properties of Wave Functions

One of the important things to note about wave functions is that the sum of the squares of the orbital wave
functions in a given subshell is the equation of a sphere. Let us take the wave functions for the orbitals of the 2p
subshell, where ρ is the radial distribution function, which is independent of orientation:
Let us take the wave functions for the orbitals of the 2p subshell, where ρ is the radial distribution function,
which is independent of orientation:
2px: ρ(3/4π)1/2sinθcosf = ρ(3/4)1/2 x

2py: ρ(3/4π)1/2sinθsinf = ρ(3/4)1/2y
2pz: ρ(3/4π)1/2cosθ = ρ(3/4)1/2z
When squared and summed, this becomes cx2 + cy2 + cz2 = (3/4π)ρ2(x 2 + y2 + z2), which is the equation for a
sphere. A similar situation holds true for both subsets of the five orbitals of a d subshell (d xy, dyz, d xz and d x -y , dz ).
2 2 2
20. Wolfgang Pauli (1900-1958) was educated at Munich. He taught physics at Göttingen, Copenhagen, and
Hamburg before joining the ETH in Zürich. He received the 1945 Nobel Prize in Physics for his work in atomic
physics. In 1940, Pauli joined the Institute for Advanced Study at Princeton University, and in 1946 was natu-
ralized a US citizen. After World War II, he returned to Zürich, where he spent the remainder of his life. Biog-
raphies of Pauli abound; see, for example, Enz, C.P. No Time to be Brief, A scientific biography of Wolfgang Pauli.
(Oxford University Press: Oxford, 2002).
21. Pauli, W. Z. Phys. 1925, 31, 765.

The filling of the orbitals around the nucleus is carried out according to the Aufbau
principle (from the German Aufbauprinzip, “principle of building up”). This principle,
named by Bohr in 1922,22 derives its name from the German word to build up. It states that
when filling orbitals around a nucleus of an atom, the lowest energy orbitals are filled first.
Like the Pauli Exclusion principle, the Aufbau principle also holds true for orbitals in
molecules.
When the application of the Pauli Exclusion and Aufbau principles leads to more than
one possible electron configuration for an atom or molecule (i.e., when the highest energy
orbital containing electrons is part of a degenerate set of orbitals), the distinction between
the possible configurations is made possible by Hund’s rule,23 first promulgated by Fried-
rich Hund.24 This rule states that the lowest energy electron configuration of an atom or
molecule where the highest energy electrons partially fill a set of degenerate orbitals is the
one in which there is the maximum possible number of unpaired electrons.
Worked Problem
4-1 The molecular orbitals of cyclobutadiene (C4H4) fall into the pattern below, where
there are three sets of degenerate bonding orbitals (C–H σ, C–C σ, and C–C π ),
with their antibonding counterparts, as well as a degenerate set of nonbonding
(n) orbitals. There are 20 valence electrons in the cyclobutadiene molecule. Com-
plete the diagram by distributing the electrons to the appropriate orbitals.
σ∗
π∗
Energy
n
π
4.3 Covalent Bonding and Molecular Orbitals
In the Lewis theory of bonding, a covalent bond is a pair of electrons shared between
two nuclei. In the more modern view, this has changed relatively little, except that the
electron pair is now placed into a molecular orbital, which encompasses both nuclei.
Molecular orbitals differ from atomic orbitals in one very important respect. Atomic
orbitals are associated with one and only one nucleus; molecular orbitals are associated
with at least two nuclei. Atomic orbitals are always labeled with the Roman alphabet
(e.g., s, p, d, f, g), whereas molecular orbitals are always labeled with Greek letters
(e.g., σ, π, ∆).
22. Bohr, N. Z. Phys. 1922, 9, 1.

23. Hund, F. Z. Pys. 1925, 33, 345; Linienspektren und periodisches Systeme der Elements (Springer: Berlin,
1927), p. 124.
24. Friedrich Hund (1896-1997) was educated at Göttingen and Marburg (PhD, Göttingen, 1922). His aca-
demic career began at Göttingen, and he held positions at Rostock, Leipzig, Jena, and Frankfurt before return-
ing to Göttingen to finish his career. Leading sources for more biographical information on this centenarian
scientist can be found at the Leipzig University web site: http://www.uni-leipzig.de/unigeschichte/professoren
katalog/leipzig/Hund_67/

Figure 4.4 The overlap of hydrogen atomic orbitals. Subtracting the wave functions, or out-of-
phase overlap, gives an antibonding molecular orbital. Adding the wave functions, or in-phase
overlap, gives a bonding orbital.
The formation of molecular orbitals from atomic orbitals is usually represented as in-
volving overlap of the two atomic orbitals to form the new molecular orbitals. Mathemat-
ically, this involves the linear combination (addition or subtraction) of the wave functions
for the atomic orbitals according to a strict set of rules: the linear combination of atomic
orbitals (LCAO) method. One of the most stringent rules for combining wave functions
(orbitals) can be set forth as a “rule of conservation of orbitals.”
During the formation of a set of molecular orbitals from a set of atomic orbitals on two or
more atoms, the mathematics mandates that the number of molecular orbitals produced
must be exactly equal to the number of atomic orbitals used. Orbitals can be altered but
neither created nor destroyed.
Molecular orbitals can be generated by coaxial overlap of orbitals to give cylindrically

symmetrical σ and σ* orbitals or by coplanar overlap of orbitals to give π and π* orbitals
with mirror plane symmetry. In forming two molecular orbitals by overlap of two atomic
orbitals (Figures 4.4 and 4.5), the only permitted combinations of atomic wave functions
(designated fa and f b for the two atoms, a and b) are (1) the sum, (1/√2)(fa + f b), termed

The 20 valence electrons of the molecule are distributed into this set of orbitals according to the Aufbau
principle. This gives the following electron configuration for the molecule, with two unpaired electrons, each
in one of the two degenerate n orbitals.
σ∗
π∗
Energy
n
π

Figure 4.5 Out-of-phase
coplanar overlap of p orbitals
gives an antibonding π*
orbital. In-phase coplanar
1/√2(φa – φb) overlap of p orbitals gives a
bonding π orbital.
antibonding
1/√2(φa + φb)
bonding
in-phase overlap) and (2) the difference, (1/√2)(fa – f b), termed out-of-phase overlap).
The factor 1/√2 is called a normalization factor and simply scales the wave function so
that its square is equal to 1.
These two combinations arise from the mathematical constraints on orbital overlap.
The molecular orbitals formed must be orthogonal (i.e., the product of their wave func-
tions must be zero), and the sum of the squares of the molecular orbitals must be equal to
the sum of the squares of the atomic orbitals from which they are formed. In-phase over-
lap gives a molecular orbital lower in energy than either of the atomic orbitals used in its
formation; this is the bonding molecular orbital.
Out-of-phase overlap gives a molecular orbital higher in energy than either of the
atomic orbitals used in its formation; this is the antibonding molecular orbital. The
Aufbau principle, the Pauli Exclusion principle, and Hund’s rule apply to molecules in ex-
actly the same way they apply to atoms. Thus, electrons occupy the bonding orbitals first,
and antibonding orbitals remain empty.
Up to this point, we have not addressed the effects of orbital energies on the efficiency
of orbital overlap. Fortunately, the relationship is both simple and logical—the efficiency of
orbital overlap increases as the energies of the two orbitals involved become more closely
matched—or more nearly equal. In particular, orbital overlap is most efficient when orbit-
als in the same electron shell are involved. A carbon 2p orbital, for example, will form a
very strong π bond when it overlaps with the 2p orbital of an oxygen atom, and it will form
only a relatively weak π bond when it overlaps with the 3p orbital of a phosphorus atom.
Hybrid Atomic Orbitals: Valence Bond Theory

The methane molecule, CH4, is known to be tetrahedral, and any bonding model that we
use to describe the structure of methane should produce this geometric result. However,
the atomic orbitals of the valence shell of carbon are not oriented at 109.471 . . .° to each
other but rather at 90° to each other. This problem is solved quite elegantly one way by
noting that one can inscribe a tetrahedron in a cube, which permits the formation of a
tetrahedral molecule from a set of orbitals that are perpendicular to each other. In this
way, one can obtain four bonding and four antibonding orbitals, as shown in Figure 4.6.
The result of this approach in methane is one σ-symmetric bonding orbital and its
corresponding σ* antibonding orbital as well as a set of three degenerate π-symmetric

Figure 4.6 Linear combina-

tions of atomic orbitals to
generate one set of molecular
orbitals for methane.
σ∗
π∗
orbitals and their corresponding π* antibonding orbitals.¶ Photoelectron spectroscopy of

the methane molecule (which gives information about the electron energies of the mole-
cule) shows two peaks in the ratio 3:1, which lends support to this model of the methane
molecule.25
A similar set of wave functions can be derived from the 12 atomic orbitals of carbon
and hydrogen for the 12 LCAO molecular orbitals of the ethylene molecule; these orbitals
are shown in Figure 4.7. There is again a pair of unique orbitals with σ and σ* symmetry
derived from the carbon 2s orbitals and the hydrogen 1s orbitals, with two sets of two
π-symmetry orbitals and their corresponding π* antibonding orbitals. These antibonding
orbitals are formed from the carbon 2px orbitals and the hydrogen 1s orbitals, and a corre-
sponding set is formed from the carbon 2py orbitals and the hydrogen 1s orbitals. The
ethylene molecule also has a pair of unique π and π* orbitals formed from the carbon 2pz
orbitals (compare with Figure 4.5).
This LCAO method for describing the bonding in molecules is well adapted to com-
puters, but the molecular orbitals rapidly become too complex for most individuals to
¶. Wavefunctions of Simple Molecules from Atomic Basis Orbitals

The wave functions of the molecular methane shown above are:
f σ = (1/2√2)(2fs + fa + fb + fc + fd)
f π(x) = (1/2√2)(2fx + fa + fb – fc – fd)
f π(y) = (1/2√2)(2fy + fa – fb + fc – fd)
f π(z) = (1/2√2)(2fz + fa – fb – fc + fd)
f π*(x) = (1/2√2)(2fx – fa – fb + fc + fd)
f π*(y) = (1/2√2)(2fy – fa + fb – fc + fd)
f π*(z) = (1/2√2)(2fz – fa + fb + fc – fd)
f σ* = (1/2√2)(2fs – fa – fb – fc – fd)
25. Hamrin, K.; Johansson, G.; Gelius, U.; Fahlman, A.; Nordling, C.; Siebahn, K. Chem. Phys. Lett. 1968, 1,
613.


tions of atomic orbitals to
generate one set of molecular
orbitals for ethylene.
pz
py
px
visualize without one. The most widely used model for visualizing bonding in molecules
describes it in terms of two types of bond: σ bonds, formed by coaxial overlap of atomic
orbitals, and π bonds, formed by coplanar overlap of p orbitals. The most stable arrange-
ment of electrons in a molecule corresponds to the one in which all atoms are linked by σ
bonds, with the minimum number of σ bonds being used. In this model, multiple bonds
consist of one—and only one—σ bond, and one or more π bonds. π Orbitals differ from
σ orbitals in one very important way; because the p atomic orbitals used in their forma-
tion have a nodal plane through the nucleus of the atom, π molecular orbitals also have a
nodal plane through the two nuclei—π electrons do not occupy the space directly between
the two nuclei. This means that π electrons are always further from the nuclei defining the
bond than are σ electrons, so that they are not so tightly bound, and they are more polar-
izable and more responsive to external electronic influences. π Bonds are more reactive
than σ bonds.
The side-by-side overlap of the p orbitals required to form the π and π* orbitals also
imposes another very stringent requirement on molecules containing π bonds. Because π
overlap is most effective when the two p orbitals are parallel and coplanar, any rotation of
the atoms at the two ends of the π bond relative to each other will weaken, and eventually
break, the π bond. Therefore, unless a compound has two π bonds between the same two
atoms (i.e., a triple bond), such rotation about the π bond is forbidden.
Problems
4-1 Draw a set of LCAO molecular orbitals for acetylene, HC ≡ CH, similar
to those drawn in Figure 4.7 for ethylene.
4-2 Draw a set of molecular orbitals for ethane similar to those in Figure 4.7 for
e thylene. (Hint: put the two carbon atoms along the x axis, with two hydrogen
atoms in the xz plane.)
The molecular orbitals generated by the LCAO approach above are all delocalized—
every molecular orbital encompasses every nucleus of the molecule. Although this

approach is ideally suited for the generation of molecular orbitals by computer programs,
it is rather less intuitive for most organic chemists, who find it much easier to visualize the
localized bonds of the Lewis model. The same holds true when it comes to discussing the
chemistry of compounds; it is often less confusing to use the simple Lewis model of bond-
ing with its localized covalent bonds.
An alternative to this process of forming delocalized molecular orbitals is provided
by valence bond theory, which is basically a theoretical form of Lewis bonding theory.
At its core, it involves the overlap of hybrid atomic orbitals to form localized molecu-
lar orbitals. The process of hybridization, 26 which is one of the simplest models for
obtaining directed atomic orbitals capable of forming localized molecular orbitals, in-
volves combining the wave functions of orbitals of a single atom according to simple
mathematical principles to generate a set of new atomic orbitals. The mathematics of
hybridization results in a set of wave functions that are also valid solutions to the
Schrödinger equation and a set of orbitals whose overall symmetry, in terms of the
electron probability distribution of the atom, remains unchanged. Hybridization of
carbon and other second-row elements always involves a 2s orbital, with one or more
2p orbitals. The unused p orbitals remain unchanged, orthogonal to the hybrid orbit-
als. In the discussion that follows, we will refer to the p orbitals by their cartesian
designations: x, y, and z.
As we discuss hybridization, it will be easy to get the impression that atoms undergo
this real, physical process before they form molecules.27 This is not now generally accepted
to be the case, although the case to the contrary has been made quite eloquently by Ala-
bugin.28 As with all versions of molecular orbital theory, hybridization theory is a useful
model that allows us to rationalize certain properties of the chemical bonds in molecules—in
this case, it is the strength, length, and orientation of covalent bonds. It is not a description
of a physically real process.
There are three common hybrids formed by second-row elements: sp, sp2, and sp3
hybrid orbitals. Hybrid orbitals are characterized by the hybridization index, which is n
for an spn hybrid orbital.29 Although the wave function for an s orbital is the equation for
a sphere with no directional component, the wave functions for p orbitals all contain an
important directional component (e.g., the directional component of the px orbital causes
the wave function to have a value of zero at all points where x = 0). Consequently, all
hybrid orbitals have a directional component.
The simplest hybrid orbitals are sp hybrids, formed from the s orbital and a single
p orbital. The hybridization of the s orbital with the px orbital gives a pair of wave func-
tions that are oriented along the x axis; sp hybrid orbitals are colinear, with the front
lobes oriented at 180° to each other (this geometry is described as linear or, occasion-
ally, as d
igonal). Note that the two unused p orbitals (the py and pz orbitals in this case)
remain unchanged and are oriented along the y and z axes, orthogonal to the hybrid
orbitals.
The set of sp2 hybrid orbitals is formed from the s orbital and two of the degenerate p
orbitals. Using the px and py orbitals in the hybridization process gives three degenerate sp2
26. (a) Pauling, L. Proc. Natl. Acad. Sci. 1928, 14, 359; J. Am. Chem. Soc. 1931, 53, 1367; The Nature of the
Chemical Bond, 3rd. ed. (Cornell University Press: Ithaca, NY: 1960), p.111ff. (b) Slater, J.C. Phys. Rev. 1931, 37,
481. (c) van Vleck, J.H. J. Chem. Phys. 1933,1, 1778. (d) Hultgren, R. Phys. Rev. 1932, 40, 891.
27. A state known as the “valence state,” an excited form of the atom has been proposed, although it is
pointed out that the carbon atom, for example, never attains this state: (a) van Vleck, J.H. J. Chem. Phys. 1933,
1, 177, 219; 1934, 2, 20. (b) Mulliken, R.S. J. Chem. Phys. 1934, 2, 782; J. Phys. Chem. 1952, 56, 295. (c) Moffitt, W.E.
Proc. Roy. Soc. A 1950, 202, 534, 548.
28. (a) Alabugin, I.V.; Manoharan, M. J. Comp. Chem. 2007, 28, 373. (b) Alabugin, I.V.; Manoharan, M.; Pea-
body, S.; Weinhold, F. J. Am. Chem. Soc. 2003, 125, 5973.
29. (a) Bingel, W.A.; Lüttke, W. Angew. Chem. Int. Ed. Engl. 1981, 20, 899. (b) Lowry, T.H.; Richardson, K.S.
Mechanism and Theory in Organic Chemistry (Harper & Row: New York, 1976), pp. 43-49.

sp sp2 sp3
Figure 4.8 Wave functions for hybrid orbitals of carbon projected on a plane containing principal
axis of the orbital. Orbital wave function calculations courtesy of Dr. Frederick W. King, Univer-
sity of Wisconsin-Eau Claire. Projection diagrams were prepared using Atom in a Box (Dauger
Research, Inc.).
hybrids in the xy plane, with one oriented along the y axis, and the other two at 120° to it;
sp2 orbitals lie in a common plane, with the front lobes oriented toward the corners of an
equilateral triangle (this geometry is most often referred to as trigonal planar). The unused
p orbital (the pz orbital in this case) remains unchanged and lies along the axis orthogonal
to the plane of the sp2 orbitals (in this case, the z axis).
The four degenerate sp3 hybrid orbitals derived from the s orbital and the complete set
of degenerate p orbitals (the px, py, and pz orbitals) are oriented toward the corners of a
tetrahedron that are defined by the Cartesian coordinates (1, 1, 1), (–1,1, 1), (1, –1, –1), and
(–1, 1, –1). This geometry is almost always referred to as tetrahedral.
The projections of the wave functions of the three types of hybrid atomic orbitals for a
carbon atom projected on the plane containing the orbital axis are plotted on the same
scale in Figure 4.8, which also shows a superimposed plot of projection of the nodal sur-
faces on the plane containing the principal axis of the orbital.
Hybrid atomic orbitals still retain some of the character of the pure atomic orbitals
from which they are derived. Thus, one can define a property of the orbital, its s character,
which for an spn orbital is 1/(1 + n). The amount of s character relates the properties of the
hybrid orbital to the extent to which the s orbital wave function contributes to the wave
function of the hybrid. All hybrid orbitals have a larger front lobe and a smaller back lobe,
with the relative size (i.e., volume) of the front lobe increasing as the s character of the
orbital increases. The sp orbital has the largest front lobe and smallest back lobe, whereas
the sp3 orbital has the two lobes closer to equal in size.
Figure 4.8 highlights another difference between hybrid orbitals and the atomic orbitals
from which they are derived. The nucleus is located on the nodal plane of a p orbital and at
the center of the spherical nodes of the s orbitals, but the nodal surface of a hybrid orbital
neither passes through the atomic nucleus nor is located symmetrically with respect to it—
the nucleus is located within the back lobe of the hybrid orbital. The diagram in Figure 4.9
shows that the nucleus most closely approaches the nodal surface in the sp3 hybrid and is
further from the nodal surface as the s character of the hybrid orbital increases.

Figure 4.9 Location of nodal surfaces of s, sp, sp2, and sp3 hybrid orbitals
Hybridization has another effect: as the s character of the hybrid orbital increases, the
front lobe becomes shorter. That is, the distance from the nucleus to where there is the
maximum probability of finding an electron becomes shorter. This, of course, puts the
electrons closer to the nucleus, so that they are held more strongly by the nucleus. It is
worth remembering at this stage that one defines an increased hold by the nucleus on the
electrons as increased electronegativity. In other words, the higher the s character of the
hybrid orbitals, the higher the electronegativity of the atom.30 The electronegativity of
carbon decreases with hybridization in the order sp > sp2 > sp3. It also means that the
length of the bond decreases (and the covalent radius of the atom decreases) as the hybrid-
ization changes from sp3 to sp2 to sp.31
The most efficient overlap of the hybrid orbital always occurs through the front lobe,
which makes σ bonds formed from hybrid atomic orbitals highly directional. In addition,
the hybridization model results in the σ bonds that a second-row atom forms by using
hybrid orbitals being stronger than those formed by the same atom from unhybridized p
orbitals.32 This means that this model predicts that an atom will form its strongest and
most directional σ bonds when it uses hybrid atomic orbitals to form them.¶ It is also
30. (a) Sanderson, R.T. J. Am. Chem. Soc. 1983, 105, 2259; J. Chem. Educ. 1988, 65, 112, 223. (b) Walsh, A.D.
Disc. Faraday Soc. 1947, 2, 18.
31. (a) Allen, F.H.; Kennard, O.; Watson, D.G.; Brammer, L.; Orpen, A.G.; Taylor, R. J. Chem. Soc, Perkin
Trans. 1 1987, 2, S1-S19. (b) Smith, M.B.; March, J. March’s Advanced Organic Chemistry. Reactions, Mecha-
nisms, and Structure, 5th ed. (Wiley-Interscience, New York, 2001), p. 20. (c) Pauling, L. The Nature of the
Chemical Bond, 3rd ed. (Cornell University Press: Ithaca, 1960), p. 224.
32. Pauling, L.; Sherman, J. J. Am. Chem. Soc. 1937, 59, 1450.
¶. Hybridization and Molecular Orbital Formation
Hybrid orbitals are formed by the combination of atomic orbitals of the same atom. Mathematically, the
process involves the linear combinations of atomic wave functions below. The process leads to degenerate or-
bitals whose orientation is determined by the coefficients of the p wave functions used in the hybridization
process. X, y, and z represent the px, py, and pz wave functions.
sp sp2 sp3
fa=(1/√2)[s + x] fa=(1/√3)[s + (√2)y] fa=(1/2)[s + x + y + z]
fa=(1/√2)[s + x] fb=(1/√3)[s + (1/√2)x – (√6/2)y] fb=(1/2)[s – x – y + z]
unchanged: y, z fc=(1/√3)[s – (1/√2)x – (√6/2)y] fc=(1/2)[s + x – y – z]
unchanged: z fd (1/2)[s – x + y – z]
unchanged: none

generally observed that lone pairs on second-row elements tend to occupy hybrid atomic
orbitals in preference to unhybridized atomic orbitals unless the atom adjacent to the atom
carrying the lone pair is sp2 or sp hybridized.
When one compares the strength of σ bonds formed from hybrid orbitals, the stron-
gest bonds are formed from sp hybrid orbitals and the weakest from sp3 hybrid orbitals.
The relative strengths of σ bonds can be related to the s character of the hybrid orbitals
used to form them. As the s character of the hybrid atomic orbitals used to form them in-
creases, σ bonds become stronger.33 In contrast to the σ bond case, the π-type overlap of
hybrid atomic orbitals to form π and π* molecular orbitals is seldom observed. Thus, all
π bonds in a molecule are formed from unhybridized p orbitals.
Some important generalizations about hybrid atomic orbitals and molecular orbitals
(covalent bonds) hold true for most organic molecules.
1. All σ bonds to carbon in organic compounds are formed from hybrid atomic orbitals,
π bonds are formed from unhybridized p orbitals, and lone pairs usually occupy hybrid
orbitals.
2. Every atom of a molecule is involved in at least one σ bond.
3. Atoms in a molecule will form the fewest σ bonds consistent with rule 2.
4. The strongest σ bonds are formed from hybrid atomic orbitals with the highest possible
s character.
5. All multiple bonds are formed from a single σ bond, with one or more π bonds.
6. The shape of a molecule is determined only by the σ bonding framework only; π bonds
have no effect on molecular shape.
The τ Bond Model of Multiple Bonds: Variable Hybridization

Multiple bonds in organic compounds can be described in two ways, the σ/π description,
which is the one that will be used in this book, and the t bond system,34 which is actually
older and in which the bonds between the carbon atoms are “bent” bonds. This descrip-
tion of bonding has been used very effectively to rationalize the bonding in cyclopro-
panes,35 where the electron density of the σ bonds is found outside the internuclear axis of
the ring, and it has been shown to work just as well as the σ/π model.36
The wave functions of the molecular methane generated from hybrid wave functions are of the simplified
form:
c σ = (1/√2)(fH + f C) c σ* = (1/√2)(fH – f C)
where f C is the wave function of a carbon hybrid atomic orbital, and fH is the wave function of a hydrogen 1s
orbital.
This can be expanded to (e.g., fx is the carbon 2px wave function):
c σa = 1/(2√2)[2fH + fs + fx + fy + fz] c σ*a = 1/(2√2)[2fH – fs – fx – fy – fz]
c σb = 1/(2√2)[2fH + fs – fx – fy + fz] c σ*b = 1/(2√2)[2fH – fs + fx + fy – fz]
c σc = 1/(2√2)[2fH + fs + fx – fy – fz] c σ*c = 1/(2√2)[2fH – fs – fx + fy + fz]
c σd = 1/(2√2)[2fH + fs – fx + fy – fz] c σ*d = 1/(2√2)[2fH – fs + fx – fy + fz]
33. (a) Pauling, L. Proc. Natl. Acad. Sci. 1949, 35, 229. (b) Walsh, A.D. Trans. Faraday Soc. 1947, 43, 60. (c)
Mulliken, R.S. J. Am. Chem. Soc. 1955, 72, 4493; J. Chem. Phys. 1951, 19, 900. (d) Coulson, C.A. Valence (Oxford
Press/Clarendon Press: London, 1952), p. 198.
34. (a) Wintner, C.E. J. Chem. Educ. 1987, 64, 587, and references therein. (b) Palke, W.E. J. Am. Chem. Soc.
1986, 108, 6543. (c) Carroll, F.A. Perspectives in Structure and Mechanism in Organic Chemistry (Brooks/Cole:
Pacific Grove, 1998), p. 47.
35. (a) Coulson, C.A.; Moffitt, W.E. J. Chem. Phys. 1947, 15, 151; Phil. Mag. 1949, 40, 1. (b) Walsh, A.D. Trans.
Faraday Soc., 1949, 45, 179. (c) Hamilton, J.G.; Palke, W.E. J. Am. Chem. Soc. 1993, 115, 4159. (d) de Meijer, A.
Angew. Chem. Int. Ed. Engl. 1979, 18, 809. (e) Wiberg, K.B. In Rappoport, Z., Ed. The Chemistry of the Cyclopro-
pyl Group (John Wiley: New York, 1987), ch. 1. (f) Rozsondai, B. In Rappoport, Z., Ed. The Chemistry of the
Cyclopropyl Group (John Wiley: New York, 1995), vol. 2, ch. 3.
36. Schultz, P.A.; Messmer, R.P. J. Am. Chem. Soc. 1988, 110, 8258; 1993, 115, 10925, 10943.

In the original form of this system, the hybridization of the two carbon atoms at each
end of a multiple bond remains at sp3, with the multiple bonds formed by noncolinear
overlap of two pairs of sp3 hybrid orbitals. The molecular geometry predicted by this
model may be improved by introducing the concept of variable hybridization,37 which
allows hybrid orbitals to have varying degrees of s and p character (i.e., a variable hybrid-
ization index).¶ For example, increasing the p character of the hybrid orbitals used to
form the C—C bonds in cyclopropane allows the smaller (60°) bond angles to be
accommodated.
Problems
4-3 The angle between two hybrid orbitals on the same atom cannot be less than 90°.
Why?
4-4 What type of orbital carries the lone pairs in each of the following anions? Give
your reasoning.
CH2 CH2CH2
(a) (b) (c)

4-5 Describe the bonding in the following ions in terms of the hybridization of the
atoms involved.
CH2 CN
(a) C=CH2 (b) (c) HC (d)

Extended p Systems: Delocalized p Orbitals of Aliphatic Compounds

LCAO molecular orbitals that are confined to two adjacent nuclei are localized molec-
ular orbitals. However, when there are more than two sp2 or sp hybridized atoms adja-
cent to each other, the potential exists for the formation of delocalized π orbitals,
37. For a useful discussion of variable hybridization, see: Carroll, F.A. Perspectives in Structure and
Mechanism in Organic Chemistry (Brooks/Cole: Pacific Grove, 1998), pp. 38-45.
¶. Variable Hybridization
The concept of variable hybridization can also be discussed in terms of a coefficient of mixing, λ, where
λ 5 m for an spm orbital. The angle between spm and spn hybrid orbitals, α, is related to the values of λ by the
following expression,a where m=√n:
1 + λm cos α = 0, or cos α = –1/λm
When the two hybrid orbitals are equivalent, this expression simplifies to
1 + λ2 cos α = 0, or cos α = –1/λ2, or cos α = –1/m
Based on the H—C—H bond angle in cyclopropane as 115.1°,b the carbon atom uses sp2.36 hybrids for the
C—H bonds. If one s orbital and n p orbitals are used in to obtain n + 1 hybrid orbitals about an atom, the hy-
bridization indices of hybrid orbitals around that atom must obey the two relationships below:
1 λ2
∑1 + λ2 = 1 and ∑ 1 + iλ 2 =n
i i i i
This now allows us to calculate the hybrid orbitals used for forming the C—C bonds of the cyclopropane
ring; the result is that sp4.92 hybrids are used, which predicts an angle between the hybrid orbitals of 101.7°. A
similar variable hybridization model of the carbon atoms in ethylenec leads to the t orbitals being formed from
sp5 hybrid orbitals oriented at 101.5° to each other.
a
For the derivation of this equation, see: Coulson, C.A. Valence (Oxford/Clarendon Press; London, 1952), p. 193.
b
Bastiansen, O.; Fritsch, F.N.; Hedberg, K. Acta Crystallogr. 1964, 17, 538.
c
Liberles, A. Introduction to Theoretical Organic Chemistry (Macmillan: New York, 1968), p. 181.


tions of p orbitals to generate
the π molecular orbitals of
the isolated allyl system. The
π molecular orbitals
ψ1 ψ2 ψ3 of the isolated allyl system.
Orbital energies increase
with the number of internu-
clear nodes (from left to
right).
where each orbital of the π system encompasses more than two nuclei. Excellent exam-
ples of this are provided by an isolated allyl system, which we used as an example for
our review of resonance theory, and by 1,3-butadiene, the prototypical conjugated
diene. In an isolated allyl group, all three carbon atoms are sp2 hybridized, with a
single unhybridized p orbital at each position. Side-by-side overlap of these three orbit-
als will give three new π orbitals (c1, c2, and c 3), each of which encompasses all three
nuclei (Figure 4.10).
1,3-Butadiene is a typical conjugated diene. The four carbon atoms are all sp2 hybrid-
ized, so that each has one unhybridized p orbital to use in the formation of the π orbital
system. Overlap of these four atomic orbitals (“basis orbitals”) must give four molecular
orbitals, and we designate these orbitals as c1, c2, c3, and c4, in order of increasing energy
(Table 4.1).
The simplest rules for combining p basis orbitals into delocalized π molecular orbitals
were formulated by Hückel in 1931.38 In this method, the energies of the orbitals are ex-
pressed in terms of two variables, α and β, where α represents the Coulomb integral, a
measure of how tightly the electron is bound to the nuclei of the atoms (and which has the
same value for all atoms of a particular element), and β represents the resonance integral,
a measure of the electron energy in the molecular orbital relative to the electron in the
isolated atoms. Both α and β are negative because they identify a stabilizing energy. The
rules themselves are quite simple for open-chain systems.
1. The number of delocalized π orbitals is equal to the number of p atomic orbitals (con-
tributing p basis orbitals) used to make them.
2. Unless the π bonding system is cyclic and delocalized, there are no degenerate orbitals.
3. The lowest energy orbital has no internuclear nodes (i.e., all π-type overlap of the con-
tributing p basis orbitals is bonding in character). The highest energy orbital has an
internuclear node between every adjacent pair of atoms (i.e., all, π-type overlap of the
contributing p basis orbitals is antibonding in character).
4. Each orbital has one more internuclear node than the orbital immediately below it in
terms of energy.
5. All nodes are distributed as symmetrically as possible between the nuclei of the π system.
6. Where there is more than one way to distribute nodes in accordance with rule 4, bond-
ing overlap is concentrated in the middle of the system.
38. (a) Hückel, E. Z. Phys. 1931, 70, 204; 1931, 72, 310; 1932, 76, 628; 1933, 83, 632; Trans. Faraday Soc. 1934, 30,
40. (b) Isaacs, N.S. Physical Organic Chemistry (Longman Scientific & Technical: London, 1987), §1.2, pp. 3-24.
(c) Carey, F.A.; Sundberg, R.D. Advanced Organic Chemistry. Part A: Structure and Mechanisms, 4th ed.
(Kluwer Academic/Plenum Publishers: New York, 2000), §1.4, pp. 31-36.

Table 4.1 Overlap of p Basis Orbitals in 1,3-Butadiene
Orbital p Orbital Overlap π Molecular Orbital Orbital Energy (eV)

c4 +2.05
c3 +0.22
c2 –9.56
c1 –12.29
Implicit in the forgoing discussion about the formation of molecular orbitals from
atomic orbitals, is an observation seldom stated explicitly.
For every bonding orbital, there is a corresponding antibonding orbital.
This also leads to another definition of a covalent bond.
A covalent bond encompasses two or more nuclei, and it consists of an occupied bonding or-
bital and an unoccupied antibonding orbital.
The application of these rules to conjugated systems larger than 1,3-butadiene can be
seen in Table 4.2, which contains the five π molecular orbitals for the 2,4-pentadienyl
cation and the six π molecular orbitals of 1,3,5-hexatriene. Careful examination of the
hexatriene orbitals shown in Table 4.2 shows that the six 2p basis orbitals do not contribute
equally to each of the six π orbitals; instead, the orbital coefficients at the individual
atoms change from one π orbital to the next. The orbital coefficients of the π orbitals of
1,3,5-hexatriene, as calculated using simplified Hückel molecular orbital theory, are given
in Table 4.3 (and used in Table 4.2). These coefficients give a reasonable approximation to
the appearance of the orbital, although not anywhere close to the high level of precision
available from modern computer programs. Still, as qualitative estimates, they are more
than adequate for most purposes.
EVEN ODD
antibonding
antibonding
non-bonding
bonding
bonding

Table 4.2 π Molecular Orbitals of 2,4-Pentadienyl Cation and 1,3,5-Hexatriene
2,4-Pentadienyl Cation 1,3,5-Hexatriene
Orbital p Basis Orbital π Molecular p Basis Orbital π Molecular Orbital

Overlap* Orbital Overlap*
ψ6
ψ5
ψ4
ψ3
ψ2
ψ1
*The basis p orbitals have been drawn to reflect their relative coefficients in the molecular orbital. They are not
drawn to scale.
Table 4.3 Hückel Orbital Coefficients of the π Orbitals of 1,3,5-Hexatriene
ϕ1 ϕ2 ϕ3 ϕ4 ϕ5 ϕ6
ψ1 0.232 0.418 0.521 0.521 0.418 0.232
ψ2 0.418 0.521 0.232 –0.232 –0.521 –0.418
ψ3 0.521 0.232 –0.418 –0. 418 0. 232 0. 521
ψ4 0.521 –0.232 –0. 418 0. 418 0. 232 –0. 521
ψ5 0.418 –0. 521 0. 232 0. 232 –0. 521 0. 418
ψ6 0.232 –0. 418 0. 521 –0. 521 0. 418 –0. 232
In extended open-chain (but not conjugated cyclic) π orbital systems, when there are
an even number of orbitals, there will be equal numbers of bonding and antibonding or-
bitals, and when the π system contains an odd number of orbitals, the extra orbital occu-
pies the middle position in energetic terms (e.g., ψ2 of the allyl system) and is a nonbonding
orbital. This is illustrated here for two typical conjugated systems: the 1,3,5-hexatriene and

2,4,6-heptatrienyl systems. The mathematics of calculating Hückel molecular orbital coef-

ficients is shown below.¶
Bond Orders and Occupancy of Molecular Orbitals

The definition of a covalent bond given above also provides a convenient way to assign
bond orders to bonds in a molecule. This is accomplished quite simply by adding the
number of electrons in bonding orbitals between two atoms in a molecule and subtracting
the number of electrons in antibonding orbitals between the same atoms. The bond order
of the bond is one half of the total. Because the strength of a bond is directly related to its
bond order, this is an important parameter of bonding to be able to predict.
Benzene and Aromaticity

The obvious next problem to address using molecular orbital theory is that of the struc-
ture of benzene and the electronic nature of aromaticity. The pursuit of the answer to this
question has been long and arduous. The fact that it is not yet over is attested to by the fact
that is still holds a fascination for organic chemists (especially computational organic
chemists) even today39—almost two centuries since the discovery of benzene itself.40 We
will discuss aromaticity and the electronic structure of aromatic compounds in Chapter 7.
¶. Hückel Molecular Orbital Theory

In this theory, the energies of the π molecular orbitals are related to α, the Coulomb integral (a measure of
how tightly the electron is bound to the nuclei of the atoms—and which has the same value for all atoms of a
particular element), and β, the resonance integral (a measure of the electron energy in the molecular orbital
relative to the electron in the isolated atoms).
Hückel’s major simplification of molecular orbital theory was to refer the energies of orbitals to α and to
make the rather important assumption that β was zero for all nonadjacent atoms of a molecule. This is a diffi-
cult assumption to justify in these days of fast computers, but it was an important simplification when all the
mathematics had to be done by hand. This leads to the following secular determinant, which can be further
simplified as shown by dividing the entire matrix by β to give the alternative form, where x = (α–E)/β (the
example is for a 2,4-pentadien-1-yl system):
α−E β 0 0 0 x 1 0 0 0
β α−E β 0 0 1 x 1 0 0
0 β α−E β 0 =0 ⇒ 0 1 x 1 0 =0
0 0 β α−E β 0 0 1 x 1
0 0 0 β α−E 0 0 0 1 x
The solution of this secular determinant gives the coefficients of the π orbitals. For acyclic, conjugated sys-
tems, the solutions are all of the form:
 2 
ψ j = ∑ Cr ,j φr and Cr ,j 5   sin[rjπ ( N 1 1 )]
 N 11 
where N is the number of atoms in the conjugated system (e.g., 4 for butadiene, 5 for pentadienyl, 6 for hex-
atriene), r designates the location of the contributing atomic 2p basis orbital within the conjugated system (i.e.,
which atom along the conjugated chain: 1, 2, 3, or 4 for butadiene; 1, 2, 3, 4, or 5 for pentadienyl), and j designates
which π molecular orbital of the set of delocalized π orbitals is under study (e.g., ψ1, ψ2, ψ3). Using this theory,
one may also calculate the approximate energy of the orbital:
jπ
E = α + 2β cos
N +1
39. There is a huge volume of literature on the subject of aromaticity: see, for example, the recent special
issues of Chem. Rev.: Chem. Rev. 2001, 101 (5) and Chem. Rev. 2005, 105 (7).
40. Faraday, M. Phil. Trans. Roy. Soc. London 1825, 115, 440.

Bonds Involving Third-Row and Higher Row Elements

The s atomic orbitals of atoms in the third and higher rows of the periodic table have (n−1)
spherical nodes at finite distances from the nucleus, and the p atomic orbitals of the third
and higher rows of the periodic table have (n−2) spherical nodes at finite distances from
the nucleus in addition to the planar node through the nucleus. This has the effect of re-
ducing the efficiency of (especially π) overlap between these elements and elements in the
second row. In fact, the most efficient overlap of atomic orbitals to form molecular orbitals
usually occurs when both elements are in the same row of the periodic table (hydrogen
being the one exception to this rule). We can see this nicely if we examine the π overlap
between the 2p orbital on carbon and the 2 p orbital on oxygen or the 3p orbital on sulfur.
S 3p
C 2p C 2p
O 2p
As is evident from the diagram at right, the overlap between the 2p orbitals of carbon and
oxygen is in phase at all points, and this should result in a low-energy bonding molecular or-
bital. In contrast, there are areas where the overlap between the 2p and 3p orbitals are in
phase, and other areas where the overlap is out of phase (i.e., antibonding in character). Thus,
we expect that this π bond will be weaker, and it is (the C=O bonds in CO2 have dissociation
energies of 192 kcal mol–1; the C=S bonds of CS2 have dissociation energies of 138 kcal mol–1).
Problems
4-6 Sketch the π molecular orbitals of 1,3,5,7-octatetraene, paying particular atten-

tion to the phases of the overlap of the p basis orbitals contributing to each
π molecular orbital and the locations of nodal planes.
4-7 It is frequently important to characterize the π orbitals in terms of their symme-
try with respect to simple symmetry elements. Symmetric orbitals are those
whose lobes have phases that are symmetric with respect to the symmetry
element (e.g., the π molecular orbital of ethylene is symmetric with respect to the
mirror plane of symmetry perpendicular to the σ plane). Antisymmetric orbitals
undergo a phase change on application of the symmetry element (e.g., the π*
orbital of ethylene is antisymmetric with respect to the same mirror plane).
Characterize each of the π orbitals of (a) 1,3,5-hexatriene and (b) the
2,4-pentadienyl radical as either symmetric or antisymmetric with respect to
(1) a C2 axis of rotation, and (2) a mirror plane of symmetry perpendicular to the
σ plane through the center of the molecule. Does a pattern emerge?
4-8 Consider the nonbonding π molecular orbitals of the allyl 2,4-pentadienyl,
2,4,6-heptatrienyl and 2,4,6,8-nonatetraenyl systems. What general feature is
common to all these orbitals?
Chapter Summary
The modern orbital model of the atom describes the electrons around the nucleus of an
atom as three-dimensional standing waves. This wave is characterized by three quantum

numbers—n, the principal quantum number (electron shell); l, the azimuthal quantum
number (electron subshell); and ml, the magnetic quantum number (orbital within a
subshell)—defining each orbital. Orbitals may be described using only their quantum
numbers, but chemists generally defer to using the terms s (l = 0), p (l = 1), d (l = 2), and
f ( l= 3) to describe the subshells of the electron shell. s Orbitals are spherically symmetri-
cal; p orbitals have one planar node, with all other nodal surfaces being spherical; and four
of the five d orbitals have two planar nodes, with the rest being spherical. The Pauli Exclu-
sion principle limits the occupancy of any orbital to two electrons, the Aufbau principle
dictates that the lowest-energy orbitals are filled first, and Hund’s rule states that when
electrons are distributed into degenerate orbitals, the number of unpaired electrons should
be maximized.
Molecular orbitals are generated by overlap of atomic orbitals in a coaxial (σ) or copla-
nar (π) fashion; mathematically, this process involves the LCAO. Every σ bonding orbital
has a corresponding σ* antibonding orbital, and every π bonding orbital has a corre-
sponding π* antibonding orbital. The LCAO model requires that the number of molecular
orbitals formed must be equal to the number of atomic orbitals used to generate them. The
geometry of most organic compounds can be addressed by using the hybridization model
of the atom; hybrids orbitals of carbon are sp (linear), sp2 (trigonal planar), and sp3 (tetra-
hedral). Bond angles other than the idealized values for these hybrid orbitals may be
accommodated by means of variable hybridization. Extended π-bonding systems may be
modeled using Hückel molecular orbital theory, which allows a qualitative (or simplified,
semiquantitative) description of the molecular orbitals to be obtained.
Key Terms
atomic orbital LCAO magnetic quantum
s orbitals molecular orbital number, ml
p orbitals σ orbitals spin quantum
d orbitals π orbitals number, ms
Aufbau principle node
Hund’s rule Pauli Exclusion principle
Hückel theory quantum numbers
hybrid atomic orbitals principal quantum
sp hybrid orbitals number, n
sp2 hybrid orbitals azimuthal quantum
sp3 hybrid orbitals number, l
Additional Problems
4-9 The favored conformation of the ester functional group is as shown below.
S uggest a reason why this conformation should be the favored one in the ester,
based on considerations of the molecular orbitals involved. (Hint: Is it easier to
delocalize electron density from the lone pairs on oxygen into the π* orbital of
the carbonyl group in one conformation than in the other? What effect would
this electron delocalization have?)
O
O
R R O
R O
R
4-10 Use similar arguments to those used in Problem 4-9 to suggest why the eclipsed
conformation of ethane should be higher in energy than the staggered
conformation.

4-11 (a) The simplified Hückel molecular orbital analysis of the benzene molecule re-
turns the result that the six π orbitals of benzene are all completely delocalized over
all six atoms of the molecule. In the lowest energy π orbital, there are no nodes per-
pendicular to the plane of the ring. The next two π orbitals are degenerate (equal
energy), and each has a single nodal plane perpendicular to the ring. The next two
orbitals are also degenerate, and each has two nodal planes perpendicular to the
ring. The highest energy π orbital has three nodal planes perpendicular to the ring.
Draw the hexagonal ring of the benzene molecule (e.g., the highest energy π orbital
is shown at right) and show the phases of the p basis orbitals in each of the six π
orbitals with the location of each of their nodal planes indicated by straight lines.
(b) Designate each of these π orbitals as symmetric (S) or antisymmetric (A) with
respect to (i) a mirror plane of symmetry perpendicular to the plane of the ring and
(ii) a C2 axis of symmetry through the plane of the ring of the benzene molecule.
4-12 The same pattern that occurs in the nonbonding orbital of odd-number open-
chain compounds also occurs in certain cyclic compounds with conjugated CH2
π-bonding systems (“alternant” systems) as well. Referring to the answer to
Problem 4-8 above, sketch the nonbonding orbital (ψ4) of the benzyl cation (at
left). How does this molecular orbital correlate with the reactivity of the cation?
4-13 The preferred conformation of 1,2-difluoropropane is the one in which the two F
fluorine atoms are gauche to each other and in which the methyl group is anti to H F
one of the fluorine atoms. This staggered conformation places the two fluorine
atoms as close together as possible while retaining the staggered arrangement of
H H
σ bonds. Provide a reasonable explanation for why this should be the preferred
conformation. Me
4-14 The complete set of molecular orbitals formed from the atomic orbitals of the va-
lence shells of two oxygen atoms to give an oxygen molecule is shown below.
What is the bond order in the oxygen molecule? What other noteworthy feature
of the oxygen molecule is revealed by this orbital diagram?
σ∗ (px)
π∗
2p 2p
π
σ (px)
σ∗ (s)
2s 2s
σ (s)
oxygen atom oxygen atom
oxygen molecule
The nitric oxide (NO) and carbon monoxide (CO) molecules have the same set of
molecular orbitals with the same sequence of energies. What is the bond order in
these molecules, and are there any noteworthy features of these molecules re-
vealed by the orbital diagrams?
4-15 Oxygen-centered free radicals fragment according to the scheme below. What
does this reaction tell about the stabilities of the radicals and the bond energies of
the products?
O O O O
+ R• C + R•
R R R R O R
R O

4-16 Terminal alkynes are much stronger acids than any other type of hydrocarbon.
Allylic hydrogens and benzylic hydrogens, also, tend to be much more easily re-
moved by strong bases than similar hydrogens in saturated hydrocarbons. Sug-
gest an explanation for these observations.
4-17 The H—C—H angle in cyclopropane is 114.97°, the C—H bond length is 1.0786Å,
and the C—C bond distance is 1.5030Å. The corresponding values for ethane are
1.094Å for the C—H bond and 1.537Å for the C—C bond. Do these values tend to
support or provide support against the theory of variable hybridization? How?
4-18 Theoretical calculations show that the ions −CH2OH and −CH2NH2 cannot be
i solated even in the gas phase but that they are unstable with respect to electron
loss (i.e., the corresponding radicals have a positive electron affinity). The anion
−
CH2SH is detectable in the gas phase, which means that the corresponding
radical has a negative electron affinity. Explain these observations using molecu-
lar orbital and/or valence bond arguments.
4-19 The α effect is the name given to the observation that nucleophiles where the
ucleophilic atom is directly bonded to another atom carrying a lone pair (e.g.,
n
hydrazine, H2NNH2, and hydroxylamine, HONH2) are much stronger nucleop-
hiles than their structural analogs that do not have this structural feature (e.g.,
methylamine, H3CNH2), even though they tend to be weaker bases. Give a rea-
soned explanation for why this might be so.
4-20 The antineoplastic compounds calicheamicin and esperamicin both undergo the
Bergman cyclization to give a diradical after they are activated by nucleophilic
attack. Why is the nucleophilic attack necessary for the Bergman cyclization to
occur in these molecules?
O CO2Me O CO2Me O CO2Me

NH NH NH
HO HO HO
H H S H S
O O O
sugar sugar sugar
S
MeS S
Rb H H Ra
Nu
DNA damage Rb Ra
calicheamicin
O CO2Me
esperamicin
NH
HO
H S
O
sugar

Chapter five
Frontier Orbitals and Chemical Reactions
5.1 Chemical Reactions: Frontier Orbitals
Now that we have discussed the bonding and molecular orbitals in individual molecules
and other entities, it is time to examine how the molecular orbitals in the reacting species
participate in a reaction to become those of the species produced.
Ultimately, all chemistry can be reduced to a question of the formation and cleavage of
chemical bonds during chemical reactions. One of the major successes of the Lewis theory
of bonding was the way in which it provided a clear qualitative picture of the bonding in
chemical compounds, so that the bonding changes occurring during chemical reactions
could be rationalized. In order for molecular orbital theory to be equally useful, it must be
capable of doing at least what Lewis theory was able to accomplish, and we are probably
justified in expecting more. Fortunately, molecular orbital theory does allow us to ratio-
nalize reactions that cannot be explained at all using Lewis theory alone.
The heart and soul of organic chemistry is how molecular orbitals in different mole-
cules (or different parts of the same molecule) interact and how electrons reorganize
themselves during chemical reactions. This is the reason why we have spent as much time
as we have reviewing molecular orbital theory. Let us begin by restating an extremely im-
portant fundamental principle.
The Pauli Exclusion principle applies to molecules as well as to atoms and absolutely forbids
placing an electron into any orbital already containing two electrons.
This means that any time electrons move from one molecule to another, they must
move from an occupied orbital on the first molecule into an empty orbital of the second. If
this electron reorganization is to result in the formation of a new covalent bond between
atoms in two different molecules, electrons from one molecule must move into a position
where they can be shared by the two nuclei between which the new bond is going to be
formed. Because all the electrons of a molecule are in orbitals, one must overlap orbitals
on both molecules for the reaction to occur. Thus, the Pauli Exclusion principle becomes
the first principle of chemical reactions.
Chemical reactions can only be initiated by overlapping a filled or half-filled (occupied)

orbital on one reactant with an empty (unoccupied) orbital on the other.
Having decided that the initiation of a chemical reaction involves the overlap of an
empty orbital with a filled orbital, we must now answer the key question—which unoccu-
pied orbital and which occupied orbital. Clearly, the reaction will proceed most readily if
the two orbitals are closely matched in energy. The filled orbitals in most molecules are
either bonding orbitals containing bonding electron pairs or nonbonding orbitals contain-
ing lone pairs. The unoccupied orbitals are either antibonding orbitals or empty atomic
orbitals. The Aufbau principle demands that the unoccupied orbitals of a molecule or ion
129

130 Advanced Organic Chemistry | Chapter five
are always at higher energy than its occupied orbitals. Therefore, the two orbitals closest to
each other in energy will be the highest energy occupied molecular orbital (HOMO), on
one reactant, and the lowest energy unoccupied molecular orbital (LUMO), on the other.
These orbitals are called the frontier orbitals of the reacting molecules, and it is the frontier
orbitals that actually govern much of the reactivity of organic compounds.
Since their emergence in the mid-1960s,1 the concepts of frontier orbitals and the conserva-
tion of orbital symmetry2 have revolutionized the way in which organic chemists look at reac-
tions, and we will cast many of our discussions of chemical reactivity in terms of the frontier
orbital concepts. As with any theory, the conservation of orbital symmetry has limitations,
especially when used to predict the outcomes of reactions of excited state reactions. Neverthe-
less, the value of the theory has been shown by half a century of successful application.
By knowing the shapes and relative energies of the orbitals involved in most organic
reactions, one can actually predict much of the reactivity of organic molecules. As implied
in our earlier discussions, π bonds are usually weaker than σ bonds (i.e., the π orbital is
usually higher in energy than the σ orbital, and the π* orbital is usually lower in energy
than the σ* orbital). Therefore, the energies of frontier molecular orbitals (FMOs), which
have important consequences for reactivity of organic compounds, generally increase in
the order (worth the effort of committing to memory):
σ < π < n < π* < σ*
With the exception of the hydrogen cation, H+, which has no electrons at all and
cannot therefore have a HOMO, all molecules and ions have both a HOMO and a LUMO.
In principle, therefore, there are always two possible HOMO-LUMO combinations for
reactions in which H+ is not a participant. Fortunately, one of these combinations is usu-
ally obviously right, and the other is usually obviously wrong. We can best illustrate the
concept of HOMO and LUMO by looking at some examples. Let us begin with the three
different reactive intermediate species with the molecular formula CH3: the methyl cation,
CH3+, the methyl radical, CH3•, and the methyl anion, CH3−.
Before we begin, a caveat must be sounded; much of the discussion below is at a rather
simplistic level, but this allows us to use it in the context of much more complicated examples
without the need for recourse to a computer. Of course, if higher levels of rigor are needed,
then one must go to the computer. However, provided that one understands the limitations of
the theory one is using, one can usually obtain reliable results without doing so.
We will begin with the methyl cation. The Lewis structure of this cation, as well as its
orbital energy level diagram and electron configuration, and its frontier orbitals are given
in Figure 5.1. There are six valence electrons in this cation, which means that the valence
electrons are all used in the formation of the three C–H σ bonds and that the central
carbon atom carries a formal positive charge.
There are only three σ bonds about the central carbon atom, the central carbon atom is sp2
hybridized: the cation is trigonal planar in shape. The remaining orbital on the central carbon
atom is the 2p orbital not used in the formation of the sp2 hybrid orbitals, and it is empty. We
can think of the HOMO simplistically as a carbon-hydrogen σ orbital, but the HOMO is actu-
ally a linear combination of all three C–H σ orbitals; the LUMO is fairly well approximated by
1. (a) Woodward, R.B.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87, 395; The Conservation of Orbital Symmetry
(Verlag Chemie/Academic Press: Weinheim, 1971)—this book is a stand-alone reprint of Angew. Chem.Int. Ed.
Engl. 1969, 8, 781. (b) Hoffmann, R.; Woodward, R.B. Acc. Chem. Res. 1968, 1, 17. (c) Fukui, K.; Fujimoto, H.
Bull. Chem. Soc. Jpn. 1967, 40, 2018; 1969, 42, 3399. (d) Fukui, K. Fortschr. Chem Forsch. 1970, 15, 1; Acc. Chem.
Res. 1971, 4, 57; Angew. Chem. Int. Ed. Engl. 1981, 21, 801. (e) Longuet-Higgins, H.C.; Abrahamson, E.W. J. Am.
Chem. Soc. 1965, 87, 2045.
2. (a) Fleming, I. Frontier Orbitals and Organic Chemical Reactions (Wiley-Interscience: New York, 1976).
(b) Gilchrist, T.L.; Storr, R.C. Organic Reactions and Orbital Symmetry, 2nd ed. (Cambridge University Press:
Cambridge, 1979). (c) Lehr, R.E.; Marchand, A.P. Orbital Symmetry (Academic Press: New York, 1970).
(e) Pearson, R.G. J. Chem. Educ. 1981, 58, 753.

Frontier Orbitals and Chemical Reactions 131
Figure 5.1 The orbital energy

σ∗ σ∗ σ∗
HOMO level diagram for the methyl
cation. The highest energy
occupied molecular orbital
(HOMO) is one of the
Energy
H n (LUMO) H
H carbon-hydrogen σ orbitals,
C H and the lowest energy unoc-
H H
cupied molecular orbital
LUMO (LUMO) is the empty p
σ σ σ orbital not used in forming
(HOMO) the sp2 hybrid orbitals of the
central carbon atom.

(LUMO) level diagram and the fron-
σ∗ σ∗ σ∗ LUMO tier molecular orbitals of the
methyl free radical. HOMO,
highest energy occupied mo-
H
H lecular orbital; LUMO,
Energy
C n (HOMO) H lowest energy unoccupied

H H H
molecular orbital.
HOMO
σ σ σ
the 2p orbital on the carbon. This means that that the LUMO of the cation is an empty p orbital.
Although it is unoccupied, because this orbital is neither bonding nor antibonding, it must be
a nonbonding orbital: not all nonbonding orbitals are occupied. Often in this book, we will use
the symbol a to denote an unoccupied nonbonding molecular orbital.
The methyl free radical has the formula CH3•, and therefore it has just one electron
more than the methyl cation for a total of seven valence electrons. Its Lewis structure,
orbital energy level diagram and electron configuration, and its FMOs are given in
Figure 5.2. These may be compared with those of the cation.

In the free radical, the unpaired (nonbonding) electron is in the fourth valence orbital
of the central carbon atom. However, whether this odd electron is in an unhybridized p
orbital or an sp3 hybrid orbital depends on several factors, and examples of free radicals of
both structural types are known. The methyl radical itself is planar. The HOMO of the
methyl radical is the p orbital containing the unpaired electron, whereas the LUMO of the
methyl radical is a C–H σ* antibonding orbital. Because the HOMO of every free radical
is occupied by only one electron instead of two, it is called the singly occupied molecular
orbital (SOMO).
The third case that we will examine here is the case of the methyl anion, CH3−, whose
Lewis structure, orbital energy level diagram and electron configuration, and FMOs are
given in Figure 5.3. This anion has one more electron than the free radical, and so it has
eight valence electrons and a formal negative charge on the central carbon atom. The va-
lence electrons are distributed as three C–H σ bonds and one lone pair. To accommodate
this arrangement of valence electrons, the central carbon atom requires four hybrid orbit-
als (one for each σ bond and one for the lone pair), and must therefore be sp3 hybridized.
The anion therefore, has a trigonal pyramidal shape, just like the ammonia molecule. The
HOMO of the methyl anion is the (nonbonding) sp3 hybrid orbital containing the lone
pair of electrons, whereas the LUMO is a C–H σ* antibonding orbital (or, more accurately,
a linear combination of all three C–H σ* orbitals).
The presence of heteroatoms can complicate the picture somewhat because of the dif-
ferent energies of the orbitals involved. There is, however, a general rule of thumb that one
can use to decide what the relative energies of the orbitals will be. In general, the more
polar the bond, the lower the energy of all the orbitals—bonding and antibonding—
associated with it.

level diagram and the fron- (LUMO)
tier molecular orbitals of the σ∗ σ∗ σ∗ HOMO
methyl anion. HOMO, high-
est energy occupied molecu-
H
lar orbital; LUMO, lowest H
Energy
energy unoccupied molecu- C n (HOMO) H

H H
lar orbital. H
LUMO
σ σ σ

Of course, the picture is not really this simple.

From the perspective of the discussion we have just had, the fortunate thing about
methyl cations, anions, and free radicals is that they have only one carbon atom and three
σ bonds. This makes the methyl system a very simple one to analyze, and what we have
done up to now is usually more than sufficient. However, as the systems become more
complex, the level of sophistication that we need to discuss them also rises (although not
to prohibitive heights). Let us look at the corresponding ethyl species. In Table 5.1, the
FMOs of the ethyl cation, the ethyl radical, and the ethyl anion are shown as obtained
from computer calculations at the B3LYP/6-31+G* level. This level of sophistication in
calculations is actually quite low, but it still provides a wealth of qualitative information
that we can use in discussing chemical reactivity.
When we consider the chemistry of the ethyl cation, we know that the electron-
deficient carbon atom dominates its reactivity: it usually behaves as the electrophile in
reactions, which means that the LUMO is by far the more important of its two FMOs.
Likewise, the reactions of the ethyl free radical all involve the unpaired electron, which
makes the SOMO (HOMO) the most important FMO in its reactions. The same analysis
of the predicted reactivity of the ethyl anion, which we know is both a powerful nucleop-
hile and a powerful base, leads to the conclusion that the orbital carrying the lone pair is
going to dominate the reactivity of this species: its reactions involve the HOMO as the
most important frontier orbital.
If we now examine these most important FMOs carefully, a remarkable consistency is
revealed. In every one of these orbitals, not only is the orbital on carbon an important
component of the orbital but also the carbon-hydrogen σ bonds on the adjacent carbon as
well. In other words, hyperconjugation plays an extremely important role in each of these
FMOs. We can generalize this observation to the molecular orbitals of most species with
sp2-hybridized atoms. In almost every one of these species, the C–H σ orbitals on the
carbon atom adjacent to the sp2-hybridized atom are involved in the HOMO or LUMO of
the species. This accounts, for example, for why carbonyl compounds with α hydrogens
Table 5.1 Frontier Orbitals of Ethyl Species, CH3CH2*
Frontier Orbital (CH3CH2+)† (CH3CH2•) (CH3CH2−)
LUMO
HOMO
(SOMO)
†
The actual structure of this ion is bridged, but computations at this low level return orbitals that can be compared
directly with those of the radical and the anion. The highest energy occupied molecular orbital (HOMO) of this cation
does not involve the p orbital on the cation carbon, so the orientation has been changed to show the σ orbitals that
participate in the HOMO.

Figure 5.4 The reactions of

the ethyl cation depend on
the point at which the nucle- Nu Nu
ophile attacks the cation
lowest energy unoccupied
molecular orbital.
H H H Nu
C C H C C H
H H H H
H H H H
C C H Nu H C C Nu
H H H H
Figure 5.5 The reactions

of the ethyl anion depend
on the point at which the
electrophile attacks the
E E
anion highest energy
occupied molecular orbital.
H H H E
C C H C C H
H H H H
H H H H
C C H E H C C E
H H H H
can react with nucleophilic species to give either addition products (nucleophilic addition)
or enolate anions (acid-base reactions), and why carbocations give products of both SN1
substitution and E1 elimination.
Let us now look at the LUMO of the ethyl cation again. Here we see that there are ac-
tually two places for the HOMO, a nucleophile, to overlap effectively with the cation—the
cation carbon and two of the β hydrogens. It is more than a coincidence that these two
positions correspond to the two possible reactions of the ethyl cation with which we are
already familiar (Figure 5.4). Overlap of the cation LUMO with the nucleophile HOMO
at the carbon atom gives us the familiar second step of the SN1 substitution reaction, with
the formation of a new carbon-nucleophile bond. If that overlap is moved to one of the
β-hydrogen atoms, however, we get the second step of the E1 elimination reaction. You

Figure 5.6 p-Overlap
between the filled C—H
H σ orbital and the empty 2p
Energy
p orbital on the carbocation
carbon leads to stabilization
of the cation.
σ
may recall that the SN1 and E1 reactions always compete—now you have a reason why (it
simply depends on exactly where the HOMO-LUMO overlap occurs).
Likewise, when we examine the HOMO of the ethyl anion, we see that the electrophile
may attack at the carbanion carbon or at the β hydrogen (Figure 5.5). In this case, the hy-
drogen atom is transferred as a hydride ion, rather than as a proton. However, in all other
ways this reaction is strictly analogous to the cation case. The transfer of a hydride anion
from a carbanion nucleophile has become a very important synthetic method for the re-
duction of carbonyl compounds.3
Conformational and Stereoelectronic Effects

The interaction of filled orbitals with empty orbitals is not restricted to reactions be-
tween molecules but is also manifested in the overlap between a filled and an empty
orbital on adjacent atoms in a molecule. Just as when atomic orbitals on adjacent atoms
overlap, the product of the overlap of molecular orbitals on adjacent atoms leads to a
change in the respective orbital energies, with the lower energy orbital becoming even
lower in energy and the higher energy orbital becoming higher in energy. The extent
to which the energy of the orbitals involved changes depends on the efficiency of the
overlap.
One major form of this type of overlap is the overlap in carbocations that leads to
stabilization of the cation by hyperconjugation. This type of overlap, and the effect on
the energy of the system, is shown in Figure 5.6. The π-type overlap between the
empty π orbital on carbon and the filled C—H σ orbital on the adjacent carbon has
the effect of lowering the energy of the filled orbital and raising the energy of the
empty orbital. However, because the energy of the carbocation depends only on the
total energy of the electrons in the filled orbitals, this leads to a lowering of the energy
of the cation.
Problem
5-1 A pair of ethyl radicals may react with each other in two different ways. Using the
SOMO above as a working model, predict the products of these two possible
reactions.
Another example of this type of overlap, between a filled orbital on one atom and an
empty orbital on the adjacent atom, is provided by the ethane molecule. When one carries
out high-level calculations on the conformers of ethane, one finds that not only does the
3. For reviews on the reduction of ketones by hydride transfer from trialkylboranes, for example: (a) Srebnik,
M.; Ramachandran, P.V. Aldrichimica Acta 1987, 20, 9. (b) Dhar, R.K. Aldrichimica Acta 1994, 27, 43. (c) Cho,
B.T. Aldrichimica Acta 2002, 35, 3. (d) Midland, M.M. Chem. Rev. 1989, 89, 1553. (e) Midland, M.M.; Greer, S.;
Tramontano, A.; Zderic, S.A. J. Am. Chem. Soc. 1979, 101, 2352. (f) Midland, M.M.; McDowell, D.C.; Hatch,
R.L.; Tramontano, A. J. Am. Chem. Soc. 1980, 102, 867. (g) Midland, M.M.; Graham, R.S. Org. Syn. 1985, 63, 57.

σ∗ σ dihedral angle change during the rotation about the carbon-carbon σ bond but that the
bond distances also change. Thus, one finds that the carbon-carbon σ bond in the staggered
conformation is slightly shorter than in the eclipsed conformation, whereas the
H H
carbon-hydrogen bonds are slightly longer. This may be viewed as reflecting an increased
H carbon-carbon bond order in the staggered conformation and a decreased carbon-hydrogen
H bond order relative to the values in the eclipsed conformation. This may be visualized in
H H terms of a π-type delocalization of electron density from the filled σ orbital on one atom
into the empty σ* orbital on the adjacent atom, as shown schematically in Figure 5.7.
The computed molecular orbitals show that even when a more sophisticated treatment us
used, the overlap is more efficient in staggered ethane.
σ∗ σ The antiperiplanar arrangement of the two C—H bonds results in the most efficient
geometry for delocalizing electrons from the σ orbital to the adjacent σ* orbital, so we
H H expect that this arrangement of bonds will be the lowest energy, leading to the staggered
conformation being the most stable. By comparison, the overlap between the same or-
H bitals in the synperiplanar geometry is much less efficient, with a partial antibonding
H component.
H H
A similar situation holds when we look at the conformations of alkenes and car-
bonyl compounds. In this case, it is overlap between the σ orbitals of the C—H bonds
Figure 5.7 π-Overlap and the π* orbital that influences conformational energy. This arrangement, where
between adjacent filled and both C—H σ orbitals can overlap with the C—C π* orbital, is predicted to be the lowest
empty orbitals in ethane is
energy, which leads to the conclusion that the eclipsed conformation is lowest energy
most efficient when the
bonds are antiperiplanar. (Figure 5.8).
Synperiplanar overlap is Lone pairs can replace the σ orbitals in the forgoing discussion. This leads to two ef-
much less efficient. fects that have been observed empirically. The first of these is the gauche effect,4 where the
gauche conformer of a disubstituted ethane becomes more favored as the electronegativity
of the two substituents increases.5 The second is the anomeric effect,6 which is the obser-
π∗
σ vation that the conformational preference of substituents at the ring carbon adjacent to
H the heteroatom in a saturated six-membered heterocycle is generally lower than the con-
formational preference of the same substituent in cyclohexane, leading to a higher per-
R
σ H centage of the axial conformer in the equilibrium mixture (Figure 5.9). The theoretical
basis for the anomeric effect has been discussed at length, with most authors proposing
Figure 5.8 π-Overlap the model just discussed, where the electron density from a lone pair is delocalized into
etween adjacent filled σ and
b the σ* orbital of the adjacent carbon-heteroatom bond.7 This rationalization is not, how-
empty π* orbitals in propyl- ever, universally accepted,8 and other rationalizations based on dipole-dipole interactions
ene is most efficient when have also been proposed.9 The anomeric effect has been found to be particularly applicable
the alkene conformation is in carbohydrates, where the β (equatorial) isomer of the six-membered hemiacetal is fre-
eclipsed.
quently found to be much less favored than the α (axial) isomer. These isomers are known
as anomers.
Y
σ* 4. (a) Huang, J.; Hedberg, K. J. Am. Chem. Soc. 1990, 112, 2070. (b) Dixon, D.A.; Matsuzawa, N.; Walker, S.C.
J. Phys. Chem. 1992, 96, 10740. (c) Wolfe, S. Acc. Chem. Res. 1972, 5, 102.
X 5. Phillips, L.; Wray, V. J. Chem. Soc. Chem. Commun. 1973, 90.
6. Monographs: (a) Kirby, A.J. The Anomeric Effect and Related Stereoelectronic Effects at Oxygen (Springer-
n Verlag: Berlin, 1983). (b) Szarek, W.A.; Horton, D. Anomeric Effect (American Chemical Society: Washington, D.C.,
1979). (c) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry (Pergamon: Oxford, 1983).
Figure 5.9 π-Overlap be- Reviews: (d) Zefirov, N.S. Tetrahedron 1977, 33, 3193. (e) Lemieux, R.U. Pure Appl. Chem. 1971, 27, 527.
tween a filled nonbonding (f) Angyal, S.J. Angew. Chem. Int. Ed. Engl. 1969, 8, 157.
7. (a) Juarista, E.; Cuevas, G, Tetrahedron 1992, 48, 5019. (b) Salzner, U.; Schleyer, P.v.R. J. Am. Chem. Soc.
orbital on the heteroatom
1993, 115, 10231. (c) Romers, C.; Altona, C.; Buys, H.R,; Havinga, E,. Top. Stereochem. 1969, 4, 39. (d) Wolfe, S.;
and the empty σ* orbital on Whangbo, M.; Mitchell, D.J. Carbohydrate Res. 1979, 69, 1. (e) Fuchs, B.; Ellencweig, A.; Tartakovsky, E.; Aped,
the adjacent atom may ac- P. Angew. Chem. Int. Ed. Engl. 1986, 25, 287. (f) Praly, J.; Lemieux, R.U. Can. J. Chem. 1987, 65, 213. (g) Booth,
count for the extra stability H.; Khedair, K.A.; Readsha, S.A. Tetrahedron 1987, 43, 4699.
of axial substituents in these 8. Box, V.G.S. Heterocycles 1990, 31, 1157.
six-membered rings. 9. (a) Pearson, R.G. J. Am. Chem. Soc. 1988, 110, 7684. (b) Hati, S.; Dhatta, D. J. Org. Chem. 1992, 57, 6056.

5.2 Using Frontier Molecular Orbitals to Categorize

Reactions and Reagents
Organizing chemical reactions and compounds into classes is a long-standing hallmark of

organic chemistry. Recall how compounds are grouped into classes based on their func-
tional groups and how reactions are classified according to their outcomes (e.g., addition,
elimination, substitution, oxidation, reduction) and mechanisms. In this chapter, we will
examine the common classes of organic reactions and categorize them in terms of the
frontier orbitals involved. Later in this book, we will expand our discussion of synthetic
reactions to retrosynthetic analysis, and the design of syntheses. For now, however, let us
focus on the frontier orbitals of the reacting species and on how the combination of fron-
tier orbitals involved directs the outcome of the reaction.
Bond-forming reactions can be broadly characterized as being unimolecular or bimo-
lecular. Because of the Pauli Exclusion principle, bimolecular reactions must always in-
volve the overlap of an empty orbital on one reactant with a filled orbital on the other: the
HOMO in one reactant (which may contain either one or two electrons) must overlap with
the LUMO of the other unless two free radicals are involved. Unimolecular reactions, on
the other hand, involve the HOMO only. Bimolecular reactions leading to bond formation
are much more common than unimolecular bond-forming reactions and include some of
the most widely used synthetic reactions known.
In simple organic compounds, there are only three types of orbitals that can function
as a HOMO—an occupied σ orbital, an occupied π orbital, or an occupied nonbonding (n
or nπ) orbital (carrying either a lone pair or single electron). Similarly, there are only three
possible types of orbitals that can function as a LUMO—an empty nonbonding molecular
or atomic (a or aπ) orbital (e.g., the 2p orbital on CH3+), an empty π* orbital, or an empty
σ* orbital. Some typical examples of these orbitals are given in Table 5.2.
The n and nπ orbitals in Table 5.1 are actually subsets of the same type of frontier
orbital—as are the a and aπ orbitals. Those orbitals designated with the subscript π are
nonbonding orbitals in conjugated systems. There are nine and only nine possible com-
binations of the three types of HOMO and the three types of LUMO; they are tabulated
in Table 5.3.10
Table 5.2 Representative Frontier Orbitals
Frontier
Orbital Examples
a Empty p orbital on B, C Al, and so on; empty d orbitals on Si, Sb, and so on
Electrophilic
aπ ψ2 of allyl cation, and so on; ψ4 of benzyl cation, and so on Electrophilic
n Lone pairs in hybrid atomic orbitals Nucleophilic
nπ ψ2 of allyl anion, and so on; ψ4 of benzyl anion, anisole, aniline, and so on Nucleophilic
π π orbital of alkene, carbonyl group, cyano group, and so on; ψ2 of diene, conjugated
carbonyl compound or nitrile, and so on; ψ3 of benzene, and so on Nucleophilic
π* π* orbital of alkene, carbonyl group, cyano group, and so on; ψ3 of diene, conjugated
carbonyl compound or nitrile, and so on; ψ4 of benzene, and so on Electrophilic
σ σ orbital (usually C—H σ orbital) Nucleophilic
σ* σ* orbital (usually C—X σ* orbital of bond to a leaving group) Electrophilic
10. (a) Lewis, D.E. J. Chem. Educ. 1999, 76, 1718. (b) Jensen, W.B. J. Chem. Educ. 2001, 78, 727.

Table 5.3 Possible Frontier Molecular Orbital Combinations in Organic Chemistry
HOMO LUMO Examples of Typical Outcome

n a Bond formation in step 2 of SN1 substitution
n π* Bond formation + bond rupture in nucleophilic or free radical addition
n σ* Bond formation + bond rupture in SN2 substitution; anomeric effects in
cyclic systems
π a Bond formation + bond rupture in electrophilic addition
π π* Bond formation + bond rupture in cycladdition
π σ* Bond formation + bond rupture in electrophilic addition
σ a Bond formation + bond rupture in cation rearrrangements
σ π* Stabilization of conformations of unsaturated compounds
σ σ* Stabilization of conformations of saturated compounds
*HOMO, highest energy occupied molecular orbital; LUMO, lowest energy unoccupied molecular orbital.
Every organic reaction known in which a new bond is formed by transfer of an elec-
tron pair from one reactant to another fits one of these HOMO-LUMO (FMO) combina-
tions. In general, we look at organic reactions in terms of the bonds being formed.
However, on occasion we will need to look at reactions in which a bond is broken and
those in which no bond is formed. Although such reactions can (with some difficulty) be
fitted into the classifications above, the relationships are less clear-cut than in reactions
in which a bond is formed; we will address such bond rupture reactions at the time we
encounter them.
The transfer of a pair of electrons from the HOMO of one molecule to the LUMO of
the other corresponds to the reaction between a Lewis acid and a Lewis base.11 The com-
pound that reacts via a filled HOMO is functioning as an electron pair donor (i.e., a Lewis
base or a nucleophile). A nucleophile, or Lewis base, participates in reactions via its HOMO.
In such reactions, the pair of electrons from the HOMO is placed into the LUMO, so that
the compound that reacts via its LUMO is functioning as an electron pair acceptor (i.e., a
Lewis acid or an electrophile). An electrophile, or Lewis acid, participates in reactions via
the LUMO. What this means, of course, is that much of organic chemistry can actually be
reduced to the reaction of a Lewis acid with a Lewis base—or the reaction of an electro-
phile with a nucleophile.
The process of examining a reaction from the perspective of what orbitals are over-
lapping and what new orbitals are formed can be thought of as a type of “orbital inven-
tory.” In generating an orbital inventory for a reaction, one need only adhere to the rules
for orbital combination that we have already discussed for atomic orbitals:
1. Orbitals may be combined in a variety of different ways but neither created nor
destroyed.
2. For every bonding molecular orbital there is a corresponding antibonding orbital.
One may take this orbital inventory to its logical conclusion and map the correspon-
dence between the orbitals of the reactants and the orbitals of the product. Such a mapping
is called an orbital correlation diagram. As the occasion arises, we will make use of both
11. (a) Jensen, W.B. Lewis Acid-Base Concepts: An Overview (Krieger Publishing Co.: Melbourne, FL, 1979).
(b) Jensen, W.B. Chem. Rev. 1978, 78, 1. (c) Jensen, W.B. Chemtech 1982, 12, 755.

the pictorial orbital diagrams and the simplified energy level diagrams when discussing
organic reactions as well as using orbital inventories and correlation diagrams. First, you
should become familiar with the basic concepts so that you can use them later.
Perturbation Approximations for Orbital Coefficients

The use of FMOs for studying organic reactions can be enhanced, especially in reactions
involving π-bonded systems, by approximating second-order effects on the coefficients of
the contributing basis orbitals in those π bonding systems. This method, which is really a
combination of simple Hückel theory and resonance concepts, gives the chemist a way to
approximate the FMOs in a more “exact” way, and this allows them to be used with greater
confidence in predicting reaction regiochemistry. The basic concepts of this approach and
its applications have been discussed in much greater detail than is possible in this single
chapter in the book by Fleming.12
H O H O H O
major minor minor

(5.1) (5.2) (5.3)
At its heart, the perturbation method for approximating the FMOs of a reacting spe-
cies leads to a prediction of the relative sizes (larger or smaller) of the lobes of the orbital
at a particular position in the orbital. Let us take acrolein (Example 5.1) as an example. The
aldehyde molecule can be represented using traditional resonance models as shown at left.
In this case, there is one major (Example 5.1; neutral), and two minor (Examples 5.2 and
5.3; dipolar) canonical forms.
When discussing the chemistry of compounds containing π bonds between unlike
atoms (e.g., a carbonyl group), one must be careful when talking about the HOMO, be-
cause the HOMO of a carbonyl group, for example, is actually a lone pair (or linear com-
bination of lone pairs), and not the C=O π orbital. For this reason, when talking about
reactions of π-bonded systems, we will use the term HOMO (π) when referring to the
highest energy occupied π molecular orbital.
When we look at the π orbital system of acrolein, we note that it is composed of four
atoms (the three sp2-hybridized carbon atoms and the sp2-hybridized oxygen atom) and four
electrons. The system will have two occupied and two unoccupied molecular orbitals. To pre-
dict its reactivity, we now need to approximate its FMOs. This can be done by separating the
orbitals into (1) a base system, which is the hydrocarbon that most closely approximates the
neutral canonical form; and (2) the perturbing influence, which is the hydrocarbon ion that
most closely resembles the bipolar canonical form.
If we apply this approach to approximating the π molecular orbitals of the acrolein mol-
ecule, we infer that the base π molecular orbitals of the acrolein molecule should be modeled
on those of 1,3-butadiene (Example 5.4) and that the perturbing influence should be the π
orbitals of the allyl cation (Example 5.5). The HOMO (π) should be ψ2 of 1,3-butadiene mod-
ified by ψ1 of the allyl cation, and the LUMO should be ψ3 of 1,3-butadiene modified by ψ2 of
the allyl cation. In similar fashion, one can approximate the π molecular orbitals of
1-methoxy-1,3-butadiene (Example 5.6) by perturbing the molecular orbitals of 1,3-butadiene
(Example 5.4) with those of the 2,4-pentadienyl anion (Example 5.7). In this case, the HOMO
(π) should be ψ2 of 1,3-butadiene modified by ψ3 of the pentadienyl anion, and the LUMO
should be ψ3 of 1,3-butadiene modified by ψ4 of the pentadienyl anion (Figure 5.10).
12. Fleming, I. Frontier Orbitals and Organic Chemical Reactions (Wiley-Interscience: New York, 1976).

Base Perturbing This removes the symmetry of the orbital coefficients and leads to the
system influence situation where there are now preferred sites of attack. It is clear that the
O superimposition of ψ1 of the allyl cation on ψ2 of 1,3-butadiene gives an
orbital where the largest orbital coefficient is at the β carbon (Figure 5.11).
The characteristic reaction of acrolein and other conjugated carbonyl
(5.1) (5.4) (5.5) compounds is nucleophilic addition. The LUMO that we have just approx-
imated strongly suggests that the preferred regiochemistry of this reac-
LUMO tion will be either 1,2- or 1,4-. We expect that nucleophiles attacking the
alkene π bond will do so preferentially at the β position. Again, because
FMO interactions become more important as the reacting species become
softer, we expect that soft nucleophiles will tend to give more attack at the
HOMO (π)
β carbon of acrolein.
Perturbation methods can also permit us to estimate the relative ener-
gies of the FMOs of a molecule. Based on the same model that we have just
base perturbation result
used, we can calculate that the energy of the HOMO (π) of acrolein will lie
Base Perturbing between those of the allyl cation [α + 2βcos(π/4)] and 1,3-butadiene [α +
system influence 2βcos(2π/5)]. Likewise, we can predict that the LUMO energy of acrolein
OR will lie between those of the allyl cation [α + 2βcos(π/2)] and 1,3-butadi-
ene [α + 2βcos(3π/5)]. This allows us to obtain the following energies for
the two frontier orbitals of acrolein:
(5.6) (5.4) (5.7) EHOMO = α + 2βcos(2π/5) + c[α + 2βcos(π/4)] (5.1)

OR ELUMO = α + 2βcos(3π/5) + c[α + 2βcos(π/2)] (5.2)
LUMO where c is a coefficient that determines the contribution of the allyl

cation wave function to the complete wave function (in other terms,
here we see the importance of the minor contributor to the resonance
hybrid). This analysis, simplified as it is, allows us to predict that the
conjugation of an alkene π bond with a carbonyl group will lead to a
HOMO (π) lowering of both the HOMO (π) and LUMO energies. We can carry out
a similar analysis with ethyl vinyl ether, which can now be approxi-
base perturbation result mated by an ethylene molecule perturbed by an allyl anion. This leads to
the conclusion that both π molecular orbitals have their energy raised
Figure 5.10 Construction of the approximate by an electron-donating group, and that the β carbon has the larger or-
frontier molecular orbitals of acrolein (left) and bital coefficient in the HOMO (π).
1-alkoxy-1,3-butadiene (right). HOMO, highest
When a π bond is formed between a pair of like atoms, the magni-
energy occupied molecular orbital; LUMO,
lowest energy unoccupied molecular orbital. tudes of the orbital coeficients are equal at the same location relative to
the center of the orbital. This is not the case, however, when the two atoms
participating in the π bond are different. One example of this is provided
Figure 5.11 The asymmetry larger lobe

in the basis orbital contribu- smaller lobe
tions to the lowest energy
unoccupied molecular or-
bital of acrolein leads to dif-
ferent outcomes with
different nucleophilic
additions

Figure 5.12 Orbital overlap to

generate the π orbitals of the
C=O group, and a compari-
son of the lowest energy un-
occupied molecular orbitals
of C=C and C=O bonds.
by the carbonyl group (Figure 5.12). Here, the overlap is between the carbon 2p orbital
and the oxygen 2p orbital. Because the carbon 2p orbital is higher in energy, we find that
the π orbital is closer in energy to the oxygen atomic orbital and the π* orbital closer in
energy to the carbon atomic orbital. This extends to the orbital coefficients as well. The π
orbital has a larger coefficient on the oxygen, and the π* orbital has a larger coefficient on
carbon. This is illustrated for the LUMOs of C—C and C—O π bonds in Figure 5.12. As
we see, the LUMO of an alkene π bond is symmetric, as expected. The LUMO of the car-
bonyl group, on the other hand, is quite asymmetric, with large lobes on carbon and
small lobes on oxygen, consistent with attack of a nucleophile on a carbonyl group occur-
ring at carbon.
Worked Problem
5-1 The Diels-Alder reaction is a cycloaddition reaction where the participating orbit-
als are ψ2 of the diene and π* of the dienophile. Using perturbation molecular
orbital theory, deduce the qualitative coefficients of the FMOs in Diels-Alder re-
action below. What is the regiochemistry of the reaction?
OMe
+
CN
§Answer below
§ Answer to Worked Problem:

The diene orbital may be viewed as ψ2 of 1,3-butadiene perturbed by ψ2 of the allyl cation. This means that the
largest lobe of the diene is at the end of the conjugated system opposite to the methoxy group.
OMe OMe OMe

OMe OMe
The dienophile orbital may be viewed as the π* orbital of ethylene perturbed by ψ2 of the allyl cation, so a
similar analysis gives the result that the larger lobe of the dienophile is at the end of the conjugated system
opposite to the cyano group.
C C CN CN
N N N

Problem
5-2 Using perturbation molecular orbital theory, deduce the qualitative orbital
coefficients in the diene ψ2 orbital and the dienophile π* orbital in each of the
Diels-Alder reactions below. Use the results of this analysis to predict the re-
giochemistry of the reactions:
NMe2 Ph
(a) + (b) +
CN CN
CN
(c) + (d) +
MeO CHO CO2H
CO2 Ph
MeO
Me3SiO
(e) + (f) +
CO2
CN
Let us now look at the nine possible FMO combinations of Table 5.2, which are all
represented by real reactions in organic chemistry, although the first six entries represent
much more common reaction types.
5.3 Categorizing Reactions Using Frontier Molecular Orbital Pairings
Frontier Molecular Orbital Overlap Between n and a Orbitals

This pairing of FMOs leads to the formation of a new σ bond by permitting transfer
of electrons from a filled nonbonding orbital to an empty nonbonding orbital. It is the
simplest of all the nine possible HOMO-LUMO combinations, because it does not
involve any antibonding orbitals. In this case, the overlap of the two nonbonding or-
bitals leads to the formation of two new orbitals (one bonding, one antibonding), as
shown in Figure 5.13. The reaction between trimethylborane and ammonia is a typical
example. In the most common case, two electrons are transferred and the net result is
the formation of a new bond without the rupture of a bond in either reactant. Overall,
the reaction converts what are in essence two atomic orbitals to a σ orbital and a σ*
orbital.
When we overlap these two orbitals, the most efficient overlap is large lobe to large lobe, so we expect that the
regiochemistry of the product will be most favorable when the two substituents on the six-membered ring are
on adjacent carbons. The stereochemistry of the reaction follows the Alder endo rule, which places both substit-
uents on the same face of the six-membered ring:
OMe OMe OMe

CN CN
+
CN

n+a Me
Me (5.8)
Br
Br
Ph N C R Ph
N C R (5.9)
Ph Ph
The most common occurrence of this pairing of orbitals in organic chemistry is during
the fast step of the SN1 reaction, where the carbocation (the Lewis acid) reacts with the
nucleophile (the Lewis base) (Example 5.8). It is noteworthy that the slow step of the SN1
reaction corresponds to the reverse of this process. This is also the key bond-forming step
in the Ritter reaction of nitriles (Example 5.9).13
Cl
Al Cl Cl
Cl Cl O Al Cl O Al Cl
O Cl Cl
Cl Cl
Cl (5.10)
The free (unbound) proton does not occur in condensed media, although the reaction
between a proton and a Lewis base belongs to this class of reactions. More importantly, per-
haps, so do the reactions of Lewis bases with Lewis acids such as aluminum chloride (e.g.,
Example 5.10), titanium tetrachloride (e.g., Example 5.11), and a wide range of boron reagents
(e.g., Example 5.12). These n + a reactions are often important steps in the mechanisms of key
synthetic reactions. For example, the complexation of the carbonyl oxygen atom by a Lewis
acid is a key step in many reactions that we most commonly categorized as nucleophilic addi-
tions: magnesium in the Grignard addition, titanium in the Mukaiyama aldol addition reac-
tion,14 and boron in the Evans asymmetric aldol addition,15 as well as the addition of
allylboranes to carbonyl compounds. Complexation of the carbonyl oxygen of an acid chlo-
ride by aluminum chloride (Example 5.10) is a key stage in the F riedel-Crafts acylation of
arenes. Similar reactions of alkyl halides with Lewis acids (e.g., Example 5.13) are key steps in
the Friedel-Crafts alkylation of arenes and alkenes ( especially enol trimethylsilyl ethers).16
Figure 5.13 Frontier molecu-

lar orbital overlap between n
and a orbitals
13. Krimer, L.I.; Cota, D. Org. React. 1969, 17, 213.

14. Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
15. Evans, D.A.; Bartroli, J.; Shih, T.L. J. Am. Chem. Soc., 1981, 103, 2127.
16. (a) Reetz, M.T.; Chatziiosifidis, I.; Löwe, U.; Maier, W.F. Tetrahedron Lett. 1979, 1427. (b) Reetz, M.T.;
Chatziiosifidis, I.; Hübner, F.; Heimbach, H. Org. Syn. 1984, 62, 95.

Cl
Cl Cl
Ti Cl Cl
Cl Cl Cl Cl Cl
Ti Ti
Cl Cl
O O O
(5.11)
BR2
R R
B B
R R
O O O
(5.12)
Cl Cl
Al Cl Cl Cl
Cl Cl Cl Cl Al
Al
Cl
Cl
Cl
(5.13)
Because this overlap of FMOs leads to the formation of a bond without requiring con-
comitant bond rupture, the relative energies of the n and a orbitals are frequently of rela-
tively little consequence in comparison to reactions where bond rupture is required.
Nevertheless, in general, the lower the energy of the LUMO, the more reactive the
electrophile or Lewis acid is, and the higher the energy of the HOMO, the more reactive
the nucleophile or base; lowering the energy of its LUMO increases the strength of a Lewis
acid, and raising the energy of its HOMO increases the strength of a Lewis base. In the
same reaction, however, these two effects are often incompatible with each other. Conse-
quently, we seldom find a strong Lewis base involved in reactions where a strong Lewis
acid is used—the Lewis acid is capable of accepting a pair of electrons from even weak
electron-pair donors, and a strong Lewis base tends to be incompatible with reaction con-
ditions where a strong Lewis acid is generated. Conversely, a strong Lewis acid is seldom
involved in reactions where a strong Lewis base is used—the Lewis base is capable of do-
nating a pair of electrons to even weak electron-pair acceptors, and a strong Lewis acid
tends to be incompatible with reaction c onditions that lead to the formation of a strong
Lewis base.
Conjugated Systems: ap and np Orbitals

OSiMe3 O
Cl
(5.14)
H2O
H2O
OH (5.15)
Br
Recall that conjugated π bonding systems with an odd number of atoms have a nonbond-
ing orbital between the bonding and antibonding orbitals. To distinguish this type of
orbital form those that are localized on a single atom, we will designate them as ap and
np orbitals. The major difference between these orbitals and the localized a and n orbitals
that we have been discussing is that these orbitals are delocalized, with lobes (i.e., sites for
reaction) at more than one location, thus permitting regioisomers to be formed in their
reactions. In a species such as the allyl cation, this nonbonding orbital is the LUMO,
whereas in systems such as an enolate anion, this orbital is the HOMO. Thus, the second

Figure 5.14 Reactions involv-

ing conjugated cations and/
LUMO or anions with frontier mo-
X
2p lecular orbital overlap be-
HOMO tween n and a orbitals.
LUMO n HOMO HOMO, highest energy oc-
ψ2 ψ2 cupied molecular orbital;
LUMO, lowest energy unoc-
cupied molecular orbital.
Me3SiO
+ :X O + R
step of the SN1 reactions of allyl halides (the left-hand example in Figure 5.14) also belongs
to the n + ap subclass of reactions, with ψ2 of the allyl cation as the ap orbital. The
Friedel-Crafts alkylation of an enol trimethylsilyl ether16,17 (the right-hand example in
Figure 5.14) belongs to the np + a subclass or reactions, where the carbocation (a) inter-
acts with ψ2 of the silyl ether as the np orbital. The interaction between an allyl cation and
an enol trimethylsilyl ether or an enamine would represent the np+ ap subclass of reac-
tions. As we shall see later in this chapter, systems such as the ones in Example 5.14 may
also be treated as a + π overlaps.
Problems
5-3 The Friedel-Crafts acylation proceeds through an electrophile generated by the

reaction between aluminum chloride and an acyl chloride. Example 5.10 above
discusses one type of electrophile that can be formed by this combination of
reactants. What is the other, and what FMOs are involved in its formation?
5-4 The reaction below can give more than one chloride as the product. What chlo-
ride should be the major product formed, and overlap of what FMOs initiates its
formation?
OH HCl
5-5 The reaction between a silyl ether and fluoride anion occurs in two stages. Write a
mechanism consistent with this and specify the orbital overlap that initiates the
reaction (i.e., which orbitals are involved?).
R R
F +
R Si OR' R Si F OR'
R R
17. Chan, T.H.; Paterson, I.; Pinsonnault, J. Tetrahedron Lett. 1977, 4183.


lar orbital overlap between n S S
and p* orbitals
n σ
C O C O + C—S σ*
π*
π H2C O C O
n
H H
H S + C O S O
H H H
Frontier Molecular Orbital Overlap Between n and π * Orbitals

This combination of FMOs initiates nucleophilic addition to a polar π bond, such as a
carbonyl group, which means that it is the FMO overlap responsible for initiating some of
the most important synthetic organic reactions available to the organic chemist. The sim-
plest illustration of a reaction initiated by this pairing of FMOs is given by the addition of
a heteroatom nucleophile to a carbonyl group (Figure 5.15). In this reaction, a new σ bond
is formed at the expense of a π bond by overlap of a filled n orbital of the nucleophile
(sulfur in the example above) with the unoccupied π * orbital of the carbonyl group. In
nucleophilic addition, the HOMO-LUMO overlap that initiates the reaction puts electrons
into an antibonding orbital, which results in rupture of the π bond. As their name implies,
antibonding orbitals are the absolute opposite of bonding orbitals, and they destabilize the
association of the two nuclei.
Whenever electrons are placed into an antibonding orbital, the bond corresponding to that
orbital is broken.
Thus, the HOMO-LUMO overlap now affects three orbitals—the n orbital of the nuc-
leophile and the π * and π orbitals of the electrophile—and the fate of all three must be
taken into account when deciding what the overall bonding change is. In this reaction, the
electrons of the nucleophile lone pair become the electrons of the new σ bond, and the
electrons in the π bonding orbital become the new nonbonding electron pair. For clarity,
the new σ* orbital has been omitted from Figure 5.6.
Reactions initiated by n + π* overlap are among the most important bond-forming
reactions in organic chemistry, and they include a wide diversity of reactions. The π* or-
bital, for example, can be the C—O π* orbital of an isolated carbonyl group; the C—N π*
orbital of an isolated nitrile group or imine; or ψ3 of an α,β-unsaturated carbonyl system,
imine, or nitrile. It can also, however, be the lowest unoccupied π orbital of an electron-
deficient aromatic ring system such as nitrobenzene, where it is the functional equivalent
of ψ3 of an α,β-unsaturated carbonyl system, or be pyridine, where it is the functional
equivalent of the C—N π* orbital of an isolated imine group.
O OAr OH O
(5.16)
H LiO OHAr

H H
Me2CuLi
(5.17)
Et2O/0°C
O O
H H
OBPS OBPS
MeC≡CLi (5.18)
96%
MeO O CHO MeO O
OH
NaNH2
(5.19)
110°C
N N NH2
When the π* orbital is the antibonding orbital of an aldehyde or ketone, the reactions
include the addition of metal enolates (e.g., Example 5.16), metal alkyls (e.g., Example 5.17)
and alkali metal alkynides (e.g., Example 5.18) to the carbonyl group to give alcohols, and
the addition of heteroatom nucleophiles and cyanide or azide anion to the carbonyl group
to give addition products. In conjugated systems, we see both 1,2- and 1,4-addition reac-
tions arising from this combination of FMOs, with the regiochemistry of the reaction
often being controlled by the hardness and softness of the two reacting species (i.e., the
HOMO-LUMO gap), as we saw in Section 5.2, above.
This combination of FMOs also corresponds to the first step in nucleophilic substitu-
tion at sp2-hybridized centers by the addition-elimination mechanism, including nucleo-
philic acyl substitution and nucleophilic aromatic substitution as well as the Chichibabin
reaction of pyridines (e.g., Example 5.19).
Problems
5-6 Using the curved arrow formalism, write a mechanism to account for the
formation of the product in each of the four examples above.
5-7 Identify the FMOs used by each of the reactants in the examples above.
Frontier Molecular Orbital Overlap Between n and σ * Orbitals

The σ-type overlap of these two FMOs is the pairing in the SN2 reaction (Figure 5.16) and in
the transfer of a proton from a Lowry-Brønsted acid to a base. In essence, this reaction is

N C C Br N C C lar orbital overlap between n
and s* orbitals
n σ∗ σ
CH4 Br Br
σ n
H3C CH3
N C + CHBr N C CH + Br
H3C CH3

basically the same as the reactions in the previous section, except that the LUMO is
RR
now a σ * orbital rather than a π * orbital—the rupture of the σ bond produces two
HO H separate species rather than simply breaking one of the two bonds of a double bond.
n σ* X All the remaining arguments remain the same. Again, the new σ* antibonding or-
RR bital has been omitted for clarity.
The second major group of reactions that is initiated by this type of FMO over-
Br Br
lap is the deprotonation of organic compounds by strong bases. There are many
Ph3P Br examples of such reactions: the deprotonation of carbonyl compounds to give eno-
late anions, base-promoted elimination by the E2 and E1cb mechanisms
n σ* Br
(Figure 5.17), and the fast deprotonation step in the E1 mechanism. The useful re-
Figure 5.17 Initial frontier molecular action between triphenylphosphine and carbon tetrabromide, also shown in
orbital overlap involving an n orbital Figure 5.8, proceeds by overlap of the nonbonding orbital on phosphorus with a
and an s* orbital C—Br σ* orbital at the bromine end.
Problem
5-8 What will be the products formed in the two reactions in Figure 5.17? Assume
that there is no further movement of electrons.
Frontier Molecular Orbital Overlap Between p and a Orbitals

The addition of a localized electrophile to a carbon-carbon π bond is an important
reaction that is involved not only in the electrophilic addition to alkenes but also in
electrophilic aromatic substitution reactions. It is initiated by the overlap of the empty
a orbital of the electrophile with the filled π orbital of the alkene, as illustrated in
Figure 5.18.

lar orbital overlap between a
and p orbitals
C C
a
σ
a
C C C C
C
σ*
C C C C
π*
H Me Me
H3C + H3C C
C Me
H Me H2

In this reaction, three orbitals are affected: the two FMOs as well as the antibonding
orbital corresponding to the HOMO. In this case, the electrons originally in the π orbital
are used to form the new σ bond, so that the second terminus of the original π bond be-
comes an atom bearing an empty nonbonding orbital.
This combination of FMOs is the pairing in the addition of carbocations to alkenes, as
in the Johnson polyene cyclization,18,19 the alkylation of enol silyl ethers by alkyl halides
and titanium tetrachloride,20 and, formally, the hydroboration of alkenes.21 It is also the
first step of the electrophilic substitution reactions of arenes and alkenes. Although reac-
tions initiated by protonation may be viewed as belonging to this class, one should also
bear in mind that the free proton does not actually exist in condensed media and that
protonation reactions really belong to the class initiated by σ* + π overlap.
CO2Me CO2Me
OH
H2SO4, HCO2H
H
20°C, 6h
(5.20)
OSiMe3 O
Cl
TiCl4, CH2Cl2, -50°C

60-62%
(5.21)
H
BH3•THF B
(5.22)
Frontier Molecular Orbital Overlap Between π and π * Orbitals

This pairing of FMOs occurs in two major reaction classes: electrophilic addition to simple
alkenes and arenes (as in the first step of electrophilic aromatic substitution) as well as in
cycloaddition reactions.
Electrophilic Addition
The critical part of the HOMO-LUMO overlap is obviously the formation of the new σ
orbital (and its associated σ* orbital, which has been omitted from Figure 5.19 for
clarity). The electrons in the complementary π orbital of the electrophile become a non-
bonding lone pair in the product, and the complementary π* orbital of the nucleophile
becomes an empty nonbonding orbital in the product. From the perspective of both
participating bonds, these reactions are addition reactions because both π bonds are
broken and r eplaced by σ bonds. From the perspective of the LUMO, this is a nucleop-
hilic addition reaction, and from the perspective of the HOMO, it is an electrophilic
addition reaction.
18. Johnson, W.S. Acc. Chem. Res. 1968 1, 1.

19. Stadler, P.A.; Nechvatal, A.; Frey, A.J.; Eschenmoser, A. Helv. Chim. Acta 1957, 40, 1373.
20. (a) Reetz, M.T.; Chatziiosifidis, I.; Löwe, U.; Maier, W.F. Tetrahedron Lett. 1979, 1427. (b) Reetz, M.T.;
Chatziiosifidis, I.; Hübner, F.; Heimbach, H. Org. Syn. 1984, 62, 95.
21. (a) Brown, H.C. Hydroboration (W.A. Benjamin: New York, 1962). (b) Brown, H.C. Boranes in Organic
Chemistry (Cornell University Press: Ithaca, NY, 1972). (c) Brown, H.C. Organic Synthesis via Boranes
(Wiley-Interscience: New York, 1975).

Figure 5.19 Frontier
olecular orbital overlap
m
between p and p* orbitals in O C
O C
electrophilic addition
π*
σ
a
C C C C
O C n
O C σ*
C C C C
π*
H H Me Me
O +
HO Me
H H H Me
This pairing of FMOs is the overlap that initiates electrophilic addition of carbonyl
and iminium groups to electron-rich alkenes, as in the Mannich reaction,22 the Mukai-
yama aldol reaction of enol trimethylsilyl ethers,23 and the Prins reaction24 of aldehydes
with alkenes in the presence of acid. It is also the first step of the acylation of vinylsilanes25
and stannanes, and the first step of electrophilic aromatic substitution, as illustrated by
the examples below.
Ph Ph
NH N
CH2(OH)2, MeCO2H
150°C, 10 h
98%
(5.23)
OSiMe3 O OH
PhCHO, TiCl4 Ph
CH2Cl2, -78°C
92%
(5.24)
22. Reviews: (a) Tramontini, M. Synthesis, 1973, 703. (b) Thompson, B.B. J. Pharm. Sci. 1968, 57, 715.
(c) Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. Engl. 1998, 37, 1044.
23. Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc. 1974, 96, 7503.
24. Review: Adams, D.R.; Bhatnagar, S.P. Synthesis 1977, 661.
25. Fleming, I.; Pearce, A. J. Chem. Soc., Chem. Commun. 1975, 633.

Pr Pr Cl
PhCHO/AlCl3
OH ionic liquid solvent O
91%
(5.25) Ph
O
SiMe3
MeCOCl, AlCl3
CH2Cl2, 0°C, 15 min
77%
(5.26)
Problem
5-9 Using the curved arrow formalism, write reasonable mechanisms for reactions
5.23, 5.24, 5.25, and 5.26.
Worked Problem
5-2 Using the curved arrow formalism, write a reasonable mechanism for reaction
5.20 and provide reasons for each step where appropriate:
CO2Me CO2Me
OH
H2SO4/HCO2H
H
20°C/6h
§Answer below

The reaction starts with the protonation of the terminal alkene π bond to give the tertiary carbocation,
which then adds to the alkene π bond in the middle of the chain to give a new tertiary carbocation. This cation
adds to the final alkene π bond in the direction to place the carbocation at the α, rather than the β position of
the ester (why is this regiochemistry preferred? Think about the electron distribution in the carbonyl group).
The cation is then trapped by water to give the final alcohol.
MeO MeO MeO

O O O
H
MeO O MeO O MeO O H

H
OH
OH OH
H H H

Cycloadditions
Cycloaddition reactions are one reaction type in a class of reactions, known as pericyclic
reactions, that involve π-bonded systems and proceed through cyclic transition states.
The Diels-Alder reaction, or [4 + 2] cycloaddition (Figure 5.20), is a typical cycloaddition
reaction. The orbital correlation diagram for this reaction shows that there are six orbitals
modified during the reaction. It is developed according to principles, now known as the
conservation of orbital symmetry, first set forth by Woodward and Hoffmann, and by
Fukui. We will look at the conservation of orbital symmetry and at pericyclic reactions in
general, in much more detail in Chapter 6.
Frontier Molecular Orbital Overlap Between π and σ * Orbitals

This situation has characteristics of both the a + π and the π + π* cases. The similarity to
H
H the a + π case becomes evident when one considers that the typical reagent in this type of
B (5.27)
O reaction (the oxonium ion has been used in Figure 5.21) is normally the immediate precur-
H sor to the carbocation electrophile in reactions like the Johnson polyene cyclization. Simi-
larly, because the proton does not occur free in condensed medium, all protonations of
alkenes actually involve the σ* orbital of the bond to hydrogen. In fact, in a formal sense,
the same set of examples used in the section on may also be used here, including the hyd-
roboration reaction (Example 5.22), where one may, in fact, view the initial electrophilic

lar orbital overlap between
π and π* orbitals in σb
cycloaddition
ψ2 π*
π*
σa
diene
(nucleophile) dienophile
(electrophile)

lar orbital overlap between C
π and σ * orbitals O σ* a
C C
C σ C
C π
H3C H2C CH3

C CH2 + H3C OH2
H3C H3C

attack of the alkene as involving not free BH3 but rather the Lewis acid-Lewis base complex
with THF (Example 5.27; the added steric bulk due to the THF molecule may also rational-
ize the high sensitivity of this reaction to steric hindrance).
The reaction with the electrophile results in the rupture of the π bond, as in the a + π
case, and in the rupture of the existing σ bond, similar to the π+ π* case. All other argu-
ments remain the same as those made for the π+ π* case. Like the π+ π* case, the char-
acterization of this reaction depends on the perspective that one adopts when carrying out
the characterization. From the perspective of the LUMO, this reaction is a nucleophilic
substitution reaction because one σ bond is broken as the new one is formed. From the
perspective of the HOMO, this reaction is electrophilic addition because the π bond is
broken and replaced by σ bonds.
Frontier Molecular Orbital Overlap Between a and σ Orbitals

This orbital pairing usually occurs with π-type symmetry, in which case it corresponds to the
orbital overlap that gives rise to both hyperconjugation in carbocations and W
agner-Meerwein
rearrangements of carbocations. In the case of hyperconjugation, the transfer of electrons
from the HOMO to the LUMO is incomplete, resulting in the energy of the σ orbital being
lowered and the energy of the a orbital being raised. Wagner-Meerwein rearrangements in-
volve the same orbital overlap, but now the electron transfer is complete, with the formation
of three new orbitals. One possible energy correlation diagram for the Wagner-Meerwein
rearrangement is shown in Figure 5.22.
This orbital overlap is also responsible for the initiation of reactions other than rear-
rangement when the electron density is freely available to the external electrophile. There
are two situations in which this is the case: when the σ bond is a C—H or other σ bond to
hydrogen, in which case a very strong electrophile is usually required, or when the bond is
in a cyclopropane or cyclobutane ring, in which case a weaker electrophile can be used.
The electron pair in σ orbitals involving hydrogen is much more accessible in the extranu-
clear space than is the σ bonding pair in other covalent bonds. Consequently, this type of
orbital overlap is most easily achieved with C—H σ bonds. The electron density in
olecular orbital overlap
m
between a and σ orbitals in
hyperconjugation and
Wagner-Meerwein
rearrangements

Figure 5.23 Frontier H R
olecular orbital overlap in
m R H
the hydride anion transfer
between carbocations H H
R R
R R R R R R
a σ σ a
H H
(5.28)
m
cyclohexanone is apparent in
the lowest energy unoccu- H H
pied molecular orbital of O O
cyclohexanone. H H
cyclopropane C—C bonds is also much more accessible to electrophiles because it does
not lie directly between the two carbon atoms.
The overlap involving a C—H σ orbital is illustrated by the transfer of a hydride anion
from an alkane to a strong Lewis acid, such as a carbocation, which is a key step in alkane
rearrangements (Example 5.28, Figure 5.23).26 Similar orbital overlap, between the C—H
σ orbital and the aπ orbital of the triphenylmethyl cation is responsible for initiating oxi-
dation of alcohols by this reagent. The reactions of cyclopropanes with simple proton acids
to give ring-opened products have been known for well over a century.
Frontier Molecular Orbital Overlap Between σ and π* Orbitals

The π-type overlap of adjacent σ and π* orbitals is a major contributing factor to the con-
formational preferences of alkenes and carbonyl compounds. It also contributes to the
unusual acidity of the α hydrogens of carbonyl compounds (and the axial α hydrogens of
cyclohexanones) by providing a mechanism for delocalization from the C—H σ bond
onto the carbonyl oxygen. These orbitals are shown for cyclohexanone in Figure 5.24. Note
how the equatorial hydrogens do not overlap well with the π* orbital and how the lobes at
the equatorial α hydrogens in the cyclohexanone LUMO are extremely small.
Problem
5-10 Consider the Wagner-Meerwein rearrangement. (a) What pair of frontier orbitals
could be used to describe the transition state for the rearrangement? (b) What does
this transition say about the favored stereochemistry of the rearranging group?
26. (a) Pines, H.; Wackler, R.C. J. Am. Chem. Soc. 1946, 68, 525, 2518. (b) Wackler, R.C.; Pines, H. J. Am.
Chem. Soc. 1946, 68, 1642. (c) Pines, H.; Abraham, B.M.; Ipatieff, V.N. J. Am. Chem. Soc. 1948, 70, 1742.
(c) Pines, H.; Aritstoff, E.; Ipatieff, V.N. J. Am. Chem. Soc. 1949, 71, 749.

Frontier Molecular Orbital Overlap Between σ and σ* Orbitals

The π-type overlap of adjacent σ and σ* orbitals has been implicated in stabilization of
staggered conformations of open-chain compounds, as we discussed in Chapter 2
(Example 5.29).27 In saturated alkane chains, it has been proposed that the stabilization
of the staggered conformation by delocalization by π-type interaction between the bond-
ing orbital with the antibonding orbital on the adjacent atom is more important than the
destabilization of the eclipsed conformation by H-H repulsion.
H H H H
H
H H H
H H H H
(5.29)
Likewise, the bromination of cyclopropanes (Figure 5.25) involves this FMO overlap be-
tween the σ* orbital of the bromine molecule and the σ orbital of the C—C bond (which you
recall, does not lie symmetrically around the C—C) axis. In addition, the molecular orbitals
in Figure 5.25 suggest that the attack of bromine, the electrophile, on the cyclopropane ring
is not at the midpoint of the C—C ring bond but displaced toward one vertex of the ring.
Problems
5-11 Which FMOs are involved in each of the following reactions? Categorize each
reaction under a reaction type (e.g., nucleophilic addition).
CH3 O CH3
(a) + HBr (b) O + H2O
OH2
(c) O + Br O (d) O + Li
O Li
OMe OMe
O
CN CN
+ CHO
(e) + (f) Li O Li O
(continues)
m
the addition of bromine to
cyclopropane
27. (a) Weinhold, F. Nature 2001, 411, 539. (b) Weinhold, F. J. Chem. Educ. 1999, 76, 1141. (c) Weinhold, F.
Angew. Chem. Int. Ed. Engl. 2003, 42, 4188. For a dissenting view, see: Bickelhaupt, F.M.; Baerends, E.J. Angew.
Chem. Int. Ed. Engl. 2003, 42, 4183.

5-12 Using the curved arrow formalism, write mechanisms for each of the reactions in
Problem 5-11.
5.4 Stereoelectronic Effects
In the preceding section, FMOs were used to categorize organic reactions according to the
FMO overlap responsible for the reaction. However, this overlap also has both regiochem-
ical and stereochemical consequences because the orbitals involved actually have a shape
that determines the three-dimensional relationship between the reacting species. This
spatial requirement imposed by the shape and orientation of the participating orbitals is
often referred to as a stereoelectronic effect. A stereoelectronic effect may be defined as a
stereochemical and/or regiochemical limitation on an organic reaction that arises from
the requirements of the FMO overlap in that reaction.
For example, the cylindrical symmetry of the σ* orbital means that reactions involv-
ing this orbital as one of the participating FMOs will lead to the requirement that the other
reagent must approach along the axis of the σ bond. One obvious consequence of this
coaxial, σ-type overlap of the FMOs (Figure 5.26, upper example) is that SN2 reactions
proceed with inversion of configuration—because the nucleophile is constrained to ap-
proach the large (back) lobe of the σ* orbital along the bond axis, inversion of configura-
tion must result. In similar vein, the overlap of adjacent σ and σ* orbitals is what allows
the E2 elimination reaction (Figure 5.26, lower example) to be concerted—for all bonding
changes to occur in a single step.
The Anomeric Effect

The π-type overlap of a filled n orbital with a σ* orbital is implicated in the anomeric
effect28 in tetrahydropyran derivatives (Figure 5.27). The anomeric effect refers to the in-
creased preference for axial orientation of an electronegative substituent at position 2 of a
Figure 5.26 Coaxial frontier H
molecular orbital overlap in
the SN2 reaction leads to Nu X
inversion of configuration at R'
carbon, and coplanar overlap
of the adjacent s and s* orbit- R
als allows the E2 reaction to
be concerted. RR
HO H
X
RR
m
the anomeric effect O O
X
X
28. (a) Deslongcamps, P. Stereoelectronic Effects in Organic Chemistry (Pergamon Press: Oxford, 1983), p. 7.
(b) Carey, F.A.; Sundberg, R.J. Advanced Organic Chemistry. Part A: Structure and Mechanisms, 4th. ed.
(Kluwer Academic/Plenum Publishers: New York, 2000), p. 151. (c) Lemieux, R.U. Pure Appl. Chem. 1971, 25,
527, (d) David, S.; Eisenstein, O.; Hehre, W.J.; Salem, L.; Hoffmann, R. J. Am. Chem. Soc. 1973, 95, 3806.

tetrahydropyran ring. This has been proposed to result from π-type overlap between the
lone pair with the σ* orbital of the bond to the electronegative substituent.
Problem
5-13 The four structures A–D below are chair-chair conformations of the molecule at
the left. Arrange them in approximate order of stability and give reasons for your
choice.
O Ph O O Ph O
Ph O
(H2C)n Ph (H2C)n
(H2C)n (H2C)n
(H2C)n NH2 NH2 NH2
NH2 NH2
One important consequence of the shapes of the orbitals involved comes from looking
at cyclization reactions involving π* orbitals. In 1976, J. E. Baldwin and his students pro-
posed a series of empirical rules for predicting the ease of regioisomeric nucleophilic
cyclization reactions. These rules are now known as Baldwin’s rules. 29
Nucleophilic Cyclizations—Baldwin’s Rules

The closure of a ring by the intramolecular reaction between a nucleophile and an
electrophile may or may not proceed as designed, depending on whether or not the FMOs
involved can adopt a favorable orientation with respect to each other. The ramifications of
this were first recognized by J. E. Baldwin, who, beginning in 1976, outlined a set of
empirical rules, summarized in Table 5.4, that permit one to predict the probable success
of intramolecular nucleophilic cyclization reactions.
The principle underlying Baldwin’s rules may be traced to the work of Bürgi and
Dunitz, who studied nucleophilic addition to carbonyl compounds and observed that
there was a favored trajectory of approach of the nucleophile to the carbonyl group.30
(Figure 5.28 illustrates this approach for the reaction between cyanide ion and acetone.) In
this preferred approach trajectory, the nucleophile makes an O—C—Nu angle of approx-
imately 110° with the C=O axis, perpendicular to the plane of the carbonyl group. This has
been attributed to the type of overlap between the nucleophile HOMO and the carbonyl
LUMO. As we can see from Figure 5.28, the lobes of the LUMO at the carbon atom are
canted back away from the oxygen atom, which makes orthogonal approach to the C=O
axis less effective than this nonlinear approach.
In the Baldwin system, the attack is defined as endo if the breaking bond is endocyclic
in the transition state of the cyclization and exo if the breaking bond is exocyclic in the
transition state of the cyclization. The electrophilic atom is designated as tet if it is sp3 hy-
bridized, trig if it is sp2 hybridized, and dig if it is sp hybridized. Based on this system,
Baldwin designated certain cyclizations as being favored and others as being disfavored.
An extensive review of Baldwin’s rules with their limitations and an updating of the rules
with respect to alkynes has been published by Alabugin.31 The most important conclusion
29. (a) Baldwin, J.E. J. Chem. Soc., Chem.Commun. 1976, 734. (b) Baldwin, J.E.; Cutting, J.; Dupont, W.;
Kruse, L.; Silberman, L.; Thomas, R.C. J. Chem. Soc., Chem.Commun. 1976, 736. (c) Baldwin, J.E.; Reiss, J.A. J.
Chem. Soc., Chem.Commun. 1977, 77. (d) Baldwin, J.E.; Kruse, L.I. J. Chem. Soc., Chem.Commun. 1977, 233. (e)
Baldwin, J.E.; Lusch, M.J. Tetrahedron 1982, 38, 2939. (f) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry Pergamon Press: Oxford, 1983), pp. 234-240.
30. (a) Bürgi, H.B.; Dunitz, J.D.; Schefter, E. J. Am. Chem. Soc. 1973, 95, 5065. (b) Bürgi, H.B.; Dunitz, J.D.;
Lehn, J.M.; Wipff, G. Tetrahedron 1974, 30, 1563. (c) Bürgi, H.B.; Dunitz, J.D. Acc. Chem. Res. 1983, 16, 153.
31. Gilmore, K.; Alabugin, V.F. Chem. Rev. 2011, 111, 6513.

Table 5.4 Baldwin’s Rules for Nucleophilic Ring Closure
X Y Y
X
X Y X Y
Nu Nu Nu
Nu
Nu
Nu 4-exo-trig
X 6-exo-dig
3-exo-tet X Y Y
X Y X
Nu Y Nu X Nu Nu
5-endo-trig 7-endo-dig
Ring Size Tet trig dig

3 exo favored exo favored exo disfavored
endo disfavored endo favored
4 exo favored exo favored exo disfavored
endo disfavored endo favored
5 exo favored exo favored exo favored
endo disfavored endo disfavored endo favored
endo disfavored endo favored endo favored
endo favored endo favored
Figure 5.28 Bürgi-Dunitz
trajectory for the addition of
cyanide ion to acetone
of that study has been to revise the predictions with respect to the additions to dig systems
to replace the “acute angle” attack postulated by Baldwin with a trajectory more in accord
with the Bürgi-Dunitz angle.
Note that Baldwin’s rules extend only to the formation of relatively small rings—up to
seven atoms. Medium-sized rings present a special problem due to intramolecular

nonbonded interactions, and when one is forming large rings by intramolecular cyclizations,
the chain is usually flexible enough to allow the correct orientation of the participating
orbitals to be attained for either cyclization outcome.
5.5 Radical Reactions
The analysis above can also be applied to reactions where free radicals are involved, but
because radical reactions occur by transfer of single electrons, rather than electron pairs,
the picture is often not quite so clear-cut. The FMO of a free radical is always the SOMO,
which requires only one electron to become completely filled.
These limitations notwithstanding, the analysis above can be applied to free radical
reactions. However, in this case, because one of the participating orbitals must be the
SOMO, there should be only three types of pairings available if a new covalent bond is to
be formed; the SOMO is not an empty orbital.
Free radical reactions fall into just two common classes, and these are initiated by
either SOMO-π* or SOMO-σ* overlap. The former of these two SOMO-LUMO pairings
leads to addition of a free radical to an alkene π bond, as shown in Figure 5.29. The latter
pairing of FMOs characterizes the intramolecular rearrangements of hydrogen atoms to
oxygen- or nitrogen-centered free radicals, as occurs in the Barton32 and Hofmann-
Löffler-Freytag33 reactions (shown in Figure 5.30).
The difficulties in applying the simple form of FMO theory to free radicals also
highlights the fact that its performance when used to analyze reactions involving ex-
cited states of the reactants is often not as good as the same analysis for reactions be-
tween ground-state molecules. As with any theory, one should interpret the results of
any prediction with care, bearing in mind the limitations imposed by the basis of the
theory itself.
Figure 5.29 Singly occupied

molecular orbital (SOMO)–
SOMO lowest energy unoccupied
new σ ( + new σ*) molecular orbital overlap in
free radical addition
C C C
new SOMO
π* (+ π)
Figure 5.30 Singly occupied

molecular orbital (SOMO)–
SOMO new σ (+ new σ*) lowest energy unoccupied
H molecular orbital overlap in
H σ* hydrogen atom transfer
new SOMO
32. Barton, D.H.R.; Beaton, J.M.; Geller, L.E.; Pechet, M.M. (1961). J. Am. Chem. Soc. 1961, 83, 4076.
33. (a) Hofmann, A.W. Ber. dtsch. chem. Ges. 1879, 12, 984. (b) Löffler, K.; Freytag, C. Ber. dtsch. chem. Ges.
1909, 42, 3431.

Problems
5-14 Draw the FMO overlap for each of the following cyclization modes: 3-endo-dig,
3-endo-trig, 3-endo-tet, 4-exo-dig, 4-exo-trig, 4-exo-tet, 5-endo-dig, 5-exo-dig,
5-endo-trig, 5-exo-trig, 5-endo-tet, 5-exo-tet, 6-endo-dig, 6-exo-dig, 6-endo-trig,
6-exo-trig, 6-endo-tet, and 6-exo-tet. Where appropriate, use one of the
compounds below to illustrate your answer (it may be necessary to use another
compound in some cases):
•
CH2• H2C
CH2

5-15 The cyclization of the 5-hexenyl cation and the 5-hexenyl radical lead to very
ifferent products, as shown below. Rationalize the differences between these
d
two reactions.
MeO2C
H
CO2Me 1) Me2CuLi, THF
Me
2) H2O, THF
H
CO2Me CO2Me
1) Me2CuLi, THF
H Me
2) H2O, THF

Chapter Summary
In this chapter, a method for categorizing organic reactions based on the FMOs involved has
been introduced. The Pauli Exclusion principle, the Aufbau principle, and Hund’s rule apply
to molecular orbitals and molecules, as well as atoms, which leads to the occurrence of FMOs.
These orbitals are the HOMO; (highest energy occupied molecular orbital), the LUMO; (the
lowest energy unoccupied molecular orbital), and, in free radicals, the SOMO (singly occu-
pied molecular orbital). These FMOs determine much of the chemistry of the molecule.
Using a very simple model for reactions not involving free radicals, we find that there
are three types of filled orbitals, or HOMOs: a filled σ orbital, a filled π orbital, and a filled
n orbital. Likewise, there are only three types of empty orbitals that can be involved: an
empty nonbonding (atomic) a orbital, a π* orbital, and a σ* orbital. This gives only nine
combinations of HOMO and LUMO for the initiation of the reaction. The application of
these principles to a range of reactions is illustrated.
The effects of the FMOs involved leads to predictions about the regiochemistry and
stereochemistry of a number of reactions, phenomena such as the anomeric effect, and
Baldwin’s rules for nucleophilic ring closure.
Key Terms
anomeric effect FMO perturbing influence

Baldwin’s rules HOMO SOMO
base system LUMO stereoelectronic effect
Bürgi-Dunitz trajectory perturbation theory

Additional Problems
5-16 Provide a reasonable explanation for the observations shown below. Why does
the alkynoic ester react, whereas the alkenoic ester does not?
MeO2C
H
CO2Me 1) Me2CuLi, THF
Me
2) H2O, THF
H
CO2Me CO2Me
1) Me2CuLi, THF
H Me
2) H2O, THF

5-17 The reaction below is known to give an alcohol by intramolecular ring opening of
the epoxide ring. What is the structure of the major product and why is this the
only product formed?
CO2Me CO2Me
O HO
CO2Me 1) Bu2Cu(CN)Li2, THF HO Bu and/or Bu
2) H2O, THF
Me Me
Me
(A) (B)
(Hint: Consider the probable mechanism of this reaction and the frontier orbitals
of the cyclization step/epoxide ring opening.)
5-18 Based on your knowledge of FMO theory and Baldwin’s rules, predict the major
organic product of each of the following reactions. Where appropriate, also
specify the stereochemistry of the final product.
O
CO2Me
O Cp2TiCl
H a cyclic radical, C9H14O5[Cp2TiCl]
H
HO
O O O OTBS Zn, TBAI
C21H40O4Si
Br
C21H39BrO4Si
1) HCl, H2O
MeO NH2 OMe C16H23NO5
2) MeO2C CO2Me (a single
OMe OMe diastereoisomer)
O
buffer, pH 5.5
5-19 The reaction shown here proceeds readily when any attempt is made to add a
rignard reagent or to reduce the sulfonate with lithium aluminum hydride.
G
Write a reasonable mechanism for the transformation and give reasons why it
occurs so readily. [Can. J. Chem. 1979, 57, 3348]
O MeMgBr O
O O
TsO

5-20 The Birch reduction of benzene proceeds through the conjugated anion shown
to give 1,4-cyclohexadiene when the reaction is carried out in the presence of a
proton donor such as ethanol or tert-butyl alcohol, but not the more stable, con-
jugated isomer. When the proton source is omitted, the major product is cyclo-
hexene. Why?
Li, NH3, (t-BuOH)
Li, NH3, t-BuOH
Li, NH3
Li, NH3, t-BuOH

5-21 The answer to Sample Problem 5-2 involved protonation of the starting material
at the alkene π bond. This is not the only position where protonation could occur.
Where else could the protonation take place, and why? Should this (these) be a
major or minor reaction pathway(s)? What would be the products generated by
protonation at this (these) position(s) and why do we not observe them?

Chapter SIX
Organic Reactions I
Pericyclic Reactions and the Conservation
of Orbital Symmetry
6.1 Introduction
In Chapter 5, we began our exploration of organic reactions by using the pairings of frontier
molecular orbitals (FMOs) as a tool for categorizing them. We now continue the discussion
by looking at some important synthetic reactions that lead to the formation of new carbon-
carbon bonds. In this chapter, we will focus on pericyclic reactions, which include such
important carbon-carbon bond-forming reactions as the Diels-Alder cycloaddition and the
Cope and Claisen rearrangements. Historically, these reactions drove the development of
frontier orbital theory and the theory of conservation of orbital symmetry.
Definitions
Concerted reactions that proceed through a fully conjugated, cyclic array of continuously
bonded atoms, with reorganization of electron density at every atom of the activated com-
plex, are known as pericyclic reactions. The transition state for a pericyclic reaction will
contain either 4n electrons, in which case it is antiaromatic, or 4n + 2 electrons, in which
case it is aromatic. We will discuss the question of aromaticity in much more detail in the
next chapter of this book. The aromatic character of the transition state determines the
stereochemistry of the reaction. One of the most important characteristics of pericyclic
reactions is that their stereochemistry can be predicted by analyzing the symmetry of the
frontier orbitals involved. Pericyclic reactions can be either unimolecular or bimolecular.
Some representative examples are shown in Table 6.1.
The most common unimolecular pericyclic reactions are sigmatropic rearrangements,
where migration of an atom to a remote site in the molecule occurs during the reaction
with concomitant migration of π bonds, and electrocyclizations, where an open-chain
Table 6.1 Representative Pericyclic Reactions
Unimolecular Bimolecular
‡ X ‡
X X
(6.1) (6.2)
n n n Y n Y n Y n
Cycloadditions
Electrocyclization
R R R ‡ R R1 ‡
R1 R2
R R1 R2
R R' R2 H
R' H
(6.3) (6.4)
R' R' H R3
n n n R3
R' R4
R'
R' R' R' R4 R3 R4
Sigmatropic rearrangement Ene reaction
163

164 Advanced Organic Chemistry | Chapter SIX
conjugated system is converted into a cyclic system with one less π bond. Both these reac-
tions involve the highest energy occupied molecular orbital (HOMO) of the starting reac-
tant. The most common bimolecular pericyclic reactions are cycloadditions, where two
species react to give a new cyclic product, and ene reactions, where a new σ bond linking
the two reactants is formed with concomitant rearrangement of a hydrogen atom.
The most common cycloaddition reactions are the Diels-Alder and carbene cycloaddi-
tion reactions. The limitations imposed by the Pauli exclusion principle mandate that, in
cycloaddition reactions the HOMO of one reactant must be paired with the lowest energy
unoccupied molecular orbital (LUMO) of the other.
One of the most important properties of pericyclic reactions to emerge during the last half
of the 20th century was the concept that, in certain cases, these reactions are subject to an in-
herent symmetry-imposed barrier. Reactions lacking this barrier are designated symmetry-
allowed, whereas those subject to this barrier are designated symmetry-forbidden.
In 1965, Woodward1 and Hoffmann2 set out the principles of conservation of orbital
symmetry—the major product of a pericyclic reaction that may give more than one prod-
uct will be that one in which the symmetry of the FMOs is preserved throughout the
reaction—to rationalize the stereochemistry of electrocyclic reactions.3 Similar conclu-
sions4 were drawn by Japanese theoretical chemist Kenichi Fukui,5 who shared the Nobel
Prize with Hoffmann in 1981.
This principle, which permits the construction of orbital correlation diagrams for
some pericyclic reactions, can be used in simplified form to determine whether a particu-
lar reaction is symmetry-allowed or symmetry-forbidden under given stereochemical
constraints. In the simplified model, the overlap leading to the new bond formation is the
key factor. If it is bonding in nature at all locations where new σ bonds are being formed,
the reaction is symmetry-allowed, and if there is any antibonding overlap involved, the
reaction is symmetry-forbidden.
Problem
6-1 Classify each of the following pericyclic reactions as a member of one of the four
classes defined in Table 6.1.
H
O
(a) (b) CN
H
CN O
O O O
:CCl2
(c) O (d)
O Cl Cl
O
1. Robert Burns Woodward (1917–1979) was educated at the Massachusetts Institute of Technology (BS,
1937; PhD, 1938) and spent almost all his career, except for a short postdoctoral at Illinois, at Harvard Univer-
sity. A synthetic organic chemist of the first water, Woodward received the Nobel Prize in 1965. More biograph-
ical details can be obtained from the following: (a) Blout, E. Biogr. Mem. Nat. Acad. Sci. 2001, 80, 1. (b) Todd,
A.; Cornforth, J.W. Biogr. Mem. Fell. Roy. Soc. 1981, 27, 628.
2. Roald Hoffmann (1937–) was educated at Columbia (BA, 1958) and Harvard (MA, 1960; PhD, 1962). His
family escaped from a Nazi labor camp and settled in the United States. After three years at Harvard as a Junior
Fellow, Hoffmann joined the faculty of Cornell University, where he remains today. In addition to his Nobel
Prize-winning chemistry, Hoffmann is also a published poet and playwright. For more biographical informa-
tion, see the Nobel Foundation web site.
3. (a) Woodward, R.B.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87, 395. (b) Longuet-Higgins, H.C.; Abraham-
son, E.W. J. Am. Chem. Soc. 1965, 87, 2045.
4. Fukui, K. Bull. Chem. Soc. Japan 1966, 39, 498.
5. Kenichi Fukui (1918–1998) was educated at Kyoto Imperial University and returned as a faculty member after
spending World War II as an army fuel chemist. He was Professor of Physical chemistry until 1982, President of
Kyoto Institute of Technology from 1982–1988, and Director of the Institute for Fundamental Chemistry until his
death. For more biographical detail, see: Buckingham, A.D.; Nakatsuji, S. Biogr. Mem. Fellows Roy. Soc. 2001, 47, 223.

Organic Reactions I 165
H
(e) (f)
6.2 π Molecular Orbitals of Conjugated Systems

and Orbital Symmetry
In order to discuss pericyclic reactions, we must first revisit the LCAO π molecular orbit-
als of conjugated systems, and examine the symmetry properties of those orbitals. We
discussed the molecular orbitals of conjugated systems at some length in Chapter 4, where
we focused on the Hückel molecular orbital theory6 for predicting the orbital coefficients
of polyenes. One of the results of Hückel theory is that the 2p orbitals do not contribute
equally to each of the π orbitals of the conjugated system; orbital coefficients at the indi-
vidual atoms change from one π orbital to the next.
Orbital Symmetry
One feature of Hückel π molecular orbitals is the alternation of symmetry properties
as the energy of the orbital increases. For example, using the π molecular orbitals of
1,3,5-hexatriene (Figure 6.1), we see that ψ1, the lowest energy orbital, is symmetric with
respect to a mirror plane of symmetry (the phase sign of no lobe changes when the sym-
metry operation is applied), as are ψ3 and ψ5. On the other hand, ψ2, ψ4 and ψ6 are antisym-
metric (the phase sign of every lobe changes when the symmetry operation is applied) with
respect to the same symmetry operation. The symmetry properties of the orbitals are ex-
actly reversed when one uses the C2 axis of symmetry as the symmetry operation.
The lowest energy Hückel π orbital is symmetric with respect to a mirror plane and
antisymmetric with respect to a C2 axis of symmetry as a result of the mathematics of
Figure 6.1 Symmetry
MIRROR PLANE ORBITALS C2 AXIS
roperties of Hückel
p
ψ6 π molecular orbitals of
(A) (S) 1,3,5-hexatriene
(S) ψ5 (A)
(A) ψ4 (S)
(S) ψ3 (A)
(A) ψ2 (S)
(S) ψ1 (A)
6. (a) Hückel, E. Z. Phys. 1931, 70, 204; 1931, 72, 310; 1932, 76, 628; 1933, 83, 632. (b) Hückel, E. Trans. Faraday
Soc. 1934, 30, 40. (c) Isaacs, N.S. Physical Organic Chemistry (Longman Scientific & Technical: London, 1987),
§1.2, pp. 3–24. (d) Carey, F.A.; Sundberg, R.D. Advanced Organic Chemistry. Part A: Structure and Mechanisms,
4th ed. (Kluwer Academic/Plenum Publishers: New York, 2000), §1.4, pp. 31–36.

Figure 6.2 Symmetry of the Energy

π orbitals of 1,3-butadiene ψ1 ψ2 ψ3 ψ4
(orbitals that are symmetric
with respect to the symmetry mirror
operation are in highlighted plane
boxes)
C2 axis
Hückel theory. The same symmetry is exhibited by the terminal lobes of these orbitals. In
a symmetric orbital, the terminal lobes have the same phase after application of the sym-
metry operation. In an antisymmetric orbital, the terminal lobes have the opposite phase
sign after application of the symmetry operation.
For a reaction to occur by a concerted mechanism, the overlap of orbital lobes at the
location where the new σ bond is to be formed must be in phase (bonding). When the
overlap is out of phase (antibonding), the reaction almost always proceeds by a stepwise
and not a concerted mechanism. Reactions leading to in-phase overlap are symmetry-
allowed, and reactions leading to out-of-phase overlap are symmetry-forbidden.
The electrocyclization of (2E,4E)-2,4-hexadiene (Example 6.1) will serve as an example
for discussing this reaction. The π molecular orbitals in 1,3-butadiene are designated ψ1,
ψ2, ψ3, and ψ4, in increasing order of energy (Figure 6.2). In the diene, ψ2 is the HOMO and
ψ3 is the LUMO. Figure 6.2 shows how the phase signs of the lobes of the four π orbitals
change or do not change when a particular symmetry element is applied to the s-cis
conformation of the diene (the required conformation to give the cyclic product). The
highlighted structures in Figure 6.2 are symmetric with respect to the symmetry
operation—there is no change of sign—in the other structures, which are antisymmetric
with respect to the symmetry element, every phase sign changes on applying the symme-
try operation. As we can see, all the phase signs of ψ2 change during the mirror plane
symmetry operation, and they remain the same after the C2 axis is applied: ψ2 is symmet-
ric (S) with respect to the C2 axis of symmetry, and antisymmetric (A) with respect to the
mirror plane.
Me H
Me
H Me
(6.1)
H Me
Me
Me H
Figure 6.2 also shows that the symmetry properties of each orbital as a whole are iden-
tical to the symmetry properties of the terminal lobes alone, so only the terminal lobes of the
participating orbitals need explicitly be used to predict the outcome of a reaction. One does
not have to know the phases of every lobe in the FMO to predict the stereochemical out-
come of an electrocyclization—it is not necessary (in most cases) to use the entire orbital to
decide whether a particular reaction is symmetry allowed or symmetry forbidden. Thus,
the stereochemical consequences of pericyclic reactions are adequately predicted by a sim-
plified process where the symmetry properties of just the terminal lobes of the participat-
ing orbitals are used. For example, the stereochemistry of the electrocyclization in Example
6.1 may be predicted using this method, as shown in Figure 6.3. In principle, the cyclization
may occur by pathways that retain either the mirror plane of symmetry, or the C2 axis of
symmetry. Because this reaction is unimolecular, the reaction proceeds via the HOMO
(ψ2), which is symmetric with respect to the C2 axis of symmetry, and antisymmetric with
respect to the mirror plane. Consequently, the reaction will proceed by the pathway that

Figure 6.3 Possible
Me
e lectrocyclic ring closures of
Me Me ψ3 ψ2 (2E,4E)-2,4-hexadiene
Me
Me Me Me Me
Me Me
Me
Me
Me
Me Me Me
Me Me
Me Me
C2 axis of symmetry in
mirror plane of reactant reactant is preserved
is preserved in product in product
preserves the C2 axis of symmetry of the HOMO (Figure 6.2) over the entire course of the
reaction, and we predict that the trans-disubstituted product will be formed.
6.3 Frontier Orbital Analysis: Stereochemical Consequences
Electrocyclizations
Now let us answer the question, “How is the new bond formed?” In the case of an electro-
cyclic reaction, this involves the rotation of the two ends of the conjugated system to
permit σ-type overlap of the 2p orbitals at the ends of the chain, as shown in Figure 6.4.
This rotation can be in the same direction (clockwise for both or counterclockwise for
both), when it is known as a conrotatory ring closure, or in opposite directions, when it is
known as a disrotatory ring closure. If the FMO is symmetric with respect to a twofold
axis of symmetry, the C2 axis of symmetry is preserved throughout the reaction by a con-
rotatory process and is lost during a disrotatory process, and if the FMO is symmetric
with respect to a mirror plane, the reverse is true.
When the reaction symmetry matches the symmetry of the FMO involved, the reaction
is favorable because it leads to bonding overlap of the terminal lobes—it is symmetry-
allowed in the ground state. When the reaction symmetry does not match the symmetry of
the FMO, however, the reaction becomes very unfavorable because it leads to antibonding
overlap of the terminal lobes—it is symmetry-forbidden in the ground state. This is illus-
trated in Figure 6.4, which shows that, if the lobes at the end of the conjugated system are out
of phase, a conrotatory ring closure is required to give bonding overlap, and that if the lobes
are in phase, a disrotatory ring closure is required to give bonding overlap. Because ψ2 for the
1,3-diene system is symmetric with respect to a C2 axis, we expect that (2E,4E)-2,4-hexadiene
should give trans-3,4-dimethylcyclobutene as the product of the reaction and that heating
trans-3,4-dimethylcyclobutene should give (2E,4E)- and/or (2Z,4Z)-2,4-hexadiene.
Cycloaddition reactions are the prototypical bimolecular pericyclic reactions. By far the
most widely used cycloaddition reaction is the Diels-Alder reaction between a diene and a
dienophile to give a cyclohexene-based product. To discuss the Diels-Alder reaction, we first
need to define some stereochemical terms. When an addition occurs to a π-bonded com-
pound, if the two new σ bonds are formed on the same face of the molecule, the addition is
said to be suprafacial with respect to that reactant. This term is gradually replacing the older
one, syn addition, in discussions of the stereochemistry of additions to unsaturated systems.

Figure 6.4 Orbital symmetry

and electrocyclization terminal lobes out of phase terminal lobes in phase
CONROTATORY CONROTATORY
bonding overlap throughout antibonding overlap throughout
FAVORED NOT FAVORED
DISROTATORY DISROTATORY
antibonding overlap throughout bonding overlap throughout
NOT FAVORED FAVORED
When the addition occurs such that the two new σ bonds are formed on opposite faces of the
reactant, the addition is antarafacial; this term is gradually replacing the older one, anti
addition. Other addition reactions that we have studied already fall into these two classes:
hydroboration is a suprafacial addition to an alkene, whereas the addition of bromine to an
alkene is antarafacial.
In a cycloaddition reaction, two new σ bonds are formed at the expense of two π
bonds. This means that the reaction may be suprafacial with respect to both reactants,
suprafacial with respect to one and antarafacial with respect to the other, or antarafacial
with respect to both (this combination is quite rare and can be ignored in most cases). The
stereochemical consequences of each of these reaction pathways are shown in Figure 6.5.
Note how suprafacial addition leads to retention of relative configuration at the reacting
centers, whereas antarafacial addition leads to inversion of relative configuration.
Cycloadditions
Cycloaddition reactions are occasionally described using a system that shows the number of
π electrons in each reacting species as well as the stereochemistry of the addition with respect
to that reacting species. For example, the Diels-Alder reaction is the reaction between a diene
(with four π electrons) and a dienophile (with two π electrons). Using this system, it is desig-
nated as a 4π + 2π cycloaddition. In addition, the reaction is suprafacial with respect to the
diene (4πs) and the dienophile (2πs), so the complete representation of the reaction in this
system is [4πs + 2πs]. A simpler system denotes the cycloaddition by the number of atoms in the
two reacting species. The Diels-Alder reaction is a [4 + 2] cycloaddition in this system, also.
Cycloaddition reactions are very amenable to the same simplified FMO analysis that we
used for electrocyclizations. In other words, only the terminal lobes of the reacting species

Figure 6.5 Stereochemical
ref. ref. outcomes of cycloadditions:
w x w x “ret.” indicates retention of
a suprafacial-
a b b configuration and “inv.”
d c c suprafacial
d indicates relative inversion of
z y zy ret. configuration relative to the
ret. reference centers, labeled “ref.”
ref. ref.
w x w x
a suprafacial
a b b (polyene)-
d c c antarafacial
d
z y yz
ret. inv.
ref. ret\f.
w x w x
b antarafacial-
a b a
d c c antarafacial
d
z y yz inv.
inv.
need be considered explicitly. The two possible HOMO-LUMO combinations for [4+2] [6+2]
the [4 + 2] and [6 + 2] cycloadditions are shown in Figure 6.6, which illustrates this
LUMO (ψ3) LUMO (ψ4)
simplified approach. Based on this simple analysis, we anticipate that the [4 + 2]
cycloaddition will be symmetry-allowed when suprafacial with respect to both
participating reactants, whereas the related [6 + 2] cycloaddition, which forms a
cyclooctadiene, will be symmetry-forbidden unless the reaction is suprafacial with
respect to one participant and antarafacial with respect to the other. In both reac-
tions, the two species react through complementary FMOs; one uses the HOMO,
and the other uses the LUMO. This observation may be extended to state that in all HOMO (π) HOMO (π)
multiorbital pericyclic reactions, one unoccupied orbital is used in the overlap that
HOMO (ψ2) HOMO (ψ3)
initiates the reaction. Note how the suprafacial overlap at both ends of each reacting
species in the [6 + 2] cycloaddition involves one antibonding interaction; this indi-
cates that the reaction with this stereochemistry has a symmetry-imposed b arrier—
it is symmetry-forbidden. Extending this analysis to cycloadditions in general
reveals that [m + n] cycloadditions are symmetry-allowed in the ground state with
suprafacial-suprafacial (or antarafacial-antarafacial) stereochemistry when m + n
= 4n + 2 (i.e., 2, 6, 10, 14) and symmetry-forbidden when m + n = 4n (i.e., 4, 8, 12). LUMO (π*) LUMO (π*)
Figure 6.6 Simplified frontier orbital

Problems analysis for cycloaddition reactions
6-2 The cycloaddition reaction below is symmetry-allowed either

suprafacial-suprafacial or antarafacial-antarafacial. What would be the
difference observed in the products of the two reactions?
D O D O
+ O O
D O D O
(continues)

6-3 The antarafacial-antarafacial overlap in Figure 6.5 is shown as given below. What
are the other possible stereochemical outcomes of an antarafacial-antarafacial
cycloaddition in this system?
x y x z
w y
w z
b c ac
b d
a d
Thermal and Photochemical Reactions

In the discussion that follows, the ideas will be developed in terms of thermal reactions:
reactions that occur in the ground state of the molecule. In addition, most of the discus-
sion will be primarily concerned with the lobes at the end of the conjugated π systems (the
terminal lobes).
However, the activation energy of organic reactions may be supplied by visible or
ultraviolet light as well as by heat. When carried out photochemically, these reactions
may be treated as occurring through the excited state of one of the reacting species.7
The absorption of light by a conjugated system is accompanied by promotion of an
electron from a lower energy ground-state orbital to the ground-state LUMO, making
the ground-state LUMO the HOMO of the excited state. This results in a reversal of the
symmetry types of the HOMO and LUMO in the excited state compared to the ground
state. As we shall see, this has important effects on the stereochemistry of a pericyclic
reaction.
6.4 Sigmatropic Rearrangements: More Details
Sigmatropic rearrangements (Example 6.2) are concerted reactions that occur through a
cyclic activated complex. They most often involve a hydrogen atom or an alkyl group as the
migrating group (R'). Regardless of the migrating group, sigmatropic rearrangements
always involve the relocation of π bonds as well as σ bonds. It is important to remember
that there are two σ bonds that participate in the sigmatropic rearrangement—one being
formed and one being broken. In the activated complex, however, the migrating group is
bonded to both ends of the conjugated π system simultaneously, so in-phase (bonding)
overlap to the migrating group is required at both ends of the conjugated π system for the
reaction to be favored.
R R R ‡ R
R
R R'
R'
(6.2)
R' n
R' n
n
R'
R' R' R'
R'
Like cycloadditions and electrocyclizations, sigmatropic rearrangements can be ana-

lyzed in terms of simplified frontier orbital analysis rather than a full orbital correlation
7. For a review containing experimental data for photochemical pericyclic ring openings, see: Lawless, M.K.;
Wickham, S.D.; Mathies, R.A. Acc. Chem. Res. 1995, 28, 493.

old bonds breaking Figure 6.7 Nomenclature of

sigmatropic rearrangements
2 ‡
1 3 2
1 3
3 3
1 2 1 2
new bonds forming

old bonds breaking
5 ‡
5 5
1H 4 1H 4 1H 4
3 3 3
1 2 1 2 1 2
new bonds forming
analysis. In the activated complex for a sigmatropic rearrangement, the two ANTARAFACIAL
halves of the activated complex are linked by two partial σ bonds—the rem-
nant of the σ bond that is broken during the reaction and the incipient stage
of the new σ bond that is formed during the reaction. To designate the rear-
rangement type, the two parts of the reactant molecule are numbered from
the σ bond that is broken toward the σ bond that is formed. The rearrange-
ment is then named for the two loci that specify the place where the new σ
bond is formed, with the two numbers in square brackets: an [m,n]-sigmatropic SUPRAFACIAL
rearrangement. Thus, in the upper example in Figure 6.7, the new bond is Figure 6.8 Stereochemistry of
being formed between position 3 of the top half of the activated complex and rearrangement
position 3 of the bottom half, making this is a [3,3] sigmatropic rearrange-
ment. In the lower example, the hydrogen atom has number 1, and it migrates to position
5 of the other half of the activated complex, so this is a [1,5]-sigmatropic rearrangement.
By analogy with cycloadditions, the stereochemistry of sigmatropic rearrangements is
defined as either suprafacial, where the breaking bond and the forming bond are on the
same face of the conjugated system, or antarafacial, where the these bonds are on opposite
faces of the conjugated system (Figure 6.8). The s tereochemistry of any particular reaction
can be predicted from an analysis of the FMOs involved.
[1,n]-Sigmatropic Rearrangements of Hydrogen

Let us begin by discussing the simplest types of this reaction, [1,3]- and [1,5]-sigmatropic
rearrangements of hydrogen (Examples 6.3 and 6.4, respectively). The simplest approach
to use to predict the stereochemistry of sigmatropic rearrangements is to divide the acti-
vated complex into two complementary systems: a cation and an anion. Thus, the stereo-
chemistry of sigmatropic rearrangement of hydrogen can be predicted using the orbitals
of a proton (LUMO, 1s) and the conjugated anion (HOMO, ψ2), or the orbitals of a hydride
anion (HOMO, 1s) and the conjugated cation (LUMO, ψ2). One may also view the reaction
as occurring by overlap of the singly occupied molecular orbitals (SOMOs) of two free
radicals; the prediction remains the same because, again, the FMOs of the two participat-
ing species remain the same (1s, ψ2).
R R H R R
H
(6.3) (6.4)
H H

Figure 6.9 Symmetry suprafacial antarafacial

roperties of sigmatropic
p
rearrangements of hydrogen
symmetry forbidden symmetry allowed
suprafacial antarafacial
symmetry allowed symmetry forbidden
For the [1,3]-sigmatropic rearrangement of hydrogen, the pair of orbitals involved is the
same regardless of the choice made: the 1s orbital of hydrogen and ψ2 of the allyl system. Of
the two possible combinations, the [1,3]-suprafacial rearrangement is symmetry-forbidden,
and the [1,3]-antarafacial rearrangement is symmetry-allowed (Figure 6.9). However, geomet-
rical constraints prevent the concerted antarafacial migration, so we expect that this reaction
will not proceed by a concerted mechanism.
For the [1,5]-sigmatropic rearrangement, the FMOs are the hydrogen 1s orbital and ψ3
of the pentadienyl system. This reaction is now symmetry-a llowed suprafacially and
symmetry-forbidden antarafacially. Because the suprafacial reaction is not prevented by
geometric constraints, concerted [1,5]-sigmatropic rearrangements of hydrogen often
occur readily.
Extending this analysis, we see that suprafacial [1, m] sigmatropic rearrangements of
hydrogen are symmetry-allowed when m + 1 = 4n + 2 and symmetry-forbidden when
m + 1 = 4n, with the corresponding antarafacial sigmatropic rearrangements obeying the
opposite symmetry rules.
[1,n]-Sigmatropic Rearrangements of Alkyl

Things change when the migrating group becomes alkyl, rather than hydrogen (Figure 6.10)
because, unlike hydrogen, carbon atoms may react using either an sp3 hybrid orbital (supra-
facial reactions, like hydrogen) or a 2p orbital (antarafacial reactions). Here, if the migrat-
ing carbon atom retains its sp3 hybridization (i.e., its stereochemistry), the analysis of the
reaction is strictly analogous to that of sigmatropic rearrangements of hydrogen. The su-
prafacial migration is symmetry-forbidden in the [1,3]-sigmatropic rearrangement, and
symmetry-allowed in the [1,5]-sigmatropic rearrangement. [1,5]-Sigmatropic rearrange-
ments occur with retention of configuration at the migrating carbon atom.
Recall that the suprafacial [1,3]-sigmatropic rearrangement of hydrogen is symmetry-
forbidden under all conditions. This is not the case for carbon, however, which can and
does participate in [1,3]-sigmatropic rearrangements. This is because the FMO of the hy-
drogen atom is the spherical 1s orbital, with a single lobe available, and an sp3 carbon atom
can rehybridize to sp2, to give a 2p orbital, which has two lobes of equal size and shape, but
opposite phase. Under these circumstances, a suprafacial [1,3]-sigmatropic rearrangement
can occur, but it must do so with inversion of configuration at the migrating carbon to be
symmetry-allowed. If we think about the transition state for this reaction, it looks some-
thing like the transition state for the SN2 reaction: the migrating carbon atom is sp2

Figure 6.10 Stereochemistry
1,5-suprafacial 1,5-antarafacial
and symmetry properties of
[1,3]- and [1,5]-sigmatropic
rearrangements of alkyl
groups. Symmetry-a llowed
reactions are highlighted in
boxes.

with retention with retention

with retention with retention

with inversion with inversion

with inversion with inversion
hybridized with the “nucleophile” partially bonded to one lobe of the 2p orbital and the
“leaving group” partially bonded to the other. Thus, [1,3]-sigmatropic rearrangements of
carbon groups can and do occur in a suprafacial manner; [1,3]-sigmatropic rearrangements
occur with inversion of configuration at the m
igrating carbon atom.
[3,3]-Sigmatropic Rearrangements
The [3,3]-sigmatropic rearrangement is a reaction that has been very effectively used to
transfer chirality from one part of a molecule to another, as we will discuss in more

Table 6.2 [3,3]-Sigmatropic Rearrangements Used in Organic Synthesis
Y Y
X X
X Y Reaction Name
O R Claisen rearrangement
O OSiR 3 Ireland ester enolate Claisen rearrangement
O OR Johnson orthoester Claisen rearrangement
O NMe2 Eschenmoser ketene N,O-acetal Claisen
rearrangement
CR 2 R Cope rearrangement
CR-O− R Oxyanion Cope (or oxy-Cope) rearrangement
detail below. Therefore, it has become a widely used reaction in modern organic synthe-
sis, and there are many versions of this reaction that have been developed since the first
report of the rearrangement by Ludwig Claisen in 1912.8 The more common named ver-
sions of the reaction are gathered in Table 6.2. Many of the extensions of the Claisen
rearrangement have originated from the study of the effects of substituents on the vinyl
ether moiety. Generally, it has been found that electron-releasing substituents on the
vinyl ether accelerate the reaction, so much of the focus of research has been involved
with the study of electron-donating substituents at this site. This work has given rise to
several variants of the parent r eaction (Table 6.3).
This rearrangement may be treated—very simplistically—as proceeding through
complementary ions (an allyl cation and an allyl anion) or as a pair of free radicals. In
either case, ψ2 is the orbital used by both partners in the activated complex, as shown
at left. Based on simple FMO analysis, one predicts that the reaction is suprafacial with
respect to both allylic substructures, and this is observed experimentally. However, it
is important to know the conformation of the activated complex in this reaction, be-
cause reactions proceeding through a chairlike transition state will give stereochemi-
cal results different from those occurring through boatlike transition states, as
illustrated in Figure 6.11.
The Claisen rearrangement emerged as an important reaction for the formation of
carbon-carbon bonds in a stereoselective manner during the last third of the twentieth
century. This resulted from its ability to generate new chiral centers with predictable ste-
reochemistry at a site in the molecule remote from existing chiral centers (“chirality
transfer”).9
8. Claisen, L. Ber. Deut. chem. Ges. 1912, 45, 3157.

Ludwig Claisen (1851–1930) studied at Bonn (PhD, 1874), with an interruption for the Franco-Prussian War.
He taught at Bonn (until 1882), at Owens College in Manchester (1882–1885), Munich (1886–1890), Aachen
(1890–1897), Kiel (1897–1904), and Berlin (1904–1907) before retiring to Godesberg and his private laboratory.
For more biographical details, see: (a) Pötsch., W. Lexikon bedeutender Chemiker (VEB Bibliographisches In-
stitut: Leipzig, 1989). (b) http://www.uni-kiel.de/ps/cgi-bin/fo-bio.php?nid=claisen&lang=e
9. Reviews: (a) Rhoads, S.J.; Raulins, N.R. Org. React. 1975, 22, 1. (b) Bennett, G.B. Synthesis 1977, 589.
(c) Ziegler, F.E. Chem. Rev. 1988, 88, 1423. (d) Blechert, S. Synthesis 1989, 71. (e) Wipf, P. In Fleming, I.; Trost, B.M.,
Eds. Comprehensive Organic Synthesis, (Pergamon: Oxford, 1991), vol. 5, p. 827. (f) Nowicki, J. Molecules 2000,
5, 1033.
Monographs and textbooks: (f) Smith, M.B. Organic Synthesis, 2nd. ed. (McGraw-Hill: Boston, 2002),
p. 1021. (g) Carruthers, W.; Coldham, I. Modern Methods of Organic Synthesis, 4th ed. (Cambridge University
Press: Cambridge, 2004), p. 244. (h) Zwiefel, G.S.; Nantz, M.H. Modern Organic Synthesis: An Introduction
(W.H. Freeman & Co.: New York, 2007), p. 390. (i) Hiersmann, M.; Nubbemeyer, U., Eds. The Claisen Rear-
rangement. Methods and Applications (Wiley-VCH: Weinheim, 2006).

CHO CHO Figure 6.11 Stereochemical

H H outcomes of suprafacial
‡ ‡ [3,3]-sigmatropic rearrange-
H O O H
ment of the E,E enol ether
O
through chair and boat tran-
sition states
OHC OHC
chair-like boat-like
Table 6.3 Representative Claisen-type Rearrangements
‡
R R R
O O O
OH O OR O OR
R R R
CHO CO2Me
O OH
∆ OH OAc
(6.5) CH3C(OMe)3
H H H H (6.6)
EtCO2H/∆/3 h
O O O O
83%
Claisen rearrangement8
Johnson orthoester variant10
O OSiR3 O
R R R
O O HO OH O NR2 O NR2
R R R
O O OH OMe
MeO
MeO Me OMe
O 1) LDA/THF/–78°C HO NMe2 (6.9)
(6.7) O
2) TBDMSCl O 100-120°C/2 h
3) 25-65°C >75% CONMe2
HO
O O HO
O 1) LDA/THF/HMPA/–78°C HO Eschenmoser variant12

(6.8)
2) TBDMSCl
3) 25-65°C
Ireland variant11
O O OH O OH O O
O R O R O R (–CO2) R
O O O
O
∆
10 (95%) (6.10)
E:Z 54:46
11
Carroll variant13
12
13
10. (a) Johnson, W.S.; Werthemann, L.; Barrett, W.R.; Brockom, T.J.; Li, T.; Faulkner, D.J.; Petersen, M.R. J.
Am. Chem. Soc. 1970, 92, 741. (b) Trust, R.I.; Ireland, R.E. Org. Syn. Coll. Vol. VI 1988, 1781.
11. (a) Ireland, R.E.; Mueller, R.H. J. Am. Chem. Soc. 1972, 94, 5897. (b) Ireland, R.E.; Mueller, R.H.; Willard,
A.K. J. Am. Chem. Soc. 1976, 98, 2868. (c) Ireland, R.E.; Wilcox, C.S. Tetrahedron Lett. 1977, 2839. (d) Pereira,
S.; Srebnik, M. Aldrichimica Acta 1993, 26, 17.
12. Wick, A.E.; Felix, D.; Steen, K.; Eschenmoser, A. Helv. Chim. Acta 1964, 47, 2425.
13. (a) Carroll, K.F. J. Chem. Soc. 1940, 704. (b) Kimel, W.; Cope, A.C. J. Am. Chem. Soc. 1943, 65, 1992.
(c) Samochvalov, G.I.; Preobazhenskii, N.A. Zh. Obshch. Khim. 1957, 27, 2501. (d) Nazarov, I.N. Zh, Obshch.
Khim. 1958, 28, 1444.

In this reaction, an allyl vinyl ether (or a substituted variant of an allyl vinyl ether) is
heated to form a carbonyl compound. In general, the reaction proceeds through a chair-
like transition state, which has been calculated to be favored by approximately 2-5 to 3.0
kcal mol−1.14 It is one of the consequences of this preferred stereochemistry that in simple
systems capable of producing both the E and Z isomer of the double bond, the E isomer
tends to be strongly preferred, because the substituent occupies a quasiequatorial position
in that activated complex.15
The [3,3]-sigmatropic rearrangement of 1,5-dienes16 is known as the Cope17 rear-
rangement. Unlike the Claisen rearrangement, where the equilibrium almost always
favors the carbonyl product, the Cope rearrangement and certain of its congeners (e.g.,
the aza-Cope rearrangement, where the carbon atom at the 2- position of the 1,5-diene
is replaced by the nitrogen atom of an iminium ion) tend to be more easily reversed.
When a 1,5-diene is heated, a new 1,5-diene is formed where the σ and π bonds of the
two allyl groups comprising the two halves of the diene system have reversed their posi-
tions. The stereospecificity of these rearrangements is illustrated by the two reactions
shown here: meso-3,4-d imethyl-1,5-hexadiene gives (2E,6Z)-2,6-octadiene as the prod-
uct (Example 6.11), whereas (±)-3,4-d imethyl-1,5-hexadiene gives (2E,6E)-2,6-octadiene
(Example 6.12).
‡
∆
(280°C)
Me Me ‡ Me (6.11)
H H H
Me Me Me
H H H
‡
∆
(6.12)
(280°C)
Like the Claisen rearrangement, the Cope rearrangement proceeds through a chair-
like transition state,18 so one need only draw the transition state in the most stable chair
conformation to assign the stereochemistry of the two π bonds in the product (e.g.,
meso-3,4-dimethyl-1,5-hexadiene gives the E,Z isomer of the product).
The Cope rearrangement is generally more facile when the reaction leads to the re-
duction of strain in the molecule, as illustrated in Figure 6.12. Thus, the energy barrier for
14. (a) Vitorelli, P.; Winkler, T.; Hansen, J.-H.; Schmid, H. Helv. Chim. Acta 1968, 51, 1457. (b) Hansen, H.J.;
Schmid, H. Tetrahedron 1974, 30, 1959. (c) Vance, R.L.; Rondan, N.G.; Houk, K.N.; Jensen, F.; Borden, W.T.;
Komornicki, A.; Wimmer, E. J. Am. Chem. Soc. 1988, 110, 2314.
15. (a) Faulkner, D.J.; Petersen, M.R. J. Am. Chem. Soc. 1969, 95, 553. (b) Faulkner, D.J.; Petersen, M.R. Tetra-
hedron Lett. 1969, 3243.
16. (a) Cope, A.C.; Hardy, E.M. J. Am. Chem. Soc. 1940, 62, 441. (b) Rhoads, S.J.; Raulins, N.R. Org. React.
1975, 22, 723. (c) Schröder, G.; Oth, J.F.M.; Merény, R. Angew. Chem. Int. Ed. Engl. 1965, 4, 752.
17. Arthur Clay Cope (1909–1966) was educated at Butler University (BS, 1929) and the University of Wis-
consin (PhD, 1932). After postdoctoral study at Harvard University, he was on the faculty of Bryn Mawr College
(1934–1941), Columbia (1942–1945), and MIT (1945–1965). Cope was President of the American Chemical Soci-
ety in 1961. For more details, see: Roberts, J.D.; Sheehan, J.C. Biogr. Mem. Nat. Acad. Sci. 1981, 60, 17.
18. (a) Doering, W.v.E.; Roth, W.R. Tetrahedron 1962, 18, 67. (b) Doering, W.v.E.; Roth, W.R. Angew. Chem.
1963, 75, 27.

Ea 33.5 Figure 6.12 Variation of acti-

vation energy of the Cope
rearrangement
Ea 23.1 Ea 19.4
O Ea 18.2 O
the Cope rearrangement of 1,5-hexadiene is 33.5 kcal mol−1,19 whereas the corresponding
values for cis-1,2-divinylcyclobutane20 and cis-1,2-divinylcyclopropane21 are 23.1 kcal
mol−1 and 19.4 kcal mol−1, respectively. Substituents capable of conjugating with the newly
formed double bonds in the product are also effective at lowering the activation energy
for the reaction. For example, the Cope rearrangement of 1,5-hexadien-3-ol initially leads
to 1,5-hexadien-1-ol, which immediately tautomerizes to the aldehyde, thus also making
the reaction irreversible. This reaction, known as the oxy-Cope rearrangement,22 becomes
even faster (by a factor in excess of 1010) when the conjugate base of the alcohol is the
reactant.23 The activation energy for the rearrangement of the conjugate base of
1,5-hexadien-3-ol is 18.2 kcal mol−1,24 even lower than the activation energy for the rear-
rangement of cis-1,2-divinylcyclopropane.
Reaction Synopses
Sigmatropic Rearrangements
R a [1,n] R a [m,n]
a a
b b b b
Rearrangement designated as [m.n]-sigmatropic rearrangement, where m and n

indicate loci of new σ bond formation based on locus of broken σ bond in starting
material
Stereochemistry: suprafacial if [m + n]=4x + 2; antarafacial if [m+n] = 4x
(continues)
19. Doering, W.v.E.; Toscano, V.G.; Beasley, G.H. Tetrahedron 1971, 27, 5299.
20. Hammond, G.S.; Deboer, C.D. J. Am. Chem. Soc. 1964, 86, 899.
21. Brown, M.J.; Golding, B.T.; Stofko, J.J., Jr. J. Chem. Soc., Chem. Commun. 1973, 319.
22. (a) Berson, J.A.; Walsh, E.J., Jr. J. Am. Chem. Soc. 1968, 90, 4729. (b) Viola, A.; Padilla, A.J.; Lennox, D.M.;
Hecht, A.; Proverb, R.J. J. Chem. Soc., Chem. Commun. 1974, 491.
Reviews: (c) Marvell, E.N.; Whalley, W. In Patai, S., Ed. The Chemistry of the Hydroxyl Group, Part 2 (Wiley:
New York, 1971), p. 738. (d) Paquette, L.A. Angew. Chem. Int. Ed. Engl. 1990, 29, 609. (e) Paquette, L.A. Synlett
1990, 67.
23. (a) Evans, D.A.; Nelson, J.V. J. Am. Chem. Soc. 1980, 102, 774. (b) Miyashi, H.; Tazato, A.; Mukai, T. J. Am.
Chem. Soc. 1978, 100, 1008. (c) Paquette, L.A.; Pegg, N.A.; Toops, D.; Maynard, G.D.; Rogers, R.D. J. Am. Chem.
Soc. 1990, 112, 277. (d) Gajewski, J.J.; Gee, K.R. J. Am. Chem. Soc. 1991, 113, 967. (e) Wender, P.A.; Ternansky, R.J.;
Sieburth, S.M. Tetrahedron Lett. 1985, 26, 4319.
24. Evans, D.A.; Golob, A.M. J. Am. Chem. Soc. 1975, 97, 4765.

Cope Rearrangement
X
R1 R2 R1 R2
∆ X
R4 R3 R4 R3
Stereochemistry: suprafacial with respect to both halves of the activated complex

Reaction occurs through a chairlike transition state.
Accelerated by electron-rich substituents (e.g., OH, O−, NR 2) at position X (e.g.,
oxy-Cope rearrangement)
Claisen Rearrangement
Y Y
R1 R1
X ∆ X
R3 R2 R3 R2
Stereochemistry: suprafacial with respect to both halves of the activated complex

Reaction occurs through a chairlike transition state.
Variants: Ireland (X=O, Y=OSiMe3); Johnson (X=O, Y=OR); Eschenmoser
(X=O, Y=NR 2); Carroll (X=O, Y=OH, R 1=RCO)
Worked Problem
6-1 Under what conditions should the following reaction occur?
§Answer below
Problems
6-4 Electrocyclization of dienes is a poor method for forming stereochemically pure

cyclobutenes. Why?
6-5 When the conjugated tetraene below is heated, the bicyclic product shown is the
only product of the reaction. Write a mechanism that accounts for its formation
and rationalize the stereochemistry.

This reaction is a [1,5]-sigmatropic shift of hydrogen.
H H H
The reaction is symmetry-allowed in the ground state with suprafacial stereochemistry, so the reaction will
proceed under thermal conditions. One only needs to heat the diene to cause the isomerization. Note how the
product is the Z diene.

H Me
Me
∆
(±)
Me Me
H
(2E,4Z,6Z,8E)
6-6 What is the major organic product of each of the following reactions? Designate
the stereochemistry of the major product.
H
∆ ∆ ∆
(a) (b) (c)
H
H
∆ ∆ ∆
(d) (e) (f)
H
H H H
∆ ∆ ∆
(g) (h) (i)
H H H
6-7 5-Methyl-1,3-cyclopentadiene is formed from the reaction between the sodium salt
of cyclopentadiene and methyl iodide at −78°C. If this diene is stored at room
temperature, it becomes a mixture of 1-methyl-1,3-cyclopentadiene, 2-methyl-1,3-
cyclopentadiene, and 5-methyl-1,3-cyclopentadiene in just a few hours. Why?
Which isomer should be formed in greatest amount and which in least?
MeI
C5H5 Me Me Me
–78°C
6-8 The reaction below is concerted. Show the stereochemistry of the final product
and rationalize its formation.
AcO H
∆
OAc
H
6-9 Predict the products of each of the following reactions.
O O O O
O 1) LDA (2 eq), THF, -70—65°C 1) LDA, THF, –78°C

O
(a) (b)
2) CCl4, 77°C, 1 h (–CO2) 2) CCl4, 77°C
O
O
O ∆ (product has ∆
(c) cis ring fusion) (d)
O O
H H
OMe
H OH Me OMe
O
NMe2 ∆
(e) (f)
∆
HO
O
∆
(g)

6.5 Cycloaddition Reactions: More Details
In 1906, Wieland discovered that 1,3-dienes would react with alkenes to form a cyclohexe-
nes,25 and Albrecht reported that 1,3-cyclopentadiene reacted with 1,4-benzoquinone to
give both 1:1 and 2:1 adducts.26 However, the structures of many of the products remained
unknown until the 1920s, when Otto Diels and Kurt Alder27 finally determined them.28
Their systematic exploration of the scope of the “diene synthesis,” as it was then called
established the reaction—now almost universally known as the Diels-Alder reaction—as
a major method for the synthesis of six-membered rings.29 Part of their legacy is the termi-
nology that we now use to describe the two participating reactants: the diene and the di-
enophile (from “diene” and the Greek, ϕιλος, philos, loving).
Categorization of Cycloadditions
Cycloaddition reactions are commonly categorized according to one of two conventions
that specify either the number of electrons used by each of the two participating species or
the number of atoms used by each of the two participating species. Cycloaddition reac-
tions share many of the traits of sigmatropic rearrangements. They are concerted reactions
(although alternative nonconcerted mechanisms have been proposed) that are both highly
regioselective and stereoselective (or, more usually, stereospecific).
The Diels-Alder reaction, which is the prototypical [4 + 2] cycloaddition reaction, has
been the subject of considerable research since the pioneering studies of Diels and Alder
in the 1920s, and its predictable stereochemical and regiochemical outcomes have made
the it one of the cornerstone reactions of modern organic synthesis. The [2 + 2] cycload-
dition corresponding to the Diels-Alder reaction is most commonly used in the form of
photochemical addition of an alkene to an enone or in the form of the addition of a ketene
to an alkene.
To achieve effective HOMO-LUMO overlap, the lobes at the ends of the diene must
overlap with the lobes at the ends of the dienophile. At the same time, the geometry of the
activated complex geometry must allow the simultaneous formation of the two new σ
25. Wieland, H. Ber. Deut. chem. Ges. 1906, 39, 1492.

26. Albrecht, W. Justus Liebvigs Ann. Chem. 1906, 348, 31.
27. Otto Paul Hermann Diels (1876–1954) received his PhD from Berlin, where he eventually became pro-
fessor. In 1916 he moved to Kiel, where he spent the rest of his professional life, retiring in 1945. Diels shared the
1950 Nobel Prize in Chemistry with his student, Kurt Alder. For more biographical detail, see: Schmauderer, E.
“Otto Diels.” In: Gillispie, C.C., Ed., Dictionary of Scientific Biography, (Charles Scribner’s Sons: New York,
1972), vol. 4, p. 90.
Kurt Alder (1902–1958) received his PhD under Otto Diels at Kiel in 1926. He remained at Kiel until 1936,
then became director of research for the German chemical giant I.G. Farben. In 1940, he moved to Cologne as
professor of chemistry, and he remained there for the rest of his life. Alder was quite young when he died in
1958—less than three weeks before his 56th birthday. For more biographical details, see: Ihde, A.J. “Kurt Alder”
Dictionary of Scientific Biography (Charles Scribner’s Sons: New York, 1970), vol. 1 p. 105.
28. Diels, O.; Alder, K. JustusLiebigs Ann. Chem. 1928, 460, 98.
29. Reviews: (a) Kloetzel, M.C. Org. React. 1948, 4, 1. (b) Holmes, H.L. Org. React. 1948, 4, 61. (c) Butz, L.W.;
Rytina, A.W. Org. React. 1949, 5, 136. (d) Walling, C. In Brooks, B.T., Ed. The Chemistry of Petroleum Hydrocar-
bons (Reinhold: New York, 1955), vol. 3, ch. 47. (e) Huisgen, R.; Grashey, R.; Sauer, J. In Patai, S., Ed. The Chem-
istry of Alkenes (Wiley-Interscience: New York, 1964), p. 878. (f) Wassermann, A. Diels-Alder Reactions:
Organic Background and Physicochemical Aspects (Elsevier: Amsterdam, 1965). (g) Sauer, J. Angew. Chem. Int.
Ed. Engl. 1966, 5, 211. (h) Wollweber, H. Diels-Alder Reaktion (Verlag, G.T.: Stuttgart, 1972). (i) Danishefsky, S.
Acc. Chem. Res. 1981, 14, 400.

bonds and the new π bond in a six-membered ring. For these reasons, the Diels-Alder re-
action must occur through the s-cis conformer of the diene. Reacting through the s-trans
conformation requires HOMO-LUMO overlap at unreasonably large distances and results
in the reaction proceeding through an activated complex resembling a trans-cyclohexene,
which is prohibitively strained. Cyclic dienes that are locked by the ring in the s-cis con-
formation (e.g., 1,3-cyclopentadiene and 1,3-cyclohexadiene) tend to be much more reac-
tive than acyclic dienes. Dienes that cannot achieve the s-cis geometry (e.g., bicyclo[4.4.0]
deca-1,6-diene) do not react in the Diels-Alder reaction at all.
locked s-cis dienes: very reactive locked s-trans diene: unreactive
Dienes such as 4-methyl-1,3-pentadiene, which can attain the s-cis conformation only
with difficulty (the s-cis conformation is some 6 kcal mol−1 higher energy than the s-trans
conformation), tend to react only extremely slowly—if at all. This particular diene, for
example, reacts with tetracyanoethylene to give a 11% yield of the [4 + 2] adduct, which is
accompanied by the [2 + 2] adduct as the major (60%) product (Example 6.13).30 The reac-
tion with maleic anhydride (Example 6.14) gives erratic results, giving two monomeric
products in varying ratios, depending on the purity of the reactants.31
NC CN
NC CN
CN CN
H NC CN CN CN (6.13)
+
CN
CN
O O
O O O
O + O (6.14)
HO OH
O O
For a concerted cycloaddition reaction to proceed, the overlap at both ends of both re-
acting orbitals must be between lobes of like phase. In the [4 + 2] cycloaddition, the FMOs
are of like symmetry type—both symmetric or both antisymmetric. To meet the in-phase
overlap requirement, therefore, the addition must be suprafacial with respect to both reac-
tants; the stereochemistry of the product of the Diels-Alder reaction will reflect its forma-
tion by suprafacial addition with respect to both reactants. There are two different
HOMO-LUMO combinations (Figure 6.13) that can be used to initiate the reaction: the
diene HOMO and the dienophile LUMO or the diene LUMO and the dienophile HOMO.
Of the two possible combinations of FMOs in the Diels-Alder reaction, the dominant
FMO overlap is the combination of the diene HOMO and the dienophile LUMO. There-
fore, any structural change that lowers the energy of the dienophile LUMO will accelerate
the reaction and any structural change that raises the energy of the dienophile LUMO will
retard it. By similar reasoning, any structural change that raises the energy of the diene
HOMO will accelerate the reaction and any change that lowers the diene HOMO energy
will retard it. Electron-withdrawing groups tend to make the π bond more polar and lower
the energy of its bonding and antibonding orbitals; electron-releasing groups have the
30. Stewart, C.A., Jr. J. Am. Chem. Soc. 1962, 84, 117.
31. (a) Goldman, N.L. Chem. Ind. (London) 1963, 1036. (b) Ichizaki, I.; Avai, A. Bull. Chem. Soc. Japan 1964,
37, 432.

olecular orbital overlaps
m
possible in [4 + 2] cycloaddi- DIENE
tions. HOMO, highest energy HOMO (ψ2)
occupied molecular orbital;
DIENOPHILE
LUMO (π*)
DIENE
LUMO (ψ3)
DIENOPHILE
HOMO (π)
Figure 6.14 Frontier orbital -0.70 -0.21

energy gaps for some repre-
sentative Diels-Alder -2.24 -2.56 -2.24 -2.56
reactions
Energy
3.52 eV
3.81 eV
5.04 eV
-5.76 6.06 eV 8.09 eV
5.83 eV -6.37
-7.28
-8.39 -8.39 -8.30
OMe CHO CHO
CHO CHO OMe
opposite effect. Therefore, electron-withdrawing substituents accelerate the Diels-Alder

reaction if they are on the dienophile and retard it if they are on the diene; electron-
releasing substituents accelerate the reaction if they are on the diene, and retard it if they
are on the dienophile. Conjugating groups (e.g., vinyl groups or aromatic rings) raise the
energy of bonding orbitals and lower the energy of antibonding orbitals, so they accelerate
the reaction if they are on either reactant.
The HOMO-LUMO energy gap is inversely related to the rate of the Diels-Alder reac-
tion,32 so the larger the gap, the slower the reaction. The energy gap between FMOs for the
diene HOMO—dienophile LUMO and diene LUMO—dienophile HOMO pairs, obtained
by simple calculations at the B3LYP/6-311++G** level in the gas phase, are shown in
Figure 6.14 for three pairs of reactants.
As is evident, when the diene carries an electron-releasing group and the dienophile
carries an electron-withdrawing group, the difference in the energy gap is more favorable
for the diene HOMO—dienophile LUMO combination of FMOs (the “normal electron
32. (a) Fleming, I. Frontier Orbitals and Organic Chemical Reactions (Wiley-Interscience: London, 1976),
p. 27. (b) Fleming, I. Molecular Orbitals and Organic Chemical Reactions; Reference ed. (John Wiley & Sons:
London, 2010), p. 297.

demand” Diels-Alder reaction) by approximately 2.5 eV. When both reacting species H
carry the same type of substituent, the normal electron demand Diels-Alder reac- secondary
tion is still favored, but now only by approximately 0.8 eV. When the complementary orbital H
pair is a diene carrying an electron-withdrawing substituent, and a dienophile overlap primary
carrying an electron-releasing substituent, reaction by diene LUMO–dienophile orbital
HOMO overlap (“inverse electron demand”) now becomes favored, by approxi- overlap
mately 4.3 eV, although the HOMO-LUMO gap (3.81 eV) is still larger than that for O
the normal electron demand Diels-Alder reaction between reactants carrying com-
plementary substituents (3.52 eV).
The substituent on the dienophile, in particular, has a defining effect on the ste- Figure 6.15 Secondary orbital overlap
reochemistry of the final cycloadduct, as was first reported by Alder and Stein.33 in the Diels-Alder reaction
Stated most simply, it is found that conjugating substituents on the dienophile tend
to become endo substituents in the cycloadduct. In a bridged ring system with both a convex
and a concave surface, the convex surface is called the exo surface, and the concave surface,
where all substituents project into the cavity, is called the endo surface. The origin of the
endo preference is generally taken to be due to secondary orbital interactions (i.e., bonding-
type interactions between the lobes of the FMOs that are not directly involved in the forma-
tion of new bonds in the product),34 although this view has been challenged in favor of a
variety of alternative effects.35 Figure 6.15 shows the primary (heavy arrows) and secondary
(dashed arrows) orbital overlaps between the HOMO of cyclopentadiene (top) and the
LUMO of maleic anhydride (bottom) in the endo orientation. Note how the secondary or-
bital overlap in this reaction is bonding in nature and therefore expected to be stabilizing.
Qualitative Perturbation Theory: Approximating Frontier Orbitals

of Substituted Alkenes and Dienes
The incorporation of heteroatoms or other species into a conjugated system affects both
the energies of the molecular orbitals of the system, and the coefficients of the π molecular
orbitals of the system. Although it is useful to be able to calculate the orbital coefficients in
order to predict the outcome of reactions, it is actually not absolutely necessary to do so.
Recall that the formation of covalent bonds by overlap of hybrid atomic orbitals is most
efficient when overlap occurs through the large front lobes of the orbitals. This allows us
to predict reaction regiochemistry with only a qualitative or
semiquantitative idea of the coefficients of the FMOs, so long as Table 6.4 Energies of π Molecular Orbitals of [H2C=NHx]*
we can predict the largest lobes of the FMOs of the reactants.
Species π π* Energy Difference (eV)
So, we have three questions.
H H
1. How does the presence of a substituent on a π bond affect C N −17.90 −8.88 9.02
the energies of the associated FMOs? H H
2. How does the presence of a substituent on a π bond affect H

C N −9.36 −0.93 8.43
the orbital coefficients of the frontier orbitals?
H H
3. Does the charge on an atom affect the energy and coeffi-
H
cients of the molecular orbitals? A series of simple calcula- −2.37 +4.62
C N 6.99
tions at the B3LYP/6-31++G** level provide us with data to H
answer this question (Tables 6.4 and, Table 6.5; Figure 6.16).
33. Alder, K.; Stein, G. Angew. Chem. 1937, 50, 510.

34. (a) Arrieta, A.; Cossío, F.P.; Lecea, B. J. Org. Chem. 2001, 66, 6178, and references cited therein. (b)
Apeloig, Y.; Matzner, E. J. Am. Chem. Soc. 1995, 117, 5375.
35. (a) Ruiz-López, M.F.; Assfeld, X.; García, J.I.; Mayoral, J.A.; Salvatella, L. J. Am. Chem. Soc. 1993, 115, 8780.
(b) García, J.I.; Mayoral, J.A.; Salvatella, L. Acc. Chem. Res. 2000, 33, 658. (c) Gajewski, J.J. J. Org. Chem. 1992, 57,
5500. (c) Xidos, J.D.; Gosse, T.L.; Burke, E.D.; Poirier, R.A.; Burnell, D.J. J. Am. Chem. Soc. 2001, 123, 5482.

Table 6.5 Frontier Molecular Orbitals of Substituted Alkenes in the Gas Phase
HOMO LUMO ELUMO− HOMO LUMO ELUMO−

Molecule Energy Energy EHOMO Molecule Energy Energy EHOMO
H
H
H H −6.61 −1.16
−7.65 −0.30 H C C
C C 7.35 (ψ2) (ψ3) 5.45
C C H
H H H H
H
H CH3 −7.00 −1.29
C C −7.15 +0.03 7.18 H 5.71
C C (ψ2) (ψ3)
H H C
H H
O
H OH −9.01 −3.12
−10.83 −0.31 H N O
C C 10.52 (ψ2) (ψ3) 5.89
C C
H H
H H
H
H NH2 −8.39 −2.24
−9.47 −0.02 H C O
C C 9.45 (ψ2) (ψ3) 6.15
C C
H H
H H
N
H F −8.25 −2.01
−12.76 −0.27 H C
C C 12.49 (ψ2) (ψ3) 6.24
C C
H H
H H
Figure 6.16 Hammett plot of

the variation of the energy of
the highest energy π orbital
(lower two traces) and lowest
energy unoccupied molecu-
lar orbital (upper two traces)
energies [B3LYP/6-311+G**]
for substituted ethylenes.
Open symbols and dashed
lines correspond to substitu-
ents that carry a lone pair on
the atom directly bonded to
the alkene π bond. Filled
symbols and lines correspond
to electron-withdrawing sub-
stituents that conjugate with
the alkene π bond by pπ-pπ
conjugation. FMO, frontier
molecular orbital; MO,
molecular orbital.
The data in Table 6.4 show that a positive charge on the nitrogen atom lowers the
energy of both the π and π* orbitals and the LUMO of the ion, and a negative charge raises
the energy of both orbitals. The energy gap between π and π* gradually increases as the
charge on nitrogen becomes more positive. The net effect of the charge changes is to bring
the HOMO of the anion much closer in energy to the LUMO of the cation (∆E = 6.51 eV),
which is in line with what we know about their chemistry; the anion is a base and nucleo-
phile, and the iminium ion is an electrophile and acid.

The molecules in Table 6.5 have been chosen to illustrate the effects of substituent
electronegativity and substituent electron withdrawing or releasing propensity. By careful
analysis of the data, we can draw three general conclusions about substitution of hydrogen
of the ethylene molecule.
1. The substitution of carbon by an electron-withdrawing conjugating group lowers

the energy of both the π and π* orbitals. The effect on the π* orbital is more
pronounced.
2. The substitution of hydrogen by a heteroatom carrying a lone pair lowers the energy of
the π orbital substantially as the electronegativity of the substituent increases but has
little effect on the energy of the π* orbital (it very slightly lowers it).
3. The substitution of hydrogen by a conjugating hydrocarbon group reduces the separa-
tion between HOMO and LUMO. The effects of triple-bonded groups on the LUMO
energy are slightly less than those of doubly bonded groups.
Predicting Regiochemistry
Often, a Diels-Alder reaction can give more than one product, especially when it is possi-
ble for both reactants to react in more than one way. Let us take the Diels-Alder dimeriza-
tion of (3E)-1,3,5-hexatriene as a typical example. As shown here, there are three possible
products for this reaction, and the question “Can we predict the major monocyclic regio-
isomer produced in this reaction?” should be asked. Based on our earlier arguments above
about the efficiency of orbital overlap, the answer is “yes.”
A B C
The HOMO-LUMO overlap leading to these products involves either ψ3 of the diene
(positions 2 and 4) and ψ4 of the dienophile (positions 1 and 2 or 3 and 4)—or ψ4 of the
diene (positions 1 and 4) and ψ3 of the dienophile (positions 1 and 2 or 3 and 4). Thus, there
are six potential modes of frontier orbital overlap that we must consider. Using the Hückel
coefficients in Table 2.3, we obtain the results collected in Table 6.6.
The results are definitive: the most efficient orbital overlap occurs when the terminal
atoms of the two reacting species form a new bond—when the overlap occurs with the two
lobes with the largest orbital coefficients superimposed. We thus predict that the major
product of this reaction would be compound A. It is reassuring to find that this is, indeed,
the observed major bimolecular cycloaddition product of this reaction.36
Table 6.6 Predicting Regiochemistry of a Diels-Alder Reaction
Diene Dienophile A B C
ψ3 ψ4 (0.52)(0.52) + (−0.42) (0.52)(0.42) + (0.52) (0.52)(0.23) + (0.42)

(−0.23) = 0.367 (0.23) = 0.338 (0.23) = 0.216
ψ4 ψ3 (0.52)(0.52) + (0.42) (0.52)(0.23) + (0.42) (0.52)(0.42) + (0.23)
(0.23) = 0.367 (0.52) = 0.338 (0.42) = 0.315
36. Kharasch, M.S.; Sternfeld, E. J. Am. Chem. Soc. 1939, 61, 2318.

Figure 6.17 Possible cycliza- A B C D E F

tion modes in intramolecular
Diels-Alder reactions
Intramolecular Diels-Alder reactions

The idea of tethering the diene to the dienophile was first proposed by Alder in 1953,37 but
the idea languished until the development of reliable methods for the synthesis of the nec-
essary trienes some two decades later. When the two reacting species in the Diels-Alder
reaction are tethered to one another, additional constraints are imposed on the course of
the Diels-Alder reaction. This has resulted in a large volume of literature that we will
simply summarize here.38
The reaction can lead to the formation of either fused-ring or bridged-ring products,
depending on the length and location of the tether. It is generally accepted that the six ex-
amples in Figure 6.17 represent the possible cyclization modes. The first two of these (types
A and B) lead to the formation of fused-ring products; the next two (types C and D) lead to
bridged-ring systems, containing a 3,5-bridged cyclohexene ring; and the last two represent
bridgehead alkenes, where the cyclohexene is bridged 1,3- (type E) or 1,4- (type F).
The outcome of an intramolecular Diels-Alder reaction is frequently determined by
the length and type of the linker between the diene and the dienophile. When this tether
is short, the dominant reaction pathway is either type A or type B, to give fused-ring prod-
ucts. In addition to structural features that assign an intramolecular Diels-Alder reaction
to one of the six classes above, the outcome of the reaction is affected by the nature and
location substituents on the system, and the length of the bridge between the diene and the
dienophile.
Fused-ring products are generally favored as products, with the proportion of fused-
ring product increasing as the bridge length is decreased. Generally, the intramolecular
and intermolecular variants of the reaction are very similar. Thus, it is observed that the
intramolecular reaction is suprafacial with respect to the diene and the dienophile moi-
eties, and that E dienes tend to react faster than Z dienes. When the stereochemistry is not
suprafacial, this generally indicates that the diene or dienophile isomerizes before the cy-
cloaddition itself. The diene stereochemistry also affects the stereochemistry of the prod-
uct: whereas an E diene can attain the reactive conformation leading to both the cis and
trans isomers of the product, the Z isomer is usually restricted to the conformation leading
to the cis isomer.39 This is illustrated in Figure 6.18 for the intramolecular Diels-Alder re-
action of 1,3,8-nonatriene.
37. Alder, K.; Schumacher, M. Fortschr. Chem. Org. Naturst. 1953, 10, 66.
38. (a) Taber, D.F. Intramolecular Diels-Alder and Alder Ene Reactions (Springer Verlag: Berlin, 1984). (b)
Ciganek, E. Org. React. 1984, 32, 1. (c) Oppolzer, W. Angew. Chem. Int. Ed. Engl. 1977, 16, 10. (d) Brieger, G.;
Bennett, J.N. Chem. Rev. 1980, 80, 63. (e) Fallis, A.G. Can. J. Chem. 1984, 62, 183. (f) Craig, D. Chem. Soc. Rev.
1987, 16, 187. (g) Roush, W.R. In Trost, B.M.; Fleming, I., Eds. Comprehensive Organic Synthesis (Pergamon
Press: Oxford, 1991); vol. 5, ch. 4.4.
39. (a) Pyne, S.G.; Hensel, M.J.; Byrn, S.R.; McKenzie, A.T.; Fuchs, P.L. J. Am. Chem. Soc. 1980, 102, 5960. (b)
Yoshioka, M.; Nakai, H.; Ohno, M. J. Am. Chem. Soc. 1984, 106, 1133.

Figure 6.18 Intramolecular
Diels-Alder reactions of Z
and E 1,3,8-nonatrienes
The question of exo versus endo orientation is more complicated in the intramolecular re-
action because the bridge often confers a strong preference for exo addition. A flexible bridge
can allow the formation of both cis- and trans-fused products, but predicting which will pre-
dominate is not necessarily a simple task, as the two examples on the right in Figure 6.18 show.
As is observed with the intermolecular reaction, the addition of a Lewis acid increases the rate
of the reaction, and, at the same time, improves the endo selectivity of the reaction.40
In similar fashion, changing the length of the bridge usually shifts the cis/trans
ratio, but the direction of the change is not always predictable at this time, although
shorter bridges tend to favor the trans ring fusion in the product. Examples 6.15 and
6.16 41 show the effects of changing the length of the bridge in two closely related sys-
tems. Note how, in both these systems, the trans product is favored, although there is
more cis product formed when the bridge contains four carbons rather than three. Note
also how, in the system above, which has a five-carbon bridge, the cis isomer is now the
favored product.
O O O
C6H6/∆ H H
+ (6.15)
catalyst
H H
Conditions Yield cis : trans
no catalyst, 155°C, 5h 90% 62 38
Et2AlCl (4 eq), 25°C, 3h 88% 100 0
LiBF4 (1.1 eq), 25°C, 3h 100% 100 0
40. Smith, D.A.; Houk, K.N. Tetrahedron Lett. 1991, 32, 1549.
41. Wulff, W.D.; Powers, T.S. J. Org. Chem. 1993, 58, 2381.

CO2Me CO2Me
H H
CO2Me C6H6, 150°C, 72 h
65%
H H
(6.16)
60 40
CO2Me CO2Me
H H
CO2Me C6H6, 150°C, 72 h
65%
H H
51 49
Carbene Additions: [2 + 1] Cycloadditions42

Few reactive intermediates have generated the interest that methylene, CH2, which is the
prototypical example of a carbene, has engendered among organic chemists, as we will see
in much more detail in Chapter 13. The most useful addition reactions of carbenes are the
concerted additions of singlet carbenes to alkenes. In these reactions, two carbon atoms
from the alkene are involved in the reaction, and one carbon from the carbene; the reac-
tion is usually called a [2 + 1] cycloaddition.
The HOMO of the singlet carbene is the sp2 hybrid orbital carrying the lone pair, and
the LUMO is the empty 2p orbital (Figure 6.19); the energy difference between the HOMO
and LUMO of this singlet carbene is one of the smallest of any organic species. Because of
its empty p orbital, the singlet carbene shows reactivity similar to a carbocation. It is an
electrophile, and it will add to nucleophilic sites in a molecule. The lone pair of electrons
in the sp2 orbital confers the nucleophilic reactivity of a carbanion on the carbene, also,
and carbenes can react with appropriate electrophiles in a molecule (although this reac-
tion is less frequently observed). The addition itself is a concerted reaction, and it can be
viewed as proceeding through the HOMO-LUMO overlap shown in Figure 6.19. In accord
with the fact that alkenes do not usually react with nucleophiles, the initiating FMO over-
lap involves the carbene LUMO.
The [2 + 1] cycloaddition of singlet carbenes to alkenes is a suprafacial addition, so that
the E alkene gives the E cyclopropane, and the Z alkene gives the Z cyclopropane. You may
notice the similarity of the FMO overlap between the alkene and the singlet carbene to
overlap between an alkene and a halogen or a peracid to generate a three-membered cyclic
heteronium ion or an epoxide. These reactions, also, are suprafacial [2 + 1] cycloadditions
where the LUMO is an antibonding orbital of a halogen-halogen or oxygen-oxygen bond
instead of an empty atomic orbital.
Figure 6.19 The frontier

olecular orbitals (FMOs) of
m R R R R
a singlet carbene (left) and C
initiating FMO overlap in LUMO (2p) C C
the addition of a singlet C
carbene to an alkene.
HOMO, highest energy
occupied molecular orbital; HOMO (sp2)
42. For a review of stereoselective cyclopropanation reactions, see Lebel, H.; Marcoux, J.-F.; Molinaro, C.;
Charette, A.B. Chem. Rev. 2003, 103, 977.

R R R R
:CR2 :CR2
Z alkene Z cyclopropane E alkene E cyclopropane
The most common method for the generation of singlet carbenes is α-elimination,
where both groups are lost from the same carbon atom instead of adjacent carbons, as
in the eliminations we have studied so far. The simplest example of an α elimination
reaction that leads to a carbene is the reaction between chloroform and a strong base
(Example 6.17). When chloroform reacts with a strong base such as potassium tert-
butoxide in the presence of an alkene such as cyclohexene, a gem-dichlorocyclopropane
is formed. The reaction proceeds through :CCl 2, dichlorocarbene, which is generated
by the α-elimination of chloride from the CCl 3— ion, itself formed by deprotonation of
chloroform. 43
Cl KOBut Cl Cl Cl
H Cl Cl (6.17)
pentane
Cl 0°C Cl Cl Cl
A second method for the production of carbenes is α-elimination from gem-dihalides

(Example 6.18). When a gem-dihalide reacts with butyllithium, a metal-halogen ex-
change reaction occurs to give an intermediate α-haloorganolithium reagent. At quite
low temperatures (above −80°C), this intermediate loses the lithium halide to give the
carbene.44
Br n-BuLi Br (–LiBr)
(6.18)
Br Li
A closely related method for the production of carbenoids is the Simmons-Smith reac-
tion,45 named for the two chemists who first developed it.46 The Simmons-Smith cyclopro-
panation reaction (Example 6.19) involves an α-halomethylzinc halide,47 which is
generated by the reaction of the dihalide with activated zinc metal (in the form of a
zinc-copper couple) or a dialkylzinc.48 The most common form in which this reaction is
used is in the addition of methylene itself, CH2, to an alkene. Thus, when methylene iodide
is treated with the zinc-copper couple in a suitable solvent (diethyl ether is commonly
used), the α-iodoorganozinc iodide analogous to a Grignard reagent is formed. In the
43. (a) Hine, J. J. Am. Chem. Soc. 1950, 72, 2438. (b) Hine, J.; Dowell, A.M., Jr. J. Am. Chem. Soc. 1954, 76,
2688. (c) Hine, J.; Dowell, A.M., Jr.; Singley, J.E., Jr. J. Am. Chem. Soc. 1956, 78, 479.
44. (a) Hoeg, D.F.; Lusk, D.I.; Crumbliss, A.L. J. Am. Chem. Soc. 1965, 87, 4147. (b) Taylor, K.G.; Chaney, J. J.
Am. Chem. Soc. 1972, 94, 8924. (c) Goldstein, M.J.; Dolbier, W.R., Jr., J. Am. Chem. Soc. 1965, 87, 2293.
45. Simmons, H.E.; Smith, R.D. J. Am. Chem. Soc. 1959, 81, 4256.
46. Howard Ensign Simmons, Jr. (1929–1998) established the existence of benzyne under J.D. Roberts at the
Massachusetts Institute of Technology (PhD, 1954). He joined E.I. DuPont de Nemours and Company and rose
to become Vice President and Senior Science Advisor of the company. He received the American Chemical
Society’s 1994 Priestley Medal. For more biographical information, see: Roberts, J.D.; Collette, J.W. Biogr. Mem.
Nat. Acad. Sci. 1999, 76 (e-book; http://www.nap.edu/readingroom.php?book=biomems&page=hsimmons.
html; retrieved July 3, 2013).
Ronald Dean Smith (1930–) was educated at the Massachusetts Institute of Technology (PhD, 1955). After
graduating, he followed his fellow student, Howard Simmons, to DuPont. He ended his career at the DuPont
Merck Pharmaceutical Company, a joint venture of Merck and Du Pont, and served on the board of editors of
Drug Development Research from 1994–2004.
47. (a) Emschwiller, G. Compt. rend. 1929, 188, 1555. (b) Emschwiller, G. Compt. rend. 1926, 183, 665.
48. (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1966, 3353. (b) Furukawa, J.; Kawabata,
N.; Nishimura, J. Tetrahedron 1968, 24, 53. (c) Ito, Y.; Fujii, S.; Masashi, N.; Kawamoto, F.; Saegusa, T. Org. Syn.
Coll. Vol. 6 1988, 327. (d) Charette, A.B.; Lebel, H. Org. Syn. Coll.Vol. 8 2004, 613.

presence of an alkene, this intermediate transfers methylene to give the cyclopropane.

Because of its particularly mild reaction conditions, the Simmons-Smith reaction has
become the preferred method for the synthesis of cyclopropanes. The Simmons-Smith
reaction is especially useful for fusing a cyclopropane ring onto a cyclic allylic alcohol
because the product is the isomer in which the carbene adds to the same face of the ring as
the hydroxyl group (which coordinates to the zinc atom).
H Zn, Et2O H
I I IZn I (6.19)
H H
The final method for the formation of singlet carbenes or carbenoids that we will dis-
cuss here is the decomposition of diazoalkanes, R 2C=N2, by ultraviolet light. Under such
conditions, a very reactive singlet carbene is produced that readily adds to any alkene to
give the cyclopropane product, although the reaction course may be complicated by par-
ticipation of the triplet carbene. A rather less reactive carbenoid species is obtained when
one decomposes the diazoalkane catalytically using a copper (free metal, as in Example
6.20, or salt) or rhodium (usually the diacetate) catalyst. Recently, chromium carbonyl
complexes (see Example 6.21) have found use as catalysts for decomposing diazoalkanes,
giving carbenoid species with approximately the same reactivity as the copper carbene
complexes.
H
CH2N2
(6.20)
Cu, Et2O
H
OR'
OR' R
Ph CO2Et R H
η2-c-C8H14Cr(CO)5
+ (6.21)
N2 CH2Cl2, 5°C Ph
CO2Et
57-78%
Intramolecular addition of a carbene to a diene (Example 6.22), proceeds to give the

products of [2 + 1] cycloaddition—not the products of [4 + 1] cycloaddition,49 a result that
is also observed in the intermolecular reaction.50
H
O O CuSO4, PhH
(6.22)
∆ MeO2C O
N2 CO2Me O
Ketene Additions: [2 + 2 ] Cycloadditions51

Under most circumstances, [2 + 2] cycloadditions to form four-membered rings do not
occur readily at room temperature. There is one exception to this, however, and that occurs
49. Hudlicky, T.; Govindan, S.V.; Frazier, J.O. J. Org. Chem. 1985, 50, 4166.
50. (a) Hahn, N.D.; Nieger, M.; Dötz, K.H. Eur. J. Org. Chem. 2004, 1049. (b)Aggarwal, V.K.; de Vicente, J.;
Bonnert, R.V. Org. Lett. 2001, 3, 2785. (c) Doyle, M.P.; Dorow, R.L.; Buhro, W.E.; Griffin, J.H.; Tamblyn, W.H.;
Trudell, M.L. Organometallics 1984, 3, 44. (d) Anciauy, A.J.; Demonceau, A.; Noels, A.F.; Warin, R.; Hubert,
A.J.; Teyssié, P. Tetrahedron 1983, 39, 2169. (e) Doyle, M.P.; Dorow, R.L.; Tamblyn, W.H.; Buhro, W.E. Tetrahe-
dron Lett. 1982, 23, 2261. (f) Wenkert, E.; Goodwin, T.E.; Rau, B.C. J. Org. Chem. 1977, 42, 2137.
51. Review: Hyatt, J.; Raynolds, P.W. Org. React. 1994, 45, 159.

orbitals of dichloroketene.
The molecule is oriented
perpendicular to the page in
the HOMO, and parallel to
the page in the LUMO.
HOMO
LUMO
Figure 6.21 Stereochemistry
L O L O of the cycloadducts of
ketenes and alkenes is deter-
L S C L S C
mined by the orthogonal
S S
approach of the two reac-
L S S L
tants. Only one lobe of the
highest energy occupied mo-
lecular orbital and one of the
L L L S molecular orbital are shown
S S S L for clarity.
S S
L O L O
when the more electrophilic component of the reaction has a pair of cumulated double
bonds. There are two carbonyl compounds that fulfill this structural requirement: the
ketenes and isocyanates. In this chapter, we will concentrate our discussion on the ketenes,
although most of what is said applies also to the additions of isocyanates to alkenes.
The reactivity of ketenes comes from the presence of the sp-hybridized carbon atom in
the center of the functional group. This carbon, which is formally part of a carbonyl group,
is particularly reactive towards nucleophiles and electron-rich π bonds.
The FMOs of dichloroketene, a widely used ketene for cyclobutane synthesis, are
shown in Figure 6.20. It is worthwhile noting that the HOMO and LUMO of this species
are orthogonal to each other, and this is critical to the reactivity of these species, since the
addition is actually not a [2 + 2] cycloaddition, but rather, a [π2s + π2s + π2a] cycloaddition
that involves the HOMO of the alkene and both FMOs of the ketene.
The stereochemistry of the reaction is one of the most interesting aspects of the cyc-
loadditions of ketenes to alkenes. Because both FMOs of the ketene are involved in the
reaction, the cycloadditions of ketenes to alkenes require an orthogonal relationship be-
tween the two reacting species at the beginning of the reaction. This leads to the two pos-
sible orientations of approach shown in Figure 6.21, where “L” represents the larger of the
two groups attached to a carbon atom, and “S” represents the smaller of the two groups.
What becomes clear from examining Figure 6.21 is that this approach leads to the more
hindered product because this initial approach places the smallest groups in closest prox-
imity during the approach of the reactants.
Ketenes are almost always prepared in situ from acid chlorides by elimination of
hydrogen chloride using triethylamine as the base, or from α-haloacid chlorides by
reductive elimination using zinc metal as the reducing agent (Example 6.23). The reac-
tivity of the ketene in the cycloaddition reaction increases as the number of electron-
withdrawing groups on the ketene double bond increases. For this reason ketenes such
as dichloroketene are often used as the electrophilic reagent in [2 + 2] cycloadditions
(Example 6.24).

O Cl O
Et3N (X=H)
C (6.23)
Zn, Et2O (X=Cl, Br, I)
X R
R R R
H O H O
Cl2CHCOCl, Et3N Zn, HOAc, ∆
(6.24)
hexane Cl (81% for 2 steps)
H Cl H
Figure 6.22 Regiochemistry O
of ketene cycloadditions to
cyclopentadiene Cl
Cl
Cl
C C O (6.25)
Cl
O O
Cl Cl
Cl Cl
Cl
C C O (6.27)
Cl O
Cl O
Cl Cl
Cl
(6.26) (6.28)
Like the Diels-Alder and carbene cycloaddition reactions we have already discussed,
ketene additions give the products of suprafacial addition to the alkene: Z-alkenes give
cis-cyclobutanone products, and E alkenes give trans-cyclobutanone products. Like the
Diels-Alder reaction, the ketene cycloaddition can also give rise to regioisomeric prod-
ucts, and, like the Diels-Alder reaction, one can usually predict the major product of the
cycloaddition by using resonance arguments similar to those which we used above.
One can predict the regiochemistry of the ketene [2 + 2] cycloaddition of a ketene to
an alkene by invoking of the addition of the carbocation carbon of the minor canonical
form to the alkene in a stepwise reaction: The addition of the carbonyl carbon should obey
Markovnikov’s rule, so the carbonyl carbon should add to the alkene to give the more
stable of the two possible carbocation intermediates (Figure 6.22). The addition of dichlo-
rocarbene to cyclopentadiene is illustrative. The carbonyl carbon adds to the diene to give
the resonance-stabilized allylic cation rather than the simple secondary cation, so the top
regioisomer is formed almost exclusively.
Ketenes are highly reactive species, and in the absence of an electron-rich alkene or other
nucleophilic species, they dimerize. Although ketene itself dimerizes to the β -lactone deriv-
ative known as diketene (Example 6.29), alkylated ketenes dimerize to cyclobutanedione
derivatives (Example 6.30). It is for this reason that ketenes are usually prepared in the pres-
ence of the ketenophile.
H O
O (6.29)
H O
O
O (6.30)

Worked Problem
6-2 What combination of diene and dienophile is needed to make each of the follow-
ing compounds? Where appropriate, be sure to specify stereochemistry.
O OEt H O
H
(a) N (b) N
H H
O MeO
§Answers below
Problems
6-10 Predict the major product of each of the following Diels-Alder reactions.
O O O CN
NC
(a) D
D (b)
O O O
CN
(c) (d) MeO
O
CN
(e) (f)
O
COCl
O
(g) (h)
1 mole 1 mole
EtO2C CO2Et EtO2C CO2Et

(i) (j) O
1 mole 1 mole 1 mole 1 mole
6-11 What combination of diene and dienophile is needed to make each of the follow-
ing compounds?
O O O
H H
(a) N NO2 (b) (c)

H O H
O
(continues)
O OEt O
H
(a) N + (b) N
H
O Me MeO
(a) This product is formed by the intermolecular Diels-Alder reaction between the imide, which must have
the Z stereochemistry, and the diene. From the stereochemistry of the product, we see that if the reaction pro-
ceeds with suprafacial stereochemistry, the diene must have the E,E stereochemistry. The product shown is the
expected endo product.
(b) This product is formed by the intramolecular Diels-Alder reaction shown. Note that the stereochemistry of the
ring junction is trans; this means that the ring junction cannot come from just one part of the reactant. The one ste-
reochemical deduction we can make unequivocally is that the dienophile part of the molecule has Z stereochemistry.

Me O
H
MeO O
(d) N NO2 (e) (f) H
COCl
MeO
H O
NC
6-12 The attempted Diels-Alder reactions below do not give the products one
might expect but the products shown, instead. Write a mechanism to ratio-
nalize the formation of this product and indicate what reactions are involved
at each step.
O CO2Me
(a) O
+ MeO2C CO2Me
CO2Me
O O H H O
O
(b) O
+ O O O
O O H H O
O H
OMOM OMOM
O H
(c)
O N O N
Ph Ph

6-13 What is the major organic product of each of the following reactions? Give all
isomers where more than one may form.
CHCl3, KOBut CHCl3, KOBut
(a) pentane (b) pentane
Br BuLi, THF, –78°C CH2N2

(c) Br cyclohexene
(d) Cu, Et2O
CHCl3, KOBut CH2I2, Zn(Cu)

(e) cyclohexane
(f) Et2O

CHCl3, KOBut CH2I2, Zn(Cu)

(g) cyclohexane
(h) Et2O
CH2I2, Et2Zn HO CH2N2

(i) Et2O
(j) Rh2(OAc)4
HO
H
OH CH2I2, Et2Zn CH2N2
(k) Et2O
(l) Rh2(OAc)4
(1 equiv.)


6-14 What is the major organic product of each of the following reactions? Where
more than one regio- or stereoisomer is possible, give all isomers (draw only one
enantiomer of racemates).
H
Cl3CCOCl, Zn Cl2CHCOCl
(a) Et2O
(b) Et3N, hexane
H
(c) Et2O
(d) Et3N, hexane
H
H
(e) Et2O
(f) Et3N, hexane
H
Reaction Synopses
Diels-Alder Reaction ([4 + 2] Cycloaddition)
Ra Ra Rb Ra Rb
R1 R2
Rf R1 R2 Rf Rf
Rb R2 R1
+ and/or
Rc R3 R4
Re R4 R3 Re Re
R4 R3
Rd Rd Rc Rd Rc
Reagents: 1,3-dienes; usually with electron-donating groups (e.g., R, RO,

R 2N); alkenes (dienophile); usually with electron-withdrawing
groups (e.g., C=O, C≡N, NO2, SO2)
Stereochemistry: suprafacial with respect to both participants; endo orientation
preferred for conjugated dienophiles
Regiochemistry: unsymmetrical dienophiles react with unsymmetrical dienes
to give mainly 1,4- or 3,4-disubstituted cyclohexenes
Carbene Cycloaddition ([2 + 1] Cycloaddition)
R1
R1 R2 R2
:CR2 R
R
R3 R4 R3
R4
Reagents: CHCl3, Me3CO—K+; R2CBr2, BuLi, Et2O; and so on (α elimination);

or CH2N2, Cu; CH2N2, [Rh(OCOCH3)2]2 and so on; or CH2I2,
Zn(Cu), Et2O; CH2I2, Et2Zn; etc. (Simmons-Smith Reaction)
Stereochemistry: suprafacial with respect to alkene
[2 + 2] Cycloaddition of Ketenes
O O R
R H
+ RL
RL RS R H RS R
Reagents: R 2CHCOCl, Et3N, Et2O; R 2CClCOCl, Zn, Et2O

Stereochemistry: suprafacial with respect to alkene
Regiochemistry: Markovnikov addition based on ketene carbonyl group as the
electrophile

1,3-Dipolar Additions52
An important type of cycloaddition reaction that we have not yet discussed involves the
concerted addition of a resonance-stabilized zwitterion to an alkene (e.g., Examples 6.31
and 6.32) or alkyne (e.g., Examples 6.33 and 6.34) to give a five-membered heterocyclic
product. These additions are also known as [3 + 2] cycloadditions, although, in terms of
the electrons involved, they are actually [π4s + π2s] additions, with the zwitterionic reactant
acting at the four-electron component. The zwitterionic reactant is known as a 1 ,3-dipole,
and a list of common 1,3-dipoles is gathered in Table 6.7.
y
x z
y y
x z x z y
x z (6.31)
y y
x z x z
x y z
y
x z
x y z x y z (6.32)
y
x z
y
x z (6.33)
y
x z
x y z
y
x z
x y z (6.34)
1,3-Dipolar cycloadditions are suprafacial with respect to the alkene component (the
“dipolarophile”), as illustrated by the addition of p-anisyl azide to dimethyl fumarate
(Example 6.35)53 and the addition of p-nitrophenyl azide to the two geometric isomers
of 1-propoxy-1-propene (Example 6.36).54 Like the Diels-Alder reaction, these cycload-
ditions tend to be favored by electron-withdrawing substituents on the alkene (the dipo-
larophile). The facile inversion of configuration of nitrogen means that we cannot
establish the t heoretically predicted suprafacial nature of the reaction with respect to
the dipole.55
52. (a) Huisgen, R. Angew. Chem. Int. Ed. Engl. 1963, 2, 565. (b) Huisgen, R. Angew. Chem. Int. Ed. Engl. 1963,
2, 633. (c) Huisgen, R.; Grashey, R.; Sauer, J. In Patai, S., Ed. The Chemistry of Alkenes (Wiley-Interscience:
NewYork, 1964), ch. 11. (d) Huisgen, R. Bull. Soc. chim. France 1965, 3431. (e) Huisgen, R. J. Org. Chem. 1976, 41,
403. (e) Firestone, R.A. Tetrahedron 1977, 33, 3009. (f) Bianchi, G.; de Micheli, C.; Gandolfi, R. In Patai, S., Ed.
Chemistry of Double-Bonded Functional Groups Part 1 (Wiley-Interscience: New York, 1977), p. 369. (g) Black,
D. St.C.; Synthesis 1975, 205. (h) L’Abbé, G. Chem. Rev. 1969, 69, 345. (i) Kauffmann, T. Angew. Chem. Int. Ed.
Engl. 1965, 4, 553. (i) Gothelf, K.V.; Jørgensen, K.A. Chem. Rev. 1998, 98, 863.
53. Huisgen, R.; Szeimies, G.; Möbius, L. Chem. Ber. 1966, 99, 475.
54. Huisgen, R.; Szeimies, G. Chem. Ber. 1965, 98, 1153.
55. For a cogent discussion of the stereochemistry of this addition and the controversy leading up to general
acceptance of the concerted mechanism, see: Houk, K.N.; Gonzalez, J.; Li, Y. Acc. Chem. Res. 1995, 28,l 81.

Table 6.7 Representative 1,3-Dipoles
Nitrogen-Centered 1,3-Dipoles
R R R
N R R N R R N R
O N
R R R R
Nitrones Azomethine imines Azomethine ylides
R R
O N C R N N C R C N C R
Nitrile oxides Nitrile imines R
Nitrile ylides
R R
C N N N N N
R Azides
Diazoalkanes
Oxygen-Centered 1,3-Dipoles
O R R O R R O R
O N
R R R R
Carbonyl oxides Carbonyl imines Carbonyl ylides
MeO
MeO H CO2Me N
N + N N (6.35)
N MeO2C H
N
MeO2C CO2Me
Me O—n-Pr NO2 H O—n-Pr

O2 N O2 N
N N (6.36)
N N H H Me H N N
n-Pr—O Me n-Pr—O Me
N3
Intramolecular 1,3-cycloaddition reactions are useful reactions for the construc-

tion of heterocyclic systems, as illustrated by the two examples below, which are from
Kozikowski’s synthesis of prostaglandins (Example 6.37), 56 and from Tufiarello’s syn-
thesis of cocaine.57
O O
O N N
PhNCO
H (6.37)
CO2Me CO2Me
Kozikowski
H N H
N ∆ N O
O O (6.38)
CO2Me CO2Me
H
CO2Me CO2Me H
Tufiarello
56. Kozikowski, A.P.; Stein, P.D. J. Am. Chem. Soc. 1982, 104, 4023
57. Tufiarello, J.J.; Mullen, G.B. J. Am. Chem. Soc. 1978, 100, 3638.

Generation of 1,3-Dipoles
Azides and nitrones are stable species that can be prepared and purified before use, but
other 1,3-dipoles are too reactive to be stored and must be formed in situ. Nitrones are nor-
mally prepared from carbonyl compounds by condensation with an N-alkylhydroxylamine
(Example 6.39).
R R O
R"NHOH (6.39)
O N
R' R' R"
Nitrile oxides are generated by two major methods: oxidation of an aldoxime by

hypochlorite or dehydration of a nitroalkane with phenyl isocyanate and triethylamine
(Example 6.40).
R N
OH
H [O]
R C N O (6.40)
[–H2O]
R NO2
Azomethine ylides (Example 6.41) and carbonyl ylides (Example 6.42) are formed by
the same reaction: the electrocyclic ring opening of a three-membered heterocycle. When
heated above 100°C, aziridines carrying electron-withdrawing substituents on the ring
carbons give azomethine ylides, and similar epoxides give carbonyl ylides by a conrota-
tory ring opening. These ring systems undergo disrotatory ring opening photochemically.
The 1,3- dipoles can be trapped in situ with appropriate dipolarophiles. 1-Alkyl-3-
hydroxypyridinium ions (Example 6.43) are representatives of a particularly accessible
class of azomethine ylides, and these compounds have been used in the synthesis of tro-
pane derivatives.
R
R
N
∆ or hν R N R
R R (6.41)
R R R R
O
∆ or hν R O R (6.42)
R R
R R R R
O O
(6.43)
N N
R R
Diazoalkanes58 are generally prepared by the base-promoted decomposition of a nitro-

soamine amide. For example, the treatment of N-methyl-N-nitroso-p-toluenesulfonamide
(Example 6.44, Z = Ts, R = H) with potassium hydroxide yields diazomethane.
58. (a) Regitz, M.; Maas, G. Diazo Compounds (Academic Press: New York, 1986). (b) Black, T.H. Aldrichim-
ica Acta 1983, 16, 3. (c) Cowell, G.W.; Ledwith, A. Quart. Rev. Chem. Soc. 1970, 24, 119. (d) Smith, P.A.S. Open-
Chain Nitrogen Compounds (W.A. Benjamin: New York, 1966).

An alternative approach to diazoalkanes is the oxida- Table 6.8 Criteria for “Click” Reactions
tion of hydrazones with HgO, Ag2O, MnO2 or Pb(OAc)4 Reaction Characteristic
(Example 6.45).
1. Modular
R
R
Z Base 2. Wide scope
N R N N (6.44)
R
NO 3. High yield
Z = RCO, ROCO, H2NCO, ArSO2, etc.
4. Inoffensive byproducts or no byproducts
R NH2 R 5. Stereospecific (enantiospecific if possible)
[O]
N N N (6.45)
R R 6. Simple reaction conditions (insensitive to water and oxygen)
7. Readily available starting materials and reagents
1,3-Dipolar Cycloadditions and “Click Chemistry” 8. No solvent or benign solvent (e.g., water) that is easily removed
In 2001, Sharpless and his coworkers introduced the term 9. Simple product isolation (no chromatography)
“click chemistry” to describe synthetic reactions that
10. High thermodynamic driving force (∆H° ≤ −20 kcal mol−1)
conformed to the set of criteria in Table 6.8.59 These reac-
tions, which were included because of their usefulness in
both large- and small-scale reactions and their adapt-
ability to modular assembly of complex molecules have become indispensable methods
for the formation of heterocyclic pharmaceuticals.
Among the most widely used “click” reactions are ring openings of strained compounds
such as epoxides and aziridines, and—important in this present discussion—1,3-dipolar cy-
cloadditions. Any online search under “click chemistry” now reveals hundreds of recent
examples of these reactions, many of them syntheses of pharmaceutical intermediates. It is
interesting to note that in a very short period of time, this new terminology has replaced
Huisgen’s original nomenclature.
The reaction between azides and terminal alkynes or cyano groups activated by an
electron-withdrawing group60 is a particularly useful reaction for the synthesis of triazoles
or tetrazoles, which are important ring systems in pharmaceuticals. The control of the
regiochemistry of the reaction between terminal alkynes and azides had been problematic
until the discovery that this reaction is catalyzed by copper (I) salts.61 The reaction has
become even more useful with the discovery that the copper (I) catalyst can be generated
in situ from copper (II) sulfate and sodium ascorbate, avoiding the formation of diacety-
lene coupling products and other byproducts. The effects of the copper (I) catalyst on the
course of the reaction are illustrated by Reactions 6.46 and 6.47. In the absence of the
catalyst, a mixture of regioisomers is o
btained, while in the presence of the catalyst, only
a single regioisomer is formed.
Ph Ph
N N
neat, 92°C, 18 h N N N N (6.46)
+
Ph
N N N O O
Ph Ph
Ph
CuSO4•5H2O (1 mol %) N
Ph O Na+ ascorbate (5 mol %) N N (6.47)
H2O-Me3COH (2:1), r.t., 8 h
(91%) O
Ph
59. Kolb, H.C.; Finn, M.G.; Sharpless, K.B. Angew. Chem. Int. Ed. Engl. 2001, 40, 2004.
60. (a) Demko, Z.; Sharpless, K.B. Angew. Chem. Int. Ed. Engl. 2002, 41, 2110. (b) Demko, Z.; Sharpless, K.B.
Angew. Chem. Int. Ed. Engl. 2002, 41, 2113.
61. (a) Rostovtsev, V.; Green, L.G.; Fokin, V.V.; Sharpless, K.B. Angew. Chem. Int. Ed. Engl. 2002, 41, 2596. (b)
Tornøe, C.W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.

Reaction Synopses
1,3-Dipolar Cycloaddition (“Click”)
R R
b
R R a c
b
a c
R R
R R
R R
b
R R a c
a b c
R R
R R
Reagents: RN3; RN3, Cu+, and so on

R 2CHNO2, PhNCO; R 2C=NOH, OCl– (nitrile oxide)
R 2C=O, RNHOH (nitrone)
R 2C=N2
Stereochemistry: suprafacial
Problems
6-15 Predict the products of each of the following reactions.
NO2 PhNCO, Et3N CH3NHOH

(a) (b) CHO
CHO
1) NH2OH Me3SiN3
(c) (d)
2) NaOCl
N3
MeO2C CO2Me
(e) S PhMe, 95°C, 5 h
N3
6-16 The following reaction sequence involves a 1,3-dipole intermediate. Suggest

the structure of the intermediate, and the structure of the final product of the
reaction sequence.
Cl HN NH
CO2Et
NH2NH2, K2CO3 O ArCHO
N MeCN, 60°C, 12 h N cat. CF3CO2H
?
(73%) EtOH
O CO2Et
O
110°C
CO2Et

6.6 Ene, Retro-Ene, and Similar Reactions
The ene reaction (Example 6.48), also known as the Alder ene reaction,62 may be viewed as
a hybrid of the Diels-Alder [4 + 2] cycloaddition reaction and a [1,5]-sigmatropic rear-
rangement, in that it is a pericyclic reaction leading to formation of a new C–C σ bond
through a six-membered cyclic transition state with concomitant group transfer of the
group at the allylic position. The compound carrying the allylic group is known as the ene,
and the compound with the π bond to which the allylic group is transferred is known as
the enophile. The group that is transferred in the ene reaction is usually electropositive,
with hydrogen and metals (especially magnesium) being most widely used. The permissi-
ble structural variation in the enophiles is quite large, with alkenes, alkynes, and carbonyl
compounds having been particularly widely used as enophiles in this reaction.
‡
Z Z Z (6.48)
+
Y Y Y
X X X
X = H, metal
XY= C=C, C≡C, C=O, C=S, C=N, N=N, N=O, Se=O, etc.
In common with the Diels-Alder reaction, where the reaction is favored by electron-
deficient dienophiles and electron-rich dienes, the ene reaction is favored by e lectron-
deficient enophiles and electron-rich enes. For this reason, ene reactions are often carried
out using electron-deficient carbonyl groups (as in formaldehyde or α-dicarbonyl com-
pounds) or sulfonylimines as enophiles, and are promoted by Lewis acid catalysts. Alkynes
make better enophiles than alkenes, whereas enols, being very electron-rich, are also
highly reactive in the ene reaction, as evidenced by the synthesis of the interesting natural
product, modhephene.63 Some typical examples of the ene reaction are provided by Exam-
ples 6.49, 6.50, and 6.51. Example 6.51 is interesting because it involves the tautomeriza-
tion of the ketone to the enol before the ene reaction.
Yb(OTf)3
Ts Ts
N Me3SiCl NH 63
+ (6.49)
Ph
Ph H Ph Ph
H2C=O-zeolite 64
C6H12, C6H14 (6.50)
(90%) HO
O O H
360°C 65
(6.51)
(85%)
H
O
62. (a) Alder, K.; Pascher, F.; Schmitz, A. Ber. dtsch. chem. Ges. 1943, 76, 27.
Reviews: (b) Oppolzer, W. Angew. Chem. Int. Ed. Engl. 1989, 28, 38. (c) Oppolzer, W. In Trost, B.M.; Fleming,
I., Eds. Comprehensive Organic Synthesis (Pergamon Press: Oxford, 1991), 5, 29.
63. Yamanaka, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2, 159.
64. Okachi, T.; Onaka, M. J. Am. Chem. Soc. 2004, 126, 2306.
65. Schostarez, H.; Paquette, L.A. Tetrahedron 1981, 37, 4431.

One especially important class of ene reactions involves the reaction of an alkene with
singlet oxygen to give an allyl hydroperoxide (Example 6.52).66 The reaction does proceed
with suprafacial stereochemistry, as required by the concerted ene mechanism, but there
is strong evidence that the reaction actually occurs by initial formation of a perepoxide (or
an epoxide O-oxide, analogous to an amine N-oxide) intermediate.67 By either mecha-
nism, the net result of the reaction is the same: transfer of hydrogen from the allyl position
to oxygen and allylic rearrangement of the alkene π bond. It is also generally observed that
singlet oxygen tends to abstract hydrogen from more congested side of the alkene, as
shown in the example at left, where the hydrogen is removed from the more hindered
benzyl group, rather than the more sterically accessible methyl group. This phenomenon
is known as the cis effect.68 The suprafacial stereochemistry of the reaction has been shown
by using a chiral deuterated substrate.69
O OH
R RH
R O RH R O R
R (6.52)
R' R' R R R'
R' R' R'
H H
DOO DOO
Ph Ph
Me Me
H H
H
ANTARAFACIAL Me Ph SUPRAFACIAL
D H
H H
HOO HOO
Ph Ph
Me Me
D D
Another ene reaction of importance in organic synthesis is the ene reaction between
selenium dioxide and alkenes (Example 6.53). In this reaction, the product isolated is the
allylic alcohol, formed by sequential ene and [2,3]-sigmatropic rearrangement reactions.
The fact that two sequential pericyclic reactions are involved in the overall reaction means
that the position of the double bond remains unaltered in the final product.
O
O Se Se OH
O OH
H Se O
HO
H H H (6.53)
Cyclic Eliminations Through Six-Membered Transition States

Although we have focused our attention to this point on pericyclic reactions that form
new C–C σ bonds, these are not the only useful reactions of this type. Pyrolysis
66. Reviews: (a) Wasserman, H.H.; Ives, J.L. Tetrahedron 1981, 37, 1825. (b) Clennan, E.L. Tetrahedron 2000,
56, 9151. (c) Prein, M.; Adam, W. Angew. Chem. Int. Ed. Engl. 1996, 35, 477.
67. (a) Hurst, J.R.; Wilson, S.L.; Schuster, G.B. Tetrahedron 1985, 41, 2191. (b) Gorman, A.A.; Hamblett, I.;
Lambert, C.; Spencer, B.; Standen, M.C. J. Am. Chem. Soc. 1988, 110, 8053. (c) Song, Z.; Chrisope, D.R.; Beak, P.
J. Org. Chem. 1987, 52, 3938. (d) Song, Z.; Beak, P. J. Am. Chem. Soc. 1990, 112, 8126.
68. (a) Orfanopoulos, M.; Bellarmine Grdina, Sr. M.; Stephenson, L.M. J. Am. Chem. Soc. 1979, 101, 275.
(b) Schulte-Elte, K.H.; Rautenmstrauch, V. J. Am. Chem. Soc. 1980, 102, 1738.
69. Orfanopoulos, M.; Stephenson, L.M. J. Am. Chem. Soc. 1980, 102, 1417.

‡ Figure 6.23 Pyrolysis
X X r eactions to give alkenes that
Y Y R1 R4 may proceed by a retro-ene
H O H O reaction involving
R2 R3 [1,5]-sigmatropic rearrange-
R1 R4 R1 R4 ment of hydrogen
R2 R3 R2 R3
X=R, OR, SR
Y=O, S
reactions to give alkenes have been known for more than a century and a half.70 Pyro-
lytic elimination reactions of esters and similar species are generally believed to pro-
ceed by a concerted, cyclic mechanism71 and are therefore best described as retro-ene
reactions. The concerted mechanism is not, however, unchallenged; Wertz and Allinger
proposed a stepwise mechanism through a carbocation stabilized by the surface on
which the reaction occurs.72
The retro-ene reaction of esters and similar species follows the general course shown
in Figure 6.23. The classes of compounds that participate in this reaction are carboxylate,73
xanthate esters,74 and carbonate esters.75
Pyrolysis of esters proceeds with suprafacial stereochemistry to give the product
of syn elimination. Thus, the two labeled esters in Examples 6.54 and 6.55 give differ-
ent labeled trans-stilbenes as the sole products of the elimination.76 The stereospeci-
ficity of this reaction makes it clear that the removal of the proton involves a syn
elimination, and the simplest rationalization for this is provided by the retro-ene
mechanism.
Me Me
O Ph D O Ph H
∆ ∆
O H O D
H Ph H Ph
Ph D Ph H
H Ph H Ph
(6.54) (6.55)
The sulfur analog of the ester pyrolysis reaction was reported by Russian chemist Lev
Aleksandrovich Chugaev77 in 1900.74 In the Chugaev elimination, the simple ester is r eplaced
by the xanthate ester, which is prepared from the alcohol by treatment of the alkoxide anion
sequentially with carbon disulfide and methyl iodide. The advantage of the Chugaev elimi-
nation is that it occurs at substantially lower temperatures that the pyrolytic elimination of
the corresponding acetate esters. The pyrolysis of the two xanthates in Example 6.56 by
70. Heintz, W. Pogg. Ann. Phys. Cghem. 1853, 93, 519.

71. Reviews: (a) DePuy, C.H.; King, R.W. Chem. Rev. 1960, 60, 431. (b) Smith, G.G.; Kelly, F.W. Prog. Phys.
Org. Chem. 1971, 8, 75.
72. Wertz, D.H.; Allinger, N.L. J. Org. Chem. 1977, 42, 698.
73. (a) Ratchford, W.P.; Rehberg, C.E. Org. Synth. 1949, 29, 2; Org. Synth. 1955, Coll. Vol. 3 30. (b) Benson, R.E.;
McKusick, B.C.; Grummitt, O.; Budewitz, E.P.; Chudd, C.C. Org. Synth. 1958, 38, 78; Org. Synth. 1963, Coll. Vol.
4, 746. (c) Putnam, R.E; Anderson, B.C.; Sharkey, W.H. Org. Synth. 1963, 43, 17; Org. Synth. 1973, Coll. Vol. 5, 235.
74. Tschugaeff, L. Ber. dtsch. chem. Ges. 1900, 33, 3118.
75. O’Connor, G.L.; Nace, H.R. J. Am. Chem. Soc. 1953, 75, 2118.
76. Curtin, D.Y.; Kellom, D.B. J. Am. Chem. Soc. 1953, 75, 6011.
77. Lev Aleksandrovich Chugaev (1873–1922) was educated at Moscow University, (M Chem, 1903, Dr
Chem, 1906) where he was a student of Markovnikov. After Markovnikov’s death in 1904, he was appointed
Adjunct at the Bacteriological Institute of Moscow University, and then, in 1908, Professor at St. Petersburg
University. For more biographical details, see: Lewis, D.E. Early Russian Organic Chemists and Their Legacy
(Springer: Heidelberg, 2012), p. 111.

Cram78 provided clear evidence that this reaction also proceeds with syn stereochemistry
and is therefore very likely a retro-ene reaction.
SMe SMe
S Me Me S Me H
∆ ∆ (6.56)
H O H O
Ph H Ph Me
Me Me Me H
Ph H Ph Me
The ease with which pyrolytic eliminations of xanthates and related compounds occur
varies with the identity of the leaving group, as shown in Example 6.57. As the data show,
the incorporation of a heteroatom on both sides of the carbonyl or sulfonyl group lowers
the temperature for the reaction: simple esters eliminate at 400°C, whereas xanthates, car-
bonates, and sulfites all eliminate below 300°C.
SMe Me OMe OMe

S O O O S
O O O O (6.57)
Me
Ph Ph Ph Ph Ph Ph Ph Ph
180°C 400°C 260°C 170°C
Problems
6-17 The decarboxylation of β-ketoacids may occur through a retro-ene mechanism.

Write a reasonable mechanism for this reaction as a retro-ene reaction and indi-
cate what is (are) the initial product(s) of the reaction.
O CO2H O R
R
R R R R
6-18 Predict the structure of the major organic product of the following reaction
[Tetrahedron Lett. 1975, 4053]:
H
O 270°C, decalin
100 min
H
Cyclic Eliminations Through Five-Membered Transition States

There are three important elimination reactions that formally occur through a five-membered
cyclic transition state. They share the common feature of rearrangement of hydrogen from
carbon to a negatively charged atom, with concomitant neutralization of a positive charge by
bond cleavage and formation of a double bond. The three species most widely used in this type
78. Cram, D.J. J. Am. Chem. Soc. 1949, 71, 3883.

of elimination are amine N-oxides (the Cope elimination [X=NR2],79 sulfoxides [X=S],80 and
selenoxides [X=Se]).81
Neither the Cope elimination nor the sulfoxide elimination is stereospecific, and both
operate at some level by two competing mechanisms.80a At low temperatures, the cyclic
mechanism (Example 6.58) operates, and the reaction is stereospecific and syn. At higher
temperatures, however, there is evidence that a free radical mechanism (Example 6.59)
also operates and that this mechanism is not stereospecific. The end result is that the ste-
reospecificity of the reaction is lowered as the reaction temperature rises. The elimination
of selenoxides occurs at or below room temperature, so these reactions are stereospecific
and syn, as required by the cyclic mechanism. Then radical mechanism is especially fa-
vored by conjugating groups β to sulfur, as demonstrated by crossover experiments (which
we will discuss at length in Chapter 8).
δ ‡
O O
Xδ
R1 R4
H X H
(6.58)
R1 R4 R1 R4 R2 R3
R2 R3 R2 R3
X = NR2, SR, SeR
H R1 R4
R4
•
O XO R1 R3
R2 R2 R3
H X
(6.59)
R1 R4
R2 R3 H R1 R4
R3
R1 R4
R2 R2 R3
Reaction Synopses
Ene Reaction
‡
Z Z Z
+
Y Y Y
X X X
X = H, metal
XY= C=C, C≡C, C=O, C=S, C=N, N=N, N=O, Se=O, etc.
Reagents:
enophiles: R 2C=CR 2; RC=CH; RCHO, L.A.; R 2CO, L.A;
RNO; ArNO; SeO2; and so on
O2, rose Bengal, hν; and so on
enes: R 2C=CH2; R 2C=CR(OH); and so on
R 2C=CR-CR 2M (e.g., M=Zn, Mg, Li)
Stereochemistry: suprafacial (syn)
Regiochemistry: hydrogen migration from most congested alylic position usu-
ally preferred in reactions with singlet oxygen
(continues)
79. Cope, A.C.; Foster, T.T.; Towle, P.H. J. Am. Chem. Soc. 1949, 71, 3929; 1953, 75, 3212.
80. (a) Kingsbury, C.A.; Cram, D.J. J. Am. Chem. Soc. 1960, 82, 1810. (b) Emerson, D.; Craig, A.; Potts, I. J.
Org. Chem. 1967, 32, 102.
81. Sharpless, K. B.; Young, M. W.; Lauer, R. F. Tetrahedron Lett. 1973, 1979.

(Reaction Synopses continued)
Pyrolytic Eliminations
Z
Y X R R B R R
∆ ∆
H O H A
R R R R
R R R R
R R R R
Ester pyrolysis: X=C, Y=O, Z=R

Carbonate pyrolysis: X=C, Y=O, Z=OR
Chugaev elimination (xanthate pyrolysis): X=C, Y=S, Z=SR
Sulfite pyrolysis: X=S, Y=O, Z=OR
Cope elimination: A=NR 2, B=O
Sulfoxide elimination: A=SR, Y=O
Selenoxide elimination: A=SeR, Y=O
Mechanism: concerted through a cyclic transition state; at high tempera-
tures a stepwise mechanism may operate
Stereochemistry: suprafacial (syn)
6.7 Orbital Correlation Diagrams
In the area of pericyclic reactions more than any other, the use of orbital correlation
diagrams can provide useful insights into the stereochemical and regiochemical course
of the reaction. The basic premise behind these diagrams is simple: every orbital in the
reacting species should correlate with a corresponding orbital in the product(s) of the re-
action. Let us take the electrocyclization reaction as a first example. The diagrams for this
reaction are the most easily constructed, and most widely used for discussing pericyclic
reactions.
Electrocyclization
As for many of these reactions, it is usually simplest to generate the orbital correlation dia-
gram from the perspective of the forward (bond-forming) reaction rather than the reverse
reaction. So, in the electrocyclization reaction, we view the reaction as a cyclization, even if
the reaction we are actually looking at may be the ring-opening. In this reaction, the net
bonding change is to reduce the number of π bonds by one and to form a new σ bond, so
the set of orbitals, ψ1, ψ2, ψ3, and ψ4, is lost and is converted into the new set of orbitals, σ, σ*,
π, and π*. We can draw these orbitals in order of increasing energy, and we can also label
them in terms of their symmetry with respect to the symmetry operation being conserved
in the reaction. In a disrotatory reaction, the mirror plane of symmetry is preserved
throughout the reaction, so the symmetry properties of the orbitals of the diene alternate,
beginning with the symmetric orbital ψ1. In the product, the two bonding orbitals are both
symmetric with respect to the mirror plane of symmetry, and the two antibonding orbitals
are antisymmetric. The labeling of the π orbitals is exactly the opposite for the conrotatory
process, where the C2 axis of symmetry is preserved, whereas the labels of the σ orbitals
remain the same.
To complete the diagram, one simply correlates the orbitals of the reactant with the
lowest energy available orbital of the same symmetry in the product, beginning with the
lowest energy orbital of the reactant. This leads to the diagram in Figure 6.24, which shows
that the HOMO of the reactant correlates with an antibonding orbital in the product in
the disrotatory reaction, regardless of whether one looks at the reaction in the direction of

Figure 6.24 Orbital correla-

tion diagrams for disrotatory
(top) and conrotatory
(bottom) electrocyclizations
σ∗ (A) of 1,3-butadiene to
ψ4 (A) cyclobutene
ψ3 (S) π∗ (A)
ψ2 (A) π (S)
ψ1 (S)
σ (S)
DISROTATORY: MIRROR PLANE PRESERVED
σ∗ (A)
ψ4 (S)
ψ3 (A) π∗ (S)
ψ2 (S) π (A)
ψ1 (A)
σ (S)
CONROTATORY: C2 AXIS PRESERVED
ring closure or the ring opening—an inherently endothermic process. This contrasts with
what is found for the conrotatory process, where all the bonding orbitals in the reactant
correlate with bonding orbitals in the product. Thus, if we were to predict the outcome of
this reaction, we would predict that the disrotatory process would have a high activation
energy—it would be symmetry-forbidden—and the conrotatory process would have a
lower activation energy—it would be symmetry-allowed. This is what is found experimen-
tally: conrotatory processes involving 4n electrons occur under thermal (ground-state)
conditions, and disrotarory processes occur photochemically.
Problem
6-19 Construct orbital correlation diagrams analogous to Figure 6.23 for the electrocy-
clization of 1,3,5-hexatriene to 1,3-cyclohexadiene and the cyclization of
1,3,5,7-octatetraene to 1,3,5-cyclooctatriene.
Cycloadditions
Orbital correlation diagrams for cycloadditions can be constructed by a similar process.
We will examine both the [2 + 2] cycloaddition and the [2 + 4] cycloaddition as the pro-
totypes of cycloadditions involving 4n and (4n + 2) π electrons. The cycloaddition is bi-
molecular, which means that there are now stereochemical consequences for both
participating molecules, with three combinations of stereochemical outcomes being

Figure 6.25 The orbital cor-

relation diagram for the +
Diels-Alder ([4 + 2] cycload-
dition) reaction
σ1*–σ2* (A)
ψ4 (A) σ1*+σ2* (S)
π* (A) π* (A)
ψ3 (S)
ψ2 (A)
π (S) π (S)
ψ1 (S) σ1–σ2 (A)

σ1+σ2 (S)
possible: suprafacial-suprafacial, suprafacial-antarafacial, and antarafacial-antarafacial.

Of these three, the suprafacial-suprafacial process is easiest to visualize, and because it
then allows the other stereochemical outcomes to be deduced, we need only try it.
[4 + 2] Cycloadditions
This cycloaddition reaction, which is typified by the Diels-Alder cycloaddition, gives rise
to the orbital correlation diagram shown in Figure 6.25. Again, we begin the process by
ordering the reacting π-type orbitals in increasing order of energy. However, we are now
forming two new σ bonds on adjacent atoms, and we need to be able to distinguish them.
We do this by using linear combinations of the orbitals (σ1(*) + σ2(*)) and (σ1(*) – σ2(*)),
which are symmetric and antisymmetric with respect to the preserved mirror plane of
symmetry for this reaction. In the diagram, we see the effects of conjugation on π orbital
energies. The π orbital of the dienophile lies between ψ1 and ψ2 of the diene, and the π*
orbital of the dienophile lies between ψ3 and ψ4 of the diene. As we can see, in this reaction,
the bonding orbitals of the reactants all correlate with bonding orbitals in the product, so
we expect the suprafacial-suprafacial reaction to be symmetry-allowed in the ground
state, as is observed experimentally.
[2 + 2] Cycloadditions
The [2 + 2] cycloaddition differs from the [4 + 2] cycloaddition (and, in fact, all other
cycloadditions) by producing a final product that has lost all the π bonds of the reactant.
The other way in which [n + n] cycloadditions are unique lies in the observation that the
orbitals involved can be described in terms of not one but two mirror planes of symmetry.
Thus, a pair of orbitals may be symmetrical with respect to one of the mirror planes and
antisymmetric with respect to the other. By convention, we describe the symmetry within
the individual molecules first and the symmetry between molecules second, as illustrated
in Figure 6.26. In this pairing of orbitals, however, we see that one of the bonding molec-
ular orbital combinations in the reactants correlates to an antibonding orbital

+ Figure 6.26 The orbital cor-

relation diagram for the su-
prafacial-suprafacial [2 + 2]
cycloaddition reaction
σ1*–σ2* (AA)
π1*–π2* (AA) σ1*+σ2* (SA)
π1*+π2* (AS)
π1–π2 (SA) σ1–σ2 (AS)

π1+π2 (SS) σ1+σ2 (SS)
combination in the product. This makes the concerted reaction symmetry-forbidden, and
we therefore expect that it will be allowed photochemically.
Problem
6-20 Construct orbital correlation diagrams analogous to Figures 6.24 and 6.25 for the
[4 + 4] cycloaddition and the [4 + 6] cycloaddition reactions.
Sigmatropic Rearrangements and Ene Reactions

As noted at the beginning of this section, orbital correlation diagrams for these reactions
are rather less straightforward to construct than the correlation diagrams for electrocy-
clizations and cycloadditions. For this reason, they are rather less widely used, in spite of
the symmetry being retained in some reactions—the Cope rearrangement, for example,
retains a C2 axis of symmetry throughout the reaction if it proceeds through a chairlike
transition state. It does. In general, the simpler interpretations of the Woodward-Hoffmann
rules described in Section 6.2 suffices for these types of reactions.
6.8 Combining Pericyclic Reactions in Sequence
Another Look at Electrocyclizations82
82. Monograph: Marvell, E.N. Thermal Electrocyclic Reactions (Academic Press: London, 1980).

Figure 6.27 Electrocyclic
ring closures of ions
Almost all electrocyclizations are, in principle, reversible, so the reaction can be used in
the forward direction to prepare cyclic products, or it can be used in the reverse direc-
tion to prepare polyenes. Given that they are the simplest of the unimolecular pericyclic
reactions, we used them in Section 6.2 to introduce many of the common features of this
type of reaction. As we discussed in this section, the thermally allowed electrocycliza-
tions of conjugated dienes (and, therefore, the electrocyclic ring opening of cyclobutenes)
are conrotatory processes in the ground state. Photochemically, the reaction occurs
with disrotatory stereochemistry. When one considers 1,3,5-hexadiene derivatives, how-
ever, the stereochemical consequences are reversed: the electrocyclic ring closure is dis-
rotatory in the ground state (the thermal reaction) and conrotatory in the excited state
(the photochemical reaction). In general, systems with 4n participating electrons are
conrotatory in the ground state and disrotatory in the excited state, and systems with
(4n + 2) participating electrons are disrotatory in the ground state and conrotatory in
the excited state.
The analysis we used earlier in this chapter to analyze the electrocyclization of polyenes
also applies to the cyclization of ionic species with odd numbers of atoms (Figure 6.27).
The electrocyclic ring closure of the allyl cation (three atoms with two π electrons) to the
cyclopropyl cation, for example, is a disrotatory process, whereas the ring closure of the
allyl anion (three atoms with four π electrons) to the cyclopropyl anion is a conrotatory
process. The Nazarov83 cyclization84 (cyclization of cross-conjugated dienones under acid
catalysis) formally involves the conrotatory cyclization of the 3-hydroxy-2,4-pentadienyl
cation. In general, it is easier to predict the stereochemistry of electrocyclizations of ions
in terms of the ring closure reaction, and here, just as with the polyenes, we find that [4n]
electron systems undergo conrotatory electrocyclization and that [4n + 2] electron sys-
tems undergo disrotatory electrocyclizations.
In conrotatory electrocyclizations, the substituent at one end of the conjugated system
rotates inward and the other rotates outward. In disrotatory reactions, both substituents
rotate inward or outward. This affects the stereochemistry of the product; in the electro-
cyclic ring opening of 3-monosubstituted cyclobutenes, for example, inward rotation of
the larger substituent gives the more hindered Z isomer of the diene.
83. Ivan Nikolaevich Nazarov (1905–1957) was educated at the K. A. Timiryazev Moscow Agricultural
Academy (Dr Chem, 1934). He was appointed to the Institute of Organic Chemistry of the USSR Academy of
Sciences and in 1947 became Professor at the Lomonosov Institute of Fine Chemicals in Moscow. In 1953, he
became a full Academician. For more biographical details, see: Lewis, D.E. Early Russian Organic Chemists and
Their Legacy (Springer: Heidelberg, 2012), p. 118.
84. (a) Nazarov, I.N.; Zaretskaya, I.I. Izv. Akad. Nauk SSSR Otd. Khim. Nauk 1941, 211 [Chem. Abstr. 1943, 37,
62437]; 1942, 200 [Chem. Abstr. 1945, 39, 16194]. Reviews; (b) Santelli-Rouvier, C.; Santelli, M. Synthesis 1983,
429. (c) Habermas, K.L.; Denmark, S.E.; Jones, T.K. Org. React. 1994, 45, 1.

CHO Figure 6.28 Possible modes

CHO of conrotatory ring opening
CHO of 2-cyclobutene-1-
carboxaldehyde.
H H
O O
"outward" "inward"
It was predicted85 in 1985 that more electron-withdrawing substituents (e.g., the al-
dehyde group) should prefer to rotate inward during the reaction. This was confirmed
experimentally: the conrotatory ring opening of 3-formyl-cyclobutene at 20–70°C gave
Z-2,4-pentadienal as the sole product (Figure 6.28).86 This has been exploited in synthe-
sis, as shown by Example 6.60, where an inward conrotatory ring opening is followed by
a disrotatory ring closure to give the cyclic ether. Outward rotation during the electror-
eversion would not give the correct stereochemistry for the second ring closure to occur.
An expansion of the early predictions has led to the results in Table 6.9, which contains
calculated activation energies for electrocyclic ring opening of some substituted cy-
clobutenes. Some typical examples of synthetically useful electrocyclizations are shown
by Examples 6.61 to 6.63, and many more are in the Organic Reactions review.87
H
O
O O (6.60)
O O
H H
BF3•OEt2, CHCl3
(6.61)88
∆, 5 d
80%
CO2Me O
O MeO CO2Me
Cu(OTf)2, 25°C, 4h OMe
OMe 89
ClCH2CH2Cl (6.62)
MeO 95% MeO
OMe
O OH OH
H
(6.63)90
CHO CHO CHO
85. (a) Kirmse, W.; Rondan, N.G.; Houk, K.N. J. Am. Chem. Soc. 1984, 106, 7989. (b) Rondan, N.G.; Houk,
K.N. J. Am. Chem. Soc. 1985, 107, 2099.
86. Rudolf, K.; Spellmeyer, D.C.; Houk, K.N. J. Org. Chem. 1987, 52, 3708.
87. Habermas, K.L.; Denmark, S.E.; Jones, T.K. Org. React. 1994, 45, 1.
88. Harding, K.E.; Clement, K.S. J. Org. Chem. 1984, 49, 3870.
89. He, W.; Sun, X.; Frontier, A.J. J. Am. Chem. Soc. 2003, 125, 14278.
90. Marshall, J.A.; Conrow, R.E. J. Am. Chem. Soc. 1980, 102, 4274.

Table 6.9 Calculated Activation Energies for Electrocyclic Ring Opening of Substituted
Cyclobutenes (in kcal mol−1)91
inward outward
+ R
R R
in out in out in out in out

R Eact (A) Eact (A) Eact – Eact Eact (B) Eact (B) Eact – Eact
F 44.3 29.2 +15.1 58.9 42.0 +17.9

CH3 38.8 33.5 +5.3 51.3 44.5 +6.8
CN 35.2 31.0 +4.2 47.2 42.9 +4.3
CHO 26.5 31.2 −4.7 38.0 42.6 −4.6
NO 25.1 29.8 −4.7 39.1 41.7 −2.6
CF3 50.9 48.3 +2.6
NH2 52.2 34.7 +17.5
OH 54.6 37.4 +17.2
C≡CH 48.2 40.6 +7.6
NO2 50.1 42.8 +7.3
COCH3 42.6 41.4 +1.2
CO2H 44.2 41.9 +2.3
A: MP2/6/6-31G//3-21G+ZPE. B: 6-31G*//3-21G
Coupling Pericyclic Reactions: Tandem and Domino Reactions92

Pericyclic reactions provide an extremely powerful arsenal for the synthetic organic
chemist, and, with recent advances in methods for the synthesis of dienes and alkenes,
it is now possible to use these reactions in concert by appropriately designing the
starting material. An example of the application of the tandem Cope-Claisen rear-
rangement is provided by a 1984 synthesis93 of a key ketoacid intermediate (Example
6.68) for steroid synthesis. The sequence begins with the homoallyl vinyl ether 6.65,
which contains a 1,5-diene moiety. When this is heated, it first undergoes a Cope re-
arrangement, to give the allyl vinyl ether 6.66, which then undergoes a subsequent
Claisen rearrangement to give the aldehyde 6.67. Note how the relative stereochemis-
try of two of the three new chiral centers is fixed by the stereochemistry of the original
tertiary ether.
The tandem Diels-Alder reaction is nicely demonstrated by the synthesis of the com-
plex polycyclic product 6.70 from an acyclic precursor by a tandem Diels-Alder sequence.94
In the first Diels-Alder reaction, the alkyne dienophile reacts to give the 1,4-cyclohexadiene
derivative 6.69, which then undergoes the second Diels-Alder reaction to give the final
product.
91. Niwayama, S.; Kallel, E.A.; Spellmeyer, D.C.; Sheu, C.; Houk, K.N. J. Org. Chem. 1996, 61, 2813.
92. The first issue of Chemical Reviews in 1996 was devoted to tandem, domino and cascade reactions. See
especially: (a) Parsons, P.J.; Penkett, C.S.; Shell, A.J. Chem. Rev. 1996, 96, 1. (b) Tietze, L.F. Chem. Rev. 1996, 96,
115. (c) Denmark, S.E.; Thorarensen, A. Chem. Rev. 1996, 96, 137. (d) Winkler, J.D. Chem. Rev. 1996, 96, 167.
93. Ziegler, F.E.; Lim, H. J. Org. Chem. 1984, 49, 3278.
94. Goldberg, D.; Hansen, J.; Giguere, R. Tetrahedron Lett. 1993, 34, 8003.

CO2Me
4 steps RO O
∆ O
H
RO
R = Me2SiCMe3
(6.64) (6.66)
(6.65)
OR
O
H OHC
H H
MeO2C
OR
(6.68) (6.67)
BF3•Et2O (6.70)
0°C, 57%
O O
(6.69)
(6.72)
8π con 8π con
Ph
CO2H
CO2H
(6.71) (6.73) CO2H
Ph
Ph
6π dis
Ph H H Ph H H
(6.74) CO2H CO2H (6.75)
[4+2] [4+2]
CO2H Ph
H
H H
(6.76) H H (6.77)
H
CO2H
H
H
Ph H
Figure 6.29 Black’s proposal for the biosynthesis of the endiandric acids
Perhaps the most spectacular application of tandem electrocyclic reactions in synthe-

sis is exemplified by the confirmation of the possibility of Black’s proposal95 (Figure 6.29)
95. Bandaranayake, W.M.; Banfield, J.E.; Black, D. St.C. J. Chem. Soc., Chem. Commun. 1980, 902.

Ph
H2/Lindlar Pd
CO2Me
CH2Cl2
CO2Me
(6.78) (6.73)
Ph
Ph
H
H H PhMe
H Ph H H Ph H H
100°C
H
CO2Me CO2Me CO2Me
H
10%
30% 12%
(6.76) (6.75)
(6.77)
Figure 6.30 Nicolaou’s biomimetic synthesis of the endiandric acids
for the biosynthesis of the endiandric acids (natural products isolated as racemic com-
pounds isolated from the Australian tree, the Dorrigo plum) by Nicolaou’s “biomimetic”
synthesis.96
Nicolaou’s synthesis (Figure 6.30) involves the synthesis of a diyne precursor, which is
hydrogenated over Lindlar palladium to give the Z,Z-diene, which then undergoes the
electrocyclic cascade to give the methyl esters of endiandric acids D and E at room tem-
perature, and the methyl ester of endiandric acid A on thermolysis.
Chapter Summary
This chapter has been devoted to reactions that demonstrate the power of the concept of the
conservation of orbital symmetry: the pericyclic reactions, which comprise electrocycliza-
tions, cycloadditions, sigmatropic rearrangements, and ene reactions (the chelotropic reac-
tions have not been discussed in this chapter). The symmetry of the π molecular orbitals has
been described in terms of the two major symmetry operations (C2 axis of rotation and σ),
and described appropriately as symmetric or antisymmetric with respect to the symmetry
operation. Pericyclic reactions can be considered as symmetry-allowed or symmetry-
forbidden. Symmetry-forbidden reactions have inordinately high activation energies and
usually occur by a stepwise mechanism. The stereochemistry of pericyclic reactions is de-
scribed as conrotatory or disrotatory for electrocyclizations and as suprafacial or antarafa-
cial for cycloadditions and sigmatropic rearrangements. The approximation of the FMO
coefficients by perturbation theory has been described. The following major synthetic reac-
tion types have been discussed: (1) electrocyclic ring opening and closure; (2) sigmatropic
rearrangements of hydrogen; (3) [1,n]-sigmatropic rearrangements of alkyl, with both re-
tention of configuration (4n + 2 electrons) and inversion of configuration (4n electrons) at
the migrating carbon; (4) the Cope and Claisen ([3,3]-sigmatropic) rearrangements; (5) the
Diels-Alder ([4 + 2] cycloaddition) reaction; (6) cycloadditions of carbenes (the Sim-
mons-Smith reaction) and ketenes; (7) cycloadditions of 1,3-dipoles and “click” chemistry;
(8) ene and retro-ene reactions, including pyrolytic elimination reactions; and (9) tandem
and domino pericyclic reactions. Finally, this chapter introduced the concept of orbital
correlation diagrams for analyzing electrocyclization and cycloaddition reactions.
96. (a) Nicolaou, K.C.; Zipkin, R.E.; Petasis, N.A. J. Am. Chem. Soc. 1982, 104, 5558. (b) Nicolaou, K.C.;
Petasis, N.A.; Zipkin, R.E. J. Am. Chem. Soc. 1982, 104, 5560.

Key Terms
1,3-dipole ene reaction pericyclic reactions

antarafacial Eschenmoser variant pyrolytic elimination
carbine HOMO retro-ene reaction
Carroll variant Ireland ester enolate sigmatropic rearrangement
Claisen rearrangement variant Simmons-Smith reaction
click chemistry Johnson orthoester variant SOMO
conrotatory ketene suprafacial
Cope rearrangement ketene addition symmetry-allowed
cycloaddition LUMO symmetry-forbidden
Diels-Alder orbital correlation diagram tandem and domino
disrotatory oxyanion Cope reactions
electrocyclization rearrangement
Additional Problems
6-21 Rationalize the stereochemistry of the reaction below. [J. Am. Chem. Soc. 1971,
93, 1777.] Why does the reaction fail when the ester groups are replaced by
methyl?
Ar
Ar
X MeO2C N CO2Me
N
MeO2C CO2Me
X
6-22 The reaction below was used as a key step in Tufiarello’s synthesis of cocaine [J.
Am. Chem. Soc. 1978, 100, 3638]. Provide a mechanism that rationalizes this
transformation.
CO2Me
O
N ∆
N CO2Me
O xylene
H
CO2Me
6-23 The reactions below have been used as key steps in the synthesis of a series of nat-
ural products. Predict the major product of each reaction. Where appropriate,
give your reasoning (e.g., is it necessary to explain why one regioisomer or stereo-
isomer of the product is expected to dominate the product mixture?).
OH
H
O (MeO)3CMe [J. Am. Chem. Soc. 2006,
(a)
O EtCO2H, 110°C 128, 15960]
H
CO2Me
∆
(b) [J. Am. Chem. Soc. 1981, 103, 6967]
O
Si
Ph Ph

CH2I2
(c) OH [J. Am. Chem. Soc. 1963, 85, 3673]
Zn(Cu)
H
N ∆
(d) [J. Org. Chem. 1991, 56, 6729]
O
O
SiMe3
(e) H LICA [Tetrahedron Lett. 1987, 28, 4629]
Me
O -78—25°C
O Me
Cl Et3N
(f) [Tet. Lett. 1985, 26, 3535]
PhMe, ∆
OMe
OH
(g) [Org. Lett. 2004, 6, 3345]
EtCO2H, ∆
O2N
Ph N C O
(h) Et3N [J. Am. Chem. Soc., 1978, 100, 6291]
S
H
HO (MeO)3CMe
(i) SiMe3
[J. Am. Chem. Soc. 1980, 102, 5122]
EtCO2H, 110°C
O
O
(j) [J. Am. Chem. Soc., 1956, 78, 1380]
MeO
OMe
CN
Me3Si O
∆ [J. Am. Chem. Soc. 1979, 101, 215]
(k) O
Me3Si (tandem reaction)
H
CH2I2
(l) Zn(Cu) [J. Am. Chem. Soc. 2008, 130, 4421]
TBSO
OPMB
1) LHMDS, Me3SiCl
O 2) HCl, H2O
(m) O [Org. Lett. 2006, 8, 1117]

CHO
(n) [Org. Lett. 2004, 6, 3345]

∆
O
H
H 1O
2 [J. Am. Chem. Soc. 1980, 102, 1738]
(o)
Tetrahedron Lett. 1968, 689]
H CO2Me
(p) C [J. Am. Chem. Soc. 1968, 90, 5336]

∆
H CO2Me
O O
Lewis acid
(q) + [J. Am. Chem. Soc. 2008, 130, 2783]
OMOM O
MeO2C
O O O
(r) [Pure Appl. Chem. 1979, 51, 689]
∆
Me OMe
TBSO
CHO
NMe2
[Angew. Chem. Int. Ed. 2008, 47,
(s)
∆ 6199]
O O O
(t) [J. Am. Chem. Soc. 2006, 128, 6012]
S N m-CPBA
N
CH2Cl2
N N N N
H H
O OEt
O Yb(OTf)3 (0.1 eq)

(u) [Org. Lett. 2005, 7, 2185.
Ni(acac)2 (0.1 eq.)
H dioxane/50°C/air
MeO OMe
O
Ph OH
∆ [Org. Lett. 2004, 6, 2503] (tandem
(v)
reaction)
OO

HO
(w) 1) CS2, NaH [Tetrahedron Lett. 1990, 31, 3409]

OH
OH 2) MeI
3) 220-230°C, HMPA
I
H ∆
(x) [J. Am. Chem. Soc., 1993, 115, 2042]
TBSO
H
6-24 The reaction below proceeds by a combination of pericyclic reactions. Give the
course of this reaction and rationalize the stereochemistry of each step in the
pathway. [J. Am. Chem. Soc. 1980, 102, 6353]
H 185°C
H
O O
O
O H H
O
O
6-25 Suggest a mechanism for the reaction below.
O O
Zn
+ Br Br

6-26 Each of the following compounds can be formed by means of a pericyclic reac-
tion. Give the reactants required for its formation.
CO2Me O
O H H
CO2Me
(a) (b) O (c)
HO
TBDPSO Me
O
HO2C O OMe
OMe OTBS
OMe
(d) N H
Me2Si (e) (f) O
Ph CO2Me CO2Me
N
CH2Ph
OH
Br H O O
Br
(g) (h) (i)
H H
H OMOM MeO O
O
N H
Ph TBSO
(j) OMe
(k) H (l)
H CN
H H
O

6-27 The reaction below has been proposed to occur as a concerted [14 + 2] cycloaddi-
tion. What is the final product, including stereochemistry? [Tetrahedron Lett.
1981, 22, 215]
N N
+ O O
N
Ph

Chapter seven
Aromaticity: The 150-Year Riddle
7.1 Benzene: The Beginning
Within 10 years of its isolation by Faraday 1 in 1825,2 benzene (Example 7.1) had been synthe-
sized from other compounds, and Mitscherlich3 had established its molecular formula as
C6H6 by means of vapor density measurements. In 1834, he synthesized benzene from ben-
zoic acid and showed that it was identical to Faraday’s hydrocarbon.4 The empirical formula
of benzene (CH) shows quite clearly that it is a highly unsaturated compound—even more
unsaturated than ethylene. And herein lay the problem for organic chemistry—it did not fit
the normal reactivity patterns that had begun to appear as a means of making organic chem-
istry less of a jungle and more a rational science. Benzene has held organic chemists in thrall
ever since.5
H
H H
H H
H
(7.1)
Like many concepts that modern organic chemists use (such as electronegativity), aro-
maticity is not particularly amenable to a single, simple definition. Most chemists have
adopted the functional definition of aromaticity being the consequence of cyclic π-elec-
tron delocalization, as proposed Jackman and Elvidge6 a half century ago. This simple
statement recognized three major manifestations of this delocalization: (1) bond lengths
are averaged, (2) the system is stabilized by resonance, and (3) magnetic properties due to
the delocalization of the π electrons in a cyclic system. Sondheimer stated it even more
simply, defining aromaticity as “the set of properties associated with cyclic conjugation.”7
1. Michael Faraday (1791–1867) was largely self-taught. In 1813 he became the protégé of Sir Humphrey Davy
at the Royal Institution. He spent the rest of his life there, becoming Fullerian Professor in 1833. Biographies of
Faraday abound; for a recent biography, see: Hamilton, J. A Life of Discovery: Michael Faraday, Giant of the
Scientific Revolution. (Random House: New York, 2004).
2. Faraday, M. Phil. Trans. Roy. Soc. London 1825, 115, 440.
3. Eilhardt Mitscherlich (1794–1863) was educated at Heidelberg and Göttingen, where he studied medi-
cine. In 1821, he succeeded Klaproth at Berlin, after spending 2 years in Berzelius’ laboratory. For more
complete biographies, see: Obituary notices of Fellows deceased. J. Chem. Soc. 1864, 13, ix-xvi (near the end of
the volume) and Schutt, H.-W. Eilhard Mitscherlich: Prince of Prussian Chemistry (American Chemical Society
and Chemical Heritage Foundation, 2004).
4. Mitscherlich, E. Ann. Chem. Pharm. 1834, 9, 39.
5. There is a huge volume of literature on the subject of aromaticity: see, for example, the special issues of
Chem. Rev.: Chem. Rev. 2001, 101 (5) and Chem. Rev. 2005, 105 (7).
6. Jackman, L.M.; Elvidge, J.A. J. Chem. Soc. 1961, 859.
7. Sondheimer, F. Pure Appl. Chem. 1964, 7, 363.
221

222 Advanced Organic Chemistry | Chapter seven
Modern spectroscopic techniques, especially nuclear magnetic resonance (NMR)

spectroscopy, have also played an important part in defining what is and is not aromatic,
as we shall see later in this chapter. The effects of the aromaticity of the ring can be seen in
the 1H NMR spectrum of the benzene molecule: the protons of the benzene molecule res-
onate at 7.27 ppm, 1.4 ppm downfield from those of the vinyl protons of 1,3-cyclohexadiene
(5.86 ppm). The “outer” protons of the aromatic macrocycle, [18]annulene8 (Example 7.2)
resonate at 10.75 ppm, with the inner protons resonating at –4.22 ppm, indicative of a
strong paratropic ring current.
H H
H H
H H H
H H
H H
H H H
H H
H H
(7.2)
Despite the advances of the last century and a half, the chemist’s view of aromaticity as
a concept may still best be described using the language of Justice Potter Stewart’s state-
ment (about hard-core pornography): “I shall not today attempt further to define the kinds
of material I understand to be embraced within that shorthand description; and perhaps I
could never succeed in intelligibly doing so. But I know it when I see it,…”9 Most organic
chemists have an intrinsic understanding of what is meant by the term, “aromatic,” in-
cluding its effects on reactivity (e.g., substitution by electrophiles, rather than addition),
but remain rather hard-pressed to provide an objective, universal definition—practically
every definition proposed to date will raise objections from some members of the organic
chemistry community.
7.2 Aromaticity and Antiaromaticity: The Hückel Molecular

Orbital Model of Cyclic Polyenes
The structure of benzene was a riddle that occupied some of the finest minds of 19th-
century organic chemistry. A somewhat more complete description of the history of the
planar hexagonal structure for benzene can be found at the end of this chapter, in
Section 7.6. The upshot of six decades of work was that, by the end of the 19th century, the
planar hexagon formula for benzene had become firmly established, and the term aromatic
had come to represent a compound derived from benzene or a compound whose reactivity
was similar to that of benzene.
The first hesitant steps toward a theoretical basis for predicting when a molecule would
be aromatic began with the Armstrong-Baeyer10 (Example 7.3) and Thiele11 (Example 7.4)
formulas for benzene. In the centric formula for benzene, each ring has a sextet of “free”
8. (a) Sondheimer, F.; Wolovsky, R. Tetrahedron Lett. 1959, 3. (b) Sondheimer, F.; Wolovsky, R.; Amiel, Y. J.
Am. Chem. Soc. 1962, 84, 274.
9. Nico Jacobellis v. Ohio, 378 U.S. 184 (1964).
10. (a) Armstrong, H.E. J. Chem. Soc. 1887, 51, 264. (b) Baeyer, A. Ann. Chem. Pharm. 1888, 245, 103.
11. Theile, J. Ann. Chem. 1899, 306, 87; Ann. Chem. 1899, 308, 333.
Friedrich Karl Johannes Thiele (1865–1918) was educated at Halle (PhD, 1890), and remained there until
1893; he taught at Munich (1893–1902), and Strasbourg (1902–1910); in 1910 he became Rector of the university.
For a more complete biography, see: Straus, F. Ber. dtsch. chem. Ges. 1927, 60, A75.

Aromaticity: The 150-Year Riddle 223
valencies, indicated by the short bonds directed toward the center of the ring, which Arm-
strong12 proposed was associated with aromatic character (actually, the structure had been
proposed 6 years earlier13 by Lothar Meyer). These centric bonds, he reasoned, meant that
there were no double bonds in the molecule, which explained the troubling lack of reactiv-
ity of the benzene ring toward reagents that attack alkenes. Although the Armstrong
theory was attractive in its relative simplicity, its empiricism did not satisfy most organic
chemists, who wanted to know just what these “centric bonds” really were. The Thiele
model was slightly more satisfying but still had its limitations. Interestingly, the “centric
bonds” of the Armstrong-Baeyer model and the partial bonds of the Thiele model both
presaged the predictions of modern resonance theory. Without knowing what these bonds
really are, the critical question—“What is needed for a molecule to be aromatic, and why
does it make a molecule aromatic?”—could not be answered. The search for an answer to
this question is as intriguing a story as any in organic chemistry.
H H
H H H H
H H H H
H H
(7.3) (7.4)
Worked Problem
7-1 Resonance can be used to predict the bond lengths and bond orders in aromatic
compounds. What bond orders are predicted for the C—C bonds of naphthalene,
based on equal contributions to the resonance hybrid from each canonical form?
§Answer below.
12. Henry Edward Armstrong (1848–1937) studied in London, then Leipzig (PhD, 1869). During his subse-
quent academic career he became a Fellow of the Royal Society and a major force in the Chemical Society of
London. For more biographical details, see: J. Chem. Soc. 1940, 1418.
13. Meyer, J.L. Die Modernen Theorien der Chemie (Maruschke and Berendt: Breslau, 1872).

There are three reasonable resonance contributors that we can write for the naphthalene molecule. These are
shown below:
Assuming equal contributions from each structure, we can now look at the bonds of the naphthalene mole-
cule in turn:
1 – 2 = 3 – 4 = 5 – 6 = 7 – 8 = (1/3)(2 + 2 + 1) = 1.67; 2 – 3 = 6 – 7 = (1/3)(2 + 1 + 1) = 1.33

1 – 8a = 4 – 4a = 4a – 5 = 8 – 8a = (1/3)(2 + 1 + 1) = 1.33 4a – 8a = (1/3)(2 + 1 + 1) = 1.33
This gives a molecule with the bond orders shown:

1.67 1.33 1.67
1.33 1.33 1.33
1.67 1.33 1.67

Problem
7-1 Write all the major resonance contributors for each of the following polycyclic
aromatic hydrocarbons, and predict the bond orders of their C—C bonds.
(a) phenanthrene (b) benzo[a]pyrene
(c) tetracene (d) pyrene
It took nearly another half century before the German physicist Erich Hückel14 pro-
vided a theoretical basis for aromaticity15 that satisfied most chemists. This work was an
outcome of his work on the π molecular orbitals of conjugated polyenes. Hückel’s molec-
ular orbital calculations, described in Chapter 4, can be applied to cyclic, planar, conju-
gated polyenes as well as open-chain polyenes. These calculations revealed an unexpected
dichotomy. Planar molecules containing a cyclic conjugated π orbital system with (4n + 2)
π electrons, where n is an integer (0, 1, 2, 3,...), were predicted to be unusually stable; these
compounds are aromatic. In contrast, planar molecules containing a cyclic conjugated π
orbital system with 4n π electrons were predicted to be unusually unstable; these com-
pounds are antiaromatic. The Hückel models led chemists to test the limits of aromaticity
as predicted by this theory. The results of these studies modified how aromaticity was
defined, and, as our instrumental and computational capabilities have grown, so the
defining characteristics of an aromatic system have continued to change.
Hückel’s calculations revealed that delocalized, cyclic π molecular orbitals have a reg-
ular pattern in their energies. Unlike the orbitals of acyclic conjugated π systems, where
each orbital is at a different energy level, cyclic, delocalized π orbitals occur as a single
lowest energy π orbital, with all higher energy π orbitals occurring as degenerate pairs. In
molecules with an odd number of atoms in the ring, there is one unique π orbital at the
lowest energy, and in molecules with an even number of atoms in the ring, the same pat-
tern holds, with the exception that there is also one unique π orbital at the highest energy.
From Hückel’s work, a set of four basic structural and electronic requirements for aroma-
ticity emerged:
1. All aromatic compounds are planar.

2. All aromatic compounds are cyclic.
3. All aromatic compounds have a conjugated, delocalized cyclic π bond system.
4. All aromatic compounds have an even number of π electrons not divisible by 4 (i.e., 4n + 2)
in the delocalized π bonding system. (Compounds with 4n π electrons are antiaromatic.)
Because almost all known aromatic compounds meet all four of these structural re-
quirements, determining whether or not a compound is aromatic simply becomes a
14. Erich Armand Arthur Joseph Hückel (1896–1980 was educated at Göttingen (PhD, 1921, under Debye).
After postdoctoral study with mathematician David Hilbert and with Max Born, his independent career took
him from Zürich (1922), to the Technische Hochschule Stuttgart (1930) and Marburg (1937). For more informa-
tion, see: Karachalios, A. Erich Hückel (1896–1980): From Physics to Quantum Chemistry (Springer: Heidel-
berg,) 2010.
15. Hückel, E. Z. Phys. 1931, 70, 204.

problem of determining whether a compound possesses all four of these characteristics.

Let us now use these four characteristics structural characteristics of aromaticity to deter-
mine whether or not the four hydrocarbons below are aromatic, antiaromatic, or
non-aromatic.
Azulene Pentalene 18-Annulene Cyclododeca-1,5,9-

(cyclooctadeca- trien-3,7,11-triyne
1,3,5,7,9,11,13,15,17-nonaene)
Each of these hydrocarbons contains a conjugated π-bonding system but not all are
aromatic. In azulene (C10H8), all ten carbon atoms are sp2 hybridized; the molecule is
planar. In a fused-ring system such as azulene, one writes the structure so that the
conjugated π system—if one is present—is located around the periphery of the mole-
cule; σ bonds between rings are ignored. If one can write the full conjugated system
around the perimeter, the system is cyclic; if not, it is not. When the azulene molecule
is written in this way, one can write the conjugated π electron system so that all five of
the π bonds—all ten of the π electrons – are involved in a linearly conjugated system.
There are 4n + 2 π electrons (n = 2), so the azulene molecule satisfies all the require-
ments for aromaticity; azulene is aromatic. When the same analysis is applied to pen-
talene (C 8H6), we find that there are eight π electrons (4n, n = 2), which means that this
hydrocarbon is antiaromatic. Although derivatives of pentalene had been prepared as
early as 1962,16 the parent hydrocarbon was prepared for the first time in an argon
matrix only in 1997.17
The next two molecules are typical representatives of a class of compounds in which
there is a single large ring with alternating π and σ bonds. These compounds, which
are known as annulenes (Latin annulus, a ring) have names that indicate the ring size;
usually they have only single and double bonds in the ring, as in [18]annulene, but they
may also have triple bonds in the ring, in which case they are usually referred to as
dehydroannulenes. Earlier in this chapter, we encountered the [18]annulene molecule,
which satisfies all the structural requirements for aromaticity: it is planar and conju-
gated, the conjugated π electron system is cyclic, and it has 4n + 2 (n = 4) electrons. It
should be aromatic. In its chemistry, [18]annulene is not as unreactive as benzene, but
it does still react as an aromatic hydrocarbon. The final compound is tridehydro[12]
annulene.18 Here, we have triple bonds in the ring, and one must remember that only
one of the two orthogonal π bonds of the triple bond can be used in determining aro-
maticity; under these rules, this hydrocarbon is antiaromatic because it has 4n (n = 3)
π electrons.
Another class of aromatic species consists of aromatic ions, all of which are character-
ized by the same planar, cyclic delocalized π electron system containing 4n + 2 π elec-
trons. Thus, one finds that the cyclopropenium ion (Example 7.5), which has two π electrons
delocalized over its three-membered ring, should be aromatic, and derivatives of this ion
do, indeed, exhibit unusual stability. The cyclopentadienide anion (Example 7.6), contains
16. Le Goff, E. J. Am. Chem. Soc. 1962, 84, 3935.

17. Bally, T.; Chai, S.; Neuenschwander, M.; Zhu, Z. J. Am. Chem. Soc. 1997, 119, 1869.
18. (a) Untch, K.G.; Wysocki, D.C. J. Am. Chem. Soc. 1966, 88, 2608. (b) Sondheimer, F.; Wolovsky, R.; Gar-
ratt, P.J.; Calder, I.C. J. Am. Chem. Soc. 1966, 88, 2610.

six π electrons delocalized over its planar five-membered ring, is also especially stable as
evidenced by the unusually high pKa (≈ 15) of the parent diene. The c ycloheptatrienylium
ion (Example 7.7, also known as the tropylium ion) contains six π electrons delocalized
over its planar seven-membered ring; it is also unusually stable. We find that cyclohepta-
triene derivatives carrying a leaving group all react rapidly under SN1 conditions. Cyclooc-
tatetraene, which is tub-shaped and non-aromatic, reacts with potassium as shown in
Example 7.8 to give the radical anion. This anion then disproportionates to give
cyclooctatetraene and the planar cyclooctatetraene dianion,19 which has ten π electrons
delocalized over its eight carbon atoms and is quite stable.
(7.5) (7.6) (7.7)
K° (7.8)
2–
Whether or not a compound is aromatic depends on the total number of electrons in

the π orbitals. We can illustrate this by looking at the cyclopentadienyl system. This
system is common to the cyclopentadienyl cation, the cyclopentadienyl free radical, and
the cyclopentadienide anion. All three of these species can be represented by five con-
tributing structures. The electron configurations of these three species are shown in
Figure 7.1. As we can see, the cyclopentadienyl cation, which has four π electrons, has
two unpaired electrons in a pair of degenerate π orbitals. In the fully delocalized form,
it is antiaromatic. The cyclopentadienide anion, on the other hand, has six π electrons,
which are all paired; it is aromatic. The free radical, by having the unpaired electron, is
strongly delocalized, but it cannot be aromatic or antiaromatic. The free radical is
non-aromatic. The cyclopentadienyl cation is difficult to prepare from simple cyclopen-
tadienyl halides by solvolysis: 5-iodo-1,3-cyclopentadiene does not react with silver per-
chlorate in propionic acid,20 for example, and the reactions of derivatives that do
solvolyze occur extremely slowly.21 The cation has been prepared by the reaction be-
tween 5-bromocyclopentadiene and antimony pentafluoride at 78K, and shown to be a
triplet in the ground state by electron paramagnetic spin resonance spectroscopy.22 In
contrast to this, the unusually high acidity of cyclopentadiene and the stability of its
conjugate base were recognized as early as 1900.23 Its gas-phase acidity relative to eth-
ylene has been determined experimentally24 as –55 ± 3 kcal mol–1, which is an indication
of how strongly stabilized the anion is.
The difference between the effects of electron delocalization in aromatic and antiaro-
matic compounds raises an especially important point about molecular energies. It is ax-
iomatic that the ground state of a molecule will be at its lowest possible energy. For an
19. Katz, T.J. J. Am. Chem. Soc. 1960, 82, 3784.

20. (a) Breslow, R.; Hoffman, R.J. J. Am. Chem. Soc. 1972, 94, 2110. (b) Breslow, R. Acc. Chem. Res. 1973, 6, 393.
21. Allen, A.D.; Sumonja, M.; Tidwell, T.T. J. Am. Chem. Soc. 1999, 119, 2371.
22. (a) Saunders: M.; Berger, R.; Jaffe, A.; McBride, J.M.; O’Neill, J.; Breslow, R.; Hoffman, J.M., Jr.; Per-
chonock, C.; Wasserman, E.; Hutton, R.S.; Kuck, V.J. J. Am. Chem. Soc. 1973, 95, 3017. (b) Wasserman, I.;
Hutton, R.S. Acc. Chem. Res. 1977, 10, 27.
23. Thiele, J. Ber Deut. chem. Ges. 1900, 33, 666. (b) Thiele, J. Chem. Ber. 1901, 34, 68.
24. (a) Rogers, D.W.; McLafferty, F.W.; Podosenin, A.V. J. Phys. Chem. 1996, 100, 17148. (b) Rogers, D.W.;
McLafferty, F.W.; Podosenin, A.V. J. Phys. Chem. 1997, 101, 4776.

Figure 7.1 Electron
configurations of
cyclopentadienyl species
Energy
D D Figure 7.2 Cycloaddition
CN D CO2Et reactions providing evidence
of the rectangular shape of
cyclobutadiene in the ground
D CO2Et (7.11) state
(7.14)
NC CO2Et
CO2Et
D D D
N hν
N
D D D
(7.9) (7.10)
NC CO2Et
CO2Et CO2Et
D D CO2Et D D D
CN D CO2Et CO2Et
(7.12)
(7.15) (7.13)
aromatic molecule, this means that the fully delocalized, aromatic structure will be the
ground-state structure of the molecule because it is especially stable. However, what are
the options for an antiaromatic compound?
In antiaromatic compounds, the effects of electron delocalization are to destabilize the
molecule (i.e., to raise its energy), which means that the delocalized (antiaromatic) form of
the molecule is actually higher in energy than the localized (non-aromatic) form. This
means that the ground-state energy of these molecules will be lower if they are not delo-
calized. Evidence that this is actually the case was provided by spectroscopy in an argon
matrix 25 and confirmed by the cycloaddition reactions of doubly deuterated cyclobutadiene
(Figure 7.2), which led to the conclusion that it is a rectangular (localized, non-aromatic)
25. Masamune, S.; Souto-Bachilier, F.A.; Machiguchi, T.; Bertie, J.E. J. Am. Chem. Soc. 1978, 100, 4889.

Energy
Energy
Reaction Coordinate Reaction Coordinate
Figure 7.3 Possible reaction pathways interconverting rectangular ground states of the
cyclobutadiene molecule
rather than a square (delocalized, antiaromatic) molecule.26 Trapping experiments

with cyclobutadiene-1,2-d2 (7.9, 7.10) using ethyl acrylate gave all three possible prod-
ucts (7.11, 7.12, 7.13), which did not rule out the possibility that the cyclobutadiene
molecule could be square. However, the same trapping reaction, using the much more
reactive dienophile, ethyl Z-3-cyanoacrylate, led to the formation of a single product
(7.14), which is only consistent with the molecule being rectangular in the ground state.
The results show that rate of equilibration of the two rectangular forms is fast com-
pared to the rate of the Diels-Alder reaction with ethyl acrylate but slow compared to
the rate of the same reaction with the more reactive dienophile. The X-ray crystal struc-
ture of 1,3-dimethylcyclobutadiene with a closely associated carbon dioxide trapped
in a crystal matrix has revealed a square ring,27 but only three carbons are planar, and
the CO2 is bent, which raises the question of whether the molecule is actually the
cyclobutadiene.
The results we have just discussed suggest that the antiaromatic form of the molecule
may not be the ground state, but may, in fact, correspond to a transition state between two
or more isomeric, non-aromatic ground states, or to a reactive intermediate in a shallow
well between the non-aromatic ground states. These possibilities are shown schematically
for rectangular cyclobutadiene in Figure 7.3.
Heterocyclic Compounds: Aromatic or Not? Where is the Lone Pair?
N O N
H
pyridine furan pyrrole
Heterocyclic compounds can also be subjected to the Hückel analysis for aromaticity,
bearing in mind that rehybridization of an atom to achieve aromaticity is an energetically
favorable process. The presence of lone pairs on the heteroatom thus provides a potential
extra source for the needed π electrons, but only one lone pair from any one heteroatom
can contribute to the aromatic π electron system. Lone pairs involved in the aromatic π
26. Whitman, D.W.; Carpenter, B.K. J. Am. Chem. Soc. 1980, 102, 4272.
27. Legrand, Y.-M.; van der Lee, A.; Barboiu, M. Science 2010, 399, 299.

electron system are usually not basic enough to be protonated by acids. Thus, in the pyr-
idine molecule, the three π bonds in the ring are sufficient to make the molecule aro-
matic, so the lone pair is localized on nitrogen, in an sp2 hybrid orbital, and it can be
protonated. In the pyrrole molecule, on the other hand, the lone pair on nitrogen is re-
quired to make up the aromatic π electron system. Thus, the electrons will formally be in
the p orbital that becomes part of the conjugated π system, with the N—H bond being
formed by overlap of the nitrogen sp2 hybrid orbital with the hydrogen 1s orbital. Because
the lone pair is not localized on the nitrogen atom, pyrrole is not protonated on nitrogen;
pyrrole reacts with acids by protonation on carbon. In the furan molecule, there are two
lone pairs on oxygen. One of the two lone pairs on oxygen is required to make up the
aromatic π electron system, but the other lone pair is not. This second lone pair, which is
in an sp2 hybridized orbital, can, in principle, be protonated by strong acids (although it
usually is not).
Problems
7-2 Which of the following hydrocarbons will be aromatic, and which will be antiar-
omatic if completely delocalized and planar?
(a) (b) (c) (d)
7-3 Which of the following compounds are aromatic? In the aromatic compounds,
are the electrons of the lone pair required to give the aromatic π electron system?
What will be the hybridization of the heteroatoms in the molecules that are not
aromatic? Why?
Me
O H N
N O
N
O O O N N O
7-4 Anthracene reacts with bromine in carbon disulfide to give the dibromide shown.
This compound slowly loses hydrogen bromide on standing to give
9-bromoanthracene.
Br Br
Br2, CS2
Br
The alternative reaction shown below does not occur.

Br Br
Br2, CS2
Br
Rationalize why the addition reaction occurs the way it does and why the slow
elimination then follows spontaneously.
(continues)

7-5 Provide a reasonable explanation for the dipole moments of the series of fulvenes
below.
R R=H 1.20 D
R=Ph 1.34 D
R R=p-ClC6H4 0.64 D
Orbital Energies of Hückel π Orbitals of Cyclic Systems

The orbital energies of the π orbitals of an aromatic ring can be calculated directly from
Hückel theory, but one particularly useful simplification of the process is to use the circle
method of Frost and Musulin.28 In this method, the ring of the molecule is drawn as a reg-
ular polygon inscribed point-down in a circle centered at α, and of radius 2β, where α and
β are as defined in Chapter 3 (α represents the Coulomb integral, a measure of how tightly
the electron is bound to the nuclei of the atoms, and is constant for all atoms of a particular
element; β represents the resonance integral, a measure of the electron energy in the molec-
ular orbital relative to the electron in the isolated atoms). Recall that both α and β are
negative because they identify a stabilizing energy. The Hückel π orbital energies for several
cyclic CnHn systems are gathered in Table 7.1. The population of these orbitals may be
determined by filling the orbitals in accord with the Aufbau principle and Hund’s rule.
One of the important outcomes of the Hückel analysis of cyclic π systems is the deduc-
tion that when there are 4n + 2 π electrons in the system, the occupied orbitals are all
filled, and the molecule is diamagnetic. On the other hand, when the system has 4n π
Table 7.1 Energies of Hückel π Orbitals of Cyclic CnHn Systems
 2π i  α-1.62β α-1.80β
E 5 α 1 β cos 
 n  α-β
α-0.45β
α+0.62β
α+1.25β
α+2β
α+2β α+2β
n=3 n=5 n=7
α-2β α-2β α-2β α-2β
α-β α-1.41β α-1.62β

α α α-0.62β
α+0.62β
α+β α+1.41β
α+1.62β
α+2β α+2β α+2β α+2β
n=4 n=6 n=8 n = 10
28. Frost, A.A.; Musulin, B. J. Chem. Phys. 1953, 21, 572.

electrons, the system will have two singly occupied π orbitals, with the result that the
compound is predicted to be a diradical and highly reactive. These compounds are desig-
nated as antiaromatic. This analysis also points out another important difference between
aromatic and antiaromatic compounds—aromatic compounds are diamagnetic and are
therefore repelled by an external magnetic field, whereas antiaromatic compounds are
paramagnetic and are therefore attracted by an external magnetic field.¶
Hückel Molecular Orbitals in Benzene and Aromatic Compounds

Every π orbital of an aromatic compound is completely delocalized over the entire ring
system. The overlap of the six 2p basis orbitals to give the six π orbitals of benzene is
shown schematically in Figure 7.4, and the overlap of the five 2p basis orbitals to give the
five π orbitals of the cyclopentadienyl system is shown in Figure 7.5.
These orbitals illustrate one characteristic of the Hückel molecular orbitals of cyclic,
delocalized π electron systems that contrasts with their open-chain analogs. Recall that
none of the Hückel molecular orbitals of open-chain polyenes is degenerate. The number
of nodal planes between the 2p basis orbitals, and hence the number of phase dislocations
in the π molecular orbital, increases by one as one moves from one π orbital to the next in
the set, in ascending order of energy. Thus, in 1,3,5-hexatriene, the lowest energy π molec-
ular orbital, ψ1, has no phase dislocations between adjacent 2p basis orbitals; ψ2, the next
¶. Calculating Hückel Orbital Coefficients and Energies of Aromatic Compounds

The major difference between the Hückel π molecular orbitals of aromatic systems and those of open-chain
π-bonded systems is the fact that the π system of aromatic compounds is cyclic and conjugated. This leads to
the following secular determinant, which is usually shown in the form where x = (α – E)/β:
α2E β 0 L 0 β
x 1 0 L 0 1
β α2E β 0M M 0
1 x 1 0 0
0 β α2E β 0 M 0 1 x 1 0 M
=0 ⇒ =0
M 0 β O β 0 M 0 1 O 1 0
0 M 0 β α 2E β 0 0 1 x 1
β 0 L 0 β α2E 1 0 L 0 1 x
This secular equation always has one unique solution at x = –2, corresponding to an orbital energy, E = α +
2β. When the system has an odd number of atoms, the remaining solutions occur as degenerate pairs of orbitals
whose energies are given by:
 2( j 2 1)π 
E j 5 α 1 2βcos   , where N is the number of atoms in the cyclic π molecular orbital system and j
 N
is the specific orbital in that system. When the system has an even number of atoms, the same set of degenerate
orbitals is obtained, but there is also there is a second unique solution at x=2, corresponding to an orbital
energy, E = α – 2β.
The coefficients of the orbitals are not as simply obtained as in the acyclic system, but one simple generaliza-
tion, at least, can be made: in one of the orbitals of each degenerate set, at least one planar node will pass
through one atomic nucleus.
The wave functions of the Hückel orbitals for benzene are:
ψ1 = (1/√6)(p1 + p2 + p3 + p4 + p5 + p6) E1 = α + 2β
ψ2 = (1/2)(p2 + p3 – p5 – p6) E1 = α + β
ψ3 = (1/√3)(p1 + ½ p2 – ½p3 – p4 – ½p5 + ½p6) E1 = α + β
ψ4 = (1/2)(p2 – p3 + p4 + p5 – p6) E1 = α – β
ψ3 = (1/√3)(p1 – ½ p2 – ½p3 + p4 – ½p5 – ½p6) E1 = α – β
ψ6 = (1/√6)(p1 – p2 + p3 – p4 + p5 – p6) E1 = α – 2β
The wave functions of the Hückel orbitals for cyclopentadienyl are:
ψ1 = (1/√5)(p1 + p2 + p3 + p4 + p5) E1 = α + 2β
ψ2 = (1/2)(p2 + p3 – p5 – p6) E2 = α + 0.618β
ψ3 = [√(2/5)](p1 + 0.309p2 – 0.809p3 – 0.809p4 + 0.309p5) E3 = α + 0.618β
ψ4 = (1/2)(p2 – p3 + p4 – p5) E 4 = α – 1.618β
ψ3 = [√(2/5)]( (p1 – 0.809p2 + 0.309p3 + 0.309p4 – 0.809p5) E5 = α – 1.618β

Figure 7.4 The Hückel π

molecular orbitals of the
benzene molecule. Four of
the orbitals occur as two
degenerate pairs of orbitals,
which differ only in the
orientation of the nodal
planes perpendicular to the
ψ6
plane of the ring. The basis p ψ4 ψ5
orbitals are drawn to convey
the relative contribution of
each to the molecular orbital,
Energy
but are not drawn accurately
to scale.
ψ2 ψ3
ψ1
Figure 7.5 The Hückel π

molecular orbitals of the
cyclopentadienyl system. ψ4 ψ5
Four of the orbitals occur as
two degenerate pairs of
orbitals, which differ only in
the orientation of the nodal
planes perpendicular to the
Energy
plane of the ring. The basis p

orbitals are drawn to convey ψ2 ψ3
the relative contribution of
each to the molecular orbital,
but are not drawn accurately ψ1
to scale.
orbital in energy, has one phase dislocation, located such that the C2 symmetry of the or-
bital relative to this node is maintained. The highest energy orbital, ψ6, has five phase
dislocations (one between every pair of adjacent 2p basis orbitals).
In the cyclic, delocalized π orbitals in Figures 7.4 and 7.5, we see the differences from
the open-chain systems emerge once we get to the degenerate pairs of orbitals. In both ψ2
and ψ3, we see that there is a single nodal plane that crosses the ring. But this leads to a pair
of phase dislocations in the orbital, rather than one. In ψ4 and ψ5, there are two nodal
planes that cross the ring and therefore four phase dislocations. The two orbitals in each
degenerate pair differ only in the way that the nodal plane is oriented in each. This leads to

another characteristic of the π molecular orbitals of cyclic systems—one of each degener-

ate pair of orbitals has a nodal plane that passes through the nucleus of at least one of the
ring atoms.
7.3 How Does One Measure Aromaticity? Criteria

for Aromaticity and Its Quantification
There are several different criteria that may be used to determine whether a compound is
or is not aromatic. Each has its limitations and drawbacks, but most are of sufficiently
general applicability that they can be used with relative confidence. The oldest criterion
used to quantify the aromatic character of a molecule is thermodynamic. It rests on the
observation that reactions of benzene and other aromatic compounds leading to non-
aromatic products are generally less exothermic than one would predict on the basis of the
simple Lewis structures of the molecules. Aromatic compounds are relatively easy to form,
unusually stable, and less reactive than one would predict a priori. The second criterion is
structural; one fundamental property of aromatic compounds is the total delocalization
of the π electrons in the cyclic, conjugated π system, with the result that the alternation of
the σ bond lengths apparent in open-chain conjugated polyenes is either absent com-
pletely or significantly reduced. The third criterion comes from the magnetic properties of
aromatic rings. In a magnetic field, the cyclic π electrons of the ring enter into motion that
generates a sustained ring current. This leads to observable effects on the 1H NMR spec-
trum, in particular, where the proton resonances of the aromatic ring are deshielded sig-
nificantly compared to the protons of a structurally similar alkene.
Based on each of these criteria, antiaromatic compounds are expected to be perfect
corollaries of their aromatic counterparts. One, they are expected to be difficult to form,
relatively unstable, and highly reactive. Two, they are expected to exist in a localized form
rather than a delocalized form to minimize the destabilizing effects of bond delocaliza-
tion. Three, they are expected to exhibit shielding of nuclei at the periphery of the ring and
strong deshielding of nuclei in the center of the ring.
Thermodynamics and Aromatic Resonance Stabilization Energy

All aromatic ring systems are stabilized by resonance. The degree of stabilization can be
measured experimentally a number of ways. For example, the resonance stabilization
energy of the benzene molecule can be determined by measuring the heat of hydrogena-
tion of benzene and comparing it with the heats of hydrogenation of cyclohexene and
1,3-cyclohexadiene. The specific value obtained depends on the assumptions made during
the calculation, but the most widely used methods yield values near 36 kcal mol–1 for
benzene.
The calculation for benzene relies on the fact that cyclohexene and benzene both pro-
duce cyclohexane on exhaustive hydrogenation. The enthalpies of hydrogenation for cyclo-
hexene, 1,3-cyclohexadiene, and benzene have been measured to a high degree of precision.29
The enthalpy for hydrogenation of cyclohexene is –28.59 kcal mol–1, which one may extrap-
olate to the enthalpy of hydrogenation of the hypothetical, localized 1,3,5-cyclohexatriene
by tripling this value to –85.77 kcal mol–1. When benzene is hydrogenated, however, the
enthalpy of the reaction is found to be –49.73 kcal mol–1. Thus, the hydrogenation of ben-
zene is 36.1 kcal mol–1 less exothermic than the hydrogenation of the hypothetical
1,3,5-cyclohexatriene.
29. (a) Kistiakowski, G.B.; Ruhoff, J.R.; Smith, H.A.; Vaughan, W.E. J. Am. Chem. Soc. 1936, 58, 137.
(b) Kistiakowski, G.B.; Ruhoff, J.R.; Smith, H.A.; Vaughan, W.E. J. Am. Chem. Soc. 1936, 58, 146.

Figure 7.6 Estimating the

aromatic resonance
stabilization energy of
benzene by hydrogenation
85.77 36.01 80.34 30.61
57.18 55.37
49.73 49.73
28.59 28.59 28.59
This model does not take into account the effects of conjugation, which are apparent
when one compares the enthalpy of hydrogenation of cyclohexene (–28.59 kcal mol–1)
with that of 1,3-cyclohexadiene (–55.37 kcal mol–1). This value is 1.81 kcal mol–1 less exo-
thermic than twice the value for cyclohexene. We may assume that this represents the
extra stabilization from (non-aromatic) conjugation of two adjacent π bonds. If we
assume that such conjugation must be taken into account for the three pairs of conju-
gated alkene π bonds in the hypothetical 1,3,5-cyclohexatriene ring, the value of the
aromatic resonance stabilization energy of benzene must be reduced by three times this
value, which leads to a value of 30.6 kcal mol–1 for the aromatic resonance stabilization
energy of the benzene molecule. It is interesting to note that the enthalpy of hydrogena-
tion of the first π bond in benzene is endothermic. These calculations are summarized
in Figure 7.6.
An estimate of the resonance stabilization energy of benzene can also be obtained
from bond energies by measuring the heats of combustion.30 The average bond energies
of a wide range of hydrocarbon molecules have been determined with sufficient accuracy
that they can be used with considerable confidence in determining ∆Hf of hydrocarbons
from the enthalpy of combustion of those hydrocarbons. When the bond energies are
used to calculate the ∆Hf of benzene, the calculated value is found to be –4180 kJ mol–1.
When the value is calculated from the measured ∆H for combustion, the value is found
to be –4343 kJ mol–1. Thus, the aromatic resonance stabilization energy of benzene found
by this method is 163 kJ mol–1 (or 39.0 kcal mol–1). This discrepancy between the values
obtained from catalytic hydrogenation and combustion is reproduced for a range of aro-
matic compounds. The values obtained from combustion are typically higher by approx-
imately 10% of the value, and they are usually considered to overestimate the actual value
by this quantity.
Regardless of which calculations one uses, they come with a caveat. Although the
heat of hydrogenation, or the heat of combustion of benzene is a measurable quantity, the
aromatic resonance stabilization energy is not; it must be deduced from the experimental
data. However, the changes necessary to convert 1,3,5-cyclohexatriene to benzene require
not only the complete delocalization of the π electrons but also the lengthening of the
double bonds and the shortening of the σ bonds. This means that inferring the resonance
30. Pauling, L. In Gilman, H., Ed. Organic Chemistry. An Advanced Treatise, 2nd Ed., (John Wiley & Sons:
New York, 1943), ch. 26, p1943.

Table 7.2 Aromatic Resonance Stabilization Energies
Stabilization Energy Stabilization Energy

Compound (kcal mol–1) Compound (kcal mol–1)
36*; 41† 27*; 40†
N
61*; 77† 16*; 24†
O
83.5a; 116† 21*; 24†

NH
91.3*; 130† 28*; 29†

S
70*
*Values taken from Reference 30.

†
Values taken from Reference 31.
stabilization energy of benzene is subject to the details of the model of the hypothetical
1,3,5-cyclohexatriene that is used. We will discuss the limitations of that model later in
this chapter, when we examine computational approaches to answering the question of
just what constitutes aromaticity. Aromatic resonance stabilization energies have been
calculated for a number of organic compounds, and a selection of these are gathered in
Table 7.2.31,32
Recognizing that the values obtained experimentally all depend on the model
chosen for the non-aromatic species, a more modern approach has been to calculate
the enthalpies for homoisodesmic reactions: reactions in which the numbers and
types of bonds in the “reaction” are conserved. These reactions do not need to be real—
capable of actually being carried out in the laboratory—but they do give reasonable
estimates of the stabilization energy. One of the most popular types of homoisodesmic
reactions involves hydrogen transfer from one reactant to another. For example, one
such reaction involves the conversion of benzene and butane to 1,3-cyclohexadiene
and cis-2-butene, 33 which gives an estimate of the resonance stabilization energy for
benzene of 34.0 ± 0.4 kcal mol–1, well in line with the values obtained by other
methods.
+ +
31. Wheland, G.W. Resonance in Organic Chemistry (John Wiley & Sons: New York, 1955), p. 98 ff.
32. Ingold, C.K. Structure and Mechanism in Organic Chemistry (Cornell University Press: Ithaca, N.Y.,
1953), p. 183.
33. Enthalpies used were from Pedley, J.B. Thermochemical Data and Structures of Organic Compounds;
Thermodynamics Research Center: College Station, TX, 1994; vol. 1

Structural Evidence of Aromaticity

The bond distances and angles of the benzene molecule are known with a very high degree
of precision from a variety of physical methods including neutron and electron34 diffrac-
tion, X-ray crystallography,35 and Raman spectroscopy.36 The ring is a planar hexagon,
with all carbon-carbon bond lengths equal at 1.397 Å and all carbon-hydrogen bond
lengths equal at 1.084 Å. The C—C bond lengths can be compared to 1.532 Å for ethane
and 1.32 Å for ethylene. The single bond length in 1,3-butadiene is 1.48 Å. Thus, we find
that there is a substantial bond alternation in the non-aromatic 1,3-butadiene (the bond
distances alternate between 1.32 and 1.48 Å). This may be contrasted with benzene, where
the bond distances are all the same, and intermediate between these two values. This loss
of C—C bond alternation is generally viewed as a diagnostic feature of aromatic systems,
although only benzene and similar totally symmetrical, monocyclic aromatic species can
achieve perfect uniformity of C—C bond distances. In naphthalene and other polycyclic
aromatic hydrocarbons, the C—C bond distances vary somewhat, but the range is still
quite restricted (typically the values lie between 1.36 and 1.45 Å). This also holds true in the
aromatic annulenes. In [18]annulene, for example, the C—C bond lengths are not uniform
but are 1.38 and 1.42 Å.37 Computations have shown that the return to localized rather
than delocalized structures for (4n + 2) systems occurs at [30]annulene, although the
molecule still retains significant aromatic stabilization.38
In 1952, Clar suggested39 that the six-membered ring with three double bonds in it (i.e.,
the true “benzene” ring) is especially stable, and that it therefore ought to contribute more
importantly to the overall resonance hybrid in polycyclic aromatic hydrocarbons. Accord-
ing to the Clar model of polycyclic hydrocarbons, the contributing structures with the
largest number of disjoint aromatic sextets will be the most important. If we apply the Clar
rule to two of the five Kekulé canonical forms of the structure of phenanthrene, for exam-
ple (Figure 7.7), we find that in one of the canonical forms (the lower one), only the middle
ring is a benzene-like aromatic sextet, and that in the other canonical form (the upper
one), there are two benzene-like aromatic sextets. This means that canonical forms of the
upper type are expected to contribute more to the overall resonance hybrid than are struc-
tures like the lower canonical form. This, in turn, leads to the conclusion that the 9,10 bond
in phenanthrene ought to exhibit a greater level of reactivity than any of the other π bonds.
It does.
The greatest strength of the Clar model is its simplicity. Electrons in Clar structures
may only be attributed to one ring, so the Clar model requires that no two aromatic
sextets in a simple fused-ring aromatic compound may share a common side—Clar sex-
tets must always be in disjoint rings. In a Kekulé structure where two rings sharing a
common side simultaneously have a sextet, the sextet must be assigned to one of the
rings; once electrons have been assigned to one ring of a structure, they cannot simulta-
neously be assigned to another—thus, only one of the rings is a true sextet (and there-
fore is written with the circle in it), and the other ring is not (and is therefore written
with two double bonds, instead). Clar analyses of the canonical forms of a large number
34. (a) Jones, P.R.L. Trans. Faraday Soc. 1935, 31, 1036. (b) Schomaker, V.; Pauling, L. J. Am. Chem. Soc. 1939,
61, 1769. (c) Bacon, G.E.; Curry, N.A.; Wilson, S.A. Proc. Roy. Soc. 1964, A279, 98.
35. (a) Cox, E.D.; Cruickshank, D.W.J.; Smith, J.A.S. Proc. Roy. Soc. 1958, A247, 1. (b) Piermarini, G.J.;
Mighell, A.D.; Weir, C.E.; Block, S. Science 1969, 165, 1250. (c) Fourme, R.; André, D.; Renaud, M. Acta Crystal-
logr. 1971, B27, 1275.
36. Langseth, A.; Stoicheff, B.P. Can. J. Phys. 1956, 34, 350.
37. (a) Bregman, J.; Hirshfeld, F.L.; Rabinovich, G.; Schmidt, G.M.J. Acta Crtstallogr. 1965, 19, 227. (b) Hirsh-
feld, F.L.; Rabinovich, G. Acta Crystallogr. 1965, 19, 235.
38. Choi, C.H.; Kertesz, M. J. Chem. Phys. 1998, 108, 6681.
39. (a) Clar, E. Aromatische Kohlenwasserstoffe, 2nd ed. (Springer: Berlin, 1952). (b) Clar, E. Polycyclic Hydro-
carbons (Academic: London, 1964). (c) Clar, E. The Aromatic Sextet (John Wiley: London, 1972.).

Figure 7.7 Clar resonance

structures for two canonical
forms of phenanthrene
compared to classical Kekulé
canonical forms. The
structure with two full six-
electron rings is the more
important contributor to the
resonance hybrid.
of polycyclic aromatic hydrocarbons quickly illustrates the usefulness of this simple

model in predicting reactivity in these compounds.
Magnetic Evidence of Aromaticity

One of the first experimental measurements that could be associated with aromaticity
in a quantitative sense is derived from the values of the magnetic susceptibility. This
criterion for aromaticity is known as the magnetic exaltation, or, earlier, the incrément
de délocalisation.40 In homogeneous medium (e.g., in solution or the gas phase), one
m
may define the mean molar magnetic susceptibility, χ , which is defined as one-third
of the trace of the magnetic anisotropy tensor:
m 1 m 1
χ 5 {χ xx 1 χ yy
m
1 χ zzm } 5 tr(χ m ) (7.1)
3 3
There are a large number of mean molar magnetic susceptibilities that have been mea-
sured, and by 1910, it had been found that they generally follow a simple set of additivity
m
rules.41 The magnetic exaltation, χ , is the difference between the measured value of and
m
the value calculated on the basis of Pascal’s additivity principle ( χ calc ):
Λ m 5 x m 2 x calc
m
(7.2)
m
where the value of is χ calc calculated on the assumption that there is no delocalization of
the π electrons in the molecule. The values of the molar magnetic susceptibility are all
negative for diamagnetic compounds, so positive value of the magnetic exaltation indi-
cates that the measured magnitude of the molar magnetic susceptibility of the molecule is
greater than the calculated value; this has been proposed as being an indicator of
aromaticity.42
The origins of the magnetic exaltation in aromatic compounds can be traced to the
ring current. The cyclic, delocalized nature of the π electron system of an aromatic com-
pound leads to a highly characteristic interaction with an external magnetic field. When
an aromatic compound is placed in a strong external magnetic field, the electrons in the π
40. (a) Pacault, A. Ann. Chim. (12e série) 1946, 1, 527. (b) Hoarau, A. Ann. Chim. (13e série) 1956, 1, 544.
(c) Bergmann, E.D.; Hoarau, J.; Pacault, A.; Pullman, A.; Pullman,B. J. Chim. Phys. Phys.-Chim. Biol. 1952, 49,
474. (d) Pacault, A.; Hoarau, J.; Marchand, A. In Advances in Chemical Physics (Wiley: New York, 1961); Vol. 3,
pp. 171–238.
41. (a) Pascal, P. Ann. Chim. Phys. 1910, 19, 5. (b) Pascal, P. Ann. Chim. Phys. 1912, 25, 289. (c) Pascal, P. Ann.
Chim. Phys. 1913, 29, 218. The values for several substituents and compounds are gathered in: (d) Ingold, C.K.
Structure and Mechanism in Organic Chemistry (Cornell University Press: Ithaca, NY, 1953), pp. 185–196.
42. (a) Benson, R.C.; Norris, C.L.; Flygare, W.H.; Beak, P. J. Am. Chem. Soc. 1971, 93, 5591. (b) Dauben, H.J.;
Wilson, J.D.; Laity, J.L. J. Am. Chem. Soc. 1968, 90, 811.

Figure 7.8 Ring currents in

aromatic molecules. The
direction of the ring current H H
is indicated by the dashed
lines, and the induced field H H
by solid lines.
H H
B0
H H
H H
H H H
H H
H H
H H H
H H
H H
orbitals begin to cycle, generating what is known as a ring current (Figure 7.8). In an aro-
matic compound, this ring current opposes the external magnetic field in the center of the
aromatic ring, with the result that it reinforces the external field at the periphery. The
effect of the ring current is to deshield the protons attached to an aromatic ring by some 2
ppm relative to simple alkenes of similar structure. Aromatic compounds are said to ex-
hibit a diatropic ring current, where the ring current generates an induced magnetic field
that opposes the external field at the center of the ring, while antiaromatic compounds
exhibit a paratropic ring current, where the ring current generates an induced magnetic
field that reinforces the external field at the center of the ring.
The real test of using ring currents to probe aromatic character came with the 1H
NMR examination of [18]annulene, which is known to be aromatic. The spectrum is
temperature-sensitive, and at –70°C, it shows two resonances in the ratio of 2:1. The
more intense resonance is at 9.28 ppm and the less intense resonance is at –2.99 ppm.
The low-field resonance is attributed to the twelve protons on the outside of the ring,
where the ring current reinforces the external field, and the high-field resonance is at-
tributed to the six protons on the inside of the ring, where the ring current opposes the
external m agnetic field.43
The first simple model for estimating the magnitude of the ring current (and, there-
fore, the resonance energy) of a compound based on the chemical shifts of the protons in
the molecule was developed by Hess, Schaad, and Kakagawa.44 In their model, the ring
current is proportional to the difference between the chemical shifts of the “inside” pro-
tons and the “outside” protons in the series of compounds shown in Figure 7.9, which in-
clude compounds with cyclic π electron systems containing from 14 to 30 π electrons. The
1
H NMR spectra of these compounds show a remarkable regularity in the chemical shifts
of the inside and outside protons. In compounds with (4n + 2) π electrons, the outside
protons are considerably downfield from the inside protons. In compounds with (4n) π
electrons, the reverse is true. In addition, as the number of π electrons increases, the dif-
ference in the chemical shifts of the inside and outside protons decreases, which is consis-
tent with the effects of aromatic resonance stabilization decreasing as the number of π
electrons increases.
43. Haddon, R.C.; Haddon, V.R.; Jackman, L.M. Curr. Top. Chem. Res. 1971, 16, 105.
44. Hess, B.A., Jr.; Schaad, L.J.; Nakagawa, M. J. Org. Chem. 1977, 42, 1669.

Figure 7.9 Variations in the

Hout chemical shifts of the inside
Hout and outside protons of
m dehydro-[n]annulenes
m
Hin Hin
m
m
m=1,2,3,4,5 m=2,3,4
Computational Evaluation of Aromaticity

The advent of high-speed computing and the high degree of confidence that can be placed
in the results of high-level computational results have revolutionized the ways that ques-
tions of aromaticity are now decided.
Within the past two decades, the difficulties of working with the ring current, which
is not directly measurable, have been overcome by using the concept of the nucleus-
independent chemical shift, or NICS, which is defined as the magnetic shielding at the
geometric center of the aromatic ring (or at a location above the center of the ring).45 This
value, which can be readily calculated to high levels of precision and is only modestly
dependent on the basis set used in the computation, was one of the first computational
variables that found widespread applicability in defining aromaticity. In an aromatic
system, the NICS value is negative (typically the more negative the value, the more strongly
aromatic the ring), and in antiaromatic systems, the NICS value is positive. A number of
NICS values for representative aromatic and antiaromatic compounds, as well as for com-
pounds that are not aromatic, are presented in Figure 7.10.
Homoisodesmic reactions, in particular, lend themselves well to the computational
determination of aromatic resonance stabilization energies because the deficiencies in the
45. (a) Schleyer, P.v.R.; Maerker, C.; Dransfeld, A.; Jiao, H.; van Eikema Hommes, N.J.R. J. Am. Chem. Soc. 1996,
118, 6317. (b) Jiao, H.; Schleyer, P.v.R.; Mo, Y.; McAllister, M.A.; Tidwell, T.T. J. Am. Chem. Soc. 1997, 119, 7075.

Figure 7.10 Nucleus- –15.1 –17.2 –7.6 –9.9

independent chemical shift
values for a series of
aromatic, antiaromatic, and
non-aromatic rings. The
values are taken from
Reference 45 (a). +27.6 +18.1 +22.7 +30.1
–2.5 +22.5 –5.1 +19.0 –19.7 –7.0
–1.1
–2.2
individual calculations tend to cancel out.46 With the level of confidence in modern basis
sets for computation, one can obtain quite good estimates of the resonance stabilization
energy. For example, the reaction between isopropyl cation and a series of conjugated and
saturated hydrocarbons has been used to obtain computed energies for the hydride trans-
fer reaction that are in excellent agreement with the observed values.47
Another computational measure of aromaticity is the harmonic oscillator model of
aromaticity (HOMA) index.48 This is a geometry-based index, given by the relationship:
α
HOMA = 1 2 n ∑ (Ropt 2 Ri ) (7.3)
2
where n is the number of bonds in the ring, Ropt is the optimal bond distance in an aro-
matic system (equal to 1.388Å), and α is a normalization factor (for CC bonds, α = 257.7)
that gives HOMA = 0 for a non-aromatic system (the localized Kekulé structure of ben-
zene) and HOMA = 1 for a system in which all bond distances are equal to the optimal
value. For benzene, the HOMA is calculated to be 0.9965. The HOMA can be dissected
into two independent contributions, which describe whether the decrease in π-electron
delocalization is due to bond alternation or bond elongation. The effect of bond alterna-
tion is designated as GEO and is defined as:
α(Ropt – Rav)2 (7.4)
The effect of bond elongation is designated as EN and is defined as:

α (R 2 R )2
n ∑ av i (7.5)
Thus, the overall decrease in aromaticity is given by HOMA = 1 – EN – GEO. The HOMA
index has generally been a useful index of aromaticity, and it correlates well with NICS values.
46. George, P.; Trachtman, M.; Boch, C.W.; Brett, A.M. Theor. Chim. Acta 1975, 38, 121.
47. Wiberg, K.B. Chem. Rev. 2001, 101, 1317.
48. (a) Kruszewski, J.; Krygowski, T.M. Tetrahedron Lett. 1972, 3839. (b) Krygowski, T.M. J. Chem. Inf.
Comput. Sci. 1993, 33, 70. (c) Bodwell, G.J.; Bridson, J.N.; Cyrañski, M.K.; Kennedy, J.W.J.; Krygowski, T.M.;
Mannion, M.R.; Miller, D.O. J. Org. Chem. 2003, 68, 2089.

Worked Problem
7-2 Using the Clar structures, predict the structure of the most likely carbocation to
be produced by the protonation of anthracene with deuterium.
D
C14H10D
§Answer below
Problems
7-6 Draw the Clar structures for each of the polycyclic aromatic hydrocarbons
shown. Benzenoid aromatic rings are highly resistant to reduction by dissolving
metals, so the major Clar contributing structures tend to show where the most
chemical resistance in the molecule resides. Based on the Clar structures, deduce
what will be the most likely dihydro compounds formed from each of these poly-
cyclic aromatic hydrocarbons by reduction with sodium in ethanol.
(a) (b) (c) (d)
(e) (f)
(continues)

The solution to this problem is best approached from the perspective of the cation since the Clar structures
for the parent hydrocarbon do not give a clear difference between choices.
(a) Protonation at position 1:
H D H D H D H D
There are four structures, each with one Clar ring, but there are two different major contributing structures
with each cation where neither of these sextets is interrupted.
(b) Protonation at position 2:
H H
D D
There are two structures, each with one Clar ring, but there is only one major contributing structures for
each cation where neither of these sextets is interrupted.
(c) Protonation at position 9:
H D H D
This ion is the only one for which there is a structure with two Clar rings. This is expected to be the major
product of protonation.

7-7 What can be deduced about the structures of the following molecules from the
chemical shifts of their protons?
Me
Hi
(a) (b) (c) Ho
Me
CH2: δ -0.5
CH3: δ -4.25 vinyl H: δ 7.8
ring H: δ 8.0-8.7 Hi: δ 10.4; Ho: δ 5.4
Another computational measure of aromaticity is the Dewar resonance energy (DRE).49

This quantity is simply the difference between the measured enthalpy of formation and the
same enthalpy calculated for the completely localized system. The computational work of
Dewar has shown that the calculated values for the enthalpy of formation of the localized
systems are actually quite dependable, so these resonance stabilization energies are actually
fairly reliable. For totally unsaturated systems containing only carbon, hydrogen, and
oxygen, CnHmOpÖq, where O is an oxygen atom linked by two σ bonds and Ö is a carbonyl
oxygen, Baird50 has shown that the DRE can be calculated using Equation 7.6:
DRE = 7.435n – 0.605m – 32.175p – 29.38q – ∆Hf0 (experimental) (7.6)
Using this approach, one finds that a compound is aromatic if the DRE is positive,
antiaromatic if the DRE is negative, and non-aromatic if the DRE is zero. Compounds
with DRE values close to zero are considered to be neither aromatic nor antiaromatic.
Baird has calculated values of the DRE for a number of compounds, and they illustrate
this point quite well. For benzene, the DRE is calculated to be +21 kcal mol–1; for cyclo-
decapentaene ([10]annulene), it is +6 kcal mol–1; for cyclobutadiene, it is –17 kcal mol–1;
and for planar cyclooctatetraene, it is –10 kcal mol–1.
The DRE can be placed on a more useful comparative basis by dividing the total DRE
by the number of π electrons in the π system. This gives the resonance energy per π elec-
tron (REPE).51 Using this parameter, one finds that a series of simple polycyclic aromatic
hydrocarbons have comparable REPE values, despite their total DREs being quite differ-
ent. Shortly after this, a modified parameter, the resonance energy per π bond (REPB)
was proposed as being more widely applicable, especially in charged systems.52
Another value that can be used as a criterion for aromaticity is the absolute hardness,
η, of the compound in question. This is defined as one half of the energy gap between the
HOMO and LUMO of the molecule in question. Zhou, Parr, and Garst have shown that
this correlates with a number of other indexes of aromaticity,53 including the REPE.
49. Dewar, M.J.S.; de Llano, C. J. Am. Chem. Soc. 1969, 91, 789.
Michael James Steuart Dewar (1918–1997) was educated at Oxford University (DPhil, 1942). His career in
theoretical organic chemistry spanned over half a century on two continents, at Queen Mary College, Chicago,
Texas at Austin, and Florida at Gainesville. For more biographical detail, see: (a) Murrell, J. N. Biogr. Mem. Fell.
Roy. Soc. 1998, 44, 129; (b) Dewar, M.J.S. A semiempirical life (American Chemical Society: Columbus, 1992).
50. Baird, N.C. J. Chem. Educ. 1971, 48, 509.
51. (a) Hess, B.A., Jr.; Schaad, L.J. J. Am. Chem. Soc. 1971, 93, 305. (b) Hess, B.A., Jr.; Schaad, L.J. J. Am. Chem.
Soc. 1971, 93, 2413. (c) Hess, B.A., Jr.; Schaad, L.J. J. Am. Chem. Soc. 1973, 95, 3907. (d) Hess, B.A., Jr.; Schaad, L.J.
J. Org. Chem. 1971, 36, 3418. (e) Hess, B.A., Jr.; Schaad, L.J.; Holyoke, C.W., Jr. Tetrahedron 1972, 28, 3657. (f )
Hess, B.A., Jr.; Schaad, L.J.; Holyoke, C.W., Jr. Tetrahedron 1972, 28, 5299. (g) ) Hess, B.A., Jr.; Schaad, L.J.;
Holyoke, C.W., Jr. Tetrahedron 1975, 31, 295. (h) Schaad, L.J.; Hess, B.A., Jr. Chem. Rev. 2001, 101, 1465.
52. Aihara, J.-I. Bull. Chem. Soc. Japan 1977, 50, 3057.
53. (a) Zhou, Z.; Parr, R.G.; Garst, J.F. Tetrahedron Lett. 1988, 4843. (b) Zhou, Z.; Parr, R.G. J. Am. Chem. Soc.
1989, 111, 7371.

Bird,54 however, found that this relationship does not always work well with heterocyclic
compounds. In these cases, he found that the absolute hardness scale used by Zhou, Parr,
and Garst needed to be modified and a value obtained on the basis of the molar refractiv-
ity used. This restored a good correlation with the REPE values for as wide range of het-
erocyclic aromatic compounds.
7.4 Möbius Aromaticity55
In 1964, Heilbronner56 published a seminal paper in which he suggested that it might be

possible for a sufficiently large cyclic π system to twist without losing conjugation, such
that there would be a phase dislocation in the system (Figure 7.11) and that such a system
could exhibit aromatic character. Möbius aromaticity has since been defined by the Inter-
national Union for Pure and Applied Chemistry (IUPAC)57 as a monocyclic array of orbit-
als in which there is a single out-of-phase overlap (or, more generally, an odd number of
out-of-phase overlaps) that reveals the opposite pattern of aromatic character to Hückel
systems. Topologically, this is the same as a Möbius strip, which is a three-dimensional
object with only a single surface. In a Möbius annulene, there is a gradual twist of the π
orbital system so that the lobes of the p orbitals at the ends of the cycle become exactly 180°
out of phase with each other, giving a phase dislocation. One of the fundamental stereo-
chemical aspects of the Möbius system is that the ring possesses a C2 axis of symmetry.
This means that in the conjugated system, the p basis orbitals on one side of the ring are
orthogonal to those on the opposite side of the ring, and this orthogonality of orientation
is now the simplest way to recognize a Möbius system.
One of the consequences of this type of topology is the extra stability of cyclic, conju-
gated π systems with (4n + 2) π electrons with Hückel (untwisted) topology might be en-
joyed by cyclic, conjugated π systems with (4n) π electrons with Möbius topology. In other
words, in Möbius annulenes, molecules with 4n π electrons should be aromatic, and mole-
cules with 4n + 2 π electrons should be antiaromatic. This intriguing possibility has led to
much research in an effort to obtain just such a system. In 1966, Zimmerman58 proposed a
mnemonic for Möbius annulenes similar to the Frost-Musulin diagram59 for Hückel annu-
lenes. In the Zimmerman mnemonic, the polygon is drawn with one side down in a circle of
radius 2β, in contrast to the Frost model, where the polygon is drawn with its vertex down.
Figure 7.11 A Möbius

annulene, showing the C2
symmetry and the phase
phase dislocation in the π bonding
dislocation system. Note how the p basis
orbitals on the right are
orthogonal to those on the
C2 axis left.
54. Bird, C.W. Tetrahedron 1997, 53, 3319.

55. Reviews: (a) Rzepa, H.S. Chem. Rev. 2005, 105, 3697. (b) Herges, R. Chem. Rev. 2006, 106, 4820.
56. Heilbronner, E. Tetrahedron Lett. 1964, 1923.
57. Muller, P. Pure Appl. Chem. 1994, 66, 1077.
58. Zimmerman, H.E. J. Am. Chem. Soc. 1966, 88, 1564.
59. Frost, A.A.; Musulin, B. J. Chem. Phys. 1953, 21, 572.

Figure 7.12 Comparison of Hückel Möbius

Frost and Zimmerman
models for predicting orbital
energies in Hückel and
Möbius planar
cyclooctatetraene
The comparison of the Hückel and Möbius planar cyclooctatetraenes is shown in Figure 7.12,
where α, β, I, and n are as defined earlier for aromatic systems, as well as in Chapter 4.
Zimmerman’s paper introduced Möbius-type aromatic systems as a theoretical possi-
bility, and efforts to identify Mobius-type aromatic species began soon thereafter. One of
the early observations to support the involvement of a Möbius-type aromatic species in a
reaction was the solvolysis of precursors of the cyclononatetraenyl cation, shown as Exam-
ples 7.16 and 7.17. In both cases, the products of the reaction had the deuterium label uni-
formly distributed throughout the product, a situation that can occur only if a symmetrical
intermediate is involved, thus providing indirect evidence that the cyclononatetraenyl
cation is fully delocalized. Computations by Schleyer revealed that for this cation,
the molecule adopts a twisted, C2-symmetric structure (Example 7.18), consistent with
Möbius-type aromaticity, rather than a planar, C2v-symmetric structure.60,¶
* *
D * * 61
Me2CO-H2O (7.16)
*
Cl 75°C *
* * OH
*
* *
D * * 62
liq. SO2 (7.17)
*
Cl –66°C *
* * Cl
*
60. Mauksch, M.; Gogonea, V.; Jiao, H.; Schleyer, P.v.R. Angew. Chem. Int. Ed. 1998, 37, 2395.
¶. Calculating Hückel Orbital Coefficients and Energies of Möbius Annulenes
The π molecular orbitals of Hückel systems have a secular determinant that has only values of β because
there is no phase dislocation in the π system. In contrast to this, the secular determinant of Möbius systems has
a single –β element (actually two, because the matrix is symmetrical), due to the single phase dislocation. This
leads to the following secular determinant, which is usually shown in the form where x = (α – E)/β:
α2E β 0 L 0 2β
x 1 0
L 0 21
β α2E β 0 1 x 10
0 β α2E M 0 1 xM
50 ⇒ 50
M O β 0 M O 1 0
0 β α2E β 0 1 x 1
21 0 L 0 1 x
2β 0 L 0 β α2E
When the system has an even number of atoms, the solutions occur as degenerate pairs of orbitals whose
energies are given by:
 (2j 2 1)π 
E j 5 α 1 2βcos  , where N is the number of atoms in the cyclic π molecular orbital system and j is
 N
the specific orbital in that system. The highest-energy orbitals in this system are at E = α – 2β. When the system
has an odd number of atoms, the same set of degenerate orbitals is obtained, but the highest-energy orbital, at
E = α – 2β, is now unique.
61. Schleyer, P.v.R.; Baborak, J.C.; Su, T.M.; Boche, G.; Schneider, G. J. Am. Chem. Soc. 1971, 93, 279.
62. Anastassiou, A,G.; Yakali, E. J. Chem. Soc., Chem. Commun. 1972, 92.

H H
H H
(7.18)
H H
HH
H
The search for a stable Möbius system capable of being studied was the object of in-
tense research for decades. It finally came to fruition in 2003, when Herges and his re-
search group reported63 the synthesis of a Möbius (4n) aromatic hydrocarbon (7.23),
although the conclusions of the Herges paper were challenged by Schleyer in 2005,64 when
a computational analysis of the Möbius C16 macrocycle and several less benzannulated
analogs were analyzed. The successful synthesis, which provided experimental support for
Heilbronner’s predictions, is shown in Figure 7.13.
The sequence involved an initial [2 + 2] photocycloaddition of syn-tricyclooctadiene to
the 9,9'-bianthracene (7.19), which possesses two strained, pyramidalized alkene π bonds.
The structure of the ladder-like photoproduct (7.20) was established by X-ray structure
analysis. The photochemical ring expansion reactions led through an unstable intermedi-
ate (7.21) to a cyclohexadiene (7.22), which was obtained as two isomers, a C2-symmetric
isomer with a trans ring junction and a Cs-symmetric isomer with a cis ring junction. The
irradiation of the mixture at shorter wavelength over a longer time period led to a mixture
of isomers from which the C2-symmetric isomer with Möbius topology was isolated and
characterized by single crystal X-ray structure analysis. The X-ray analysis revealed that the
C—C bond distances in the Möbius hydrocarbon (7.23) varied from 1.361-1.456Å, corre-
sponding to a HOMA value of 0.50 for the nine bonds of the polyene bridge of the molecule
and an overall HOMAl of 0.35. By comparison, the Cs-symmetric (Hückel) isomer showed
much greater variability in the bond distances, with a HOMA index of 0.05 for the same
nine bonds in the polyene bridge. This indicates that the Möbius isomer has the hallmarks
of aromaticity; in contrast, the Hückel isomer does not. The twist in the polyene bridge also
shows a remarkable difference: the amount of twist in the Möbius (aromatic) ring system is
not more than 35°, while the Hückel system escapes antiaromaticity by twisting the central
π bond of the polyene bridge by 103° relative to the neighboring π bonds of the bridge.
Figure 7.13 The first synthesis

of a Möbius aromatic
hydrocarbon
hν/30 min
PhH
(7.19) (7.20) (7.21)
hν/24 h
(7.22) (7.23)
63. Ajami, D.; Oeckler, O.; Simon, A.; Herges, R. Nature 2003, 426, 819.
64. Castro, C.; Chen, Z.; Wannere, C.S.; Jiao, H.; Karney, W.L.; Mauksch, M.; Puchta, R.; van Eikema
Hommes, N.J.R.; Schleyer, P.v.R. J. Am. Chem. Soc. 2005, 127, 2425.

Figure 7.14 An expanded Mes Mes

porphyrin showing Möbius-
Hückel switching
NH N
Ph Ph
N HN
Mes Mes
(7.24)
Mes Mes
NH HN
Ph Ph
N N
Mes Mes
Hückel topology
Mes Mes
NH HN
Ph Ph
N N
Mes Mes
Möbius topology
A synthesis of a compound capable of unambiguous existence as a Möbius aromatic

system was provided by the expanded porphyrin 7.24,65 whose properties are both solvent-
and temperature-dependent. One of the two conformers of the macrocycle has the phenyl-
ene rings stacked face-to-face—Hückel topology; in contrast, the other conformer has
them stacked face-to-edge—Möbius topology. Figure 7.14 shows the conformations of the
two phenylene rings and an approximate macrocycle geometry. In both topological forms,
the ring is twisted; this gives the Möbius system the required C2 symmetry and the Hückel
conformer the required C2v symmetry. The structural and spectroscopic evidence all indi-
cate that the Möbius conformer of this 28 π e– macrocycle is preferred at low temperature,
in polar solvents, and that it is, in fact, aromatic at 203 K.
7.5 Homoaromaticity
In systems where two π bonds are sufficiently close spatially but not necessarily adjacent
to each other in the molecule, it is still possible for a significant interaction between them
to occur, provided that both the orientation and the separation of the p orbitals allows
significant overlap. This process, which is analogous to the conjugation of adjacent π
bonds in a molecule, is termed homoconjugation.
65. Stępień, M.; Latos-Grażyński, L.; Sprutta, N.; Chwalisz, P.; Szterenberg, L. Angew. Chem. Int. Ed. 2007, 46, 7869.

Figure 7.15 Aromatic and

homoaromatic carbocations:
aromatic cyclopropenium
cation (7.25), monohomocy-
clopropenium cation (7.26),
(7.25) bishomocyclopropenium
(7.26) (7.27) cation (7.27), trishomocyclo-
(7.28) propenium cation (7.28),
aromatic tropylium cation
(7.29), and monohomotro-
pylium cation (7.30)
(7.29) (7.30)
In 1956, Doering suggested that the terminal sp2 carbons in cycloheptatriene should be
close enough for a homoconjugative interaction to occur between them, and he argued
that this interaction would constitute the formation of an aromatic π electron system.66
This type of interaction, where the formal cyclic conjugation is interrupted by an interven-
ing sp3 hybridized atom, is termed homoaromaticity.67 The subject of homoaromaticity
has been reviewed many times since its proposal in 1956.68
Clear criteria for homoaromaticity were proposed by Childs and Cremer and their
coworkers in the mid-1990s.69 Homoaromaticity requires both the presence of homocon-
jugation and manifestations of “aromaticity.” This includes electron delocalization in a
closed cyclic system, bond orders that approach those of a true aromatic system, charge
delocalization in charged systems, a stabilizing resonance energy greater than 2 kcal mol–1,
and magnetic effects that tend toward equalization of the chemical shifts of carbon atoms
in the homoaromatic ring with effects of a diatropic ring current.
Where it can occur, homoaromaticity is especially evident in carbocations, where it
leads to (often dramatic) stabilization of the cation, or enhancement in the rate of its for-
mation. A wide range of homoaromatic cations known, and some of these types are shown
in Figure 7.15. The carbocations (7.26), (7.27), and (7.28) in Figure 7.14 are all based on the
aromatic two-electron cyclopropenium cation (7.25). They simply involve inserting a
methylene group into one of the ring bonds of the cation, thus expanding the ring by one
carbon and formally interrupting the conjugation by one carbon. One can continue this
process until all three of the ring bonds are replaced to give a six-membered ring. The
cation (7.30) in the lower row is derived from the aromatic six-electron tropylium ion
(7.29) by the same process.
66. Doering, W.v.E.; Laber, G.; Vonderwahl, R.; Chamberlain, N.F.; Williams, R.B. J. Am. Chem. Soc. 1956, 78, 5448.
67. (a) Winstein, S. J. Am. Chem. Soc. 1959, 81, 6524. (b) Winstein, S.; Sonnenberg, J.; deVries, L. J. Am. Chem.
Soc. 1959, 81, 6523.
68. (a) Winstein, S. Chem. Soc. Spec. Publ. 1967, 21, 5. (b) Winstein, S. Q. Rev. Chem. Soc. 1969, 23, 1411. Reprinted
in Carbonium Ions; Olah, G.A.; Schleyer, P.v.R., Eds. (Wiley-Interscience: New York, 1972); Vol. III, p 965. (c) Story,
P. R.; Clark, B. C., Jr. In Carbonium Ions; Olah, G.A.; Schleyer, P.v.R., Eds.; (Wiley-Interscience: New York, 197)2;
Vol. III, p 1007. (d) Warner, P. In Topics in Nonbenzenoid Aromatic Chemistry; Nozoe, T., Breslow, R., Hafner,
K., Ito, S., Murata, I., Eds. (Hirokawa Publishing Co.: Tokyo, 1977); Vol. II, p 283. (e) Paquette, L.A. Angew.
Chem., Int. Ed. Engl. 1978, 17, 106. (f) Childs, R.F. Acc. Chem. Res. 1984, 17, 347. (g) Williams, R.V.; Kurtz, H.A.
Adv. Phys. Org. Chem. 1994, 29, 273. (h) Cremer, D.; Childs, R.F.; Kraka, E. In The Chemistry of the Cyclopropyl
Group; Rappoport, Z., Ed. (J. Wiley & Sons: Chichester, 1995); Vol. 2, p 339. (i) Childs, R.F.; Cremer, D.; Elia, G.
In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed. (J. Wiley & Sons: Chichester, 1995); Vol. 2, p 411.
(j) Williams, R.V. Chem. Rev. 2000, 100, 1185.
69. (a) Cremer, D.; Childs, R.F.; Kraka, E. In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed. (J.
Wiley & Sons: Chichester, 1995); Vol. 2, p 339. (b) Childs, R.F.; Cremer, D.; Elia, G. In The Chemistry of the Cy-
clopropyl Group; Rappoport, Z., Ed. (J. Wiley & Sons: Chichester, 1995); Vol. 2, p 411.

The trishomocyclopropenium cation was the first homoaromatic species to be pre-

pared and characterized. Winstein and Sonnenberg found that solvolysis of the trans
tolylate, Example 7.31, was faster than the solvolysis of the cis isomer, Example 7.32, and
that the solvolysis of the trans isomer (but not the cis isomer) led to complete scrambling
of the deuterium among the three possible positions.70 Similar observations were made in
the case of solvolysis of 7-norbornenyl systems: the solvolysis of 7-anti-norbornenyl to-
sylate (Example 7.34) is much faster than that of the 7-syn isomer (Example 7.33).71 Again,
this rate increase was attributed to the homoaromatic character of the carbocation (in this
case, a bishomocyclopropenium cation).
D OTs D
(7.31)
D trans D
OTs
D
D (7.32)
D
D cis
X X
slow fast
(7.33) (7.35) (7.34)
Like aromatic compounds, homoaromatic species are expected to be unusually

stable, and the preponderance of evidence suggests that this is the case in homoaromatic
cations. One may expect that homoaromaticity should be accompanied by bond dis-
tance changes in keeping with the bond distance equalization characteristic of a romatic
species, and that there may also be distortion of bond angles, also, if this improves
the homoconjugation. This type of geometric effect has been observed in a series of
bishomocyclopropenium ions.72
The one anion that has been repeatedly cited as homoaromatic is the bicyclo[3.2.1]octa-
3,5-dien-1-yl anion (Example 7.36). In the parent hydrocarbon, the rate of hydrogen-deu-
terium exchange is 105 times faster than the corresponding allyl system, and
homoaromaticity in the anion has been inferred to rationalize this observation.73 The large
upfield shift of the methylene protons in this anion suggests that there is a diatropic ring
current, which would support claims of homoaromaticity for this anion.74 These conclu-
sions, however, are not without dispute, and Werstiuk and Ma75 have carried out compu-
tations of the same anion. They found no evidence for a ring current, which would, of
course, argue against homoaromaticity in this anion.
70. (a) Winstein, S.; Sonnenberg, J. J. Am. Chem. Soc. 1959, 81, 6523. (b) Winstein, S.; Sonnenberg, J. J. Am.
Chem. Soc. 1961, 83, 3235. (c) Winstein, S.; Sonnenberg, J. J. Am. Chem. Soc. 1961, 83, 3244.
71. Woods, W.G.; Carboni, R.A.; Roberts, J.D. J. Am. Chem. Soc. 1956, 78, 5653.
72. (a) Laube, T. Acc. Chem. Res. 1995, 28, 399. (b) Laube, T. J. Am. Chem. Soc. 1989, 111, 9224. (c) Laube, T.;
Lohse, C. J. Am. Chem. Soc. 1994, 116, 9001. (d) Evans, W.J.; Forrestal, K. J.; Ziller, J.W. J. Am. Chem. Soc. 1995,
117, 12635.
73. (a) Brown, J.M.; Occlowitz, J.L. Chem. Commun. 1965, 376. (b) Jiao, H.; Schleyer, P.v.R. In AIP Conference
Proceedings 330: E.C.C.C. 1, Computational Chemistry; Bernardi, F., Rivail, J.-L., Eds. (American Institute of
Physics: Woodbury, NY, 1995); p. 107. (c) Freeman, P.K.; Pugh, J.K. J. Org. Chem. 2000, 65, 6107.
74. (a) Brown, J.M. Chem. Commun. 1967, 638. (b) Winstein, S.; Ogliaruso, M.; Sakai, M.; Nicholson, J.M. J.
Am. Chem. Soc. 1967, 89, 3656.
75. (a) Werstiuk, N.H.; Ma, J. Can. J. Chem. 1999, 77, 752. (b) Werstiuk, N.H.; Ma, J. Can. J. Chem. 1996,
74, 875.

(7.36)
As is illustrated by the case of the anion above, the study of homoaromaticity is facili-
tated by modern computational methods for analysis of data, even more than aromaticity.
In part, this is because the replacement of conjugation by homoconjugation means that
the properties one associates with a fully aromatic system are, of necessity, attenuated,
which means, in turn, that the experimental data can sometimes be ambiguous. In addi-
tion, one is often dealing with species that are reactive, transient, or not capable of being
isolated pure or in crystalline form, and whose spectra can be difficult to interpret. Com-
putational results in such cases can be a powerful adjunct to the experimental data that
helps to make the case for a homoaromatic system.
Aromatic Transition States

In pericyclic reactions, which we discussed in detail in the previous chapter of this
book, the concerted movement of electrons during the reaction involves, at some
point in the reaction pathway, the delocalization of the electrons in a closed, cyclic
system. This situation represents a logical extension of the concept of homoaromatic-
ity, and it leads, in turn, to the concept of the aromatic transition state, which is de-
fined as a transition state in which there is a closed, delocalized system of 4n + 2
electrons.
Based on the work of Dewar76 and Zimmerman,77 one can deduce that ground-state
pericyclic reactions will proceed by Hückel transition states if 4n + 2 electrons are in-
volved, and by Möbius transition states if 4n electrons are involved. Common reactions
proceeding via Hückel aromatic transition states are the Claisen and Cope rearrange-
ments (Example 7.37), the Diels-Alder addition (Example 7.38), and suprafacial [1,5]sig-
matropic rearrangements of hydrogen (Example 7.39). The Cope rearrangement, especially,
has been the object of intense study.78
‡
(7.37)
‡
(7.38)
‡
H H H
(7.39)
76. Dewar, M.J.S. Tetrahedron 1966, Suppl. 8, 75.

77. Zimmerman, H.E. Acc. Chem. Res. 1971, 4, 272.
78. (a) Black, K.A.; Wilsey, S.; Houk, K.N. J. Am. Chem. Soc. 1998, 120, 5622. (b) Roth, W.R.; Gleiter, R.; Pas-
chmann, V.; Hackler, U.E.; Fritzsche, G.; Lange, H. Eur. J. Org. Chem. 1998, 961. (c) Hrovat, D.A.; Duncan, J.A.;
Borden, W.T. J. Am. Chem. Soc. 1999, 121, 169. (d) Hrovat, D.A.; Beno, B.R.; Lange, H.; Yoo, N.-Y.; Houk, K.N.;
Borden, W.T. J. Am. Chem. Soc. 1999, 121, 10529. (e) Doering, W.v.E.; Wang, Y. J. Am. Chem. Soc. 1999, 121, 10967.
(f) Oliva, J.M. Theor. Chem. Acc. 1999, 103, 1. (g) Staroverov, V.N.; Davidson, E.R. J. Am. Chem. Soc. 2000, 122, 186.

Concerted reactions proceeding through Möbius transition states are frequently car-
ried out photochemically. They include [2 + 2] photocycloadditions of alkenes to give cy-
clobutanes (Example 7.40) and the suprafacial [1,7]sigmatropic rearrangement of hydrogen
(Example 7.41).
‡
(7.40)
‡
H H H
(7.41)
7.6 The Rest of the Story: The History and Mythology of Benzene
H
H H
H H
H
Kekulé 1865
As indicated at the beginning of this chapter, solving the structure of benzene occupied
the finest minds of 19th-century organic chemistry. The first to propose the cyclic struc-
ture for benzene was August Kekulé, in 1865.79,80 Kekulé’s claim is rendered the more
romantic by the story, which he himself promulgated about his theory, as told by his eulo-
gist, Francis Robert Japp,81 during the Kekulé Memorial Lecture of the Chemical Society of
London in 1898:
According to his own version, the idea came to him during a dream. “I was sitting, writing
at my text-book; but the work did not progress, my thoughts were elsewhere. I turned my
chair to the fire and dozed. Again the atoms were gambolling before my eyes. This time the
smaller groups kept modestly in the background. My mental eye, rendered more acute by
repeated visions of the kind, could now distinguish larger structures, of manifold confor-
mation: long rows, sometimes more closely fitted together; all twining and twisting in
snake-like motion. But look! What was that? One of the snakes had seized hold of its own
tail, and the form whirled mockingly before my eyes. As if by a flash of lightning I awoke;
and this time also I spent the rest of the night in working out the consequences of this
hypothesis.”
“Let us learn to dream, gentlemen,” adds Kekulé, “then perhaps we shall find the truth...
but let us beware of publishing our dreams before they have been put to the proof by the
waking understanding.”
Whether or not the Kekulé dream story is fact or apocryphal romanticism is

still the topic of hot—even vitriolic—debate (some versions of the story have him
79. Kekulé, A. Bull. Soc. Chim. 1865, 3, 98.

80. Kekulé’s original formula was of the “sausage formula” variety, which made the molecule difficult to vi-
sualize as a cyclic compound. The formula that we now routinely use to represent the benzene molecule—and
call the Kekulé structure—was actually introduced by Albert Ladenburg.
81. Japp, R. J. Chem. Soc. 1898, 73, 100.

daydreaming while riding a London bus), and the truth will probably never be known.
In the 1990s—nearly a century after Kekulé’s death—it even resulted in a lawsuit
against the Division of the History of Chemistry of the American Chemical Society!
Still, Kekulé’s dream is now firmly entrenched as part of the folklore of organic chem-
istry. More importantly, Kekulé’s 1865 paper supplied the first widely disseminated
structure for benzene—dreamt up or not—that provided a rational basis for discus-
sion of its chemistry.
Immediately, chemists recognized that there were problems fitting the known chemistry
of benzene to the Kekulé structure because of its double bonds. Based on the Kekulé struc-
ture, benzene should react as a highly unsaturated compound. It does not. Furthermore, the
Kekulé structure predicts that there should be two ortho isomers of dibromobenzene—one
where both bromine atoms are on the same double bond and one where they are on different
double bonds—as Albert Ladenburg82 (then a junior faculty member at Heidelberg) pointed
out. But only one ortho isomer exists.
Br Br Br Br Br
Br Br Br
ortho ortho meta para
The attempts to resolve these inconsistencies between the structure and the chemistry
of the benzene molecule led to many benzene structures being proposed within 5 years of
Kekulé’s paper. New structures continued to be proposed until the end of the 19th century.
Some of the structures are given below.
At this point, it is worthwhile dispelling some quasi-historical inaccuracies that
have crept into the benzene story over the years. One of these concerns an earlier struc-
ture proposed by Austrian physicist Johann Loschmidt that has been interpreted as
being the first cyclic structure proposed for this molecule. It was not, as Loschmidt
himself admitted in his monograph, Loschmidt’s intention to represent a cyclic struc-
ture for the benzene molecule because he did not know the arrangement of the six
carbon atoms of the benzene molecule. He simply used a larger version of the Dalton
symbol for carbon to represent them and he arranged the hydrogens symmetrically
about it (Loschmidt’s representation contains a mirror plane and two C2 axes and a pair
of C2 axes, but no C 6 axis).83
In similar fashion, the structure designated as Dewar benzene was not seriously pro-
posed as a structure for benzene by Sir James Dewar at all, but it was just one of seven
possible structures for benzene he pointed out could be built with a set of models that he
had developed!84 It was proposed as a reasonable structure for benzene by (1) Georg
82. Albert Ladenburg (1842–1911) was educated at Heidelberg (PhD, 1863). His career began in Heidelberg
in 1868; he moved to Kiel in 1872 and Breslau in 1889. He received many honors during his lifetime, including
the Davy medal of the Royal Society. For his autobiography, published posthumously, see: Ladenburg, A. Leb-
enserinnerungen, (Trewendt & Granier, Breslau, 1912).
83. For a lucid account, see: Roth, H.D. Bull. Hist. Chem. 2013, 38, 29.
84. Dewar, J. Proc. Roy. Soc. Edinburgh 1867, 6, 82.

Städeler85 of the University of Zürich, in 1868,86 and (2) Hermann Wichelhaus87 of the
University of Berlin, in 1869.88 Likewise, the structure now known as the Armstrong-Baeyer
centric formula89 was actually first proposed by Lothar Meyer in 1872.90
H H
H H H H H H
H H H
H H H H
H H H H H H
H H H H H H
H
H H
(7.3) (7.4)
Claus 1867 [Dewar 1867[ Ladenburg 1869 L. Meyer 1872 Thiele 1899
Städeler 1868 Armstrong-Baeyer
Wichelhaus 1869 1877-1878
Except for the Ladenburg formula,91 all the formulas proposed retain the original
structural feature of the Kekulé formula: the planar six-membered ring of carbon atoms
with a hydrogen atom at each vertex. The problem to be resolved, of course, was to explain
the lack of reactivity of the benzene molecule and the number of isomeric substituted
benzenes that exist.
The Claus,92 Ladenburg, and Armstrong-Baeyer formulas for benzene sought to ad-
dress the problem of the lack of typical alkene reactivity by assigning structures devoid of
any double bonds. In the Claus formula,93 all the “diagonal” bonds are long bonds; in the
Ladenburg formula, the molecule is not planar but prismatic; and in the Armstrong-Baeyer
formula, the fourth valence of each carbon atom is directed toward the center of the ring
in a rather undefined way. Thiele modified the Kekulé structure by adding the “partial
valencies” between the double bonds. His own research with conjugated dienes had shown
him that these compounds often react by 1,4- rather than 1,2-addition, and he proposed
the partial valence concept to rationalize this reactivity.94 By being cyclic, benzene should
be unusually unreactive.
Of course, someone with Kekulé’s ego could not remain passive in the face of the ob-
jections to his structure. In order to answer them, Kekulé proposed that the double bonds
were in a continual state of flux, an idea that approximates, but does not attain, the modern
concept of resonance. Kekulé believed that what we now would call canonical forms actu-
ally represented real compounds that were in rapid equilibrium with each other. Städeler’s
modification of Kekulé’s structure is really a compromise between the original Kekulé
85. Georg Karl Andreas Städeler (1821–1871) was educated at Göttingen (PhD, 1845). Städeler built his in-
dependent career at Göttingen and then at Zurich, working in both organic chemistry and inorganic analysis.
For a more complete biography, see: Kraut, G.S. Ber. dtsch. chem. Ges. 1871, 4, 425.
86. Staedeler, G. J. prakt. Chem. 1868, 103, 105.
87. Carl Hermann Wichelhaus (1842–1921) studied at Bonn, Göttingen, Heidelberg (PhD, 1863), Ghent, and
London. He joined the faculty at Berlin in 1867and became Professor of Chemical Technology in 1871. He
retired to Heidelberg in 1916; from 1877–1880 he was also Director of the Patent Office. For more biograhical
details, see: Deutsches Biographisches Lexikon. Biographisches Handbuch deutscher Männer und Frauen der
Gegenwart; (Verlagsbuchhandlung Schulze & Co.: Leipzig, 1905); p. 1564.
88. Wichelhaus, H. Ber. Deut. chem. Ges. 1869, 2, 197.
89. (a) Armstrong, H.E. J. Chem. Soc. 1887, 51, 264. (b) Baeyer, A. Ann. Chem. Pharm. 1888, 245, 103.
90. Meyer, J.L. Die Modernen Theorien der Chemie (Maruschke and Berendt: Breslau, 1872).
91. Ladenburg, A. Ber. Deut. chem. Ges. 1869, 2, 272. Ladenburg actually proposed a planar structure with
the same linkages, but he stated that the prismatic version was preferred.
92. Karl Ludwig Claus (1838–1900) was educated at Marburg and Göttingen (PhD, 1862). He immediately
joined the faculty of the University of Freibourg, where he spent the rest of his life. Claus was one of the first to
recognize the importance of structure in organic chemistry; his planar structure for benzene was unique in not
requiring any double bonds. For a more complete biography, see: Vis, G.N. J. Prakt. Chem. 1900, 62, 127.
93. Claus, A. Theoretische Betrachtungen un den Anwendung zur Systematik der Organischen Chemie (Frei-
borg, 1867).
94. Thiele, J. Ann. Chem. 1899, 306, 87; Ann. Chem. 1899, 308, 333.

structure and the Claus formula, but he also espoused Kekulé’s idea of constant flux to
avoid the objections raised by the presence of the two double bonds in his structure.
Thanks to the resonance theory developed by Linus Pauling, today we represent the ben-
zene molecule as the resonance hybrid of the two canonical forms shown; frequently, the
π bonds of the ring are represented by a circle.
There are 12 possible isomeric substitution patterns of benzene by one or more iden-
tical substituents. As the number of chemically different substituents on a ring in-
creases, the number of possible isomers also increases. As shown, the bromination of
o‑dichlorobenzene gives only two compounds, while the bromination of o-chlorotolu-
ene, on the other hand, gives four compounds. It was by studies of this type that Wil-
helm (Gugliemo) Körner 95 was able to establish that all six carbons of the benzene ring
are equivalent, as well as being able to identify the substitution patterns in benzene
derivatives.96
Cl Cl Cl
+
Cl Cl Br Cl
Br
Br
Me Me Me Br Me Me
+ + +
Cl Cl Br Cl Cl Cl
Br
Problems
7-8 How many monobromobenzenes would be expected for (1) Kekulé’s formula,
(2) Claus’ formula, (3) von Baeyer’s formula, (4) Dewar’s (Städeler’s) formula, and
(5) Ladenburg’s formula for benzene if the bonds do not move? How many dibro-
mobenzenes? How many tribromobenzenes?
7-9 How many isomers of dibromochlorobenzene could possibly be formed from
each of the isomeric dibromobenzenes in Problem 7-8?
7-10 How many isomers of chlorobromofluorobenzene are possible? How many of
these could be formed from each of the three isomers of bromofluorobenzene?
7-11 An isomer of xylene is treated with nitric acid under conditions that give a mono-
nitroxylene. Separation of the reaction mixture gives three different products.
What was the structure of the original xylene?
95. Gugliemo (Wilhelm) Körner (1839–1925) was educated at Giessen (PhD, 1864) and he then studied with
Kekulé until 1867. When Kekulé left Ghent for Bonn, Körner moved to Cannizzaro’s laboratories in Palermo. In
1870 the “Scuola Superiore di Agricoltura” was founded at Milan, and Körner became the first Professor of
Organic Chemistry. For a more complete biography, see: J. Chem. Soc. Trans. 1925, 127, 2973.
96. Körner, W. Gazz. Chim. Ital. 1874, 4, 303.

Chapter Summary
The topic of this chapter, aromaticity, is one of the oldest problems in organic chemistry,
and it is still not fully solved. The first general theoretical model for aromaticity was devel-
oped by Erick Hückel. Hückel aromatic molecules are planar, cyclic, delocalized and have
(4n + 2) π electrons. Molecules with the same structural characteristics but with 4n π
electrons are Hückel antiaromatic. In aromatic compounds, C—C bond lengths tend
toward an average value, with bond-length alternation becoming more pronounced as the
size of the ring increases. This bond alternation may be quantified by means of the HOMA
parameter, which ranges from 1.0 for aromatic compounds to 0.0 for non-aromatic com-
pounds. The stability of an aromatic compound is measured by aromatic resonance stabi-
lization energy, which must be determined indirectly from experimental data or
computationally (e.g., by homoisodesmic reactions). Magnetic methods to quantify aro-
matic character include (1) a diatropic (aromatic) or paratropic (antiaromatic) ring current
in the 1H NMR spectrum and (2) magnetic exaltation, which is the increase in the molar
magnetic susceptibility. Computational methods for quantifying aromaticity include (1)
the NICS at the center of the ring or above the center of the ring can define aromaticity or
antiaromaticity of the ring (negative NICS values correspond to aromaticity in the ring);
(2) the DRE, which is positive for an aromatic compound and negative for an antiaromatic
compound; (3) the REPE, which is similar to the DRE, but is approximately constant for
any system; (4) the REPB, which is similar to the REPE, but is more reliable in charged
systems; and (5) the absolute hardness, which is defined as half the HOMO-LUMO gap.
The energies of the Hückel π molecular orbitals of aromatic annulenes can be predicted
using the Frost-Musulin circle, and the stability of aromatic compounds can be predicted
using the Clar model. Möbius aromaticity was predicted in 1964, and the relative energies
of orbitals can be predicted using the Zimmerman circle. Möbius complements Hückel
aromaticity; 4n systems are aromatic, and (4n + 2) systems are antiaromatic.
Key Terms
absolute hardness Harmonic oscillator model Möbius aromaticity

antiaromatic of aromaticity (HOMA) nucleus-independent chemi-
aromatic homoaromatic cal shift (NICS)
aromatic resonance stabili- homoisodesmic reaction paratropic ring current
zation energy Hückel antiaromaticity resonance energy per π
Clar sextet Hückel aromaticity bond (REPB)
Dewar benzene Kekulé structure resonance energy per π
Dewar resonance energy Körner proof electron (REPE)
(DRE) Ladenburg benzene Zimmerman circle
diatropic ring current magnetic exaltation
Frost-Musulin circle Möbius antiaromaticity
Additional Problems
7-12 The left-hand compound shown below is predicted to be aromatic according to

Hückel’s rule. There are two extreme structures that one can draw for the molecule;
the canonical form on the left consists of three furan rings linked by three vinyl
bridges, and the canonical form on the right consists of an [18]annulene bridged by
three oxygen atoms. The compound shows proton signals at δ 8.66 and 8.88. The

“normal” chemical shift for furan β protons is 7.0 ppm. Which of these canonical
forms do you expect to make a greater contribution to the resonance hybrid, and
why? The sulfur analog of the left-hand compound shows proton resonances at δ
6.73 and 6.77. What does this observation suggest? How does your answer compare
if the left-hand compound is changed to the molecule on the right?
O
O O
O O O O
O O
O
7-13 Would the compounds below be expected to exhibit Hückel or Möbius aromatic-
ity? Give your reasons.
O
(a) O
(b) (c) S (d) O
O

7-14 The compounds below can all be described as bridged annulenes, but there is evi-
dence in some cases that this may not be the most accurate description of the
molecules. What alternative description is consonant with the structures drawn?
(a) (b) (c)

7-15 The cyclic allene below is aromatic. Does it exhibit resonance of the type shown
by simple benzene derivatives? If it does, draw at least one other resonance
contributor.
7-16 The Hückel analysis of [14]annulene indicates that it should be aromatic, since it
has 14 π electrons (4n + 2, n = 3). However, the spectra and reactivity of this
molecule at room temperature suggest that it is essentially a simple polyene, with
little or no aromatic character. At –60°C, however, the 1H NMR spectrum splits
into two resonances at δ 7.6 and 0.0, in the ratio 5:2. The single crystal X-ray
structure of [14]annulene shows that the molecule is significantly distorted from
planarity. Rationalize these observations and answer the question, “is [14]annu-
lene aromatic or not?”
7-17 The ester below exhibits only one resonance in the 1H NMR spectrum other than
the methyl resonances. This resonance occurs at δ 8.45. Provide a reasonable ex-
planation for this observation. What other properties would you predict for this
compound on the basis of your analysis?
CO2Me
MeO2C
MeO2C
CO2Me

7-18 Diphenylcyclopropenone has a dipole moment of 5 D, and the stretching fre-

quency of its carbonyl group is 1650 cm–1. The carbonyl stretching frequency of
cyclopropanone is greater than 2000 cm–1. Provide a reasonable explanation for
these observations. What does your answer suggest about the infrared stretching
frequency of the α-diketone shown below the diphenylcyclopropenone? (The in-
frared stretching frequency of α-diketones is typically near 1750 cm–1.)
7-19 In Example 7.15, we discussed the formation of a Möbius aromatic cation from
deuterium-labeled 9-chlorocyclonona-1,3,5,7-tetraene by dissolving in liquid
sulfur dioxide (a strongly ionizing medium). The reaction leads to products in
which the deuterium is statistically scrambled. Is there a reasonable rationaliza-
tion of the observed result that does not involve a Möbius aromatic cation?
7-20 When 5-bromo-1,3-cyclopentadiene reacts with antimony pentafluoride at 78K, a
carbocation is formed that exhibits an electron paramagnetic spin resonance
(EPR) spectrum consistent with a triplet diradical. What inferences do these re-
sults allow to be made about the cation formed in this reaction? Are these deduc-
tions in accord with predictions? Why or why not?
7-21 The cyclobutadiene dianion, C4H42–, is predicted by simple Hückel analysis to be
aromatic, and the dilithium salt of some derivatives of this ring system is,
indeed, planar [Organometallics 2002, 21(6), 1072]. However, the structure of the
free dianion (in the absence of the counterions) is calculated to be bent, not
planar, with one of the negative charges localized. What would cause this
difference?
7-22 The pKa values for the three hydrocarbons below in DMSO solution are as shown
below each structure. Rationalize these values.
pKa 18.0 20.1 22.6
7-23 The compounds below are all 14 π e– species and so all should, in principle, be
aromatic, with a diatropic ring current. The 1H NMR spectra of the compounds
are summarized in the table.
δMe (ppm) –1.82 –4.53 –2.06 –4.25

δH (ppm) 8.74 8.17 8.77 8.64
δH (ppm) 8.24 8.00 8.74 8.60
δH (ppm) 7.50 7.82 8.04 8.11
The resonances of the ring protons are all consistent with the ring current being
similar in all for compounds, but there is a clear difference when it comes to the
methyl resonances. Using models to analyze the shapes of the molecules, suggest
why the chemical shifts of the methyl resonances vary so widely.

7-24 Based on the observation that the square planar ring in the sequestered
1,3-d imethylcyclobutadiene structure is not completely planar and the obser-
vation that the carbon dioxide molecule is bent, the authors of the paper [Sci-
ence 2010, 329, 299] propose that the interaction between the two molecules
trapped in the host lattice is a significant van der Waals interaction rather than
a covalent bond. After reading the paper, is this position reasonable or not?
You may find the following papers useful in formulating your answer to this
question: Science 2010, 330, 1047c-e, available online, and Chem. Commun.
2011, 47, 1851. The following blog also contains a very instructive dialog among
the major players on this question: http://www.ch.ic.ac.uk/rzepa/blog/?p=2828
(retrieved July 11, 2013).
Me
Me
O
O

Chapter eight
Physical Organic Chemistry

and Reaction Mechanisms
8.1 Introduction
In Chapter 1, we briefly reviewed the process of writing reaction mechanisms and the
elementary processes in the steps of most common organic reactions (heterolysis and
homolysis of bonds). In this chapter, we will continue expand on these discussions,
with more focus on how evidence for the existence of reactive intermediates is gar-
nered and on how this evidence is integrated into a model for the mechanism of the
reaction.1
In modern usage, a reaction mechanism is defined as the set of elementary reactions
required to convert reactants to products. In other words, it is a step-by-step description
of the transformation of reactants to products. As part of this description, a reaction may
be designated as concerted, in which case the conversion of reactants to products takes
place in a single step, or it may be stepwise, in which case at least one reactive intermediate
is involved. The individual steps of stepwise reactions seldom proceed at the same rate,
which means that one of the steps becomes the rate-limiting step or rate-determining
step. In order for a proposed mechanism to merit serious consideration, it must fit the
observed stoichiometry, it must explain the observed kinetics, and it must make predic-
tions that pass the test of experiment.
All organic reactions can be discussed in terms of the reaction coordinate diagram, or
reaction energy profile, and deducing this diagram for a reaction is also an important part
of elucidating the overall reaction mechanism. The reaction coordinate diagram simply
traces the change in potential energy of a single reacting molecule (or set of reacting mol-
ecules) through the bonding changes from reactant to product. Stable species—species
formally capable of being isolated and studied, including reactive intermediates—appear
as valleys along the reaction coordinate; the depth of the valley determines if this is what
is termed a metastable intermediate, which is usually difficult or impossible to isolate, or
a stable intermediate, which can sometimes be isolated and studied. If the valley between
peaks in the reaction coordinate diagram is very shallow, this is usually interpreted as
indicating that the intermediate is metastable. Unstable species (species that have lifetimes
less than one molecular vibration) appear as peaks in the reaction coordinate diagram.
These species are transition states and designated by the cross of Lorraine (‡). They cannot
be isolated under any circumstances.
1. General textbooks discussing mechanism and theory in chemistry: (a) Ingold, C.K. Structure and Mechanism
in Organic Chemistry (Cornell University Press: Ithaca, 1953). (b) Lowry, K.S.; Richardson, T.M. Mechanism and
Theory in Organic Chemistry, 3rd. ed. (Harper & Row: New York, 1987). (c) Sykes, P. A Guidebook to Mechanism in
Organic Chemistry , 2nd ed. (John Wiley & Sons: New York, 1965). (d) Gould, E.S. Mechanism and Structure in
Organic Chemistry (Holt,, Rinehart and Winston: New York, 1959). (e) Gardiner, W.C., Jr. Rates and Mechanisms
of Chemical Reactions (Benjamin: New York, 1969). (f) Carroll, F.A. Perspectives on Structure and Mechanism in
Organic Chemistry (Brooks/Cole: Pacific Grove, 1998). (g) Carey, F.A.; Sundberg, R.J. Advanced Organic Chemis-
try. Part A: Structure and Mechanism, 4th ed. (Kluwer Academic/Plenum: New York, 2000).
259

260 Advanced Organic Chemistry | Chapter eight
Figure 8.1 Reaction Activated Activated

coordinate diagram showing Complex 1 Complex 2
intermediate
Energy
Intermediate
Extent of Reaction
Reactive intermediates are, as their name implies, chemically reactive species that are
formed during the course of a chemical reaction but which are neither the reactant nor the
product. They represent minima on the potential surface of a reaction (valleys in the typ-
ical reaction coordinate diagram). The difference between an intermediate and an acti-
vated complex is that the potential minimum for the intermediate is deep enough to
contain at least one stable vibrational energy level; an activated complex occurs at a saddle
point on the surface and does not contain any stable vibrational level (Figure 8.1).
There are five reactive intermediates where the reactivity is centered on carbon, that
commonly occur in organic reactions: carbocations, carbanions, free radicals, carbenes,
and arynes; and one where the reactivity is centered on nitrogen: nitrenes, which are ni-
trogen analogs of carbenes. Of these, the carbanions are electron-rich electron-pair
donors; the free radicals have an unpaired electron; and the others are electron-deficient,
electron-pair acceptors.
R R R
R R R R R R
carbanion free radical carbocation
R
N
R R
carbene nitrene aryne
Very often, the formation of these intermediates is endothermic, which usually results in
the formation of the reactive intermediate being the rate-determining step of the reaction in
which they occur. This makes their formation amenable to study by kinetic measurements.
More recently, it has become possible to study these intermediates directly by spectroscopy,
and rapid advances in computer speed and the sophistication and reliability of the predictions
of computer programs has made their study by molecular orbital calculations reliable, also.
All reactions may be described in terms of a potential energy surface that allows one
to trace the path from reactants to products. A simple potential surface for a concerted,
two-bond reaction is shown as Figure 8.2 (a). The path between reactants and products lies
in a valley on the potential surface. When the complete potential surface is examined,
stable species appear as potential wells, and transition states as saddle points. In
Figure 8.2(a), there are two potential wells, corresponding to the reactant (labeled R) and
product (labeled P), and a single saddle point (labeled with the cross of Lorraine). Al-
though organic chemists do not often use the potential energy surface as a whole, a

Physical Organic Chemistry and Reaction Mechanisms 261
A B + C A + B C
P
R
e
AB
nc
‡
ta
Bo
is
D
nd
nd
D
Bo
is
ta
BC
nc
(a)
e
A B A + B+ C A + B C
P
R
‡ ‡1 ‡2
Energy
e
AB
nc
ta
Bo
is
R
D
nd
nd
D
Bo
is
I
ta
BC
nc
e
(b) Reaction Coordinate (c)
‡2
‡1
‡2 ‡1
Energy
Energy
I I
R
R
P P
(d) Reaction Coordinate (e) Reaction Coordinate

Figure 8.2 (a) Potential energy surface for a concerted reaction, (b) reaction coordinate diagram
for a concerted reaction, (c) potential energy surface for a reaction with (d) reaction coordinate
diagram for a two-step reaction with the first step rate determining, and (e) reaction coordinate
diagram for a two-step reaction with the second step rate determining

Figure 8.3 The Corsican

stage of the 2013 Tour de
France. Image from
Wikimedia Commons,
licensed under the Creative
Commons Attribution-Share
Alike 3.0 unported. http://
en.wikipedia.org/wiki/
File:Tour_de_France_2013_
stage_03.png
modified (simplified) form has been used in discussing the timing of bonding changes and
in making predictions about the effects of changes in the reactants on the structure of the
activated complex, or transition state.
Reactions can also be described by means of a reaction coordinate diagram, or a re-
action energy profile. This diagram shows the variation in the potential energy of the
system along the floor of the energy valley between reactants and products, much like the
altitude maps that are used on television to describe stages of the Tour de France (e.g.,
Figure 8.3, from the 2013 Tour). The potential surface in Figure 8.2 (a) has only one saddle
point, so there is only one activated complex for this reaction, and the reaction coordinate
diagram has only a single maximum and two minima—Figure 8.2 (b).
Not all reactions are concerted, as the lower three examples in Figure 8.2 show. In
Figure 8.2 (c), a potential surface for a stepwise reaction passing through a reactive inter-
mediate (labeled I) is shown. In this case, there are two saddle points (i.e., two activated
complexes or transition states), labeled ‡1 and ‡2. These two transition states may be of
equal energy, or, much more commonly, one will be of higher energy than the other. When
the energy of ‡1 is higher than the energy of ‡2, the reaction coordinate looks like Figure
8.2 (d); if the opposite is true, the reaction coordinate looks like Figure 8.2 (e).
At the end of this introduction, it is worth repeating that, of course, one must always
bear in mind that one cannot prove a mechanism, but only disprove it.2 All mechanisms,
as written, are simply the best model available to explain the experimental observations at
the time they are proposed and are always subject to modification if better data are ob-
tained that contradict one or more details of the mechanistic model.
8.2 Solvents and Solubility
It is a rare organic reaction, indeed, that is not carried out in a solvent. When one considers
the fundamental processes involved, the process of forming a solution is, in many ways, a
form of chemical reaction between the solvent and the solute: the solvent forms new solvent-
solute bonds at the expense of solvent-solvent and solute-solute bonds. The function of a
solvent in a reaction is twofold. It provides a common medium where the two reactants can
undergo the collision required to initiate the reaction, and it exerts a moderating on the rate
2. This assertion is not universally accepted: (a) Buskirk, A.; Baradaran, H. J. Chem. Educ. 2009, 86, 551.
(b) Brown, T.L. J. Chem. Educ. 2009, 86, 552. (c) Lewis, D.E. J. Chem. Educ. 2009, 86, 554. (d) Yoon, T. J. Chem.
Educ. 2009, 86, 556. (e) Wade, P.A. J. Chem. Educ. 2009, 86, 558.

of the reaction, allowing one to modulate the rates of extremely exothermic reactions by
changing reactant concentrations. There is a large body of literature that deals with the ef-
fects of solvent on reaction rates, beginning with the work of Nikolai Aleksandrovich Men-
shutkin3 on the formation of tetraethylammonium iodide,4 and encompassing a wide range
of nucleophilic displacements.5
There are four major types of interactions between solvent and solute: London disper-
sion forces, dipole-dipole interactions, hydrogen bonding, and ion-dipole interactions.
Which of these forces operates depends on the nature of both the solvent and the solute,
but the solvent polarity may be the most important solvent property because many reac-
tions involve both covalent and ionic reagents.6
The weakest intermolecular forces are London dispersion forces,7 which are short-
range, uniformly attractive forces between molecules due to temporary dipoles arising
from asymmetric instantaneous electron distribution, and first proposed by German-born
physicist, Fritz London.8 London dispersion force occurs between all molecules, polar and
non-polar. Polar molecules can also participate in dipole-dipole interactions, which are
slightly stronger attractive forces between permanent dipoles.
London dispersion forces and dipole-dipole interactions are commonly referred to
under the collective term, van der Waals forces, after Johannes Diderik van der
Waals,9 the Dutch physicist who first explained deviations from ideal behavior by
gases by proposing that attractive forces exist between molecules of gases. The radius
at which these forces of attraction are strongest is called the van der Waals radius of
an atom or molecule; molecules compressed together within their van der Waals radii
strongly repel each other.
Quantifying the effects of solvent on the rate of a reaction is not a simple task, which
means that a variety of scales for solvent polarity have been developed over the years. The
simplest measures of solvent polarity are its dipole moment (μ) and dielectric constant (ε).
However, neither of these measures is, by itself, sufficient to describe the effects of solvent
on many reactions. Several scales for solvent polarity, in particular, have been developed,
and we will examine these in detail in the next chapter.
Many times, one of the reagents in a reaction is ionic. The solubility of ionic compounds
in a solvent frequently correlates with the dielectric constant of the solvent, which is a mea-
sure of how effectively the solvent shields ions from the effect of adjacent charges, and how
3. Nikolai Aleksandrovich Menshutkin (1842–1907) was educated at St Petersburg University (Dr Chem,
1869), and remained there as Professor after graduation. He rose to become Dean of the faculty, and in 1902 he
was appointed to the Petersburg Technological Institute. For more biographical details, see: Menschutkin, B.
Ber. dtsch. chem. Ges. 1907, 40, 5087.
4. Menshutkin, N. Z. Phys. Chem. 1890, 5, 589; 1891, 6, 41.
5. The effects of solvent on the rates of SN1 and SN2 reactions have been the subject of especially intense inves-
tigation. For general discussions, see: (a) Ingold, C.K. Structure and Mechanism in Organic Chemistry (Cornell
University Press: Ithaca, NY, 1953), pp. 345–355. (b) Gould, E.S. Mechanism and Structure in Organic Chemistry
(Holt, Rinehart and Winston: New York, 1959), pp. 184–185. (c) Carroll, F.A. Perspectives on Structure and
Mechanism in Organic Chemistry (Brooks-Cole: Pacific Grove, 1998): pp. 329–332. (d) Carey, F.A.; Sundberg,
R.L. Advanced Organic Chemistry, Part A: Structure and Mechanisms, 4th ed. (Kluwer Academic/Plenum Pub-
lishers; New York, 2000), pp. 290–295.
6. An excellent discussion of the various solvent parameters, and the process of solvation is given in Isaacs,
N.S. Physical Organic Chemistry (Longman Group UK: Harlow, Essex, 1987), Ch. 5, pp. 171–209.
7. (a) London, F. Z. Physik 1930, 63, 245. (b) London, F. Trans. Faraday Soc. 1937, 33, 8.
8. Fritz Wolfgang London (1900–1954) was educated at Bonn, Frankfurt and Munich (PhD, 1921 in philos-
ophy). He and his brother fled the Nazi persecution, and after the war, London became Professor at Duke
University. For more details, see: Gavroglu, K. Fritz London: A Scientific Biography (Cambridge University
Press: Cambridge, 2005).
9. Johannes Diderik van der Waals (1837–1923) was educated at Leiden (PhD, 1873). In 1877, he was ap-
pointed as Professor of Physics at the University of Amsterdam, where he developed his Nobel Prize-winning
equation for gas behavior in 1881. For more biographical details, see the Nobel Foundation web site.

Table 8.1 Dielectric Constants (D) and Dipole Moments (μ) of strongly the solvent solvates an ion. The force of attraction
Common Solvents between ions separated by a distance r is given by
Solvent D μ
F = –(1/D)(q1q2/r2) (Eq. 8.1)
Acetic acid 6.17 1.68
Acetone 20.6 2.69 where D is the dielectric constant of the medium (the di-
electric constant of a vacuum is 1) and q1 and q2 are the
Acetonitrile 35.9 3.53
charges on the ions. In hexane, the value of D is low,
Benzene 2.27 0 which means that the force of attraction between the ions
Chloroform 4.80 1.15 is not reduced very much by intervening solvent mole-
cules. In water, on the other hand, the value of D is 80—
Dichloromethane 8.9 1.14
the force between ions in water is only 1.25% of that
Diethyl ether 4.2 1.15 between the same ions separated by the same distance in
Dimethylformamide (DMF) 36.7 3.24 a vacuum. Generally, as the dielectric constant decreases,
the reactivity of ionic species becomes more extreme.
Dimethyl sulfoxide (Me2SO) 46.5 4.06
Anions become stronger bases and stronger nucleophiles,
Ethanol 24.5 1.66 and cations become stronger acids and stronger electro-
Ethyl acetate 6.02 1.82 philes. The solvent dielectric constant can have a dramatic
effect on reactivity, but one must be careful to remember
Hexane 1.89 0.085
that it is not the only solvent property that is important,
Hexamethylphosphoric triamide 29.3 4.31 as has been shown by carrying out the hydrolysis of acid
(HMPA) chlorides in several different mixtures of solvents with
Methanol 32.7 2.87 the same overall dielectric constant.10 Dipole moments
Pyridine 12.9 2.37 and dielectric constants of a range of common solvents
are gathered in Table 8.1.
Tetrahydrofuran 7.58 1.75 The effects of hydrogen bonding and dipole-dipole in-
Water 78.4 1.8 teractions on molecular properties are illustrated by the
data in Table 8.2, where the boiling points of the covalent
hydrides of the main-group elements are collected.
Table 8.2 Boiling Points of the Covalent Hydrides Among these hydrides, ammonia (–33°C), water (100°C),
IIIA IVA VA VIA VIIA
and hydrogen fluoride (22°C) have remarkably high boil-
ing points, especially given their low molecular weights.
B C N O F This effect is also shown (albeit to a lesser extent) by the
–92.59 –161.6 –33.35 100.0 19.74 boiling points of the six methyl compounds in Table 8.3;
Al Si P S Cl methanol (CH3OH) and methylamine (CH3NH2) have
–112 –87.7 –60.7 –85.09 two of the highest boiling points, despite having two of
Ga Ge As Se Br the lowest molecular weights.
–88 –62.5 –41.2 –66.78 When a solute dissolves in a solvent to form a solu-
tion, two sets of forces must be broken and replaced by
In Sn Sb Te I
–52.5 –17 –2 –35.41 attractive forces between solute and solvent particles (sol-
vation): the forces between particles (molecules or ions) in
Tl Pb Bi Po At the solute and the intermolecular forces between mole-
≈22
cules of the pure solvent. Thus, forming a solution is ulti-
mately a compromise between energy loss because of the
rupture of solute-solute bonds and solvent-solvent bonds and energy gain due to the for-
Table 8.3 Boiling Points of mation of solute-solvent bonds. The balance between these forces determines the solubil-
Methyl Compounds
ity of a compound in a solvent.
VA VIA VIIA For example, the water solubility of an ionic compound is determined by the balance
Me–NH2 Me–OH Me–F between the loss of energy due to the rupture of ionic bonds in the solute lattice and hy-
–6.3°C 65°C –78.4 drogen bonds in the solvent, and the energy gain due to the formation of solvating
Me–PH2 Me–SH Me–Cl
–14°C 6.2°C 24.2
10. (a) Brown, D.A.; Hudson, R.F. J. Chem. Soc. 1953, 3352. (b) Hudson, R.F.; Saville, B. J. Chem. Soc. 1955, 4114.

Figure 8.4 Models of the

isomeric butyl alcohols
showing the partial charges.
Non-polar regions are light
grey negative regions are
Me(CH2)3OH (Me)2CHCH2OH EtCH(OH)Me Me3COH black and positive regions
are dark grey
ion-dipole bonds. Because a non-polar (low dielectric) solvent cannot form such ion-
dipole bonds to stabilize the individual ions by solvation, most ionic compounds are insol-
uble in non-polar solvents. For similar reasons, most non-polar molecules are not very
soluble in water because the energy loss due to rupture of the hydrogen bonds between
water molecules (which must be broken to allow room for the solute molecules) is not
compensated for by any sufficiently strong solvating dipole-dipole bonds.
The solvent solvates all of the reactants in the reaction, which means that reactions
are not as we simplistically write them, but are between solvated species instead. In turn,
this means that in order for the reaction to proceed, we must remove solvent molecules
from around each reactant to permit contact between the reacting species—we must
break solvent-solute bonds. The stronger the force of attraction between the solvent mol-
ecule and the solute, the more difficult this is to accomplish, and therefore, the slower the
reaction will be.
These effects can be visualized by considering the water solubility of the isomeric
butyl alcohols (structures in Figure 8.4). The polar part of the molecule is the O—H
group, which can form hydrogen bonds with water molecules to compensate for the
water-water hydrogen bonds that are lost when the alcohol dissolves. The remaining part
of all four molecules is a non-polar hydrocarbon group, and this will participate only in
much weaker van der Waals interactions with the water molecules, so we expect that the
alcohol with the most compact alkyl group will probably have the highest water solubil-
ity. In 1-butanol, the alkyl group is elongated, which requires that many more water-water
hydrogen bonds be broken to accommodate the alkyl group than in tert-butyl alcohol,
where the alkyl group is very compact. The other two alcohols both have more compact
alkyl groups attached to the carbon bearing the OH group, and so their water solubility
(sec-butyl alcohol ≈ 12.5 g/100 mL H2O; isobutyl alcohol ≈ 10 g/100 mL H2O) is interme-
diate between that of 1-butanol (≈ 9 g/100 mL H2O) and tert-butyl alcohol (miscible with
water in all proportions).
Polar solvents used in organic reactions are usually characterized as being protic or
aprotic dipolar. Protic solvents are solvents containing an OH group capable of forming
strong hydrogen bonds: water, acetic acid, formic acid, or aqueous alcohol mixtures are
most widely used. They tend to solvate all ionic species—both cations and anions—very
strongly, and this strong solvation stabilizes both types of ionic solutes. Conversely,
aprotic dipolar solvents, such as acetone, dimethyl sulfoxide, and hexamethylphosphoric
triamide, typically have a strong dipole whose negative end is easily accessible for solvat-
ing cations but whose positive end is sterically congested, preventing it from being avail-
able for strong solvation of anions.11 They lack an O—H bond capable of solvating anions.
11. (a) Sheehan, J.C.; Bolhofer, W.A. J. Am. Chem. Soc. 1950, 72, 2786. (b) Zaugg, H.E.; Horrom, B.W.;
Borgwardt, S. J. Am. Chem. Soc. 1960, 82, 2895. (c) Zaugg, H.E.; Dunnigan, D.A.; Michaels, R.J.; Swett, L.R.;
Wang, T.S.; Sommers, A.H.; DeNet, R.W. J. Org. Chem. 1961, 26, 644. (d) Barlow, G.H.; Zaugg, H.E. J. Org.
Chem. 1972, 37, 2246. (e) Zaugg, H.E.; Rataczyk, J.F.; Leonard, J.E.; Schaefe, A.D. J. Org. Chem. 1972, 37, 2249.
(f) Zaugg, H.E.; Leonard, J.E. J. Org. Chem. 1972, 37, 2253. (g) Smiley, R.A.; Arnold, C. J. Org. Chem. 1960, 25,
257. (h) Friedman, L.; Shechter, H. J. Org. Chem. 1960, 25, 877. (i) Paquette, L.A.; Philips, J.C. Tetrahedron Lett.
1967, 4645. (j) Magnera, T.F.; Caldwell, G.; Sunner, J.; Ikuta, S.; Kebarle, P. J. Am. Chem. Soc. 1984, 106, 6140.
(k) Mitsuhashi, T.; Yamamoto, G.; Hirota, H. Bull. Chem. Soc. Jpn. 1994, 67, 831. (l) Okamoto, K. Adv.
C arbocation Chem. 1989, 1, 181.

Table 8.4 Relative Activity of Chloride Ion in 1.0M So although they tend to solvate cations well, they tend to
Tetraethylammonium Chloride in Common Solvents solvate anions only poorly. This results in a less pro-
Solvent Activity ∆E a (kcal mol )
–1 nounced stabilization of ionic reactants and products in
a reaction compared to the same reaction in a protic sol-
Acetonitrile 2.00 3 106 12.0 vent. Non-polar species, or species with dispersed
Dimethylformamide 3.16 3 106 12.3 charges, are better solvated by aprotic dipolar solvents.
Stronger solvation of the reactants of a reaction than the
Dimethyl sulfoxide 3.16 3 105 10.9
activated complex will tend to raise the activation energy
Methanol 1.00 3.40 of a reaction and retard its rate, whereas stronger solva-
Water 0.0032 0.00
tion of an activated complex than the reactants will lower
the activation energy and increase the reaction rate. In
1961, Australian chemist A. J. Parker12 summarized the
results of several workers by suggesting that larger, more polarizable anions were better
solvated by aprotic dipolar solvents than smaller, less polarizable anions, leading to the
observed reversal of reactivity of anions in aprotic dipolar solvents compared to protic
solvents like methanol.13 Parker’s proposals are corroborated by the activity coefficients
of anions in aprotic dipolar solvents.14 Representative values for chloride anion are gath-
ered in Table 8.4.
The aprotic dipolar solvents were one solution to the problem of having to dissolve
ionic and non-polar compounds in the same solution to effect reactions, but they are by
no means the only way to accomplish this. In the late 1960s and early 1970s,15 the tech-
nique of phase transfer catalysis was introduced, especially by the work of Makosza,16
Brändström,17 and Starks.18 This technique relies on the fact that it is possible to prepare
ionic compounds that are more soluble in hydrocarbon (e.g., benzene) and relatively
non-polar (e.g., chloroform, ethyl acetate) than in water. These ionic compounds are
characterized by having a central atom with a formal charge surrounded by large alkyl
groups: tetraalkylammonium salts where the total number of carbon atoms in the
cation is greater than about 12 to 16 are quite soluble in relatively non-polar solvents:
tetrabutylammonium chloride is soluble in benzene, for example. The surface poten-
tials of two cations (tetrabutylammonium and octadecyltrimethylammonium) used as
phase transfer catalysts are shown. In both cases, the positively charged nitrogen atom
is relatively inaccessible and cannot be easily solvated directly, with the result that the
solubility of compounds with this ion is dominated by the non-polar alkyl groups on
the nitrogen.
12. Alan James Parker (1933–1982) was educated at the University of Western Australia (UWA) (PhD, 1957).
After five years abroad, he returned to Australia to positions at UWA, the Australian National University, and
Murdoch University, in turn. He made major contributions in metallurgy. For more details, see: Cole, A.R.H.,
Watts, D.W., Hist. Records Aust. Sci., 1986, 6, 399.
13. (a) Miller, J.; Parker, A.J. J. Am. Chem. Soc. 1961, 83, 117. (b) Parker, A.J. Quart. Rev. Chem. Soc. 1962, 16,
163. (c) Parker, A.J. Adv. Org. Chem. (Wiley: New York, 1965), Vol. 5, p. 1.
14. (a) Parker, A.J. Chem. Rev., 1969, 69, 1. (b) Parker, A.J. Pure Appl. Chem. 1981, 53, 1437.
15. Reviews: (a) Dockx, J. Synthesis 1973, 441. (b) Dehmlow, E.V. Angew Chem. Int. Ed. Engl. 1974, 13, 170;
1977, 16, 493. (c) Starks, C.M.; Liotta, C.L.; Halpern, M. Phase Transfer Catalysis: Fundamentals, Applications
and Industrial Perspectives (Chapman and Hall: New York, 1994). (d) Makosza, M.; Fedorynski, M. Adv. Catal.
1987, 35, 375. (e) Dehmlow, E.V.; Dehmlow, S.S. Phase Transfer Catalysts, 3rd ed. (VCH: New York, 1993).
(f) Halpern, M.E., Ed. Phase-Transfer Catalysis: Mechanisms and Syntheses (ACS: Washington, D.C., 1997).
(g) Sasson, Y.; Neumann, R., Eds. Handbook of Phase Transfer Catalysis (Blackie: London, 1997). (h) Nelson, A.
Angew. Chem. Int. ed. Engl. 1999, 38, 1583.
16. (a) Makosza, M.; Serafinowa, B. Rocz. Chem. 1965, 39, 1223. (b) Makosza, M.; Wawrzyniewicz, W. Tetra-
hedron Lett. 1969, 4569.
17. Brändström, A.; Gustavii, K. Acta Chem. Scand. 1969, 23, 1215.
18. Starks, C.M. J. Am. Chem. Soc. 1971, 93, 195.

Bu4N+
C18H35NMe3+
Bu4N+ (MeCO)2CH−
When these compounds dissolve in non-polar solvents, they do so as solvated ion pairs,
where the cation and the anion are in contact with each other, and so the bonds between the
ions are not completely broken (the ion pair tetrabutylammonium acetylacetonate is
shown). However, in the ion pair, the anion is much more accessible to another molecule
than it would be in water, making it a much more reactive species than in aqueous solution.
We also see the effect of solvent dielectric on reactivity: as the dielectric constant decreases,
the reactivity of ionic species becomes more pronounced: anions become stronger bases
and nucleophiles, cations become stronger acids and electrophiles.
By vigorously mixing a solution of a sodium salt (e.g., sodium cyanide) in water with a
solution of a tetraalkylammonium chloride or hydrogen sulfate in an organic solvent that
is immiscible in water, one can establish the equilibrium shown in Example 8.1, which
allows one to dissolve the nucleophilic anion in the non-polar organic solvent, where it is
a much more powerful nucleophile.
R R
N Cl + CN N CN + Cl (8.1)
R R aq R R aq
R R
org org

An alternative method for increasing the solubility of ionic reagents in relatively

non-polar solvents is the use of crown ethers. These compounds, whose ability to en-
hance the solubility of metal ions in organic solvents by complex formation was first
reported by Nobel Laureate, Charles J. Pedersen in 1967,19 are cyclic ethers that selec-
tively bind alkali metal cations, especially. They are named according to a simple mne-
monic in which the number of atoms in the ring is separated from the number of
oxygen atoms by the word, “crown.” The space-filling model of the potassium-selective
ether, 18-crown-6, is shown as Example 8.2; the lithium complex of the lithium-selec-
tive 12-crown-4 is shown as Example 8.3. Since their discovery, crown ethers have
found an important place in organic synthesis.20
O O
(8.2) Li (8.3)
O O
Ionic Liquids
The push toward “green” chemistry in the last decade of the 20th century saw the rise of a
new class of solvents for use in organic reactions. These solvents consist of low-melting
ionic solids and are generally referred to as ionic liquids. The advantages of ionic liquids as
solvents in “green” chemical reactions quickly became apparent. Because the liquid is
composed solely of ions, it is nonvolatile, which eliminates the use of (often toxic and usu-
ally regulated) volatile organic solvents.21 Although predicting the melting points of ionic
organic salts is rather hit-and-miss, there is now a sufficiently wide range of low-melting
salts available for use as solvents in organic reactions that the use of these ionic liquids is
now relatively straightforward.
Ionic liquids have a number of especially useful properties that make them attractive
as solvents for a wide range of reactions:
1. They are excellent solvents for a wide range of solutes, including both ionic and molec-
ular species, which allows unusual pairings of solutes to be brought into solution
together.
2. They are highly polar.
3. They are composed of noncoordinating ions, which means that they can be used with
solutes that would suffer from coordination by the solvent.
19. Pedersen, C.J. J. Am. Chem. Soc. 1967, 89, 2495.

20. For representative reviews, see: (a) Pedersen, C.J.; Frensdorff, H.K. Angew Chem. Int. Ed. Engl. 1972, 11,
16. (b) Christensen, J.J.; Eatough, D.J.; Izatt, R.M. Chem. Rev. 1974, 74, 351. (c) Gokel, G.W.; Durst, H.D. Synthe-
sis 1976, 168. (d) Izatt, R.M.; Christensen, J.J. Synthetic Multidentate Macrocyclic Compounds (Academic Press:
New York, 1978). (e) Hiroaka, M. Crown Compounds: Their Characteristics and Applications (Kondasha: Tokyo,
1982; Elsevier: Amsterdam, 1982).
21. Reviews and Monographs: (a) Welton, T. Chem. Rev. 1999, 99, 2071. (b) Wasserscheid, P.; Keim, W. Angew.
Chem., Int. Ed. 2000, 39. 3772. (c) Sheldon, R.A. Chem. Commun. 2001, 2399. (d) Dupont, J.; de Souza, R.F.;
Suarez, P.A.Z. Chem. Rev. 2002, 102, 3667. (e) Rogers, R.D.; Seddon, K.R. Ionic Liquids; ACS Symp. Ser, 2002,
818. (f) Rogers, R.D.; Seddon, K.R. Ionic Liquids as Green Solvents; ACS Symp. Ser, 2003, 856. (g) Rogers, R.D.;
Seddon, K.R. Ionic Liquids IIIB: Fundamentals, Progress, Challenges and Opportunities; ACS Symp. Ser, 2005,
902. (h) Plechkova, N.V.; Rogers, R.D.; Seddon, K.R. Ionic Liquids: From Knowledge to Application; ACS Symp.
Ser, 2009, 1030. (i) Wasserscheid, P., Welton, T., Eds. Ionic Liquids in Synthesis, 2nd ed.; (Wiley-VCH: Wein-
heim, 2007).

4. They are often immiscible with organic solvents and with water, which makes them a
useful highly polar alternative to both.
5. They do not evaporate under conditions of high vacuum, which makes them unique
among solvents.
The most common room-temperature ionic liquids in use today are N,N'-dialkylimid-
azolium salts, where the anion is typically a fluorinated anion such as BF4–, PF6–, Tf2N– (or
similar anions). The alkyl groups of the imidazolium ion are frequently methyl and a
higher alkyl group. One of the first room-temperature ionic liquids was 1-ethyl-3-
methylimidazolium tetrafluoroborate ([emim][BF4]; Example 8.4), prepared by heating
the imidazolium chloride with silver tetrafluoroborate in methanol.22 The corresponding
n-butyl compound, [bmim][BF4] (Example 8.5), has become popular because its prepara-
tion is especially easy.23
Et N N Me n-Bu N N Me
BF4 BF4
[emim][BF4] (8.4) [bmim][BF4] (8.5)
These solvents, from their composition, might reasonably be expected to be quite
polar: one expects a high dielectric constant, for example, from a liquid composed solely
of ions. However, polarity is a notoriously difficult concept to quantify, so just how polar
these liquids are considered to be depends on the measure being used to define the solvent
polarity. If one uses the simplest such measure, the ability to dissolve and stabilize ionic
salts, ionic liquids are obviously highly polar, but if one uses a more quantitative scale, one
often finds that these solvents (especially the solvents with larger organic groups) resemble
highly polar organic liquids such as dimethyl sulfoxide. This is nicely illustrated by the
nucleophilicity of anions toward n-alkyl sulfonates in ionic liquids: the second-order rate
constants of the SN2 reactions of azide, halide, and isothiocyanate anions with 1-hexyl or
1-octyl methanesulfonate in the ionic liquid all lie between the rate constants for the cor-
responding reactions in methanol and dimethyl sulfoxide.24
Ionic solvents lend themselves to a wide range of applications. They have been used as
solvents in widely disparate reactions, including Friedel-Crafts reactions,25 catalytic hy-
drogenation,26 hydroformylation,27 Suzuki coupling,28 and oxidation of benzylic alcohols
by sodium hypochlorite.29 One fascinating application of ionic liquids in synthesis in-
volves the osmium tetroxide hydroxylation of alkenes. Osmium tetroxide is expensive,
toxic, and highly volatile, but it has been found that—remarkably—solutions of osmium
tetroxide in the ionic liquid [emim][BF4] do not lose osmium tetroxide even over the
course of several months, and that the osmium tetroxide solution can be used and reused
with an organic co-oxidant several times over without losing activity (Example 8.6).30
22. Wilkes, J.S.; Zaworotko, M.J. J. Chem. Soc., Chem. Commun. 1990, 965.
23. Dyson, P.J.; Grossel, M.C.; Srinivasan, N.; Vine, T.; Welton, T.; Williams, D.J.; White, A.J.P.; Zigras, T. J.
Chem. Soc., Dalton Trans. 1997, 3465.
24. Landini, D.; Maia, A. Tetrahedron Lett. 2005, 46, 3961.
25. Boon, J.A.; Levisky, J.A.; Pflug, J.L.; Wilkes, J.S. J. Org. Chem. 1986, 51, 480.
26. Brown, R.A.; Pollet, P.; McKoon, E.; Eckert, C.A.; Liotta, C.L.; Jessop, P.G. J. Am. Chem. Soc. 2001, 123, 1254.
27. (a) Chauvin, Y.; Mussmann, L.; Olivier, H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2698. (b) Favre, F.;
Olivier-Bourbigou, H.; Commereuc, D.; Saussine, L. Chem. Commun. 2001, 1360.
28. Matthews, C.J.; Smith, P.J.; Welton, T. Chem. Commun. 2000, 1249.
29. Xie, H.; Zhang, S.; Duan, H. Tetrahedron Lett. 2004, 45, 2013.
30. Yanada, R.; Takemoto, Y. Tetrahedron Lett. 2002, 43, 6849.

Ph OsO4/NMMO•H2O HO OH
(8.6)
[emim][BF4] Ph
Ph Ph
Run: 1 2 3 4 5
Yield: 95 93 96 95 93
Problems
8-1 Arrange the following molecules in increasing order of their expected boiling
points. Give reasons for your choice.
(a) CH3(CH2)3CH3; (CH3)4C; (CH3)2CHCH2CH3
(b) CH3CH2CH2CH2N(CH3)2; N(CH2CH3)3; (CH3)2NC(CH3)3
(c) CH3(CH2)3N(CH3)2; (CH3)2CH(CH2)2NHCH3; (CH3)3CH(CH2)2NH2
8-2 Arrange the following compounds in increasing order of their solubility in water.
Give reasons for your rankings.
(a) CH3(CH2)3OH; (CH3)3COH; CH3CH2CH(OH)CH3; (CH3)2CHCH2OH
(b) CH3(CH2)4OH; CH3(CH2)2CH(OH)CH3; (CH3CH2)2CHOH;
CH3CH2C(CH3)2OH
8-3 n-Butyl alcohol (CH3CH2CH2CH2OH) and diethyl ether (CH3CH2OCH2CH3)
have the same solubility in water, but the boiling point of diethyl ether is 35°C
while the boiling point of n-butyl alcohol is 118°C. Explain these observations.
8-4 Sodium cyanide is a strong nucleophile in ethanol solution, and an even more
powerful nucleophile in dimethylformamide (DMF) solution. However, the reac-
tion between 1-bromobutane and sodium cyanide in hexane proceeds extremely
slowly, despite the fact that the solvent is aprotic. Why?
8.3 Reaction Kinetics31
The first step in the process of elucidating a reaction mechanism usually involves measur-
ing the kinetics for the reaction under study. Kinetic measurements at a single tempera-
ture provide the rate law of the reaction. This gives the kinetic order of the reaction, from
which one may deduce the molecularity of the reaction; the rate constant, k, for the reac-
tion; and the identity of those species participating in the reaction up to and including the
rate determining step.
The determination of kinetics for a reaction involves the measurement of the rate of
change of the concentration of the reactants or products with respect to time. One can
write the differential rate law for a typical reaction in the form:
d[R] d[P]
2 5 k[A]a [B]b ... or 5 k[A]a [B]b ... (Eq. 8.2)
dt dt
where [R] is the concentration of the reactant being monitored; [P] is the concentration of
the product; k is the rate constant for the reaction; [A], [B], and so on, are the
31. For general textbooks on kinetics, see: (a) House, J.E. Principles of Chemical Kinetics (Wm. C. Brown:
Dubuque, 1997). (b) Frost, A.A.; Pearson, R.G. Kinetics and Mechanism (John Wiley & Sons: New York, 1953).

concentrations of the individual reactants; and a, b, and so on, are the exponents for the
individual reactants.
First-Order Reactions
The simplest case of a rate law is for a reaction where the rate varies directly with the con-
centration of one of the reactants (a first-order reaction):
d[A] d[P]
2 5 k[A] or 5 k[A] (Eq. 8.3)
dt dt
Rearranging this equation gives an alternative form that can be integrated to give a
more useful form of the rate equation, integrated rate law for the reaction. For a first-
order reaction, the integrated rate law is of the form:
ln[A]t = ln[A]0 – kt (Eq. 8.4)
In other words, a plot of ln[A] versus time for a first-order reaction will be linear, with
a slope of –k and a y intercept of ln [A]0.
Second-Order Reactions
Reactions exhibiting second-order kinetics fall into two classes: those where only one
reactant appears in the rate law and those where two reactants appear in the rate law. The
former reactions obey a rate law of the form:
d[A] 1 1
2 5 k[A]2 , which integrates to 5 kt 1 (Eq. 8.5)
dt [A]t [A]0
In this case, a plot of 1/[A] versus time will be linear, with a slope of k and a y intercept
of 1/[A]0.
The second type of second-order reaction has a rate law that is first order in both reac-
tants. These reactions obey a rate law of the form:
d[A] d[B]
2 52 5 k[A][B] (Eq. 8.6)
dt dt
In this case, the kinetics are less simple, but one can obtain the integrated rate law:
[A]t [A]
ln 5 {k([B]0 2[A]0 )}t 1 ln 0 (Eq. 8.7)
[B]t [B]0
This gives a linear graph when ln([A]t/[B]t) is plotted against time, with a slope of
k([B]0-[A]0) and a y intercept of ln([A]0/[B]0).
More frequently, reactions such as this are run under conditions where one reactant is
in great excess over the other. Under these conditions, the kinetics simplify to approximate
first-order kinetics, because the change in concentration of the excess reagent is small
enough to be neglected (i.e., [B]t ≈ [B]0). Reaction kinetics measured under these conditions
are said to be measured under pseudo–first-order conditions. The pseudo–first-order rate
constant when B is in excess, for example, is related to the true second-order rate constant
by the simple relationship:
k = kobs[B] ≈ kobs[B]0 (Eq. 8.8)
This approach may also be applied to higher order reactions in two reagents by using a
large excess of one reagent over the other. In this case, the order of the reaction with

Figure 8.5 Plots of the ln [A]0

integrated rate laws of (a) a slope = k slope = k([B]0–[A]0)
first-order reaction, (b) a slope = –k
[A]t
second-order reaction with 1/[A]
ln
[B]t
only one reactant appearing ln [A]
1/[A]0 [A]0
ln
in the rate law, and (c) a [B]0
second-order reaction with time time
time
two reactants appearing in
the rate law (a) (b) (c)
respect to each reactant must be determined separately, of course, by using each of the
reactants as the excess reagent.
The most common forms of the integrated rate laws for first- and second-order reac-
tions are shown in Figure 8.5.¶
Making Deductions from the Rate Law

Simple nucleophilic substitution reactions at saturated carbon provide useful models for
how one approaches elucidating a mechanism from a rate law. The first mechanistic pro-
posals about these reactions were set forth in the first decades of the 20th century by a
variety of investigators.32 The process of finding out whether or not a reactive intermediate
is involved in a reaction has changed little since the pioneering work of Hughes and Ingold
between 1927 and 1933.
If any of the reactants present in the balanced, stoichiometric equation for a reac-
tion is not represented in the rate law, at least two steps must be required to complete
bond rupture and bond formation. The case of the SN 1 substitution reaction is illus-
trative. For this reaction, only one of the stoichiometric reactants appears in the rate
law. If we use the SN 1 reaction between tert-butyl bromide and water as the example,
¶
The Mathematics:
First-order reactions:
t t
d[A] d[A] d[A] [A]
1 kdt ⇒ 2∫
[A] ∫0
2 5 k[A] ⇒ 2 5 k dt ⇒ ln 0 5 kt ⇒ ln[A]t = ln[A]0 – kt
dt [A] 0
[A]t
Second-order reactions
(i) Rate laws involving a single reagent:
t t
d[A] d[A] 1 1 1 1
2 5 k[A]2 ⇒ 2∫ 2
5 ∫ k dt ⇒ 2 5 kt ⇒ 5 kt 1
dt 0
[A] 0
[A]t [A]0 [A]t [A]0
(ii) Rate laws involving two different reagents:

d[A] d[B]
2 52 5 k[A][B]
dt dt
In this case, the rate equation is most simply solved by denoting the amount of excess reagent ([B]0–[A]0) by
the term x. This now changes the rate law to:
t t
d[A] d[A]  1  [A] 1 x  1  [A]0 1 x
5 k[A]([A] 1 x ) ⇒ 2∫
[A]([A] 1 x ) ∫0
2 5 k dt ⇒ kt 52  ln t 1   ln ⇒
dt 0
 x [A]t  x [A]0
 [A]t   [A]0 1 x   [A]t   [B]0   [A]t [A]0

(kx )t 5 ln    [A]  ⇒ (kx )t 5 ln     ⇒ ln [B] 5 {k([B]0 2[A]0 )}t 1 ln [B]
[A]
 t 1 x   0   [B]t   [A]0   t 0
32. (a) Fischer, E. Justus Liebigs Ann. Chem. 1911, 381, 123. (b) Werner, A. Ber. Deut. chem. Ges. 1911, 44, 873.
(c) Werner, A. Justus Liebigs Ann. Chem. 1912, 386, 1. (d) Pfeiffer, P. Justus Liebigs Ann. Chem. 1912, 386, 92.
(e) Gadamer, J. J. prakt. Chem. 1913, 78, 312. (f) Meisenheimer, J. Justus Liebigs Ann. Chem. 1912, 386, 126.
(g) Le Bel, J.-A. J. chim. phys. 1911, 9, 323. (h) Lewis, G.N. Valence and Structure of Atoms and Molecules (Chem-
ical Calatog Co.: New York, 1923), p. 113. (h) London, F. Z. Elektrochem. 1929, 35, 552. (i) Lowry, T.M. Inst. inter.
chim. Solvay, Conseil chim. (Brussels), 1925, 130.

it is clear that both reactants are required to form the C—O bond, but the rate law
(Equation 8.9) is first-order:
Me3C–Br + H2O → Me3C–OH + HBr

Rate = k[Me3CBr] (Eq. 8.9)
Taken together, these two facts require that this reaction must occur in a minimum of
two steps: (1) the cleavage of the carbon-halogen bond, which occurs before or during the
slow step of the reaction, and (2) the formation of the carbon-oxygen bond, which must
occur in a subsequent kinetically fast step. The reaction coordinate diagram for this reac-
tion is shown as Figure 8.6; the reaction is a multistep reaction composed of the three ele-
mentary reactions shown on the left-hand side of the diagram. This diagram reinforces an
important point. Kinetics can tell us that the reaction proceeds in a stepwise manner in-
volving at least one reactive intermediate and allows us to pinpoint the slow bonding
change, but kinetics alone cannot tell us how many steps are required to convert reactants to
products (i.e., about the complete mechanism). To complete the picture, other information
is required.
The foregoing discussion shows us that the rate law may allow us to deduce that a re-
action proceeds in a stepwise manner. Unfortunately, a similar simple deduction cannot
be made in the case of reactions where every reactant appears in the rate law. In these
cases, one cannot deduce from the rate law alone whether or not a reaction is concerted,
but additional evidence from other studies (e.g., stereochemical studies) is needed before
one can make that determination. This is illustrated nicely by base-promoted elimination
reactions.
R 2CH-CR 2X + RO– → R 2C=CR 2 + ROH + X–

Rate = k[RX][RO–] (Eq. 8.10)
In the case of both the E2 and E1cb mechanisms, the rate law is of the form shown in
Equation 8.10, where both the alkyl halide and the base appear in the rate law. The
‡
Me δ
+ 3C Br
Me Me3C + Br (8.7) Me Br ‡
δ Me δ
Me
Me OH2
H2O + Me3C Me3C OH2 (8.8) δ
Me
‡
Hδ
Me3C OH2 Me3C OH H (8.9) Me
Energy
Me Me Oδ
Me H
Me Me
Me Me
Me Br Me OH2
Me Me Me
Me OH
Me
Reaction Coordinate
Figure 8.6 Reaction coordinate diagram for the SN1 substitution of tert-butyl bromide

Xδ ‡
R ‡
R R X
R R δ
R R
R Xδ ‡
H H
R R
Bδ Bδ R
R δ
Energy
Energy
R X
R
R
R
R X
R X R
R R
R R R H R R R
H R
R R R R
Reaction Coordinate Reaction Coordinate

(a) (b)
Figure 8.7 Reaction coordinate diagrams for base-promoted (a) E2 and (b) E1cb elimination from
an alkyl halide. Both reactions have the same rate law: rate = k[RX][base].
difference between the two mechanisms is that the E2 reaction is concerted, whereas the
E1cb reaction is stepwise, with proton transfer to the base to give a carbanion intermediate
as the rate-determining step. These two mechanisms can, however, be distinguished by
stereochemical and isotope exchange studies—the concerted E2 reaction lacks a pathway
for exchange of hydrogen and has a strict stereochemical constraint (the elimination is
antarafacial), whereas the E1cb reaction does not have the a strict stereochemical con-
straint and does have a pathway for hydrogen exchange between the carbanion intermedi-
ate and the solvent. The reaction coordinate diagrams for these two related reactions are
Preequilibrium and Catalysis

The E1 elimination reaction between tert-butyl alcohol and phosphoric acid at elevated
temperatures gives isobutylene and water, and it obeys a second-order rate law, shown as
Equation 8.11.
Me3COH → Me2C=CH2 + H2O

Rate = k[Me3COH][H+] (Eq. 8.11)
In the reaction, the concentration of acid appears in the rate law, but the acid does not
appear in the stoichiometric equation for the reaction. This is the classical definition of a
catalyst. The rate law tells us that the reaction between tert-butyl alcohol and the strong
acid either precedes the rate-determining step or is part of the rate-determining step. A
variety of other experiments can be carried out to demonstrate that the former situation
applies to this reaction and that the alcohol reacts with the protons in a rapid, reversible
reaction to give an intermediate that then participates in the rate-determining step of the
reaction. This situation is also often referred to as a pre-equilibrium. The reaction coordi-
nate diagram for this reaction is shown in Figure 8.8. This reaction also shows one

‡ Figure 8.8 Reaction
Me δ ‡
δ δ H Me coordinate diagram for the
Me OH2
H δ acid-catalyzed dehydration
Me
H Me of tert-butyl alcohol
δ H ‡
Energy Me
Me Oδ
Me H Me
Me
Me
Me
Me OH2
Me Me
Me OH H Me
Me
H Me
Reaction Coordinate
‡ Figure 8.9 Reaction
Me δ ‡
δ Me δ coordinate diagram for the
Me OH2 δ
Me Br reaction between tert-butyl
Me
Me alcohol and bromide ion in
δ H ‡ the presence of strong acid
Me
Energy
Me Oδ
Me H Me
Me
Me
Me
Me OH2
Me Me
Me OH Me
Me Me Br
Me
Reaction Coordinate
important characteristic of catalysts: they always appear in the rate equation of a reaction,
even if they do not appear in the overall stoichiometric equation.
Deducing a Rate Law from a Reaction Coordinate Diagram

The reaction coordinate diagram for the reaction between tert-butyl alcohol and bro-
mide ion in the presence of a strong acid is shown in Figure 8.9. The reaction coordinate
is very similar to that of the E1 elimination that we have just discussed, and we will now
use this diagram to make some deductions about the form of the rate law for the reac-
tion. There are three steps required in the reaction to convert the tert-butyl alcohol to
tert-butyl bromide, and these can be represented by the elementary reaction in reactions
8.12 to 8.14.
Me3COH + H+ → Me3COH2+ (Eq. 8.12)

Me3COH2+ → Me3C+ + H2O (Eq. 8.13)
Me3C+ + Br– → Me3CBr (Eq. 8.14)
The second transition state is the highest point in the diagram, so we can deduce that
the unimolecular heterolysis reaction 8.13 is the rate-determining step of the reaction.
Based on this, we can write a rate law for the reaction of the form:
Rate = k[Me3COH2+] (Eq. 8.15)
We cannot measure the concentration of the tert-butyl alcohol conjugate acid directly,
but we can deduce it from the expression for the equilibrium constant for reaction 8.12:
[Me3COH12 ]
K eq 5 ⇒ [Me3COH12 ] 5 K eq[Me3COH][H1] (Eq. 8.16)
[Me3COH][H1]
which leads to:
Rate = kKeq[Me3COH][H+], or Rate = kobs[Me3COH][H+] (Eq. 8.17)
In this reaction, the observed rate constant kobs is a composite constant that is the
product of the first-order rate constant for reaction 8.13 and the equilibrium constant for
reaction 8.12 (the pre-equilibrium reaction). Note that bromide anion does not participate
in the reaction until after the rate-determining step, so its concentration does not appear
in the rate law.
Predicting a Rate Law from a Mechanism

The base-promoted elimination reactions of certain halides and similar compounds can
be viewed under some circumstances as taking place in a stepwise manner, where the re-
active intermediate is the carbanion formed by deprotonation of the halide, as shown in
Figure 8.10. This sequence of reactions is characterized by three rate constants: k1, the rate
constant for deprotonation of the substrate by base; k−1, the rate constant for deprotona-
tion of the conjugate acid of the base by the carbanion; and k2, the rate constant for the loss
of the leaving group from the carbanion.
Based on this mechanistic scenario, we can write the rate expression for the formation
of the product, which is formed by unimolecular decomposition of the carbanion.
Rate = k2[R–] (Eq. 8.18)
Clearly, we may or may not be able to determine the carbanion concentration, but it
would be better to write a rate law in terms of species that we can easily measure (RX and
B−). This means that we will need to find expressions for the concentration of the anion in
terms of the concentrations of the other species. One way to accomplish this is to apply the
Figure 8.10 The E1cb

mechanism for elimination
X k1 X
+ BH
H k-1
B k2 (8.10)

steady-state approximation to the reaction analysis. This approximation relies on the fact
that because the carbanion is likely to be a high-energy species, it is most likely to react as
soon as it is formed, so that only a small, constant (or very nearly so) concentration of the
intermediate is ever present in the reaction mixture after a short initiation period.
The carbanion intermediate is formed in a bimolecular reaction with a rate equal to
k1[RX][B−]. It can be lost in two ways: it can continue on to product, with a rate equal to
k2[R−], or it can react with the conjugate acid of the base to revert to starting material, with
a rate equal to k−1[R−][BH]. At the steady state, the change in concentration of the c arbanion
is zero, which leads to the expression below:
k1[RX][B−] = k2[R−] + k−1[R−][BH] (Eq. 8.19)
This can be rearranged to

k1[RX][B2]
R  ( k2 1 k21 [ BH ]) 5 k1 [ RX ] B  , or R  5
2 2 2
(Eq. 8.20)
( k2 1 k21[BH])
which gives the final form of the rate law:
k2 k1[RX][B2]
Rate 5 (Eq. 8.21)
( k2 1 k21[BH])
Depending on the relative values of the rate constants, this expression can be simpli-
fied further. For example, if k2 is much greater than either of the other two rate constants,
this equation simplifies to:
Rate = k1[RX][B−] (Eq. 8.22)
In another possible scenario, k1 is much greater than the other two rate constants. This
would lead to complete deprotonation of the substrate before the rate-determining step,
making the concentrations of B– and HB constant and simplifying the kinetics to:
k2[B]
Rate = kexp[RX], where kexp 5 (Eq. 8.23)
k2 1 k21[HB]
Worked Problem
8-1 The reaction of 1,1-dimethoxycyclohexane when heated in the presence of strong
acid is:
OMe H ,∆
OMe + MeOH
OMe
The rate law for this reaction is: Rate = k[C8H16O2][ H+]
Write a mechanism, and draw a reaction coordinate diagram consistent with this
rate law.
Problems
8-5 There are six major mechanisms for base-promoted β-elimination to give
alkenes: E1, E2, E1cbI, E1cbR, E1cbip, and E1anion. The rate laws for these mecha-
nisms are as follows:
(continues)

E1: Rate = k[RX]
E2: Rate = k[RX][B−]
E1cbI: Rate = k[RX][B−]
E1cbR: Rate = k[RX][B−] if the solvent is B—H
E1cbip: Rate = k[RX]B−]
E1anion: Rate = kexp[RX] provided that [B−]>[RX]
Draw reaction coordinate diagrams similar to Figures 8.6 to 8.8 for the E1cb elim-
ination of Br− from Ph2CHCH2Br by each of the E1cb mechanisms above.
8-6 You are asked to carry out an elimination reaction that proceeds by one of the six
mechanisms (you do not know which) in Problem 8-5. Under the conditions you
are using, the reaction is complete in one 3-hour laboratory period. You now find
out that that you can actually use one half the amount of solvent, which makes
the reaction much less expensive to carry out. How long will it now take for the
reaction to be complete, based on each of the mechanisms in Problem 8-5? How
would you tell if the reaction is E1, E2, or E1cb?
8-7 Draw appropriate reaction coordinate diagrams for the experimental condi-
tions specified below and use them to predict the effects on the rate of those
experimental conditions (you may want to use the Hammond postulate
here):
(a) Increased solvation of the reactants.
(b) Increased solvation of the activated complex.
(c) Increased solvation of the products.
(d) Preferential solvation of the reactants over the products.
(e) Preferential solvation of the products over the reactants.

Although H+ does not appear in the overall balanced equation for this reaction, it does appear in the rate law.
This very strongly suggests that the proton is involved in the reaction as part of a pre-equilibrium. This gives
the mechanism below, with the corresponding reaction coordinate diagram. [Note how the high-energy carbo-
cation intermediate is resonance-stabilized.]
H
H H
OMe O Me
OMe OMe OMe
OMe OMe
OMe
H
Energy
MeO OMe
MeO OMe
OMe

8-8 The two reactions below occur by the same concerted mechanism, but the effects
of solvent on the rate constant for the reaction are opposite in the two reactions.
Provide a reasonable rationalization for these observations.
KN3/solvent
Br N3 DMF > MeOH
Et3N/solvent
Br NEt3 Br MeOH > DMF
8-9 The formation of alkali metal complexes with crown ethers proceeds best in
non-polar solvents (benzene or dichloromethane), but the complexes are unstable
when heated in alcohols. Why?
8-10 Like carbocations, free radicals can be stabilized by adjacent heteroatoms bear-
ing lone pairs of electrons. Provide a reasonable explanation of this by drawing
the contributors to the resonance hybrid of the acetone radical anion
(MeCOMe)•−.
8.4 Activation Parameters from Kinetic Studies
The rate constant for a reaction is temperature-dependent. The relationship between the value
of the rate constant and temperature is the Arrhenius equation,33 whose most usual form is
k 5 Ae2Ea / RT (Eq. 8.24)
where k is the rate constant for the reaction; Ea is the activation energy for the reaction; A
is the pre-exponential factor, or frequency factor, for the reaction (related to the probabil-
ity that a given collision will actually result in a reaction); R is the ideal gas constant; and
T is the kelvin temperature. By plotting the logarithm of the rate constant k against (1/T),
one obtains a straight line with slope (–Ea/R) and y intercept log A. This gives one the ac-
tivation energy Ea for the reaction and the Arrhenius pre-exponential factor A, which is
related to the entropy of activation.
On the basis of transition state theory,34 two simple relationships emerge: (1) between
the activation energy Ea and the enthalpy of activation ∆H‡ and (2) between the Arrhenius
pre-exponential factor A and the entropy of activation ∆S‡:
 RT  ∆RS
‡
Ea 5 ∆H‡ 1 RT A5 e (Eq. 8.25)

 N 0 h 
where N0 is Avogadro’s number and h is Planck’s constant. The entropy of activation, in

particular, gives useful information about the formation of the activated complex for a
reaction: reactions for which ∆S‡ is negative always involves bringing greater order to the
system as the activated complex is formed, and this is usually interpreted in terms of a
bimolecular activated complex or loss of rotational degrees of freedom. However, this still
needs to be interpreted carefully, because the organization of solvent in the activated com-
plex may reverse the sign of the activation entropy in reactions where the disorder of the
33. Arrhenius, S. Z. physik. Chem. 1889, 4, 226.

34. (a) Eyring, H. J. Chem. Phys. 1935, 3, 107. (b) Evans, M.G.; Polanyi, M. Trans. Faraday Soc. 1935, 31, 875.
(c) Glasstone, S.; Laidler, K.;. Eyring, H. The Theory of Rate Processes (McGraw-Hill: New York, 1941). (d) Laidler,
K.J.; King, M.C. J. Phys. Chem. 1983, 87, 2657. (e) Truhlar, D.G.; Hase, W.L.; Hynes, J.T. J. Phys. Chem. 1983, 87,
2664. (f) Pechukas, P. In Miller, W.H., Ed. Dynamics of Molecular Collisions. Part B (Plenum Press: New York,
1976), p. 239. (g) Pechukas, P. Ann. Rev. Phys. Chem. 1981, 32, 159.

Table 8.5 Standard Entropies of Activation for Some Organic Reactions
Reaction ∆S‡ (e.u.) Ref.
‡ –34
+ (8.11) 35
–26 36
Bu Bu ‡
N N N N 2 Bu• + N2 (8.12) +19 37
Bu Bu
‡
(8.13) –8 38
O O O
‡
δ+ δ– (8.14) –6.6
Cl Cl + Cl 39
O O O 2 Me3CO• (8.15) +13.8 40

O
H
‡
(8.16) –11.7 41
H
*The negative value reflects the greater order imposed on the solvent by solvation of the incipient positive and
negative charges.
reacting species actually increases. Some standard entropies of activation for several or-
ganic reactions are given in Table 8.5.
The volume of activation for a reaction may be calculated from the dependence of the
rate constant on pressure. But, a plot of ln k versus P has a slope of –∆V‡, which is very
small (the effects of pressure are orders of magnitude smaller than the corresponding ef-
fects of temperature). This necessitates making measurements over a range of tens or hun-
dreds of atmospheres. In addition, interpreting volumes of activation is complicated by
solvation and desolvation during the reaction, just like interpreting entropies of activation
in solution. However, in non-polar, poorly solvating solvents, one may conclude that reac-
tions with negative volumes of activation generally proceed through a highly ordered,
compact transition state (e.g., the Diels-Alder reaction), while reactions with a positive
volume of activation often proceed through a looser, less ordered transition state.
8.5 Correlating Reaction Rates: Linear Free Energy Relationships
The idea that one might be able to predict the rate of an organic reaction based on the rate
of a known reaction is an attractive one to most organic chemists. Similarly, being able to
35. Wassermann, A. Monatsh. Chem. 1952, 83, 543.

36. (a) Kistiakowsky, G.B.; Lacher, J.R. J. Am. Chem. Soc. 1936, 58, 123. (b) See, also, Table 1 in Frost, A.A.;
Pearson, R.G. Kinetics and Mechanism (John Wiley & Sons: New York, 1953), p. 101.
37. Blackham, A.U.; Eatough, N.L. J. Am. Chem. Soc. 1962, 84, 2922.
38. Schuler, F.W.; Murphy, G.W. J. Am. Chem. Soc. 1950, 72, 3155.
39. Grunwald, E.; Winstein, S. J. Am. Chem. Soc. 1948, 70, 846.
40. Bartlett, P.D.; Hiatt, R.R. J. Am. Chem. Soc. 1958, 80, 1398.
41. Hammond, G.S.; DeBoer, C.D. J. Am. Chem. Soc. 1964, 86, 899.
08-Lewis-Chap08.indd 280 14/08/15 4:24 PM

predict the effects of a small structural change on the equilibrium constant for a revers-
ible reaction is also attractive. However, it is also obvious that any differences between
the system used as the basis for the prediction and the system under scrutiny must be
small—the reactions must be closely related—for the predicted result to engender
confidence.
The idea that changing the substituents directly attached to a reacting center will
change the rate constant for a reaction or the equilibrium constant for an equilibrium
reaction is reasonably intuitive. We expect that if we take the SN2 reaction of butyl halides
(Example 8.17), for instance, that 1-bromobutane, a typical primary halide, will react
faster than 2-bromobutane, its secondary isomer, while replacing the 1-bromobutane
with 1-chlorobutane will slow the reaction down even further due to the stronger bond
to the leaving group. It is comforting to find that these predictions are borne out by
experiment.42
NaI, Me2CO
R X R I (8.17)
40°C
R = n-Bu, X = Cl: k = 1.55x10–5 L mol–1s–1

R = n-Bu, X = Br: k = 5.09x10–3 L mol–1s–1
R = s-Bu, X = Br: k = 8.79x10–5 L mol–1s–1
What may be less intuitive is the thought that changing substituents at a location
remote from the reacting center—especially if those substituents are not capable of conju-
gating with the reacting center—should have an effect of reaction rates or equilibria. We
can see evidence that they do, by looking at the ionization constants of acids: halogenated
carboxylic acids have pKas that rise as the halogen is moved further from the carbonyl
group along the alkyl chain (Example 8.18), and substituted benzoic acids also have pKa
values that vary with the substituent.
Cl
pKa 2.86
CO2H
pKa 4.05 (8.18)

Cl CO2H
pKa 4.52
CO2H
Cl
In 1935,43 Louis P. Hammett44 addressed the possibility of a relationship between reac-
tion rates and equilibrium constants in the following way.45 “The idea that there is some
sort of relationship between the rate of a reaction and the equilibrium constant is one of the
most persistently held and at the same time most emphatically denied concepts in chemical
theory. Many organic chemists accept the idea without question and use it, frequently with
considerable success, but practically every treatise on physical chemistry points out that such
a relationship has no theoretical basis and that it is in fact contradicted in many familiar
cases.” He then proceeded to show that for certain reactions, at least, there actually is a
relationship between the rate constants and the equilibrium constants.
42. Pace, R.D.; Regmi, Y. J. Chem. Educ. 2006, 83, 1344.

43. Hammett, L.P. J. Am. Chem. Soc. 1935, 57, 125.
44. Louis Plack Hammett (1894–1987) was educated at Harvard, Zürich, and Columbia (PhD, 1922). After
graduation, he remained at Columbia, where he spent his entire career. Hammett was a pioneer of physical or-
ganic chemistry, which term he coined, and was responsible for both the Hammett equation and the Hammett
acidity constant. For more biographical details, see Westheimer, F.H. Biogr. Mem. Nat. Acad. Sci. 1997, 72, 136.
45. Hammett, L.P. J. Am. Chem. Soc. 1937, 59, 96.

In 1937, he went further and analyzed the rate and equilibrium data for 37 organic re-
actions of compounds with an aromatic ring, which led to him taking the first steps to
place the qualitative observations (“conventional wisdom”) on a quantitative footing.
Since these first steps, the area of physical organic chemistry devoted to correlating the
rates of organic reactions has blossomed. Today, a variety of linear free energy relation-
ships is available to the organic chemist to quantify the effects of ring substituents and
solvent on reaction rates.
It should be borne in mind during the following discussions that writing a linear free
energy relationship between two reactions has implications that should be remembered
when interpreting the results of such a relationship. First and foremost, there is an implicit
assumption that the two reactions are reasonable models for each other—the choice of
model can be critical in obtaining a successful correlation (e.g., the choice of σ, σ+, or σ−
can have a dramatic effect on the fit of the data in certain reactions). This also means that
the ability of the linear free energy relationship to correlate experimental data depends on
the appropriateness of the model reaction chosen.
Substituent Effects: the Hammett Equation

The effects of remote substituents on the free energy of reaction ∆G are exercised as both
enthalpy and entropy contributions. Hammett suggested that in reactions where the sub-
stituent is remote from the reaction center, the effects of substituents would be derived
almost exclusively from the enthalpy contribution ∆H. He based this conclusion on the
postulate that because the substituted aromatic ring is basically unchanged during the
reaction, one would expect changes at the molecular level in the region of the substituent
(e.g., solvation) to be very small. This means that the entropy contributions from the sub-
stituent to the free energy change would be close to zero. This is illustrated schematically
in Figure 8.11, where the shaded region shows the region where the greatest changes during
the reaction are expected to occur. It is worth noting that ortho substituents are located
close enough to this region that we may expect that they will not obey the same simple
relationships as the meta and para substituents because of steric effects. Of course, these
arguments do not hold if there is strong resonance between the substituent and the react-
ing center, because that will lead to major changes in the electron density (and hence, the
solvation) of the ring during the reaction.
Hammett’s original proposal was that, in a series of substituted aromatic compounds
undergoing the same reversible reaction in the side chain, it should be possible to relate the
equilibrium constants for the reactions by the following equation:
log10 (K/K0) = σρ (Eq. 8.26)§
In this equation, which now bears his name, there are two constants characteristic of
the reacting system. There is a substituent constant, σ, which measures the effect of the
Figure 8.11 Schematic of the

region affected during a side-
chain reaction of substituted
aromatic compounds * * *
X
X
X
§. The logarithms in almost all of the equations in this chapter are in base 10. The term “log” will be used to
designate log1= throughout the chapter; for natural, or Napierian logarithms, the term “ln” will be used.

substituent on the position of equilibrium, and a reaction constant, ρ, which measures the
effect of the reaction type on the position of the equilibrium.
Showing that this equation represents a linear free energy relationship is fairly straight-
forward. We begin by expanding the log term to get Equation 8.27:
log (K/K0) = log K − log K0 = σρ (Eq. 8.27)
Using the relationship between log K and ∆G, we can re-write equation 8.27 in the form:
−∆G/2.30 3RT − (−∆G0/2.303RT) = σρ (Eq. 8.28)
which can be rearranged to:
∆G = ∆G0 − (2.303RT)σρ (Eq. 8.29)
Equation 8.29 relates the free energy of the reaction where the reactant carries the
substituent of interest to the free energy of the same reaction where the reactant carries a
standard substituent.
By replacing the free energy of reaction with the free energy of activation, it is possible
to obtain a second form of the Hammett equation that relates reaction rates:
log (k/k0) = σρ, or ∆G‡ = ∆G0‡ – (2.303RT)σρ (Eq. 8.30)
The Hammett equation has four unknowns, so a standard system is required to cali-
brate the equation and make it useful. The standard reaction chosen by Hammett was the
ionization of substituted benzoic acids (8.19, reaction constant ρ = 1) with hydrogen as the
standard substituent (σ = 0). The ρ value for a reaction gives an estimate of the type and
amount of charge development at the reaction center. Reactions with ρ > 1 tend to be
characterized by more negative charge at the reacting center; reactions for which ρ < 1 tend
to be characterized by increased positive charge at the reacting center. Some typical reac-
tion ρ values are collected in Table 8.6.
There is a vast literature46 discussing the effects of substituents on the rates of chemical
reactions, and the construction of Hammett plots often provides an early indication of the
nature of the reaction under study. In its original form, the Hammett equation works well
for reactions in the side chain when no new interaction by resonance between the substit-
uent and the side chain develops during the reaction. Thus, meta substituents tend to give
the closest agreement with the Hammett equation.
As the importance of conjugation between the reaction center and the substituent in-
creases, deviations from the Hammett equation become more pronounced. As the result
of work by a number of research groups, two new substituent constants, σ+ and σ−, were
proposed. The former is useful for reactions in which positive charge is developed in a
46. Reviews: (a) Hammett, L.P. Physical Organic Chemistry (McGraw-Hill: New York, 1940), ch. 6. (b) Jaffé,
H.H. Chem. Rev. 1953, 53, 191. (c) van Bekkum, H.; Verkade, P.E.; Wepster, B.M. Rec. trav. chim 1959, 78, 815.
(d) Topsom, R.D. Prog. Phys. Org. Chem. 1976, 12, 1. (e) Unger, S.H.; Hansch, C. Prog. Phys. Org. Chem. 19776, 12,
91. (f) Levitt, L.S.; Widing, H.F. Prog. Phys. Org. Chem. 1976, 12, 119. (g) Ritchie, C.D.; Sager, W.F. Prog. Phys. Org.
Chem. 1964, 2, 323. (h) Ehrenson, S. Prog. Phys. Org. Chem. 1962, 2, 195. (i) Charton, M. Prog. Phys. Org. Chem.
1981, 13, 119. (j) Pross, A.; Radom, L. Prog Phys. Org. Chem. 1981, 13, 1. (k) Taft, R.W.; Topsom, R.D. Prog. Phys.
Org. Chem. 1987, 16, 1. (l) Topsom, R.D. Prog. Phys. Org. Chem. 1987, 16, 85. (m) Topsom, R.D. Prog. Phys. Org.
Chem. 1987, 16, 125. (n) Charton, M. Prog. Phys. Org. Chem. 1987, 16, 287. (o) Ehrenson, S.; Brownlee, R.T.C.; Taft,
R.W. Prog. Phys. Org. Chem. 1973, 10, 1. (p) Stock, L.M.; Brown, H.C. Adv. Phys. Org. Chem. 1963, 1, 35.
Books and monographs: (q) Hine, J. Structural Effects on Equilibria in Organic Chemistry (Wiley: New York,
1975). (r) Johnson, K.F. The Hammettt Equation (Cambridge University Press: New York, 1973). (s) Wells, P.R.
Linear Free Energy Relationships (Academic Press: New York, 1968).

Table 8.6 Hammett ρ Values for Some Representative Organic Reactions*
Reaction ρ Value
O O
Ar C Ar C (8.19) 1 exactly
OH O
O HN3
Ar C Ar NH2 (8.20)
Cl2C=CHCl −1.415
OH
45°C
O OH O
Ar C Ar C
80% Me2CO/H2O (8.21) +2.299
OMe O
15°C
O H O
Ar C Ar C
80% EtOH-H2O (8.22) +0.144
OEt OH
100°C
Ar H (cat.) Ar
40% dioxane-H2O (8.23) −4.672
OH OH
30°C
O OH O
2 Ar C Ar C + Ar CH2OH
50% MeOH/H2O (8.24) +3.63
H O
15°C
*Values taken from Jaffé, H.H. Chem. Rev. 1953, 53, 191.
location capable of conjugating directly with the substituent; it is based on the solvolysis
of substituted cumyl chlorides in 90% acetone-water.47 The latter is useful for reactions in
which negative charge is developed in a location capable of conjugating directly with the
substituent; it is based on the ionization of substituted phenols.48 Because the substituent
at the meta position seldom interacts strongly by resonance with the side chain, σ+ and
σ− constants are usually only quoted for para substituents.
The use of the σ+ constant is nicely illustrated by the plots for the ethanolysis of triaryl-
methyl chlorides in 40% ethanol–60% ether solution.49 The data for the reactions are plotted
versus σ and σ+ in Figure 8.12. When the data are plotted against the original Hammett σ
values, the plot is curved or has a clear inflection point when the sign of the σ constant changes.
In contrast to this, the plot versus σ+ is linear over the whole range of reactions studied.
As the study of substituent effects on chemical reactions matured, the number and
type of substituent constants also increased from the original set of three (σ, σ+, and σ−).
There was a realization that substituents interact with the aromatic ring by both inductive
and resonance mechanisms, which, of course, meant that σ was almost certainly a com-
posite variable containing both inductive, σI, and resonance, σR, contributions, a sugges-
tion first made by Taft.50 The relationship between these substituent constants is:
σ = σI + σR (Eq. 8.31)
47. Brown, H.C.; Okamoto, Y. J. Am. Chem. Soc. 1958, 80, 4979.
48. (a) Miller, J. Aust. J. Chem. 1956, 9, 61. (b) Fujita, T.; Iwasa, J.; Hansch, C. J. Am. Chem. Soc. 1964, 86, 5175.
(c) Cohen, L.A.; Jones, W.M. J. Am. Chem. Soc. 1963, 85, 3397.
49. Nixon, A.C.; Branch, G.E.K. J. Am. Chem. Soc. 1936, 58, 492.
50. (a) Taft, R.W. In Newman, M.s., Ed. Steric Effects in Organic Chemistry (John Wiley & Sons: New York,
1956), ch. 3. (b) Taft, R.W., Jr. J. Am. Chem. Soc. 1957, 79, 1045.

Figure 8.12 Hammett plots

for the ethanolysis of
triarylmethyl chlorides
The inductive effect of the substituent is a through-bond effect due largely to electro-
negativity of the substituent. It is almost always accompanied by a field effect, which is a
through-space effect, and which may be, in fact, the dominant effect.51 This is especially
the case when the substituent is charged (e.g., NR 3+ or CO2–). The measurement of the in-
ductive component, σI, required a system incapable of interacting by resonance but still
geometrically rigid. To isolate the inductive term (although still mixed with the field effect
of the substituents), the pKa values of 4-substituted bicyclo[2.2.2]-octane-1-carboxylic
acids (Example 8.25) were used as the standard.
CO2H CO2
(8.25)
X X
An alternative interpretation of the dual character of the Hammett σ constant is that

of Swain and Lupton,52 who proposed that the σ constant was related to a field constant (F)
and a resonance constant (R) by the relationship:
log (k/k0) = fF + rR (Eq. 8.32)
where f is the contribution to σ from field effects and r is the contribution from resonance.
An earlier approach to separating the inductive/field effects and resonance effects is that
proposed by Yukawa and Tsuno,53 whose equation:
log(kx /k0) = ρ[σ + r(σ+ – σ)] (Eq. 8.33)
51. E.g., the field effect appears to dominate the substituent effects on the pKa’s of 4-substituted bicyclo[2.2.2]
octane-1-carboxylic acids and cubane-1-carboxylic acids: (a) Cole, T.W., Jr.; Mayers, C.J.; Stock, L.M. J. Am.
Chem. Soc. 1974, 96, 4555. (b) Wilcox, C.F.; Leung, C. J. Am. Chem. Soc. 1968, 90, 336.
52. Swain, C.G.; Lupton, E.C., Jr. J. Am. Chem. Soc. 1968, 90, 4328.
53. (a) Yukawa, Y.; Tsuno, Y. Bull. Chem. Soc. Japan 1959, 32, 965. (b) Yukawa, Y.; Tsuno, Y. Bull. Chem. Soc.
Japan 1959, 32, 971.

Table 8.7 Substituent Constants for Linear Free Energy Relationships
Substituent σm σp σ+ * σ−* σI σR F R
NH2 −0.16 −0.66 −1.3 0.12 −0.82 0.38 −2.52

Me −0.07 −0.17 −0.31 −0.04 −0.11 0.01 −0.41
Ph 0.06 −0.01 −0.17 0.10 −0.11 0.25 −0.37
OH 0.12 −0.37 −0.92 0.25 0.46 −1.89
OMe 0.12 −0.27 −0.78 −0.2 0.27 −0.61 0.54 −1.68
F 0.34 0.06 −0.07 0.02 0.50 −0.45 0.74 −0.60
I 0.35 0.18 0.13 0.39 −0.16 0.65 −0.12
CHO 0.35 0.42 1.04 0.25
CO2H 0.37 0.45 0.42 0.44 0.66
Cl 0.37 0.23 0.11 0.46 −0.23 0.72 −0.24
COMe 0.38 0.50 0.87 0.28 0.16 0.50 0.90
Br 0.39 0.23 0.15 0.44 −0.19 0.72
CO2R 0.37 0.45 0.48 0.68 0.30 0.14 0.47 0.67
CF3 0.43 0.54 0.45 0.08 0.64 0.76
CN 0.56 0.66 0.66 0.90 0.56 0.13 0.90 0.71
NO2 0.71 0.78 0.79 1.24 0.65 0.15 1.00 1.00
*
These values are for para substituents only.
contains the original Hammett equation with a correction for the resonance effect of the
substituent for strongly interacting substituents. The parameter r is the contribution from
resonance to stabilization of the transition state. In practice, one determines the value of ρ
from the Hammett plot using the substituents for which σ+ = σ, and then one obtains the
value of r by plotting [(log k/k0)/ρ – σ] versus (σ+ – σ) for the substituents for which σ ≠ σ+.
The slope of this plot is r. The various σ values of a number of common substituents are gath-
ered in Table 8.7. (The values in Table 8.3 are taken from compilations in Reference 54.)
Worked Problem
8-2 In a competition experiment where exchange does not occur, one can construct
kinetic data for use in a Hammett plot. An example of this is provided by the
selective activation of the benzyl position of substituted toluenes under rhodium
catalysis (Organometallics 2010, 29, 624). Construct a Hammett plot from these
data using the σp values from Table 8.3; what can you deduce about the nature of
the transition state for the reaction from this plot?
Me Rh(tpp)
X Me X
150°C, N2 Rh(ttp)
54. (a) Ritchie, C.D.; Sager, W.F. Prog. Phys. Org. Chem. 1964, 2, 323. (b) Hansch, C.; Leo, A.; Unger, S.; Kim,
K.H.; Nikaitani, D.; Liem, E.J. J. Med. Chem. 1973, 16, 1207. (c) Swain, C.G.; Unger, S.H.; Rosenquist, N.R.;
Swain, M.S. J. Am. Chem. Soc. 1983, 105, 492. (d) Hine, J. Structural Effects on Equilibria in Organic Chemistry
(Wiley-Interscience: New York, 1975). (e) Ehrenson, S.; Brownlee, R.T.C.; Taft, R.W. Prog. Phys. Org. Chem.
1973, 10, 1.

The ratios obtained are as follows:

Substituent Me t-Bu F Cl CF3
σp –0.14 –0.15 0.06 0.23 0.54

log10 (k X/k H) 0.45 0.45 0.16 –0.19 –0.28
§ Answer below.
Solvent Effects
Reactions where charge is developed in the activated complex (e.g., the rate determin-
ing step of the SN1 and E1 reactions) are especially sensitive to the effects of solvent due
to the importance of solvation in stabilizing the incipient ions. The effects of solvent
were the subject of a systematic study by Grunwald and Winstein, 55 who proposed a
linear free energy relationship similar to the Hammett relationship for the effects
of solvent:
log (k/k0) = mY (Eq. 8.34)
In the Grunwald-Winstein equation, which is restricted to protic (hydroxylic) sol-

vents, k is the rate constant for the reaction in the solvent of interest, k0 is the rate constant
for the same reaction in the standard solvent, Y is the solvent ionizing power, and m is the
sensitivity of the substrate to solvent ionizing power. As with the Hammett equation, the
Grunwald-Winstein equation is a multiparameter reaction that must be based on a stan-
dard substrate and solvent. For this purpose, the standard reaction, for which m was as-
signed the value of 1, was the solvolysis of tert-butyl chloride, and the standard solvent,
assigned a Y value of 0, was 80% v/v ethanol-water. To obtain the Y values of other sol-
vents, the same solvolysis reaction was carried out in those other solvents, with the
Y values then being assigned on the basis of the simple equation:
kt2BuCl, solvent
Y 5 log (Eq. 8.35)
kt2BuCl, 80% EtOH
The original Grunwald-Winstein relationship is based on the assumption that the sol-
volysis of tert-butyl chloride proceeds by a limiting SN1 mechanism. This has several im-
portant implications for the mechanism. One, there is no nucleophilic assistance to the
displacement by solvent (i.e., there is effectively no covalent interaction between the sol-
vent and the developing carbocation center in the activated complex). Two, the rate-
determining step in the reaction is the formation of a solvated carbocation, not an oxonium
ion. Three, the nucleophile attacks a fully developed carbocation to form the substitution
product (i.e., Path 8.26 rather than Path 8.27).
55. (a) Grunwald, E.; Winstein, S. J. Am. Chem. Soc. 1948, 70, 846. (b) Winstein, S.; Grunwald, E.; Jones, H.W.
J. Am. Chem. Soc. 1951, 73, 2700. (c) Fainberg, A.H.; Winstein, S. J. Am. Chem. Soc. 1956, 78, 2770.

The Hammett plot has a slope of –1.14, but the plot omitting the CF3 substituent (which does not carry a lone
pair capable of delocalizing a positive charge and which does not hyperconjugate well with a cation center,) has
a slope of –1.57 and is a better straight line. These observations are both consistent with the development of a
substantial positive charge on the benzylic carbon that is resonance-stabilized by the lone pair on the substitu-
ent. The Hammett plot works equally well with Taft σ+ parameters,; in this case, the slope is –1.50, which leads
to the same conclusions as with the simple Hammett σp parameters.

Me ‡ Me
δ δ
Me Cl Me Cl (8.26)
Me Me Me
Me Cl
Me H Me ‡ H Me
δ δ
δ O Cl O Me Cl (8.27)
HS Me Me S Me
Like the Hammett equation before it, the Grunwald-Winstein equation has also been
the subject of considerable investigation, especially with respect to the covalent participa-
tion or nonparticipation of solvent. The reason for this is that many, if not most, SN1 sub-
stitution reactions do not follow the limiting mechanism but have some degree of
nucleophilic assistance from solvent. Not surprisingly, the relationship has undergone
refinement as our understanding of the role of solvent in organic reactions has grown.
Studies of rearrangements during solvolysis reactions of norbornyl halides led Schleyer
to the conclusion that many solvolysis reactions of tertiary halides involve, to some degree,
nucleophilic assistance from the solvent. As a result, Schleyer and his coworkers introduced
the YOTs scale, based on the solvolysis of 1-adamantyl tosylate (Example 8.28).56 The choice
of this substrate was predicated on two important considerations: (1) nucleophilic assis-
tance by solvent from the back side is prevented by the adamantane ring system57 and
(2) any alkene formed would be a bridgehead alkene in violation of Bredt’s rule,58 which
would suppress elimination during solvolysis. These workers then proposed a modified
equation, where the solvent ionizing power, YOTs, and the solvent nucleophilicity, N, are
treated separately59:
log(k/k0) = lNOTs + mYOTs (Eq. 8.36)
OTs In this equation, m is a measure of the susceptibility of the substrate to the ionizing
power of the solvent (YOTs) and l is a measure of the sensitivity of the substrate to solvent
nucleophilicity.
As pointed out above, the initial substrate for establishing the YOTs scale was 1-adamantyl
tosylate. Subsequently, it was found that, within experimental error, YOTs values obtained
(8.28)
from the solvolysis of 2-adamantyl tosylates (Example 8.29) were equal to the values ob-
S tained from the solvolysis of 1-adamantyl tosylates. This allowed the scale to be extended to
solvents for which YOTs was negative or zero. It had been argued that the axial hydrogens in
H
H the 1,3-positions relative to the leaving group would prevent the solvent from providing
nucleophilic assistance from the back side; the experimental results support this argument—
although the absolute rates for the solvolysis reactions were different, the YOTs values were
OTs the same, within experimental error.
(8.29) The value of the nucleophilicity parameter, N, was calculated by comparing the sol-
volysis of 1-adamantyl tosylate, which is assumed to be immune to nucleophilic participa-
tion by the solvent, with the solvolysis of methyl tosylate, which should be especially
susceptible to nucleophilic participation by solvent, in the same series of solvents. By set-
ting the value of l (the susceptibility of the substrate to solvent nucleophilicity) to unity for
56. (a) Fry, J.L.; Lancelot, C.J.; Lam, L.K.M.; Harris, J.M.; Bingham, R.C.; Raber, D.J.; Hall, R.E.; Schleyer,
P.v.R. J. Am. Chem. Soc. 1970, 92, 2538. (b) Raber, D.J.; Bingham, R.C.; Harris, J.M.; Fry, J.L.; Schleyer, P.v.R. J.
Am. Chem. Soc. 1970, 92, 5977.
57. Fort, R.C., Jr.; Schleyer, P.v.R. Adv. Alicyc. Chem. 1966, 1, 283.
58. (a) Bredt, J. Liebigs Ann. Chem. 1924, 437, 1. (b) Buchanan, G.L. Chem. Soc. Rev. 1974, 3, 41. (c) Szeimies,
G. In Abramovich, R.A., Ed. Reactive Intermediates (Plenum Press: New York, 1983), vol. 3, p. 299.
See also: (d) Maier, W.; Schleyer, P.v.R. J. Am. Chem. Soc. 1981, 103, 1891. (e) Harnisch, J.; Baumgärtel, O.;
Szeimies, G.; Van Meerssche, M.; Germain, G.; Declercq, J. J. Am. Chem. Soc. 1979, 101, 3370. (f) Engel, P.S.;
Keys, D.E.; Kitamura, A. J. Am. Chem. Soc. 1985, 107, 4964.
59. Schadt, F.L.; Bentley, T.W.; Schleyer, P.v.R. J. Am. Chem. Soc. 1976, 98, 7667.

the solvolysis of methyl tosylate, one can determine the Table 8.8 Solvent Ionizing Power and Nucleophilicity Parameters
solvent nucleophilicity parameter N.60 Solvent Y YOTs NOTs
 k F3CCO2H 1.84 4.57 −5.56
N 5 log   20.3Y (Eq. 8.37)
 k0  MeOTs H 2O 3.49 4.1 −0.44
It would be convenient if the range of solvent ionizing (F3C)2CHOH-H2O (97:3) 2.46 3.61 −4.27
power and solvent nucleophilicity could be expressed
F3CCH2OH 1.04 1.80 −3.00
using a single scale, but the effects of solvent are very sus-
ceptible to the identity of both the substrate and the leav- F3CCH2OH-H2O (85:15) 1.92 −2.01
ing group. Thus, there are a variety of Y scales that have F3CCH2OH-H2O (50:50) 2.14 −0.93
been set up for use with a variety of substrates and leaving
HCO2H 2.05 3.04 −2.35
groups. The YCl and YBr scales are based on solvolysis of
1-adamantyl chloride and 1-adamantyl bromide,61 and the MeCO2H −1.64 −0.61 −2.35
YI scale is based on 1-adamantyl iodide.62 For a more com- EtOH −2.03 −1.75 0.00
plete discussion of a number of scales of solvent ionizing
EtOH-H2O (80:20) 0.00 0.00 0.00
power, one should consult the review by Bentley.63 Values
of Y, YOTs and NOTs are collected in Table 8.8. EtOH-H2O (50:50) 1.66 1.29 −0.09
EtOH-H2O (20:80) 3.05 3.32 −0.34
The Salt Effect 64
MeOH −0.92 −0.04
When ionic salts are added to a reaction solvent, the ionic MeOH-H2O (80:20) 0.47 −0.05
strength and dielectric constant of the solution are raised, MeOH-H O (50:50) 2.00 −0.19
2
so that the solvent effectively becomes more polar as the
salt concentration increases. Provided that neither of the MeOH-H2O (20:80) 3.39 −0.35
ions present in the added salt duplicates an ion produced Me2CO-H2O (80:20) −0.94 −0.42
in the reaction (“common ions”), the addition of a salt to Me CO-H O (50:50)
2 2
1.40 1.26 −0.39
a reacting solution has the effect of accelerating reactions
where polar solvents are used. This is known as the salt Me2CO-H2O (20:80) 2.91 3.05 −0.38
effect, and it can provide useful information about the Dioxane-H2O (90:10) −2.03 −2.41 −0.51
possible mechanisms of a reaction. Depending on the re-
Dioxane-H2O (80:20) −1.30 −0.29
action and the solvent, the salt effect can vary directly
with the added salt concentration,65 the logarithm of the Dioxane-H2O (20:80) 2.88
added salt concentration, or the square root of the added
66
salt concentration.67
Salt effects in non-polar solvents can be especially dramatic. Thus, Winstein68 found
that the solvolysis of 4-methoxyneophyl p-toluenesulfonate in diethyl ether containing
dissolved lithium perchlorate was increased by a factor of 105 relative to the same reaction
60. (a) Schadt, F.L.; Bentley, T.W.; Schleyer, P.v.R. J. Am. Chem. Soc. 1976, 98, 7667. (b) Bentley, T.W.; Carter,
G.E. J. Org. Chem. 1983, 48, 579. (c) Bentley, T.W. Adv. Chem. Ser. (American Chemical Society: Washington,
D.C., 1987), No. 215, ch. 18.
The value, m=0.3, in this equation is contested: (d) Kevill, D.N.; Lin, G.M.L. J. Am. Chem. Soc. 1979, 101, 3916.
(e) Kevill, D.N. Adv. Chem. Ser. (American Chemical Society: Washington, D.C., 1987), No. 215, ch. 19. (f) Kevill,
D.N.; Anderson, S.W. J. Org. Chem. 1986, 51, 5029. (g) Kevill, D.N.; Rissman, T.J. J. Org. Chem. 1985, 50, 3062.
61. (a) Bentley, T.W.; Carter, G.E. J. Am. Chem. Soc. 1982, 104, 5741. (b) Bentley, T.W.; Bowen, C.T.; Parker, W.;
Watt, C.I.F. J. Am. Chem. Soc. 1979, 101, 2486.
62. Bentley, T.W.; Carter, G.E.; Roberts, K. J. Org. Chem. 1984, 49, 5183.
63. Bentley, T.W.; Llewellyn, G. Prog. Phys. Org. Chem. 1990, 17, 121.
64. Monograph: Loupy, A.; Tchoubar, B. Salt Effects in Organic and Organometallic Chemistry (VCH: Wein-
heim, 1992).
65. (a) Fainberg, A.H.; Winstein, S. J. Am. Chem. Soc. 1956, 78, 2763. (b) Fainberg, A.H.; Winstein, S. J. Am.
Chem. Soc. 1956, 78, 2780. (c) Perrin, C.L.; Pressing, J. J. Am. Chem. Soc. 1971, 93, 5705.
66. (a) Bateman, L.C.; Church, M.G.; Hughes, E.D.; Ingold, C.K.; Taher, N.A. J. Chem. Soc. 1940, 979.
(b) Winstein, S.; Friedrich, E.C.; Smith, S. J. Am. Chem. Soc. 1964, 86, 305.
67. Winstein, S.; Klinedinst, P.E., Jr.; Robinson, G.C. J. Am. Chem. Soc. 1961, 83, 885.
68. Winstein, S.; Smith, S.; Darwish, D. J. Am. Chem. Soc. 1959, 81, 5511.

in the absence of the added salt. In fact, the acceleration of the reaction in ether becomes
so great that above 0.036 M lithium perchlorate, ether becomes a better ionizing solvent
than acetic acid. In this system, the effects of added salt could be fit to a simple first-order
linear relationship:
k = k0 (1 + b[LiClO4]) (Eq. 8.38)
where k is the first-order rate constant in the presence of added lithium perchlorate, and
k0 is the same rate constant in the absence of lithium perchlorate. Pocker69 made similar
observations on the ionization of trityl chloride in lithium perchlorate/ether solution. In
fact, this solution has become a popular high ionic strength, nonaqueous solution for
carrying out a wide range of organic reactions.70 It is particularly interesting to note that
this solution actually promotes the ionization of allyl vinyl ethers.71
The Brønsted Catalysis Law

When the transfer of a proton from one reactant to another is an important part of the
reaction mechanism, the rate of the reaction will generally reflect the participation of
the acid. The timing of the proton transfer (before the rate-determining step or during
the rate-determining step) affects the terminology used to discuss the participation
of acid. As we discussed earlier, if the proton transfer does not occur during the rate-
determining step but during an earlier step, the reaction is said to be subject to specific
acid catalysis. Specific acid catalysis involves only the proton H+ as the acid, so one finds
that reactions carried out in different buffers at the same pH (and, therefore, the same
[H+]) proceed at the same rate, regardless of the identity of the acid in the buffer.
Reactions that are catalyzed by strong acid (solvated protons) with proton transfer
occurring before the rate-determining step are said to undergo specific acid catalysis.
When the reaction involves the transfer of a proton from one molecule to another (as
against a simple proton) during the rate-determining step, the reaction is subject to
general acid catalysis. In such reactions, the rate of the proton transfer will depend on the
identity of the acid, and will reflect the rates of proton transfer from an acid to the s ubstrate.
In these cases, each acid will appear as an individual term in the rate law:
kobs 5 k0 1 kH 1 [H] 1 k1[HA1 ] 1 k2[HA 2 ] 1 ... (Eq. 8.39)
Reactions subject to general acid catalysis often obey what is known as the Brønsted
catalysis law:72
k = CKaα or log k = α log Ka + log C = log C − pKa (Eq. 8.40)
The value of α, which according to the original theory, has a maximum value of 1 and a
minimum value of zero, is often interpreted as correlating with the sensitivity of the reaction
to the change in the acid catalyst, just as the Hammett ρ value correlates with the sensitivity
of the reaction to changes in the substituent.73 When the value of α is close to 1, this may be
taken as evidence of specific acid catalysis of the reaction by H+. When the value of α is close
to zero, this is frequently taken to mean that catalysis of the reaction is by solvent alone.
69. Pocker, Y.; Buchholz, R.F. J. Am. Chem. Soc. 1970, 92, 2075.
70. Reviews: (a) Grieco, P.A. Aldrichimica Acta 1991, 24, 59. (b) Balasubramanian, K.K. Acros Organics Acta
1999, 6, 12. (c) Gunanathan, C. Synlett 2002, 649.
71. (a) Grieco, P.A.; Clark, J.D.; Jagoe,, C.T. J. Am. Chem. Soc. 1991, 113, 5488. (b) Palani, N.; Chadha, A.;
Subramanian, K.K. J. Org. Chem. 1998, 63, 5318.
72. (a) Brönsted, J.N.; Pedersen, K.J. Z. physik. Chem. 1924, 108, 185. (b) Brönsted, J.N. Chem. Rev. 1928, 5, 231.
73. (a) Bender, M.L. Chem. Rev. 1960, 60, 53. (b) Lewis, E.S. J. Phys. Org. Chem. 1990, 3, 1.

Figure 8.13 Brønsted plot for

the acid-catalyzed hydrolysis
of phenyl diethyl
orthoformate at constant
ionic strength
Values of α intermediate between the two extremes are usually taken as evidence of general
acid catalysis of the reaction. The value of α has also come to be widely interpreted as con-
veying the extent of proton transfer in the transition state,74 although this interpretation is
not universally accepted, especially following the discovery of reactions for which α > 1.75
An excellent example of a reaction subject to general acid catalysis is the acid-catalyzed
hydrolysis of orthoesters (Example 8.30).76 In the hydrolysis of phenyl diethyl orthofor-
mate in 1:1 THF-water, the rate constants for hydrolysis in the presence of a wide range of
weak acids ranging from cyanoacetic acid (pKa 3.74) to cacodylic acid (dimethylarsonic
acid, pKa 7.50) obey the Brønsted rate law, with an α value of 0.47, as shown in Figure 8.13.
The α value of 0.47 is consistent with general acid catalysis of this reaction.
OEt THF–H2O + 2 EtOH
(8.30)
O OEt acid OH + HCO2H
The complement of general acid catalysis is general base catalysis. General base catal-
ysis follows a law completely analogous to that for general acid catalysis:
k = C/Kaβ or log k = β log (1/Ka) + log C = log C + pKa (Eq. 8.41)
It can be shown that for a given acid-conjugate base pair, α + β ought to be equal to 1,
but, as alluded to briefly above, there are now examples of reactions for which α > 1.
8.6 Isotope and Element Effects
If a bond that undergoes a change during the rate-determining step of a reaction is replaced
by either a bond to a heavier isotope of the same element, or a bond to a different element,
the rate of the reaction will almost always change, or the position of an equilibrium will
74. Leffler, J.E. Science 1953, 117, 340.

75. (a) Streitwieser, A., Jr.; Kaufman, M.J.; Bors, D.A.; Murdoch, J.R.; MacArthur, C.A.; Murphy, J.T.; Shen,
C.C. J. Am. Chem. Soc. 1985, 107, 6983. (b) Wiseman, F.; Keestner, N.R. J. Phys. Chem. 1984, 88, 4354. (c) Bord-
well, F.G.; Boyle, W.J., Jr.; Yee, K.C. J. Am. Chem. Soc. 1970, 92, 5926. (d) Pross, A. J. Org. Chem. 1984, 49, 1811.
(e) Jencks, W.P.; Brant, S.R.; Gandler, J.R.; Fendrisch, G.; Nakamura, C. J. Am. Chem. Soc. 1982, 104, 7045.
(f) Hupe, D.J.; Wu, D. J. Am. Chem. Soc. 1977, 99, 7653. (g) Hupe, D.J.; Pohl, E.R. J. Am. Chem. Soc. 1984, 106,
5634. (h) Agmon, N. J. Am. Chem. Soc. 1980, 102, 2164. (i) Murdoch, J.R. J. Am. Chem. Soc. 1972, 94, 4410.
76. Anderson, E.; Fife, T.H. J. Org. Chem. 1972, 37, 1993.

Table 8.9 Element Effect in almost always shift. This technique provides a corollary to the measurement of substituent
Substitution and Elimination and solvent effects by directly probing the bonding changes in the transition state. When
of Alkyl Halides the reacting bond is replaced by a bond to a heavier isotope, the ratio of rate or equilibrium
Halide Relative Rate constants is known as an isotope effect. When the reacting bond is replaced by a bond to a
different element (i.e., the leaving group is replaced by a different atom), the ratio of rate
Me3C–F 1
constants is known as the element effect.
Me3C–Cl ≈ 105 k RF
Me3C–Br ≈ 25–60 k RCl The Element Effect
Me3C–I ≈ 1.5–4.5 k RBr When the leaving group atom is changed, the strength of the bond being broken is also
changed. This means that the ∆G0 for the reaction will also change, making the reaction
either more less endothermic than the original reaction. Using arguments based on the
Hammond postulate, we would predict that, the weaker the bond to the leaving group, the
less endothermic the reaction, the lower its activation energy, and the faster its rate. Al-
though this argument is somewhat simplistic, it is still useful in allowing us to make some
statements about transition state structure: a large element effect implies that there is sub-
stantial rupture of the bond to the leaving group in the transition state. Conversely, a null
element effect (where the element substitution has no effect on the rate of the reaction)
strongly implies that the bond is not broken in the rate-determining step. The element
effect is well illustrated by the unimolecular nucleophilic substitution and elimination
reactions of alkyl halides; as the leaving group is changed from fluoride to chloride to
bromide to iodide, the rate constant for the reaction increases (Table 8.9).77
Isotope Effects
The situation with isotope effects is rather more subtle, but the same effect is observed
overall. In introductory courses in chemistry, the statement is often made that all isotopes
of a particular element are chemically identical and that they participate in the same reac-
tions to give the same products. As far as it goes, this statement is true, but it is a major
oversimplification. In fact, isotopic substitution does affect the chemistry and physics of a
compound in one very important way: it affects the energy content of the molecule at a
given temperature, and so affects both the position of equilibrium in reversible reactions
(an equilibrium isotope effect) and the rate constant of the reaction (a kinetic isotope
effect) in all reactions. Kinetic isotope effects, for example, are determined by measuring
the rates of the same reaction for two isotopic isomers, or isotopomers (molecules differ-
ing only in the isotopic constitution, but not in structure or stereochemistry).
The origins of the isotope effect lie in the vibrational energies of the molecules and
transition states involved. Applying the Schrödinger equation to a simple harmonic oscil-
lator (the simplest model of a vibrating bond, like a vibrating spring that obeys a Hooke’s
Law relationship), we find that the energy of the system is described by:
Ev = hv0(v + ½) (Eq. 8.42)
where v is the quantum number specifying the vibrational energy level of the molecule.
This shows that even at the lowest vibrational energy level, the vibrational energy of the
molecule is 1/2 hv 0, which is known as the zero point energy of the molecule, and is vibra-
tional energy that the molecule possesses even at 0 K.
77. (a) Hughes, E.D.; Shapiro, U.G. J. Chem. Soc. 1937, 1177. (b) Cooper, K.A.; Hughes, E.D. J. Chem. Soc. 1937,
1183. (c) Cooper, K.A.; Hughes, E.D.; Ingold, C.K. J. Chem. Soc. 1937, 1280. (d) Hughes, E.D.; MacNulty, B.J. J.
Chem. Soc. 1937, 1283. (e) Church, M.G.; Hughes, E.D.; Ingold, C.K. J. Chem. Soc. 1940, 966. (f) Shorter, J.;
Hinshelwood, C.N. J. Chem. Soc. 1949, 2412. (g) Brown, H.C.; Fletcher, R.S. J. Am. Chem. Soc. 1949, 71, 1849.
(h) Brown, H.C.; Stern, A. J. Am. Chem. Soc. 1950, 72, 5068.

One can calculate the vibrational frequency of the zero level vibration from the
relationships:
1 k 1 1 1
v0 5 and = + (Eq. 8.43)
2π µ m m1
m 2
where k is the vibrational force constant for the bond, μ is the reduced mass of the mole-
cule, and m1 and m2 are the masses of the atoms at the ends of the bond. This shows that
the frequency of vibration, and therefore the zero-point energy of the molecule, is sensi-
tive to isotopic substitution.
The same situation applies to vibrations of the activated complex, with the exception
that the separation between vibrational energy levels is usually much smaller. This means
that the activation energy for the reactions of the two isotopomers will be different if the
bond to the labeled atom is broken (endothermic—high activation energy) or formed
(exothermic—low activation energy) in the rate-limiting step (Figure 8.14).
The situation in polyatomic molecules is basically the same as in a simple diatomic
molecule, with these exceptions. The vibrations of bonds more than about three bonds
removed from the labeled atom are not affected and those not directly involving the
labeled atom are often only marginally affected. Thus, we may focus only on the labeled
bond without introducing major errors into the discussion.78 For those who are interested
in a more mathematical discussion of the theoretical basis of the kinetic isotope effect,
several reviews and monographs are available.79
Kinetic isotope effects are categorized as primary isotope effects when the bond to the
labeled atom is broken or formed and secondary isotope effects when the bond to the la-
beled atom remains intact. Typically, primary isotope effects are predominantly due to the
loss of the zero point energy of the stretching vibration of the bond being broken, and
secondary isotope effects arise from the changes in the frequency of bending vibrations
Figure 8.14 The potential

ACTIVATED COMPLEX energy diagram for two
isotopomers of a diatomic
molecule in the ground state
and the transition state of a
reaction involving rupture
Ea < *Ea of the labeled bond
Ea
Energy
*Ea
REACTANT
low mass
isotopomer
high mass
isotopomer
Interatomic distance
78. Sims, L.B.; Lewis, D.E. In Buncel, E.; Lee, C.C., Eds. Isotopes in Organic Chemistry (Elsevier: Amsterdam,
1984); Vol. 6; p. 161.
79. (a) Kresge, A.J. J. Am. Chem. Soc. 1980, 102, 7797. (b) Wiberg, K.B. Chem. Rev. 1955, 55, 713. (c) Westheimer,
F.H. Chem. Rev. 1961, 61, 265. (d) Collins, C.J.; Bowman, N.S., Eds. Isotope Effects in Chemical Reactions (Van
Nostrand Reinhold: New York, 1970). (e) Melander, L. Isotope Effects on Reaction Rates (Ronald Press: New
York, 1960). (f) Melander, L.; Saunders, W.H., Jr. Reaction Rates of Isotopic Molecules (John Wiley: New York,
1980). (g) Willi, A.V. Isotopeneffekte bei chemischen Reaktionen (Thieme Verlag: Stuttgart, 1983).

involving the labeled atom. Unless they are specified otherwise, most isotope effects are
assumed to be primary isotope effects.
In a reaction where the bond to the labeled atom is completely broken, the difference
in activation energies may be expected to be at a maximum. We can calculate the maxi-
mum expected value of the isotope effect in such a reaction by calculating the difference
in zero point energy for the two isotopomers from the Planck relationship (E = hv 0/2) and
the Arrhenius relationship for the rate constant:
k 5 Ae2Ea / RT , which gives k / k * 5 e ∆Ea / RT 5 e hc( ∆ν )/ 2 k T (Eq. 8.44)
where c is the velocity of light that converts the frequency in cm−1 to frequency in s−1 and k
is the Boltzmann constant (which is the value of the gas constant in Joules per molecule).
Using these relationships, we can obtain approximations to the maximum value of the
isotope effect for a series of isotopic substitutions. As can be seen from the data in
Table 8.10, the most dramatic changes in rate are greatest for substitutions with hydrogen
isotopes, but measurable differences can be observed for many other atoms (“heavy-atom
isotope effects”).80
When the reaction proceeds by simple cleavage of the bond to the labeled atom, the
value of the isotope effect is expected to be near the maximum value. However, atom
transfer reactions (reactions where the rupture of one bond is compensated by formation
of a new bond to the transferring atom) are much more common in organic chemistry.
Examples of such reactions are SN2 substitution (the transferring atom is carbon), E2 and
E1cb elimination (the transferring atom is the β hydrogen), deprotonation α to a carbonyl
group (the transferring atom is the α hydrogen), and nucleophilic addition to carbonyl
groups (the transferring atom is the carbonyl carbon).81
In 1961, Westheimer predicted that the isotope effect of a reaction where the labeled
atom is transferred from one atom to another should pass through a maximum value as
the structure of the transition state changes from reactant-like to product-like (now
known as the Westheimer maximum).82 The maximum value occurs when the force con-
stants of the two partial bonds to the atom being transferred are equal, because the fre-
quency of the symmetrical stretching vibration involving the labeled atom becomes
independent of the mass of the labeled atom (v = v*) at this point.
We can see this from a less mathematical viewpoint in Figure 8.15. The three reac-
tion coordinate diagrams represent an endothermic reaction, where the transition state
occurs late along the reaction coordinate and strongly resembles the product; a thermo-
neutral reaction, where the transition state is “central” on the reaction coordinate and
resembles neither the reactant nor the product strongly; and an exothermic reaction,
where the transition state occurs early along the reaction coordinate and strongly re-
sembles the reactant.
80. The value of a kinetic isotope effect can be calculated from vibration frequencies of the reactant and
transition state alone:
‡ 3 N 27 
( ) 
‡
 1 2 exp(2u ) 
2ui* 3 N 26 
k ν  ν  1 ‡  1 2 exp ν 1
5 L ∏  ν * exp 2 2 (ui 2 ui* )  ∏  ν * exp  2 (ui 2 ui* ) 1 2 exp 2u*i

k *  ν *L  i 

1 2 exp(2ui )
‡

 i  ( )
i 

where u = hv/kT and the asterisk refers to the heavy isotope. Vibration frequencies labeled with the cross of
Lorraine (‡) refer to the transition state, and the others refer to the reactants. The quantity (v L)‡ is the reac-
tion coordinate frequency, and corresponds to the mixed translation-vibration through the transition state.
See (a) Bigeleisen, J. J. Chem. Phys. 1949, 17, 675. (b) Bigeleisen, J.; Goeppert-Mayer, M. J. Chem. Phys. 1947,
15, 261. (c) Wolfsberg, M.; Stern, M.J. Pure Appl. Chem. 1964, 8 325. (d) Bell, R.P. The Proton in Chemistry, 2nd
ed.; (Cornell University Press: Ithaca, 1979), ch. 11. (e) Sims, L.B.; Lewis, D.E. In Buncel, E.; Lee, C.C., Eds.
Isotopes in Organic Chemistry (Elsevier:Amsterdam, 1984), vol. 6, ch. 4.
81. Streitwieser, A., Jr.; Jagow, R.H.; Fahey, R.C.; Suzuki, S. J. Am. Chem. Soc. 1958, 80, 2326.
82. Westheimer, F.H. Chem. Rev. 1961, 61, 265.

Table 8.10 Maximum Theoretical Values of Primary Kinetic Isotope Effects

Isotope
change µ light / µ heavy Limiting ratio v light (cm−1) v heavy (cm−1) Maximum k/k*
H→D ≈ 3000 ≈ 2120 8.3‡

(m2 1 2) 1
(0.7071)
2 (m2 1 1) 2
12
C→14C ≈ 1400 ≈ 1300 1.3
12 (m2 1 14 ) 12
(0.9258)
14 (m2 1 12 ) 14
14
N→15N ≈ 1350 ≈ 1300 1.12
14 (m2 1 15 ) 14
(0.9661)
15 (m2 1 14 ) 15
16
O→18O ≈ 1250 ≈ 1180 1.19
16 (m2 1 18 ) 16
(0.9428)
18 (m2 1 16 ) 18
32
S→34S ≈ 1000 ≈ 970 1.08
32 (m2 1 34 ) 32
(0.9701)
34 (m2 1 32 ) 34
35
Cl→37Cl ≈ 700 ≈ 680 1.05
35 (m2 1 37 ) 35
(0.9726)
37 (m2 1 35 ) 37
‡
The maximum limiting ratio observed experimentally for H/D isotopomers actually close to 1.35, which
leads to a maximum value of k/k* nearer to 5.5 (see Reference 81).
‡ ‡ ‡
Energy
Energy
Energy
P R
(a) (b) (c)

R P
R P
Reaction Coordinate Reaction Coordinate Reaction Coordinate
Figure 8.15 Reaction coordinate diagrams for (a) endothermic reactions, (b) thermoneutral
reactions, and (c) exothermic reactions
In the endothermic reaction, the transition state occurs late and strongly resembles the
product. The zero point energy of the bond to the transferring atom in this transition state
will be close to the zero point energy of the completely formed bond in the product. In the
exothermic reaction, the transition state is early and strongly resembles the reactant. The
zero point energy of the bond to the transferring atom in this transition state will be close
to the zero point energy of the unbroken bond in the reactant. In the thermoneutral reac-
tion, there is substantial loss of bonding compared to both the reactant state and the prod-
uct state, so the loss of zero point energy is at a maximum, leading to a maximum kinetic
isotope effect.

Secondary Isotope Effects

Secondary isotope effects are isotope effects that are measured at a position where the
bond to the isotopically labeled atom is neither broken nor formed. Except for isotopes of
hydrogen, secondary isotope effects are usually negligible in magnitude. However, sub-
stitution by deuterium at a position where there is bonding change at carbon can give
useful information about the hybridization of the carbon atom in the transition state.
Secondary isotope effects reflect changes in the frequencies of bending vibrations, rather
than stretching vibrations, as happens with primary isotope effects. Any change that
tightens the bonding around the atom bonded to the labeled hydrogen (e.g., going from
an sp2 to an sp3 hybridized state at carbon) usually leads to increases in the frequency of
bending vibrations involving the labeled atom and hence to an inverse secondary isotope
effect (hk/Dk < 1). These kinds of isotope effects are seen, for example, in the isomerization
of maleic acid to fumaric acid catalyzed by thiocyanate anion (Example 8.31), for which
k/ k = 0.86 at 25°C.83 Similar effects are seen in SN2 reaction, where the trigonal bipyra-
H D
midal transition state is much more crowded than the sp3-hybridized starting compound;
the SN2 reaction of methyl bromobenzenesulfonate with methoxide ion to give dimethyl
ether has a secondary deuterium isotope effect of 0.96.84 The reverse situation also holds
true: when the bonding change loosens the bonding to the labeled hydrogen, the frequen-
cies of the bending vibrations decrease, and the isotope effect is normal. The heterolysis
of the carbon-oxygen bond of the 4,4'-dimethoxybenzhydryloxonium ion ( Example 8.32) has
a secondary isotope effect of 1.15.85
‡
(D)H H(D) (D)H H(D) (D)H CO2H
SCN δ− δ− (8.31)
SCN
HO2C CO2H HO2C CO2H HO2C H(D)
H2O H(D) H(D)
(8.32)
MeO OMe MeO OMe
Using Element and Isotope Effects to Postulate Mechanism

and Transition State Structures
Element and isotope effects provide clear evidence of specific bond cleavages in the rate
determining steps of a reaction. A good example of the application of both element effects
and kinetic isotope effects to a mechanistic problem is provided by the base-promoted
dehydro-halogenation of 2,2-diaryl-1,1,1-trihaloethanes.86 For this reaction, there are data
available (Table 5.7) for both the element effect (kBr/kCl) and the deuterium isotope effect
(Hk/Dk). In addition, the reaction is subject to general base catalysis, with Brønsted
β values for the chloride of 0.61 for alkoxide ion bases, and 0.54 when the phenoxide bases
are included, and 0.57 and 0.50 for the corresponding bromide.
In this reaction, the values of the deuterium isotope effect and the element effect are
both substantial with all bases, indicating that the cleavage of both the C—H and the
C—X bonds is important in the transition state. Several mechanisms might be consistent
with these observations: the E2 mechanism, where both bonds are broken in a single step,
83. Seltzer, S. J. Am. Chem. Soc. 1961, 83, 1861.

84. Johnson, R.R.; Lewis, E.S. Proc. Chem. Soc. 1958, 52.
85. Stewart, R.; Gatzke, A.L.; Mocek, M.; Yates, K. Chem. Ind. (London) 1959, 331.
86. Fontana, G.; Frenna, V.; Gruttadauria, M.; Natoli, M.C.; Noto, R. J. Phys. Org. Chem. 1998, 11, 54.

Table 8.11 Base-Promoted Elimination of Diaryltrihaloethanes

CCl3 CBr3
MeO OMe MeO OMe
Base MeO OMe MeO OMe
MeO–/MeOH H
k/Dk 4.91 k Br/kCl 26.1
EtO–/EtOH H
k/Dk 5.66 k Br/kCl 27.5
Me3CO /Me3COH
– H
k/ k 3.53
D
k Br/kCl 22.0
PhO –/EtOH H
k/Dk 4.55 k Br/kCl 40.4
4-O2NC6H4O–/EtOH H
k/Dk 3.5 k Br/kCl 52.2
and the E1cb mechanisms, where the two bonds are broken sequentially. Based on the data
in Table 8.11, the most likely candidate for this reaction is the E2 mechanism, because the
deuterium isotope effect and the concomitant element effect give effective proof that there
is simultaneous C—H and C—X bond cleavage in the transition state for the reaction.
This process has been applied especially widely to enzymatic reactions, as evidenced
by recent reviews of aspects of the subject.87 In a typical procedure, the transition state
structure is first deduced by bond order–vibrational analysis methods88 and then followed
by completing the model with more modern computational methods. The procedure ad-
vocated by Schramm89 is a modern extension of the successive labeling-theoretical ap-
proaches advocated earlier.90 Schramm’s synopsis of the method is instructive.
Element and isotope effects provide clear evidence of specific bond cleavages in the
rate determining steps of a reaction. A good example of the application of both element
effects and kinetic isotope effects to a mechanistic problem is provided by the base-
promoted dehydrohalogenation of 2,2-diaryl-1,1,1-trihaloethanes.91 For this reaction, there
are data available (Table 8.11) for both the element effect (kBr/kCl) and the deuterium iso-
tope effect (Hk/Dk). In addition, the reaction is subject to general base catalysis. Brønsted β
values for the chloride are 0.61 for alkoxide ion bases and 0.54 when the phenoxide bases
are included and 0.57 and 0.50 for the corresponding bromide.
1. Synthesize compounds labeled at locations where the possibility of bonding change is

to be probed (successive labeling92).
2. Measure the kinetic isotope effects at these positions to a reasonably high degree
(≈ 0.5%) of precision.
3. Compute a truncated (“cutoff”) transition state model, complete with bond lengths
and bond angles, using bond order–vibrational analysis methods.
87. (a) Schramm, V.L. Acc. Chem. Res. 2006, 36, 588. (b) Berti, P.J.; McCann, J.A.B. Chem. Rev. 2006,
106, 506.
88. (a) Sims, L.B.; Lewis, D.E. In Buncel, E.; Lee, C.C., Eds. Isotopes in Organic Chemistry (Elsevier: New
York, 1984), vol. 6, p. 161. (b) Berti, P.J.; Schramm, V.L. In Truhlar, D.G.; Morokuma, K., Eds. Transition state
modeling for catalysis (Amercan Chemical Society: Washington, D.C., 1999), p. 473. (c) Sims, L.B.; Burton,
G.W.; Lewis, D.E. BEBOVIB-IV, QCPE No. 337 (Quantum Chemistry Program Exchange, Department of
Chemistry, Indiana University, Bloomington, IN, 1977). (d) Huskey, W.P. J. Am. Chem. Soc. 1996, 118, 1663.
(e) Casamassina, T.E.; Huskey, W.P. J. Am. Chem. Soc. 1993, 115, 14.
89. Schramm, V.L. Ann. Rev. Biochem. 1998, 67, 693.
90. Sims, L.B.; Lewis, D.E.; Netherton, L.T. In Duncan, W.P.; Susan, A.B., Eds. Synthesis and Applications of
Isotopically Labeled Compounds (Elsevier: Amsterdam, 1982), p. 261.
91. Fontana, G.; Frenna, V.; Gruttadauria, M.; Natoli, M.C.; Noto, R. J. Phys. Org. Chem. 1998, 11, 54.
92. Fry, A. Pure Appl. Chem. 1964, 8, 409.

4. Transfer these parameters as fixed values to a semiempirical calculation for optimiz-

ing the complete transition state model.
5. Compute the wave function to determine the electron distribution at the van der
Waals surface.
Problems
8-11 The Hammett ρ constants for elimination reactions from a series of substituted
2-phenylethyl derivatives is given below.
X
base
Y Y
X = I, ρ = 2.07; X = Br, ρ = 2.14; X = OTs, ρ = 2.27; X = Cl, ρ = 2.61;

X = +SMe2, ρ = 2.75; X = F, ρ = 3.12; X = +NMe3, ρ = 3.77
What conclusions do you draw about the mechanisms of these reactions from
these data? What experiments would you carry out to test these conclusions?
8-12 The Hammett ρ value for the acid catalyzed hydrolysis of substituted benzamides
in water at 100°C is +0.118, and the ρ constant for the corresponding alkaline
hydrolysis in water at 100°C is +1.055. Rationalize the difference in these two
values in terms of what the ρ value tells us about the electron density at the
carbonyl carbon during the rate-limiting step of the reaction.
8-13 The Grunwald-Winstein m value for the solvolysis of 1-adamantyl bromide in
40% aqueous ethanol is 1.20. The activation parameters for the same reaction are
∆H‡ = +21.0 kcal mol−1, and ∆S‡ = –6.2 eu. Which mechanism (SN1 or SN2) do
these data best support for this solvolysis? Based on this conclusion, explain the
activation parameters for the reaction.
8-14 Consider the E1cb mechanisms in Problem 8-5. Which of these reactions will ex-
hibit general base catalysis, and which will exhibit specific base catalysis? Why?
8-15 Predict the probable magnitudes of the primary deuterium isotope effects (large,
medium, small, or null) and element effects (large, small, or null) for the six
mechanisms of elimination in Problem 8-1. Assume that the substrate is an ethyl
halide.
8-16 The rate constants for the unimolecular Cope elimination of a series of substi-
tuted 2-phenylethyldimethylamine N-oxides in 90% dimethyl sulfoxide-10%
water at 65°C are given as follows:
O
NMe2
∆
X X
X = OMe, k = 0.67 ± 0.05 × 10−5; X = Me, k = 1.4 ± 0.2 × 10−5;

X = H, k = 3.1 ± 0.7 × 10−5; X = Cl, k = 8.2 ± 1.2 × 10−5;
X = NO2, k = “too fast for convenient measurement”
Construct a Hammett plot from these data and deduce the likely arrangement of
partial charges in the transition state.

8.7 Trapping and Crossover Experiments
Detecting and characterizing reactive intermediates is an important part of elucidating a

reaction mechanism. Trapping experiments, or competition experiments, often provide
the most direct information about a reactive intermediate involved in a reaction; they in-
volve carrying out the reaction in the presence of a second molecule capable of reacting
with the intermediate and diverting it from the normal pathway.93 The structure of the
reactive intermediate is then deduced from the structure of the product.
One of the oldest examples of this type of trapping reaction is provided by the ad-
dition of bromine to alkenes.94 In this reaction, which is now agreed to proceed through
a three-membered bromonium ion,95 the existence of the ion was deduced from two
important facts: the addition to simple alkenes was anti, and when the reaction was
carried out in the presence of added nucleophiles, mixed products were obtained. In-
terpretation of the ratio of products from added nucleophiles has led to the conclusion
that the bromonium ion from 2-butene has a lifetime on the order of 10–10 seconds in
methanol.96
This same type of intermediate also demonstrates the utility of steric hindrance in
stabilizing reactive species by preventing subsequent reactions well enough to allow its
isolation and characterization. An excellent example of this is provided by the case of the
bromonium ion. Although most are very short-lived, that from adamantylidene-
adamantane has been crystallized as the tribromide salt (Example 8.33) and had its struc-
ture determined by single crystal X-ray structure analysis.97
Br2 (8.33)
Br
Br Br Br
In similar fashion, strong evidence for the existence of o-benzyne was obtained by
carrying out the reaction believed to form benzyne in the presence of reactive dieno-
philes such as furan (Example 8.34),98 tetraphenylcyclopentadienone (Example 8.35),99
or anthracene (Example 8.36).100 All of these reactions provided crystalline products
whose structures were consistent with their formation by a Diels-Alder reaction with
benzyne. Benzyne is, in fact reactive enough to give similar products with benzene101 and
naphthalene.102
93. For a discussion of competition methods, see: Huisgen, R. Angew. Chem. Int. Ed. Engl. 1970, 9, 751.
94. (a) Francis, A.W. J. Am. Chem. Soc. 1925, 47, 2340. (b) Biilmann, E. Rec. trav. chim. 1917, 36, 313.
(c) Gomberg, M. J. Am. Chem. Soc. 1919, 41, 1414. (d) Read, J.; Williams, M.M. J. Chem. Soc. 1920, 117, 359.
(e) Read, J.; Hook, R.G. J. Chem. Soc. 1920, 117, 1214. (f) Read, J.; Andrews, A.C.P. J. Chem. Soc. 1921, 1774.
(g) Read, J.; Hurst, E. J. Chem. Soc. 1922, 989. (h) Read, J.; Hurst, E. J. Chem. Soc. 1922, 2550. (i) Read, J.; Reid,
W.G. J. Chem. Soc. 1928, 745. (j) Conant, J.B.; Jackson, E.L. J. Am. Chem. Soc. 1924, 46, 1727. (k) Jackson, E.L. J.
Am. Chem. Soc. 1926, 48, 3166. (l) Meinel, K. Ann. Chem. 1934, 510, 129. (m) Bartlett, P.D.; Tarbell, D.S. J. Am.
Chem. Soc. 1936, 58, 466. (m) Backer, H.J.; Strating, J. Rec. trav. chim. 1934, 53, 525. (n) Bockemüller, W.; Hoff-
mann, F.W. Ann. Chem. 1935, 519, 165.
95. Roberts, I.; Kimball, G.E. J. Am. Chem. Soc. 1937, 59, 947.
96. Nagorski, R.W.; Brown, R.S. J. Am. Chem. Soc. 1992, 114, 7773.
97. Slebocka-Tilk, H.; Ball, R.G.; Brown, R.S. J. Am. Chem. Soc. 1985, 107, 4504.
98. Wittig, G.; Pohmer, L. Angew. Chem. 1955, 67, 348.
99. Fieser, L.F.; Haddadin, M. J. Org. Syn. 1966, 46, 107.
100. Friedman, L.F.; Logullo, F.M. J. Org. Chem. 1969, 34, 3089.
101. Brewer, J.P.N.; Heaney, H. Tetrahedron Lett. 1965, 4709.
102. Miller, R.G.; Stiles, M. J. Am. Chem. Soc. 1963, 85, 1798.

O
O (8.34)
Ph Ph
Ph Ph Ph
O Ph
(8.35)
Ph
Ph
(8.36)
Free radicals have been trapped by the use of nitroso compounds (e.g., Example 8.37)
or nitrones (e.g., Example 8.38) to give very stable nitroxide free radicals that can be de-
tected by electron paramagnetic resonance spectroscopy. This process, known as spin
trapping, gives a product free radical from whose spectrum the structure of the original
free radical can often be deduced.
O O O
N N N (8.37)
Ra R Ra R Ra R
R R R R R R
Ra N Ra N Ra N (8.38)
R O R O R O
Crossover experiments provide a method to distinguish between intramolecular and

intermolecular mechanisms for a reaction. This type of experiment is performed by
carrying out the reaction with a mixture of two slightly different reactants and then ana-
lyzing the product mixture. If the reaction proceeds by an intramolecular (nondissocia-
tive) mechanism, no possibility exists for the exchange of groups between reactants.
Therefore, only two products will be formed, and each will be clearly derived from only
one of the two reactants. If the reaction involves the formation of reactive intermediates,
such as cations, anions, or radicals (i.e., it proceeds through a dissociative mechanism),
the possibility exists for the intermediate from one of the starting compounds to react
with the complementary intermediate from the other. Thus, the reaction allows for the
possibility of four different products, two of which are crossover products, where there has
been an exchange of groups between reactants, to be formed. Crossover experiments have
been especially useful in the study of rearrangement reactions. A typical example of a re-
action studied by using crossover experiments is the Claisen rearrangement of allyl phenyl
ethers (Examples 8.39 and 8.40). These studies show that the cross-over products, Exam-
ples 8.43 and 8.44, are not produced, suggesting that the mechanism for this reaction is
not dissociative.103
103. Tarbell, D.S. Org. React. 1944, 2, 1.

C D
A B C D A B *A *B
C D'
A' B' C' D' A' B' *A' *B' C' D
C' D'
(8.41) (8.43)
O OH OH
(8.39)
O OH OH
(8.40)
(8.42) (8.44)
non-dissociative dissociative
products products
One must bear in mind a caveat when interpreting the results of crossover experiments.
If crossover products are observed, it is unambiguous that they must be formed in some
type of dissociative process. However, this does not mean that all the products are formed
in a dissociative reaction. The non-crossover products may be formed in either a dissocia-
tive reaction or in a competing nondissociative reaction. The problem is more subtle in
cases where crossover products are not observed, because this does not necessarily rule out
the dissociative pathway. It is possible that the products of the initial dissociation are reac-
tive enough that they recombine to give the product before they can diffuse away from each
other. In this case, what are called cage effects operate: the two reactive intermediates are
held in the same solvent cage long enough to react completely with each other.
Problems
8-17 Draw the structures of the expected products when benzyne is trapped by (a)
benzene; (b) naphthalene; (c) 1,3-cyclohexadiene.
8-18 In reactions that proceed by multistep mechanisms, it is sometimes possible to pre-
pare one of the key reactive intermediates by an alternative route. This was done by
Porter and Zuraw (J. Chem. Soc., Chem. Commun. 1985, 1472) in their study of the
rearrangement of allylic hydroperoxides. Using this paper as a guide, discuss what
information this kind of experiment might provide. Are there any limitations?
8.8 The Variable Transition State and the Concept

of the Mechanistic Spectrum
The idea of the variable transition state is not new. It forms the basis, for example, for the
Hammond postulate,104 where the effects of structural changes in the reactants and

roducts are related to the structure and energy of the transition state. In such discus-
p
sions, we speak of “early” and “late” transition states.
We have already defined the terms concerted and stepwise, but on occasion we will
need to make even finer distinctions about the relative timing of bonding changes in a
reaction—the extent of bond making and bond breaking in the transition state. Of course,
by definition all the bond-making and bond-breaking processes in a concerted reaction
must all occur during the same step, but this does not necessarily imply that they occur at
the same rate.105 The structure of the activated complex may reveal that bond breaking is
well in advance of or lags behind bond making, in which case the reaction may be termed
non-synchronous, or that the two processes do, in fact, occur at the same rate, in which
case the reaction may be termed synchronous.106 Differences in the relative extent of bond
making and bond breaking in the transition state leads to the concept of a mechanistic
spectrum for a reaction—illustrating the effect of substituents on transition state struc-
ture. Isotope effects represent a particularly powerful method for the elucidation of tran-
sition state structure when they are measured for a series of different isotopomers of the
reactant, the process known as successive labeling.107
Quantitative or semiquantitative discussions about transition state structure are facilitated
through the use of transition state maps, also known as More O’Ferrall-Jencks diagrams.108
These are simplified representations of the potential energy surfaces, with the bonding changes
defined in terms of the bond orders of the participating bonds. These diagrams allow one to
make predictions about the effects of substitutions on the transition state for the reaction and
to show the dynamics of the activated complex as it passes through the transition state. A typ-
ical example of the More O’Ferrall-Jencks diagram is shown as Figure 8.16.
Figure 8.16 More O’Ferrall-

H
Jencks diagram for
β-elimination reactions
0 E1-like E2
A
•
C—X bond order
B•
C
2
•
1 D
•F •
E
•
3
1
E1cb-like E2
X X
1 0
H C—H bond order
105. This question and the question of synchronicity in bond formation and rpture has been reviewed: Adv.
Phys. Org. Chem. 1992, 29.
106. Reviews: (a) Bernasconi, C.F. Adv. Phys. Org. Chem. 1992, 27, 119. (b) Bernasconi, C.F. Adv. Phys. Org.
Chem. 2010, 44, 223.
107. Fry, A. Pure Appl. Chem. 1964, 8, 409.
108. (a) More O’Ferrall, R.A. J. Chem. Soc. B 1970, 274. (b) Jencks, D.A.; Jencks, W.P. J. Am. Chem. Soc. 1977,
99, 7848.

In this figure, the mechanistic spectrum for β-elimination reactions is represented.

The axes of the diagram represent the bond orders of the two bonds being broken. Ver-
tical movement from the starting compound along the axis corresponds to C—X bond
rupture to give the carbocation intermediate characteristic of the E1 mechanism of
elimination. Horizontal movement eventually leads to C—H bond rupture to give the
carbanion intermediate characteristic of the E1cb reaction. These stepwise mechanisms
therefore follow a path around the edges of the diagram. All other activated points
within the diagram have some degree of both C—H and C—X bond rupture, and corre-
spond to activated complexes for the concerted reactions. It is evident that there are
many possible options for concerted transition states, as illustrated by points A–E on the
diagram. Positions A and B locate transition states where C—X bond rupture is in ad-
vance of C—H bond rupture: they are transition states for E2 reactions with different
degrees of E1 character. Conversely, positions D and E locate transition states where
C—H bond rupture is in advance of C—X bond rupture: they are transition states for E2
reactions with different degrees of E1cb character. The points C and F locate transition
states where C—H and C—X bond rupture have occurred to the same extent (“central”
transition states).
The lines in the diagram show possible reaction pathways for a variety of concerted
reactions. These allow us to discuss the other important feature of the activated com-
plex: its dynamics as it passes through the transition state. This is best illustrated by the
activated complex F, where there are three different possible reaction coordinate path-
ways shown. In pathway 1, all points between the reactant and activated complex are
characterized by having the same amount of C—H and C—X bond rupture, with no
charge development at either carbon, and the reaction coordinate motion is a combina-
tion of equal contributions from C—H and C—X bond rupture. In pathway 2, the reac-
tion coordinate motion is dominated by C—X bond rupture, with little contribution
from C—H bond rupture. In pathway 3, on the other hand, the reaction coordinate
motion is dominated by C—H bond rupture, with little contribution from C—X bond
rupture. The details of the reaction coordinate motion are best answered by a combined
successive labeling-t heoretical approach.109 One example of a reaction for which such
an approach has been very successful is the E2 elimination of trimethylamine from
2-phenylethyltrimethtlammonium cation. The available isotope effect data for this re-
action are gathered in Table 8.12.110
The data reveal some important features of the transition state for this reaction imme-
diately. One, there are substantial deuterium and 14C isotope effect at the β carbon, which
indicates that there is partial cleavage of this bond in the transition state for the reaction.
Two, there are small 15N and α-14C isotope effects, indicating cleavage of the carbon-
nitrogen bond in the transition state. Three, there is an almost null secondary deuterium
isotope effect and an almost constant 14C isotope effect at the α carbon, which is consistent
with a situation where σ bonding loss to nitrogen is largely compensated for by π-bond
formation to the β-carbon (i.e., there is little charge development at this site).
When we take all these observations together, we find that the best transition state
model for the data is an E2 transition state but that carbon-hydrogen bond rupture is in
advance of carbon-nitrogen bond rupture: the reaction is an E1cb-like E2 reaction. Theo-
retical calculations reveal an E1cb-like E2 transition state with a partial charge of approx-
imately 0.2 e– developed at the β carbon.111
109. Sims, L.B.; Lewis, D.E.; Netherton, L.T. In Duncan, W.P.; Susan, A.B., Eds. Synthesis and Applications of
Isotopically Labeled Compounds (Elsevier: Amsterdam, 1982), p. 261.
110. Data in the table are taken from: (a) Smith, P.J.; Bourns, A.N. Can. J. Chem. 1974, 52, 749. (b) Bourns, A.N.;
Smith, P.J. Proc. Chem. Soc. 1964, 366. (c) Eubanks, J.R.I.; Sims, L.B.; Fry, A. J. Am. Chem. Soc. 1991, 113, 8821.
111. Lewis, D.E.; Sims, L.B.; Yamataka, H.; McKenna, J. J. Am. Chem. Soc. 1980, 102, 7411.

Table 8.12 Isotope Effects for the Hofmann Elimination of 2-Phenylethyl-Trimethylammonium

Salts (Ar—CH2—CH2—NMe+3)
Ar RO– Isotopomer k/k*
C 6H 5 EtO /EtOH/40°C
–
β-D2 3.23 ± 0.04
C 6H 5 HO–/H2O/90°C α-D2 1.02 ± 0.01
C 6H 5 EtO –/EtOH/40°C 15
N 1.0142 ± 0.0004
C 6H 5 EtO –/EtOH/40°C α-14C 1.044 ± 0.002
C 6H 5 EtO –/EtOH/40°C β-14C 1.041 ± 0.001
4-MeOC6H4 EtO –/EtOH/40°C β-D2 2.64 ± 0.04
4-MeOC6H4 EtO –/EtOH/40°C 15

N 1.0137 ± 0.0009
4-MeOC6H4 EtO –/EtOH/40°C α-14C 1.050 ± 0.002
4-MeOC6H4 EtO –/EtOH/40°C β-14C 1.040 ± 0.002
4-ClC6H4 EtO –/EtOH/40°C β-D2 3.48 ± 0.06
4-ClC6H4 EtO –/EtOH/40°C 15

N 1.0114 ± 0.0009
4-ClC6H4 EtO –/EtOH/40°C α-14C 1.041 ± 0.002
4-ClC6H4 EtO –/EtOH/40°C β-14C 1.044 ± 0.002
4-CF3C6H4 EtO –/EtOH/40°C β-D2 4.15 ± 0.05
4-CF3C6H4 EtO –/EtOH/40°C 15

N 1.0088 ± 0.0006
4-CF3C6H4 EtO –/EtOH/40°C α-14C 1.032 ± 0.005
4-CF3C6H4 EtO –/EtOH/40°C β-14C 1.044 ± 0.004
4-O2NC6H4 EtO –/EtOH/40°C α-14C 1.019 ± 0.005
4-O2NC6H4 EtO –/EtOH/40°C β-14C 1.042 ± 0.003
Between the 1960s and 1970s, Swain and Thornton set forth a number of rules112 that
can be used in conjunction with the More O’Ferrall-Jencks diagram to make predictions
of substituent effects on transition state structure. The upshot of their work was that we
can divide the effects of substituents into two components: parallel effects, which are the
effects of the structural change on the mixed translation–vibration motion along the reac-
tion coordinate (these are the effects one would predict on the basis of the Hammond
postulate, for example), and perpendicular effects, which are the effects of the structural
change on the true vibrations of the activated complex.
These effects are indexed to the reaction coordinate and so are relatively easy to discuss
in terms of the More O’Ferrall-Jencks diagram for the reaction. Parallel effects result in a
shift of transition state along the direction of the reaction coordinate either toward reactant
or product. Perpendicular effects result in a shift of the transition state structure perpen-
dicular to the reaction coordinate. If we use the β-elimination reaction, as in Figure 8.16, as
112. (a) Swain, C.G.; Thornton, E.R. J. Am. Chem. Soc. 1962, 84, 817. (b) Swain, C.G.; Thornton, E.R. J. Am.
Chem. Soc. 1962, 84, 922. (c) Thornton,, E.R. J. Am. Chem. Soc. 1967, 89, 2915. (d) Steffa, L.J.; Thornton, E.R. J.
Am. Chem. Soc. 1967, 89, 6149. (e) Winey, D.A.; Thornton, E.R. J. Am.Chem. Soc. 1975, 97, 3102.

our example, we see that the four corners of the diagram correspond to the four stable
species: the reactant, the product alkene, the carbanion formed by abstraction of the β-hy-
drogen, and the carbocation formed by loss of the leaving group. These are four bonds that
are involved in the reaction (i.e., whose stretching motions become part of the reaction
coordinate): the σ bond between the base and the β-hydrogen, the σ bond between the
β-hydrogen and the β-carbon, the σ bond between the α-carbon and the leaving group,
and the carbon-carbon π bond. In the course of the reaction, the B—H bond is formed, the
C—H bond breaks, the C—C π bond forms, and the C—X bond breaks, which makes the
overall reaction coordinate motion (Example 8.45) a coupled asymmetric stretching
motion of these four bonds.
C X
H C (8.45)
B
Let us begin by looking at a classical E2 reaction with a central transition state, indi-
cated by a heavy black dot in Figure 8.17. If the bond to the leaving group becomes stronger,
this will lower the energy of both the reactant and the carbanion, because both these spe-
cies have the C—X bond, but will not affect the energy of the carbocation or the product,
which do not. This will reduce the energy of the entire bottom edge of the diagram and will
tend to move the structure of the transition state away from the diagonal toward the bottom
edge of the diagram, as predicted by the Hammond postulate. We expect to see the reaction
become more E1cb-like as the bond to the leaving group becomes stronger. At the same
time, because we have lowered the energy of the reactant but not the energy of the product
alkene, we expect to see the transition state move toward the product, as predicted by the
Hammond Postulate. We predict that the perpendicular component of the shift will there-
fore be toward the bottom edge of the diagram and that the parallel component will be
toward the product. The resultant is that we predict that the E2 reaction will, indeed,
become more E1cb-like and that the structural change will affect mainly the C—H bond
(toward the open circle in Figure 8.17).
The situation changes somewhat when we examine an E1cb-like E2 reaction because
the reaction coordinate motion changes (Figure 8.18), becoming dominated by proton
transfer until after the transition state is passed.113 Stretching of the C—X bond is relatively
unimportant at the transition state, so we expect the parallel effect of increasing the
Figure 8.17 Increasing bond

H strength to the leaving group
in an E2 reaction
carbocation alkene
X X
H
reactant carbanion
113. Smith, P.J.; Bourns, A.N. Can. J. Chem. 1974, 52, 749.

Figure 8.18 Increasing bond

strength to the leaving group H
in an E1cb-like E2 reaction
carbocation alkene
2"
lE
tra
en
"c
X X
H
reactant carbanion
strength of the bond to the leaving group to be small. The perpendicular effect of the
change should be to move the transition state toward the bottom edge of the diagram.
Again, the position of the predicted new transition state is indicated by an open circle. We
predict that the transition state will become even more strongly anionic, with less C—X
bond rupture in the transition state.
Problems
8-19 Modify the More O’Ferrall-Jencks diagram in Figure 8.17 to represent each of the
following reactions:
(a) nucleophilic substitution of an alkyl halide
(b) oxidation of a secondary alcohol to a ketone
(c) addition of singlet carbene to an aldehyde to give an epoxide
(d) nucleophilic acyl substitution of an acid chloride by methoxide anion
(e) addition of dichloroketene (Cl2C=C=O) to an alkene to give a cyclobuta-
none. (Hint: ketenes often react as though they were zwitterions
R 2C=C+—O−.)
8-20 In the discussion of the element effect in Section 8.6, we came to the conclusion
that the reaction probably proceeds by the E2 mechanism. The authors of the paper
(J. Phys. Org. Chem. 1998, 11, 54) reach the conclusion that the reaction proceeds by
the E1cbI mechanism. Evaluate both positions (E1cbI and E2), and suggest experi-
ments that could be used to distinguish between the two mechanisms.
8-21 The element effect for the reaction between a halobenzene and amide ion in
liquid ammonia reveals the order of reactivity as:
PhBr > PhI > PhCl >> PhF
When deuterated halobenzenes react with amide ion in liquid ammonia

(NH3), fluorobenzene-2,6-d2 undergoes 100% loss of deuterium before any aniline
is formed. With chlorobenzene-2-d, aniline formation occurs at approximately
twice the rate of deuterium exchange, and bromobenzene-2-d gives aniline with-
out loss of deuterium.
Rationalize these results and sketch the reaction coordinates for the reaction of
each of the halobenzenes with amide anion in liquid ammonia.

8.9 Using Regiochemistry and Stereochemistry
The stereochemistry and regiochemistry of organic reactions has been a subject of study
for well over a century, beginning with the two empirical rules for predicting the re-
giochemistry of reactions that are still taught in introductory organic chemistry courses:
Markovnikov’s rule for addition114 and Zaitsev’s rule for elimination.115
The regiochemistry and stereochemistry of reactions can provide strong evidence
about reaction mechanism in appropriate circumstances. For example, concerted reac-
tions generally occur stereospecifically: one stereoisomer of the reactant gives one stereo-
isomer of the product, and a different stereoisomer of the reactant gives a different
stereoisomer of the product. The reason why concerted reactions tend to be stereospecific
is stereoelectronic in origin. In order for a concerted reaction to proceed, all the molecular
orbitals involved must be aligned correctly to permit the reorganization of electrons
during the single step of the reaction. Thus, the observation that a reaction is stereospecific
can often be used to suggest that the mechanism of the reaction might be concerted. We
see this in the E2 and SN2 reactions: the E2 reaction occurs with antarafacial stereochem-
istry, whereas the SN2 reaction occurs with inversion of configuration.
The corollary of this is not, however, true: the observation of stereospecificity alone is
not always an indicator of concertedness. One must be careful about inferring that a reac-
tion is concerted because it occurs stereospecifically. A good example of such a reaction is
the addition of a halogen to an alkene π bond, for which one can propose both stepwise
and concerted mechanistic pathways. Due to geometric constraints, the concerted reac-
tion, which would proceed through a four-membered transition state, is forced to proceed
with suprafacial (syn) stereochemistry. Because this stereospecific reaction actually occurs
with antarafacial (anti) stereochemistry, the reaction stereochemistry cannot be recon-
ciled with a concerted mechanism. One must conclude that this reaction occurs by a step-
wise mechanism involving at least one reactive intermediate.
The regiochemistry of organic reactions is often less useful than stereochemistry,
but there are occasions where the observation of differences in regiochemistry can be
used fruitfully in making deductions and predictions about reactions. For example,
Markovnikov’s rule was originally defined in structural terms of the alkene, but it was
later defined in terms of the relative energies of the two possible regioisomeric carbocation
intermediates. Knowing that the addition of electrophiles to alkene π bonds must obey
Markovnikov’s rule places certain limitations on the structure and type of intermediate
involved in the reaction.
Probably the most famous regiochemical problem that led to mechanistic informa-
tion was the addition of hydrogen bromide to alkenes, eventually solved by Kharasch.116
It had been observed that although both HCl and HI added to alkenes according to
Markovnikov’s rule, the addition of HBr was rather random. Kharasch and Mayo noted
that the amount of anti-Markovnikov addition correlated with the ability of the allyl
bromide in their study to oxidize ferrous ion; they termed the observation “the peroxide
effect.” The reversal of regiochemistry, they reasoned, meant that in the reactions carried
out in the presence of peroxides, the bromine must add first to the alkene π bond to give
the reactive intermediate, whereas in the absence of peroxides, the proton adds first to
give the more stable of the two possible carbocations. This ultimately led to the deduction
that the function of the peroxides was to generate bromine atoms from the hydrogen
bromide and that these bromine atoms added to the alkene π bond to give the more stable
free radical.
114. (a) Markownikoff, V. Ann. Chem. Pharm. 1870, 133, 228. (b) Markownikoff, V. Compt. rend. 1875, 82, 668.
(c) Markownikoff, V. Compt. rend. 1875, 82, 728. (d) Markownikoff, V. Compt. rend. 1875, 82, 776.
115. Saytzeff, A. Ann. Chem. Pharm. 1875, 179, 296.
116. Kharasch. M.S.; Mayo, F.R. J. Am. Chem. Soc. 1933, 55, 2468.

Problem
8-22 Draw a More O’Ferrall-Jencks diagram for an SN2 reaction and use it to deduce
the probable effects of each of the following changes in bond strengths on the
structure of a transition state located in the exact center of the diagram. Assume
that the reaction coordinate motion of the reference reaction lies along the diago-
nal of the diagram.
(a) Increasing the C—nucleophile (C—Nu) bond strength.
(b) Increasing the C—leaving group (C—X) bond strength.
(c) Decreasing the strength of both the C—Nu and C—X bonds.
(d) Increasing the strength of both the C—Nu and C—X bonds.
(e) Decreasing the strength of the C—Nu bond and increasing the strength
of the C—X bond.
(f) Increasing the strength of the C—Nu bond and decreasing the strength
of the C—X bond
8.10 The Reactivity-Selectivity Principle117
Most chemists have an intuitive feel for the reactivity-selectivity principle: that the more
reactive a species is, the less selective it is. We see this in the reactions of free radicals with
alkanes, where the more reactive radicals are less selective in abstracting hydrogen atoms
than the less reactive radicals. This can be seen from the data in Table 8.13, where the reac-
tivity of radicals toward C—H bonds is compared to abstraction of a methyl hydrogen.
However, the reactivity-selectivity principle is far from universal. Although it works
with simple one-bond and two-bond reactions such as hydrogen atom transfer reactions,
it frequently fails in more complex reactions such as E2 eliminations, where there are four
bonds changing in the activated complex or reactions where changes in solvation make a
major contribution to the reaction coordinate.
Table 8.13 Selectivity of Radicals Toward C—H Bonds

Radical (X•) CH3—H RCH2—H R 2CH—H R 3C—H D (X—H)
F• 0.5 1 1.2 1.4 135

Cl• 0.004 1 4.3 7.0 103
Br• 0.002 1 780 1700 87
I• 1 18 71
HO• 0.04 1 7 45 118
H• 1 4.8 40 105
CF3• 0.06 1 8.3 90 105
CH3• 0.09 1 10 80 104
Data from Kerr, J.A. In Kochi, J., Ed. Free Radicals (Wiley-Interscience, New York, 1973), vol. 1, ch. 1.
117. Review: Pross, A. Adv. Phys. Org. Chem. 1977, 14, 69.

Chapter Summary
This chapter has introduced the field of physical organic chemistry, which may be broadly
defined as physical chemistry applied to the properties and reactions of organic com-
pounds. In this chapter, mechanistic types have been more rigorously defined as con-
certed or stepwise, and the concept of the rate-limiting step has been introduced. The
relationship between the potential energy surface for the reaction and the reaction coor-
dinate diagram (reaction energy profile) has been defined, as have the meanings of acti-
vated complexes and transition states. In practice, these terms are often used as full
synonyms, but in formal terms, the term activated complex, refers to a static structure,
and the term, transition state, refers to a dynamic species. Reaction kinetics and the
k inetic order of reactions have been discussed, and the use of the rate law in making de-
ductions about reaction mechanism has been explored. The role of trapping and cross-
over experiments in deducing a mechanism has been discussed. The Arrhenius equation
and the activation parameters of a reaction have been considered, as have the Hammett
equation and the various parameters arising from the original σ and ρ constants. The
Grunwald-Winstein relationship for solvent effects on reactions has been discussed, as
has the Brønsted catalysis law and the salt effect. Element and isotope effects have been
introduced, and the distinction made between primary and secondary isotope effects has
been pointed out; this discussion was extended to the concepts of the variable transition
state and a mechanistic spectrum. The chapter concluded with a short discussion of the
reactivity-selectivity principle.
Key Terms
activated complex Grunwald-Winstein primary kinetic isotope
activation energy relationship effect
aprotic dipolar solvent Hammett constants pseudo–first-order kinetics
Arrhenius equation Hammett equation rate constant
Brønsted catalysis law ionic solvent rate law
catalysis isotopomers rate-limiting step
concerted kinetic isotope effect (rate-determining
crossover experiment linear free energy step)
dielectric constant relationships reaction coordinate
dipole moment London dispersion force diagram
element effect mechanistic spectrum reaction energy profile
equilibrium isotope molecularity reaction kinetics
effect More O’Ferrall-Jencks reactive intermediate
first-order kinetics diagram reactivity-selectivity
general acid catalysis potential energy surface principle
general base catalysis pre-equilibrium solvent parameters N, Y
Additional Problems
8-23 The Morita-Baylis-Hillman reaction is a reaction between an aldehyde and a

Michael acceptor that is catalyzed by a tertiary amine or phosphine base to give
a densely functionalized product. Early work on the mechanism of this reaction
showed second-order kinetics and led to the mechanism shown below being pro-
posed for the reaction.

More recent kinetic work has shown that the reaction proceeds according to
the rate law:
Rate = [RCHO]2[R 3N][H2C=CH-EWG]
O
H
R O OH
H
EWG EWG EWG EWG
slow R R
R3N R3N
R3N
(a) What changes does this rate law require in the activated complex for the
reaction? Suggest a structure for the activated complex for the reaction.
(b) Based on your proposed activated complex, what would the rate-determining
step of the reaction be? Would this reaction be subject to a kinetic isotope effect
and which atom should be labeled to see that isotope effect if it is expected?
(c) When the Morita-Baylis-Hillman reaction is carried out in the presence of
an alcohol, the rate law changes to:
Rate = [RCHO][R 3N][H2C=CH-EWG][ROH]
How is this change in the rate law reflected in the structure of the activated
complex?
8-24 Consider the effects of changing the substituent on the aromatic ring of the
benzyl halide undergoing SN2 substitution in the reaction corresponding to the
More-O’Ferrall-Jencks diagram.
X Nu
Ar
Ar
Nu
adduct product
X
Ar
Ar
reactant carbocation
(a) Describe the structure of the activated complex if it occurs at the point indi-
cated by the heavy dot.
(b) If the reaction coordinate motion corresponds to the full line in the diagram,
what will be the effects on the activated complex structure be of changing the
substituent at the para position on the ring to a more electron-withdrawing
group?
(c) How does the effect of changing the substituent at the para position to a more
electron-withdrawing group change the structure of the activated complex if
the reaction coordinate motion corresponds to the dashed line in the diagram?

8-25 The [2 + 2] cycloaddition of diphenylketene to styrene has been studied exten-

sively by the successive labeling technique. The primary and secondary isotope
effects given in the table below have been measured for the reaction, which has
been shown to be stereospecific and sym (suprafacial) with respect to the styrene
by the use of specifically monodeuterated styrenes.
O
O
C
+
Ph Ph Ph Ph
Ph Ph
(a) Based on the available data, suggest a structure for the activated complex of
this reaction. Give reasons for your answer.
(b) What would you expect the activation parameters for the reaction (∆H‡ and
∆S‡) to be in qualitative terms (large, small, positive, negative)?
Isotopomer kie Isotopomer kie Isotopomer kie
D H H H Ph
*
1.23 ± 0.03 * 1.0055 ± 0.0005 C O 1.08 ± 0.005
Ph H Ph H Ph
H D H H Ph
0.879 ± 0.004 * 1.007 ± 0.003 * C O 1.01 ± 0.003
Ph H Ph H Ph
H H
0.889 ± 0.004
Ph D
8-26 Using the Hammond postulate and the expression for Gibbs free energy (∆G =
∆H – T∆S), provide a reasonable explanation for why E2 elimination is favored
over SN2 substitution and why E1 elimination is favored over SN1 substitution, at
high temperatures. Are the effects of temperature the same in both unimolecular
and bimolecular reaction types?
8-27 The rate of the E2 elimination reaction between alcoholic potassium hydroxide
and 1-bromobutane or 2-bromobutane under reflux can be measured using a
gas buret to measure the volume of butenes formed in the reaction. If the
same quantities of alkyl halide and base are used in the same volume of
ethanol, one finds that 1-bromobutane gives only about 30% as much butene
as 2-bromobutane. Why?
8-28 The reaction shown may proceed by a free radical chain mechanism or an ionic
mechanism involving a tertiary carbocation.
(a) Draw both mechanisms.
(b) One way to probe this mechanistic question is to study the effects of chang-
ing solvent on the rate of the reaction. If the solvent is changed from benzene
to acetic acid, what will be the effect on the rate of the reaction if it proceeds
through each of these mechanisms?
O
S N
N ∆
O
solvent
S

8-29 The hydrolysis of strained β-lactones can be accomplished under conditions of

both acid and base catalysis. When the reaction is carried out using an optically
active lactone and 18O labeled water, the data in the table are obtained.
Reactant pH –2 to 0 pH 3 to 8 pH 10 to 12
*
OH OH *
OH
O
O OH O
*OH O OH O
Is the mechanism constant over the entire range of pH? If it is not, what mecha-
nisms operate under what conditions, and how does the mechanism change?
8-30 In aqueous solution, diacetone alcohol Me 2 C(OH)CH 2 COMe decomposes
into acetone in a process catalyzed by sodium hydroxide. The observed
first-order rate constant is dependent on the concentration of the catalyst,
as shown in the table. Rationalize these observations. [Data from J. Am.
Chem. Soc. 1929, 51, 3215.]
[NaOH] (mM) kobs
5.0 2.32 × 10–3

10.0 4.67 × 10–3
20.0 9.40 × 10–3
40.0 1.92 × 10–2
100. 4.79 × 10–2
8-31 When the initial concentrations of two reactants (A and E) in a bimolecular reac-
tion are not equal, the integrated rate law takes the form:
1   [E]0   [E]  
kt 5  ln   2 ln  t   , where [E]0 and [A]0 are the initial
[E]0 2[A]0   [A]0   [A]t  
concentrations of the two reacting species, and [E]t and [A]t are their concentra-
tions at time t. The reaction is carried out using 1H NMR as a tool for monitoring
concentrations. Based on the data below, where the internal standard peak refers
to a resonance from a compound that is not consumed in the reaction, calculate
the rate constant for the reaction.
Initial concentrations: [A]0 = 0.558 M; [E]0 = 0.730 M.
Area of Internal
Time Area of peak A (H1) Area of Peak E (H3) Standard Peak
21 2.69 10.34 43.03

42 1.93 7.61 37.80
60 1.73 7.04 39.22
79 1.48 6.25 39.53
97 1.31 5.56 39.55
100 1.28 5.56 39.61
119 1.15 5.08 39.42

8-32 The quantity h0 is related to the Hammett acidity parameter H0 as h0 = 10–Ho,

which makes it a good approximation to the activity (or concentration) of H+
(aq) in aqueous solutions of strong acids up to 5 M. The observed first-order rate
constant for the acid-catalyzed hydrolysis of the strained compound, β-propio-
lactone, changes with the concentration of the acid. Provide an interpretation of
the effects of acid. Include in your answer a mechanism for the reaction, a reac-
tion coordinate diagram, and a rate law for the reaction. [Data from J. Am.
Chem. Soc. 1950, 72, 3267.]
H2O CO2H
O HO
O
H0 kobs H0 kobs
−0.58 3.65 × 10–3 −2.28 69.9 × 10–3

−0.94 5.38 × 10–3 −1.72 17.6 × 10–3
−1.01 5.21 × 10–3 −0.73 5.39 × 10–3
−1.24 8.89 × 10–3 −1.28 9.52 × 10–3
−1.55 14.41 × 10–3 −1.57 13.1 × 10–3
−1.84 32.2 × 10–3 −1.64 18.9 × 10–3
−1.85 32.6 × 10–3 −2.22 57.3 × 10–3
8-33 When optically active threo-3-p-anisylbutyl tosylate reacts with water in 50%
aqueous ethanol, the product of the reaction is (±)-threo-3-p-anisyl-2-butanol.
Explain these observations.
H H
OTs H2O OH
H EtOH H
MeO MeO
optically active racemic
8-34 When 2,4,6-trinitroanisole is heated with sodium ethoxide, the product obtained
is a mixture of 1-ethoxy-2,4,6-trinitrobenzene and starting material. When the
reaction mixture is not heated, a red solid that gives the following microanalysis
data is obtained: C, 34.74; H, 3.24; N, 13.50; Na, 7.39%. What is the solid and how
is it formed?
OMe OEt
O2 N NO2 NaOEt O2N NO2
EtOH
NO2 NO2
8-35 When cyclohexenone is converted to its cyclic ethylene ketal under standard con-
ditions, the product obtained is the rearranged ketal shown. Suggest a mecha-
nism for this transformation and provide a reasonable rationalization for the
observed results.
HO OH O
O
TsOH, PhH O
∆

8-36 In a 1957 review (Chem. Rev. 1957, 57, 935], Long and Paul refer to a conclusion
reached by Zucker and Hammett that specifies that if a reaction has a rate law
with a linear dependence on H0, the activated complex involves only the substrate
and a proton, whereas if the reaction has a rate law that depends on [H+], the acti-
vated complex is composed of the substrate, a proton, and a molecule of water.
What are the major assumptions leading to this hypothesis and under what con-
ditions might it not apply?
8-37 The YOTs values for solvents do not give a good correlation for reaction rates of
alkyl chlorides. What is the origin of this apparent limitation of this solvent pa-
rameter? (Hint: Consider the solvation requirements of the products of the sol-
volysis reaction.)
8-38 The regiochemistry of protonation of the guanidine derivative shown is con-
trolled by the substituent X. When a complete series of protonations is carried
out using both electron-releasing and electron-withdrawing substituents, the
Hammett plot of the equilibrium constants for the protonation is linear with a
relatively large negative ρ value. What does this tell about the regiochemistry of
the protonation? What would be the results of the Hammett plot if protonation
occurred at the alternative site?
H
Me2N H Me2N Me2N
N N N
Me2N X Me2N X Me2N X
8-39 The hydrolysis of 2-deoxy-adenosine monophosphate, dAMP, is catalyzed by

acid. Kinetic isotope effects for the reaction have been measured for labeling at a
number of locations on the dAMP molecule, as shown at right.
12
k/14k = 1.004±0.002 14
k/15k = 1.022±0.003
O 14
k/15k = 0.985±0.002
HO P
O N
HO O N NH2
H
H T H H
k/ k=1.012±-.002 N N 14
k/15k = 0.997±0.006
(for 3H2 material) HO H H
Hk/Tk=1.253±-.002
H
H
k/Dk=1.091±-.002 k/Dk=1.113±-.007
Based on these isotope effects, what qualitative deductions can be made about the
transition state for this reaction?
8-40 The rate law for the substitution of 2-benzyloxytetrahydropyran (BzTHP, shown)
by methanol in toluene containing a catalytic amount of p-toluenesulfonic acid
(TsOH) is of the form:
Ph
O O O
Rate = k[BzTHP][TsOH]
(a) Is this reaction concerted or stepwise? Why or why not?
(b) Draw a reasonable reaction coordinate diagram for this reaction.
8-41 The reaction between the phthalimide N-oxyl radical and a variety of substituted
toluenes gives the data in the table below (J. Org. Chem. 2003, 68, 9364). Construct
Hammett plots from these data using all three substituent parameters: σ, σ +, and σ −.

Which of the plots gives the best fit to a straight line? What does this tell you about
the nature of the transition state for the hydrogen atom transfer?
O O
X X
N O + H3C N OH + H2C
O O
Substituent k 2 (L mol s )
–1 –1
Substituent k 2 (L mol–1 s–1)
p-OMe 10.3 p-Br 0.595

p-Me 5.95 p-CO2H 0.272
m-Me 3.06 m-CO2H 0.200
H 0.620 p-NO2 0.119
A temperature study of the same reaction with toluene in acetic acid gives the
following results:
Temperature 17°C 25°C 40°C 55°C 70°C

k 2 (L mol s )
–1 –1
0.81 1.2 2.4 4.4 7.8
What is the activation energy of this reaction? What are the values of ∆H‡ and
∆S‡ for this reaction?
8-42 The heterocyclic ring of N-aryl-4-chloro-1,8-naphthalimides had been assumed
to be inert to nucleophilic attack until 2013, when the these substances were re-
ported to react with butylamine to give N-butyl-4-chloro-1,8-naphthalimide
[Org. Biomol. Chem. 2013, 11, 4390]. The kinetic data for the reactions of a series
of substituted N-aryl-4-chloro-1,8-naphthalimides with butylamine are given in
the left-hand table below. What do these data allow one to deduce about the tran-
sition state structure of the reaction?
Cl Cl
BuNH2, r.t.
O N O O N O
The reaction also exhibits a dependence on the alcohol solvent, as shown in the
right-hand table. Construct a Brønsted plot based on the data given. Is this reac-
tion subject to any type of acid catalysis?
Substituent kobs (min–1) Alcohol kobs (min–1)
m-Cl 2.02 ± 0.04 × 10−3 MeOH 5.02 ± 0.06 × 10−3

p-Br 7.9 ± 1.2 × 10−4 n-PrOH 3.06 ± 0.04 × 10−3
m-OMe 3.21 ± 0.6 × 10−4 i-PrOH 2.07 ± 0.13 × 10−3
H 1.64 ± 0.07 × 10−4 t-BuOH 1.14 ± 0.10 × 10−3
MeOCH2CH2OH 10.4 × 10−3

8-43 The SN1 and E1 reactions share a common rate law and reaction mechanism
through the slow step of the reaction. These two mechanisms frequently operate
together, so the product of the reaction is a mixture of alkene and the substitution
product. It is known that increasing the reaction temperature tends to favor elim-
ination over substitution and that keeping the reaction temperature low tends to
favor substitution over elimination. Provide a reasonable explanation for these
observations using both kinetic and thermodynamic arguments as well as appro-
priate reaction coordinate diagrams.

Chapter nine
Reactive Intermediates I
Carbocations
9.1 Carbocations1
The ionization of organic compounds was established in 1902, when Walden showed that
triphenylmethyl chloride would dissolve in sulfur dioxide to give an electrically conduct-
ing solution (Example 9.1).2 Carbocations are electrophiles characterized by an sp2-
hybridized, positively charged central carbon atom with three σ bonds (Example 9.2).
They are typically formed by one of two major processes: heterolysis of a bond to a leaving
group and protonation of a π bond. Although electrochemical oxidation of a neutral pre-
cursor such as a free radical may be used to generate a carbocation,3 it is less common.
Cl Cl (9.1)
H H
R C H (9.3)
R (9.2) H
R H
Carbocations were called carbonium ions until the 1970s, but in 1971 American chem-
ist George Olah, winner of the 1994 Nobel Prize in Chemistry, suggested that this term
should be reserved for cations such as CH5+ (Example 9.3). Here, there are more than four
groups simultaneously bonded to the carbon atom (i.e., “onium” ions should be cations
where the atom carrying the formal charge has a coordination number one higher than
the coordination number of the same atom when formally neutral). Olah also suggested
(1) that the term carbenium ion should be used to discuss the types of cations formed
during SN1 and electrophilic addition reactions4 and (2) that the term carbocation be used
1. Monographs: (a) Olah, G.A.; Schleyer, P.v.R. Carbonium Ions, 5 vols. (Wiley: New York, 1968–1976).
(b) Bethell, D.; Golg, V. Carbonium Ions (Academic Press: London, 1963).
Reviews: (c) Deno, N.C. Prog. Phys. Org. Chem. 1964, 2, 129. (d) Stang, P.J. Prog. Phys. Org. Chem. 1973, 10,
205. (e) Schleyer, P.v.R.; Allen, L.C. Top. Stereochem. 1973, 7, 253. (f) Olah, G.A. Top. Curr. Chem. 1979, 80, 19.
(g) Kebarle, P. Ann. Rev. Phys. Chem. 1977, 28, 445.
2. Walden, P. Ber. dtsch. chem. Ges. 1902, 35, 2018.
3. (a) Corey, E.J.; Bauld, N.l.; LaLonde, R.T.; Casanova, J., Jr.; Kaiser, E.T. J. Am. Chem. Soc. 1960, 82, 2645.
These authors suggest that this occurs when the Kolbe electrolysis fails to give the expected radical dimer:
(b) Walker, J.; Carmack, M. J. Chem. Soc. 1900, 77, 374. (c) Linstead, R.P.; Shepard, B.R.; Weedon, B.C.L. J.
Chem. Soc. 1951, 2854. (d) Finkelstein, M.; Peterson, R.C. J. Org. Chem. 1960, 25, 136.
4. Olah, G.A. CHEMTECH 1971, 1, 566. In 1902, Moses Gomberg suggested that “carbonium ion” may be
inappropriate: Gomberg, M. Behrett. 1902, 35, 2397. For a history of the name, “carbonium ion” see Traynham,
J.G. J. Chem. Educ. 1986, 63, 930.
317

318 Advanced Organic Chemistry | Chapter nine
Table 9.1 Calculated Enthalpies (kcal mol−1) of Hydride Transfer as a generic term to indicate a carbon-centered cation.5
+
from Fluorinated Hydrocarbons to CH in the Gas Phase and
3
Although the International Union of Pure and Applied
Lowest Energy Unoccupied Molecular Orbital (LUMO) Energies Chemistry (IUPAC) has accepted these definitions,6 the
of Fluorinated Cations organic chemistry community has been slow to embrace
R2 R2 the term “carbenium ion,” choosing instead to adopt
R1 + CH3 R1 + CH4 Olah’s second suggestion and to call intermediates with a
R3 R3 positively charged carbon atom “carbocations.”
∆E ELUMO Carbocations are electrophiles. Their reactivity is
R1 R2 R3 (B3LYP/6-31+G*) (eV) due to the presence of a carbon atom lacking a complete
octet and is modulated by the groups bonded to the
CH3 CH3 CH3 −239.3 −8.8 electron-deficient carbon atom. As would be predicted,
CH3 CH3 CH2F −229.2 −9.2 electron-releasing groups stabilize the cation and reduce
its reactivity, and electron-withdrawing groups destabi-
CH3 CH3 CHF2 −212.9 −9.8
lize the cation and increase its reactivity. The modula-
CH3 CH3 CF3 −204.2 −10.1 tion of carbocation reactivity can be discussed in terms
of two competing effects: the inductive effect7 and the
CH3 CH2F CF3 −192.0 −10.6
resonance effect or mesomeric effect.8 The inductive
CH3 CHF2 CF3 −176.5 −11.1 effect transmits the effects of electronegativity through
CH3 CF3 CF3 −168.7 −11.3 the σ bonds of the cation, and it is attenuated as the
number of intervening σ bonds increases.
CH2F CF3 CF3 −156.0 −9.2 The operation of the inductive effect (actually com-
CF3 CF3 CF3 −126.2 −12.9 prised of two components: the inductive effect itself,
which passes through bonds, and the field effect,9 which
CH3CH2CH2 CH3 CH3 −243.3 −8.5
passes through space) is illustrated by the calculated en-
CH3CH2CHF CH3 CH3 −235.1 −8.8 thalpies of the gas phase hydride transfer reactions from
fluorinated isoalkane derivatives to methyl cation to give
CH3CHFCH2 CH3 CH3 −238.7* −8.5
the fluorinated tert-alkyl carbocations summarized in
FCH2CH2CH2 CH3 CH3 −237.1† −8.6 Table 9.1. The energy of the lowest energy unoccupied
FCH2CH2CH2 CH3 CH3 −247.1‡ −8.0 molecular orbital (LUMO) of each cation mirrors the
trend in reaction energy for its formation.§ The reaction
*
The conformation of this ion places the fluorine atom physically closer to energies are also shown in Figure 9.1.
the cation carbon than the other fluorinated 1,1-dimethylbutyl cations.
The first ten rows of Table 9.1 show the cumulative
†
Extended-chain conformation.
‡
Cyclic conformation. e
ffects of increasing fluorine substitution on the energy of
the tert-butyl cation; each fluorine atom makes the over-
all reaction less exothermic (i.e. reduces the stability of the carbocation). Density func-
tional theory (DFT) calculations at the B3LYP/6-31+G* level show an linear decrease in
the exothermicity of the reaction of 12.3 kcal mol−1 per fluorine atom as fluorine atoms are
added to the cation. The last four rows of Table 9.1 show the attenuating effects of
5. Olah, G.A. J. Am. Chem. Soc. 1972, 94, 808.

6. Gold, V.; Loening, K.L.; McNaught, A.D.; Sehmi, P. Compendium of Chemical Terminology: IUPAC Rec-
ommendations (Blackwell Scientific Publications: Oxford, 1987).
7. (a) Lewis, G.N. Valence and the Structure of Atoms and Molecules (Chemical Catalog Company: New York,
1923), p. 139. (b) Ingold, C.K. Structure and Mechanism in Organic Chemistry (Cornell University Press: Ithaca,
1953), pp. 67–71. (c) Gould, E.S. Mechanism and Structure in Organic Chemistry (Holt, Rinehart and Winston:
New York, 1950), pp. 200–209. (d) Friedl, Z.; Hapala, H.; Exner, O. Coll. Czech. Chem. Comm. 1979, 2928.
8. (a) Ingold, C.K. Structure and Mechanism in Organic Chemistry (Cornell University Press: Ithaca, 1953),
pp. 73–90. (b) Gould, E.S. Mechanism and Structure in Organic Chemistry (Holt, Rinehart and Winston: New
York, 1950), pp. 212–220, esp. footnote 23 on p. 217. (c) Wheland, G.W. Advanced Organic Chemistry, 3rd, ed.
(John Wiley & Sons: New York, 1960), p. 86. (d) Ingold, C.K.; Ingold, E.H. J. Chem. Soc. 1926, 1310. (e) Robinson,
R. Outline of an Electrochemical Theory of the Course of Organic Reactions (The Institute of Chemistry of Great
Britain and Ireland: London, 1932). (f) Robinson, R. I. Soc. Dyers Clourists, Jubilee Issue 1934, 65. (g) Ingold,
C.K. J. Chem. Soc. 1933, 1120. (h) Ingold, C.K. Chem. Rev. 1934, 15, 225.
9. Roberts, J.D.; Moreland, W.T., Jr. J. Am. Chem. Soc. 1953, 75, 2167.
§. Calculations in this chapter were performed with Spartan 08 version 1.2.1 for Mac.

Reactive Intermediates I 319
Figure 9.1 Calculated
enthalpies of hydride transfer
reactions between methyl
cation and fluorinated
isobutanes to give methane
and fluorinated tert-butyl
carbocations in the gas phase
intervening σ bonds, and we see that the enthalpy of the gas-phase reaction decreases as
the fluorine is moved further from the position of the cation carbon (i.e., the carbocation
becomes more stable, or less destabilized as the fluorine is moved further from the cation
carbon). The data also reveal that placing the fluorine in a location physically close to the
cation carbon lowers the energy of the cation. When the fluorine is in a location where it
can form a cyclic heteronium ion, the reaction is actually more favorable than the depro-
tonation of the non-fluorinated compound.
Simple alkyl groups are electron-releasing by the inductive and field effects in the order:
CH3— < CH3CH2— < (CH3)2CH— < (CH3)3C—
When the hybridization changes, the inductive effect changes direction, and unsatu-
rated alkyl groups are generally weakly electron-withdrawing by the inductive effect (as
expected from the change in electronegativity with hybridization), in the following order:
R 2C=CR— < RC≡C—
All major mechanisms for stabilizing carbocations delocalize the positive charge by
π-type overlap of the empty 2p orbital of the charged carbon atom of the carbocation
with an occupied orbital. This charge delocalization is usually described in terms of
three common mechanisms: (1) conjugation, where the occupied orbital is an adjacent
π bond or lone pair; (2) hyperconjugation, where the occupied orbital is an adjacent σ
bond; or (3) bridging, where the occupied orbital is a non-adjacent σ or π bond. Charge
delocalization by conjugation or hyperconjugation generates a classical cation, whereas
delocalization by the third mechanism generates a non-classical cation. In principle,
each of these mechanisms of charge delocalization may operate, although one usually
dominates.
Problem
9-1 Suggest reasons for the relative orders of energy of the fluorinated 1,1-dimethylbu-
tyl cations shown in Table 9.1.

Figure 9.2 The
hydroxymethyl cation (top)
H H H H
and the allyl cation (bottom).
C O C O
The orbitals are the lowest
H H
energy unoccupied
molecular orbitals of the two
cations.
H H H H
C C C C
H C H H C H
H H
Conjugation
Conjugation with a lone pair on an atom directly bonded to the cation center is the most
effective process for stabilizing carbocations. The effectiveness of this conjugation is due to
the fact that conjugation results in a π-bonded heteronium ion, rather than the simple
substituted carbocation. This is illustrated in Figure 9.2 by the hydroxymethyl cation,
H2COH+, which is shown computationally to be the conjugate acid of formaldehyde. In
contrast to this, conjugation with a π bond allows the delocalization of the positive charge
but always results in a structure that has one formally electron deficient atom. This is illus-
trated in Figure 9.2 for the allyl cation, H2CCHCH2+.
One can use resonance arguments to predict this same relative order of stability—all
non-hydrogen atoms in the major canonical form of the heteroatom-stabilized cation have
complete outer-shell octets, and at least one non-hydrogen atom in the π bond−stabilized
cation lacks a complete outer-shell octet.
Hyperconjugation
Where there is no lone pair or π bond available for stabilizing a carbocation by conjuga-
tion, stabilization can occur through hyperconjugation,10 a π-type delocalization of the
electrons from the σ orbitals of the bonds at the β carbon into the empty p orbital on the
charged (α) carbon. This is shown in Figure 9.3, where the orbital overlap for hyperconju-
gation is shown. Below the orbital overlap diagram is the LUMO of the ethyl cation calcu-
lated at the AM1 level.11 In this orbital, which the simple valence-bond approach predicts
to be the empty 2p orbital on the cation carbon, we see what resembles the involvement of
Figure 9.3 Orbital overlap for two of the C—H σ orbitals of the methyl group simultaneously in the delocalization of the
hyperconjugation in cations charge by π-type overlap with the 2p orbital.
(top) and the lowest energy
The view of hyperconjugation as π-type delocalization of σ electrons can be used not
unoccupied molecular
orbital of the ethyl cation only as a mechanism for stabilizing electron-deficient species such as carbocations but also
(bottom) as a rationale for electron delocalization (from the σ orbital into an adjacent σ* orbital) to
stabilize the staggered conformation of alkanes. The effectiveness of hyperconjugation has
10. (a) Wheland, G.W. J. Chem. Phys. 1934, 2, 474. (b) Mulliken, R.S.; Riecke, C.A.; Brown, W.G. J. Am. Chem.
Soc. 1941, 63, 41. (c) Lofthus, A. J. Am. Chem. Soc. 1957, 79, 24. (d) Deasy, C.L. Chem. Rev. 1945, 36, 145. (e) Baker,
J.W. Hyperconjugation (Oxford University Press: London, 1952). (f) Becker, F. Angew. Chem. 1953, 65, 97.
(g) Wheland, G.W. Resonance in Organic Chemistry (John Wiley & Sons: New York, 1955), §3.10, 9.27. (h) Dewar,
M.J.S. Hyperconjugation (Ronald Press:New York, 1962). (i) Shiner, V.J.; Campaigne, E., Eds. Conference on
Hyperconjugation (Pergamon: New York, 1959); Tetrahedron 1958, 5, 105. (j) White, J.C.; Cave, R.J.; Davidson,
E.R. J. Am. Chem. Soc. 1988, 110, 6308.
11. This very unsophisticated level of theory permits us to look at the primary carbocation structure. At higher
levels of sophistication, the bridged-ion structure is obtained, as we will discuss in greater detail in Section 9.2.

been correlated with the reactivity of substituted aromatic hydrocarbons in electrophilic

aromatic substitution. Based on the rates of electrophilic aromatic substitution, one can
deduce that C—H σ bonds are much more effective at stabilizing a positive charge than
C—C σ bonds, which is consistent with the observed order of reactivity of benzenes substi-
tuted by simple alkyl groups toward electrophiles.12 This phenomenon is also known as the
Baker-Nathan effect,13 after the authors14 of the first paper to document that alkyl groups
attached to an aromatic ring facilitated displacements of benzylic halides in an order oppo-
site to that of the inductive effects of the alkyl groups.
CH3— > CH3CH2— > (CH3)2CH— > (CH3)3C—
Comparison of Conjugation and Hyperconjugation

Let us now compare the effectiveness of the two mechanisms, conjugation and hypercon-
jugation, in stabilizing cations. The first fact to bear in mind is that the effectiveness of
charge delocalization in carbocations is decided by the occupied molecular orbital in-
volved in the charge delocalization; it is generally observed that a π orbital or a non-
bonding electron pair is more effective than a σ orbital. This means that, as a general rule,
conjugation is more effective at stabilizing a carbocation than hyperconjugation. When
hyperconjugation is the only mechanism available for delocalizing the positive charge, it
most effective when the occupied molecular orbital is a σ orbital involving an electropos-
itive element (e.g., H or Si). Taking both of these factors into account, one may predict that,
when the number of alkyl groups attached to the charged carbon is the same, conjugated
cations are more stable than saturated cations and that saturated alkyl cations become
more stable as the number of carbon-hydrogen σ bonds at the β carbons increases. The
stability of simple hydrocarbon carbocations increases in the order:
CH+3 < RCH+2 (1°) < R 2CH+ (2°) < R 3C+ (3°) ≈ H2C=CHCH2+ (1° allyl)
The order of cation stability given above can be seen nicely in the series of isomeric
carbocations in Table 9.2, where the enthalpies calculated for the gas-phase deprotonation
of trans-4-ethyl-1-vinylcyclohexane and 1,4-diethylcyclohexene by methyl cation using are
gathered. These values were obtained using DFT methods at the B3LYP/6-31+G* level.
Based on the data in Table 9.2, we can see that saturated secondary cations are around
10 kcal mol−1 less stable than saturated tertiary cations in the gas phase and that the incor-
poration of a double bond at the allylic position lowers the cation energy by another 10 to
16 kcal mol−1 in this system. Although the size of the energy differences is reduced by sol-
vation, the general order of stability remains the same in solution as in the gas phase.
Computations of the structure and energy of the primary carbocation in Table 9.2 return
a bridged structure instead of the simple primary carbocation, and this structure has an
energy some 14 kcal mol−1 above that of the corresponding secondary carbocation. Other
12. (a) de la Mare, P.B.; Robertson, P.W. J. Chem. Soc. 1943, 279. (b) Berliner, E.; Berliner, F. J. Am. Chem. Soc.
1949, 71, 1195.
13. (a) Baker, J.W.; Nathan, W.S. J. Chem. Soc. 1935, 1844. (b) Baker, J.W. J. Chem. Soc. 1939, 1150. (c) Hughes,
E.D.; Ingold, C.K.; McNulty, B.J. J. Chem. Soc. 1940, 909.
14. John William Baker (1898–1967) was educated at Imperial College (PhD, 1925, DSc, 1928), where he
came under the influence of Ingold. He spent his entire independent career at Leeds, but, surprisingly, never
rose to the rank of Professor. He published over 100 papers and monographs in physical organic chemistry.
Wilfred Samuel Nathan (1910–1961) was educated at University College, Bangor (PhD, 1935), and after a
year at Leeds with Baker, he moved to University College, London, to work with Ingold. Within a year, he had
joined B.P., and he remained with this company for the rest of his life.
For more biographical details on Baker and Nathan, and a detailed description of the discovery of the
Baker-Nathan effect, see: Saltzman, M.D. Bull. Hist. Chem. 2012, 37, 82.

Table 9.2 Calculated ∆H°react for Formation of Isomeric calculations at this level do not return the primary carbo-
+
Carbocations C10H17 by Hydride Transfer to Methyl Cation cation or this bridged ion but return the secondary cation,
in the Gas Phase which would indicate that the barrier to rearrangement in
∆H°react this system may be especially low. This is consistent with
Cation Type (B3LYP/6-31+G*) two facts. One, to date, no bona fide observation of a pri-
mary carbocation has been made. Two, the calculated
minimum energy of even the ethyl cation (which must
1° −221.8*
be—formally, at least—a primary carbocation) occurs for
a structure in which the two carbon atoms are bridged by
a hydrogen.15 As expected, the change in hybridization of
2° −235.2 the carbocation carbon from sp2 to sp raises the energy of
the vinyl carbocations significantly; vinyl carbocations are
more difficult to make, and much more reactive than their
3° −246.3
saturated counterparts.
Similar calculations for the reaction between methyl
cation and a series of 2-substituted propanes, summarized in
2° −238.6 Table 9.3 and shown graphically in Figure 9.4, give an inter-
esting picture of the relative efficiency of stabilization of a
carbocation by an adjacent double bond or heteroatom.
What emerges confirms the general statement above.
Homoallylic −240.7* Hyperconjugation is less efficient as a method for stabilizing
a cation than conjugation with an alkene or an aromatic ring
(in this case, the difference is 6.5−18 kcal mol−1) but more
Allylic (1° ↔ 3°) −255.1 stable than conjugation with an alkyne triple bond (the
effective electronegativity of the sp-hybridized carbon is
quite high, so this is an electron-withdrawing substituent).
Stabilization by a second-row element bearing a lone
Allylic (2° ↔ 2°) −254.3
pair is considerably more efficient, with the least electro-
negative element (N) being most efficient at stabilizing the
cationic charge. The halogen series, which combines elec-
Allylic (2° ↔ 3°) −264.4 tron withdrawal by the inductive effect with electron re-
lease by conjugation is also informative: fluorine, despite
being the most electronegative, and therefore the most
Vinyl (1°) −203.6 strongly electron-withdrawing, halogen, is actually not the
least efficient at stabilizing the adjacent positive charge.
Recall that the efficiency of π overlap decreases as the p
Vinyl (2°) −224.7 orbitals come from different electron shells, and here it
would appear that the effectiveness of delocalization of the
*This energy is for the bridged, non-classical (see §9./4) cation shown. cation changes with the efficiency of the π overlap: 2p-2p
(C−F) > 2p-3p (C−Cl) > 2p−4p (C−Br).
Aromatic and Homoaromatic Carbocations

In Chapter 7, we discussed aromatic carbocations at some length. In these ions, the stabi-
lization of the cation by conjugation is supplemented by the additional stabilization con-
ferred by the aromaticity of the cation, and this results in an equalization (or close to it) of
the bond lengths in the carbocation. This is revealed by the X-ray crystal structures of the
15. (a) Hoffmann, R.; Radom, L.; Pople, J.A.; Schleyer, P.v.R.; Hehre, W.J.; Salem, L. J. Am. Chem. Soc. 1972,
94, 6221. (b) Raghavachari, K.; Whiteside, R.A.; Pople, J.A.; Schleyer, P.v.R. J. Am. Chem. Soc. 1981, 103, 5649.
(c) Ausloos, P.; Rebbert, R.E.; Sieck, L.W.; Tiernan, T.O. J. Am. Chem. Soc. 1972, 94, 8939. (d) Vorachek, J.H.;
Meisels, G.G.; Geanangel, R.A.; Emmel, R.H. J. Am. Chem. Soc. 1973, 95, 4078. (e) Klopper, W.; Kutzelnigg, W.
J. Phys. Chem. 1990, 94, 5625.

Table 9.3 Calculated Enthalpies of Hydride Transfer to Methyl Cation in the Gas Phase to Form
Substituted Isopropyl Cations
Product Cation ∆H (B3LYP/6-31+G*) Product Cation ∆H (B3LYP/6-31+G*)
−242.4 −227.0
F
−249.9
−226.2
Cl
−238.6
−226.7
Br
H
N −286.6
−209.6
C
N
O
−262.8
−214.8
CHO
H
N
CH −257.3 −199.7
NO2
O
O SiMe3 −241.9
CH −236.2
O
Me SiMe3
S −267.8
−258.7
Me
tropylium (Example 9.4) and triphenylcyclopropenium (Example 9.5) cations. The forma-
tion and manipulation of aromatic cations is rendered especially easy by their high stabil-
ity. Thus, the tropylium ion is sufficiently unreactive that the ultraviolet (UV) spectrum of
its tetrafluoroborate salt can be measured in aqueous solution.
1.434 Å 1.370 Å
1.47 Å 1.458Å
1.373 Å
ClO4
ClO4 1.376 Å
1.417 Å
16 17
(9.4)16 (9.5)17
16. Kitaigorodskii, A.I.; Strichkov, Y.T.; Khotsyanova, T.L.; Vol’pin, M.E.; Kursanov, D.N. Izv, Akad. Nauk
SSSR 1960, 39.
17. Sundaralingam, M.; Jensen, L.H. J. Am. Chem. Soc. 1966, 88, 198.

Figure 9.4 Calculated enthalpies of the reaction for the formation of substituted isopropyl
carbocations by hydride transfer reactions to methyl cation
Structure of Carbocations
The structures of a number of carbocations have been established by X-ray crystallogra
phy, and the structures all clearly show that the carbon carrying the formal charge is
planar—sp2 hybridized—in alkyl cations. Some typical carbocations are shown as
Examples 9.6 to 9.8. The structures of carbocations are also in accord with the discussion
we have had about the mechanisms for their stabilization. The structures of the two
acylium ions ( Examples 9.7 and 9.8), in particular, show clearly that the formally charged
carbon is sp-hybridized and that the carbon-oxygen bond is a triple bond rather than a
double bond, in agreement with the simple resonance picture of these cations.
SbF6
NH2
O 1.097 Å
SbF6 C
1.44 Å ClO4
1.396 Å
O 1.116 Å
C
H2N NH2 Me 1.378 Å Me 1.509 Å
18 18 19 19 20 20
(9.6) (9.7) (9.8)
18. Gomes de Mesquita, A.H.; McGillavry, C.H.; Eriks, K. Acta Crystallogr. 1965, 18, 437.
19. Boer, F.P. J. Am. Chem. Soc. 1966, 88, 1572.
20. Chevrier, B.; Le Carpentier, J.M.; Weiss, R. J. Am. Chem. Soc. 1972, 94, 5718.

Spectroscopy of Carbocations
Carbocations, being among the oldest known reactive intermediates, have been the subject
of study by almost every method used by organic chemists. The fact that the earliest carbo-
cations prepared were colored (the triphenylmethyl cation is yellow) made them candidates
for study by UV-visible spectrophotometry. In general, an extended π bonding system is
required for a molecule to absorb in the easily accessible regions of the UV-visible spectrum
(λmax> 200 nm), and carbocations (even the tert-butyl cation) show sufficient electron delo-
calization to meet this criterion. The absorption maxima and intensity of absorption of a
number of common cations are given in Table 9.4. Carbocations formed by protonation of
alkenes have been used as indicators for determining H0 values for acids.21
Carbon-13 nuclear magnetic resonance (NMR) spectroscopy is easily the most power-
ful spectroscopic technique for the study of carbocations. Stable solutions of many types
of carbocations can be prepared in superacid media (e.g., FSO3H containing the extremely
powerful Lewis acid SbF5—an acid strong enough to protonate an alkane22). The 13C NMR
spectra of carbocations not stabilized by conjugation with either a π bond or a lone pair
show a resonance for the positively charged carbon near 330 ppm, consistent with the high
degree of electron deficiency at this position. The α carbons of tertiary cations appear at
chemical shifts close to those of ketones with similar structures (typically 20 to 35 ppm);
the α carbons of secondary carbocations appear some 20 to 40 ppm downfield from those
of tertiary carbocations (close to 60 ppm).23,24,25
Table 9.4 Ultraviolet-Visible Spectra of Selected Carbocations
Cation Counterion Solvent λmax (nm) log10 ε Ref.
Me
SbF6− (FSO3−) FSO3H/SbF5 < 210 — 24
Me Me
H
292 3.46
SbF6− (FSO3−) FSO3H/SbF5 20
440 4.58
Ph Ph
Ph
403 4.59
SbF6− (FSO3−) FSO3H/SbF5 20
429 4.59
Ph Ph
Me
H 318 4.04
Me SbF6− (FSO3−) FSO3H/SbF5 370 3.64
H 480 3.08
Me
247 3.06
Br− H2O/HBr 25
275 3.64
Me
H 256 3.94
Me BF4− HF/BF3
355 4.04
H
Me
21. Deno, N.C. Surv. Progr. Chem. 1964, 2, 155.

22. Olah, G.A.; Schlosberg, R.H. J. Am. Chem. Soc. 1968, 90, 2726.
23. (a) Olah, G.A.; White, A.M. J. Am. Chem. Soc. 1969, 91, 5801. (b) Olah, G.A. Angew. Chem. Int. Ed. Engl.
1973, 12, 173.
24. Olah, G.A.; Pittman, C.U., Jr.; Waack, R.; Doran, M. J. Am. Chem. Soc. 1966, 88, 1488.
25. Doering, W.v.E.; Knox, L.H. J. Am. Chem. Soc. 1954, 76, 3203.

The spectra of non-classical carbocations (whose structures we will discuss in much more
detail in Section 9.5) show the resonance of the positively charged carbon close to 100 ppm,
some 200 ppm upfield from the carbon resonance of simple carbocation. For example, the
cyclopentyl carbocation has a single resonance at 97.1 ppm in SbF5-ClSO2F, and the positively-
charged carbon in the norbornyl carbocation resonates at 90.7 ppm26 in SbF5-SO2. In keeping
with the delocalization of the positive charge and the reduction in the overall electron-deficient
character of the cation carbon, substituted benzyl cations resonate near 230 ppm, with strongly
electron-releasing groups in a position to conjugate with the charge moving the resonance up
to 70 ppm upfield from the simple benzyl cation position.27
Worked Problem
9-1 The structure calculated for the ion [Me2C—CHO]+ is not planar but has the car-
bonyl group twisted out of the plane of the carbocation carbon. Suggest a reason-
able rationalization of this result.
O
Me
Me
H
§Answer below.
Problems
9-2 Provide a reasonable explanation for why the calculated ∆Hreact for the formation
of the cation [Me2C—CHO]+ by hydride transfer to CH3+ is more exothermic
than that for the formation of the cation [Me2C—CN]+.
9-3 Provide a reasonable explanation for the order of energies for the ions Me2CF+,
Me2CCl+ and Me2CBr+ in Table 9.3 and Figure 9.4.
26. Olah, G.A.; White, A.M. J. Am. Chem. Soc. 1969, 91, 3954.
27. (a) Olah, G.A.; Mo, Y.K.; Halpern, Y. J. Am. Chem. Soc. 1972, 94, 3551. (b) Olah, G.A.; Halpern, Y.; Mo,
Y.K.; Liang, G. J. Am. Chem. Soc. 1972, 94, 3554. (c) Olah, G.A.; Schlosberg, R.H.; Porter, R.D.; Mo, Y.K.; Kelly,
D.P.; Mateescu, G.D. J. Am. Chem. Soc. 1972, 94, 2034.

In order to answer this question, we need to examine both possible conformers: the planar conformer and
the non-planar, and we need to determine what factors in these conformers stabilize or destabilize these con-
formations. In the planar conformer, the empty 2p orbital on the positively charged carbon atom is in perfect
alignment with the π bonding system, which would result in the generation of a delocalized π orbital system.
If we look at this π orbital system in terms of resonance, we see that this places a positive charge on an
electron-deficient oxygen in the minor contributor. Such an interaction is inherently destabilizing.
Me O Me O
Me Me Me
Me H Me H Me H Me H Me H
ψ1 ψ2 ψ3 very high energy!
In the orthogonal conformer, the π-type interaction is no longer a factor. In this conformer, instead, the
possibility exists that the lone pair on oxygen may be able to interact (at least to some extent) with the empty 2p
orbital and so lead to a small level of stabilization similar to that observed in three-membered onium ions. This
effect, even small, is stabilizing.
O O O
Me Me Me
Me Me Me
H H H

9.2 Rearrangements
Up to now, we have discussed structure of carbocations without considering how their

stability might affect the outcome of a reaction in which they may be involved, except for
the rate of the reaction. However, the relative stability of the carbocation intermediate also
affects such reactions in another very important way: reactions involving carbocations
often give products with rearranged carbon skeletons. This occurs because the rearrange-
ment of a less stable carbocation to a more stable carbocation is extremely favorable. The
SN1 reaction of neopentyl bromide in aqueous ethanol (Example 9.9)28 as well as the E1
dehydration of pinacolyl alcohol with anhydrous oxalic acid (Example 9.10)29 both offer
examples of reactions that give products with rearranged carbon skeletons.
Br H2O/EtOH
HO + EtO + (9.9)
(SN1)
OH (CO2H)2/∆
+ (9.10)
5 : 2
The data in Table 9.2 suggest that the enthalpy difference between “primary” and sec-
ondary carbocations is more than 14 kcal mol−1, the enthalpy difference between second-
ary and tertiary carbocations is typically another 10 kcal mol−1, and the enthalpy difference
between saturated and allylic carbocations is a typically a further 10 kcal mol−1. These
large differences in enthalpy mean that carbocation rearrangements are very exothermic.
+
Table 9.2 (redux) Calculated ∆H°react for Formation of Isomeric Carbocations C10H17 by Hydride
Transfer to Methyl Cation in the Gas Phase
Cation Type ∆H°react (B3LYP/6-31+G*)
1° −221.8*
2° −235.2
3° −246.3
2° −238.6
Homoallylic −240.7*
Allylic (1° ↔ 3°) −255.1
(continues)
28. Dostrovsky, I.; Hughes, E.D. J. Chem. Soc. 1946, 166.

29. (a) Whitmore, F.C.; Rothrock, H.S. J. Am. Chem. Soc. 1933, 55, 1100. (b) Whitmore, F.C.; Rothrock, H.S.
J. Am. Chem. Soc. 1932, 54, 3431.

+
Table 9.2 (redux) Calculated ∆H°react for Formation of Isomeric Carbocations C10H17 by Hydride
Transfer to Methyl Cation in the Gas Phase
Cation Type ∆H°react (B3LYP/6-31+G*)
Allylic (2° ↔ 2°) −254.3
Allylic (2° ↔ 3°) −264.4
Vinyl (1°) −203.6
*This energy is for the bridged, non-classical (see §9./4) cation shown.
Thus, the Hammond postulate30 predicts that the activation energies for the exothermic
rearrangements should be extremely low, so that the reaction should be rapid. The compu-
tational results for the primary carbocation in Table 9.2 certainly suggest that this is the
case, because, depending on the exact starting geometry, computations at the B3LY-
P/6-31+G* level can return either the secondary carbocation as the minimum-energy
structure or the bridged ion.
There are, of course, limitations on carbocation rearrangements: (1) groups usually
rearrange only to the adjacent carbon atom and (2) rearrangements occur rapidly only if
the rearrangement leads to a more stable cation—if there is no net gain in stability from
the rearrangement, it is usually slow. This is nicely illustrated by the dehydration of
4-methyl-2-pentanol at 140°C, a reaction that gives a mixture of alkenes (Figure 9.5).31
In this reaction, we see that the secondary cation formed initially undergoes direct
elimination to the alkene just over 50% of the time, and that slightly less than 50% rear-
ranges by hydride shift to an isomeric secondary cation. Approximately 70% of this sec-
ondary cation, in turn, undergoes a hydride shift to the more stable tertiary cation, while
only 10% of the same cation undergoes a methide shift to give an isomeric secondary car-
bocation: the more exothermic rearrangement is strongly favored.
Rearrangements of an alkyl group or hydrogen atom to an adjacent atom in a carbocation
are called 1,2-rearrangements or Wagner-Meerwein rearrangements (after Egor Egorevich Vag-
ner,32 or Georg Wagner, who first reported them in 1899,33 and Hans Leb(e)recht Meerwein,34

31. This reaction forms the basis of an undergraduate experiment in gas chromatography: Nienhouse, E.J. J.
Chem. Educ. 1969, 46, 765. The experimental percentages reported here are the averages of those reported by
students at the University of Wisconsin−Eau Claire in 2005. Compare with the literature values:
4-methyl-1-pentene, 5.2%; 4-methyl-2-pentene (E and Z) 69.4%; 2-methyl-1-pentene, 3.8%; 2-methyl-2-pentene,
19.9%; 3-methyl-2-pentene (E and Z), 1.9%
32. Egor Egorevich Vagner (Georg Wagner, 1849–1903) was educated under Zaitsev at Kazan and under
Butlerov at St. Petersburg, where he also became assistant to Menshutkin. His career was in Poland, first at the
Novo-A leksandriya Institute of Agriculture and Forestry, then at Warsaw University. Vagner was a brilliant
chemist and a bon vivant of the first water. For more biographical details, see: Lewis, D.E. In Patterson, G.D.;
Rasmussen, S.C., Eds. Characters in Chemistry; A Celebration of the Humanity of Chemistry. ACS Symp. Ser.
2013, 1136, ch. 9.
33. (a) Wagner, E.E. Zh. Russ. Phys. Khim. Obshch. 1899, 31, 680. (b) Wagner, G.; Brickner, W. Ber. dtsch.
chem. Ges. 1899, 32, 2302. (c) Wagner, G. Ber. dtsch. chem. Ges. 1900, 33, 2121.
34. Hans Leb(e)recht Meerwein (1879–1965) was educated at Bonn (PhD, 1903). His career took him from
Charlottenburg to Bonn to Königsberg to Marburg, where he became the first Director of the Chemical Insti-
tute. Meerwein’s name is celebrated in two reactions, and the Meerwein salts. For more biographical details,
see: Jaenicke, L. Chem. uns. Zeit 1992, 20, 187.

3.6%
β−elimination
3.6%
β−elimination 58%
52%
OH2
44% ~H 6.3% β−elimination
β−elimination ~CH3
27% 2.0% 4.5%
β−elimination ~H ~H
25% 30%
β−elimination
5.1%
5.1%
β−elimination β−elimination
1.4% 3.1%
1.4% 3.1%
Figure 9.5 Acid-catalyzed dehydration of 4-methyl-2-pentanol at 140°C. The percentages indicate

the average percent of the original alcohol that reacts by that particular pathway.
whose research35 expanded Wagner’s original observations). Establishing the involvement of

carbocations in these rearrangement reactions is generally attributed to American chemist
Frank Whitmore,36 who proposed the carbocation-based mechanism for the Wagner-Meerwein
rearrangement.37
Generally, the rearrangement of a hydrogen atom occurs more rapidly than the rear-
rangement of an alkyl group. During the course of the Wagner-Meerwein rearrangement,
the migrating group remains bound to the rest of the cation; chiral alkyl groups migrate
with retention of configuration. A careful examination of the activated complex in Figure 9.6
reveals that the activated complex for a 1,2-rearrangement reaction is very similar to the ac-
tivated complex for electrophilic addition of an electrophile (proton or carbocation) to an
alkene, and this means that Markovnikov addition and carbocation rearrangement have the
same driving force governing them: the more stable cation is the preferred final product. At
the same time, note how the activated complex for the rearrangement bears a striking re-
semblance to the bridged-ion structure for the primary carbocation in Table 9.2.
35. (a) Meerwein, H.; Unkel, W. Liebigs Ann. Chem. 1910, 376, 152. (b) Meerwein, H. Liebigs Ann. Chem. 1913,
396, 200; 1914, 405, 129; 1918, 417, 255. (c) Meerwein, H.; van Emster, K. Ber. dtsch. chem. Ges. 1920, 53, 1815;
1922, 55, 2500. (d) Meerwein, H.; Gérard, L. Liebigs Ann. Chem. 1923, 435, 174. (e) Meerwein, H.; Hammel, O.;
Serini, A.; Vörster, J. Liebigs Ann. Chem. 1927, 453, 16.
36. Frank Clifford Whitmore (1887−1947) was educated at Harvard and worked at Minnesota, Northwest-
ern, and Pennsylvania State University. His major contributions were to the theory of carbocation rearrange-
ments. For more biographical details, see: Marvel, C.S. Biogr. Mem. Nat. Acad. Sci. (National Academy of
Science: Washington, D.C., 1954), p. 287.
37. (a) Whitmore, F.C. J. Am. Chem. Soc. 1932, 54, 3274. (b) Whitmore, F.C.; Johnston, F. J. Am. Chem. Soc. 1933,
55, 5020. (c) Whitmore, F.C.; Rothrock, H.S. J. Am. Chem. Soc. 1932, 54, 3431. (d) Whitmore, F.C.; Fleming, G.H.
J. Am. Chem. Soc. 1933, 55, 4161. (e) Whitmore, F.C.; Wittle, E.L.; Popkin, A.H. J. Am. Chem. Soc. 1939, 61, 1586.
It is interesting that Whitmore refused call his reactive intermediate a “carbonium ion,” and that, in fact, he
explicitly excluded the equivalency of his neopentyl intermediate and the carbonium ion proposed by Meer-
wein: Whitmore, F.C.; Fleming, G.H. J. Chem. Soc. 1934, 1269.

R R ‡ R R
R
R
H
H
H
H H H
H H
Ra H H
R R ‡
R
R Ra
Rc
Rb
Ra
Rc Rc
Rb R
R
H H
H H Rb
Figure 9.6 The Wagner-Meerwein shift of hydrogen (top) and alkyl (bottom). Both reactions
pass through an activated complex whose orbital arrangement closely resembles the overlap of
the π bond of an alkene with the empty orbital of an electrophile during an electrophilic addition
reaction.
Problems
9-4 What is the product of each of the following reactions if each is carried out under
ideal SN1 conditions? Write the mechanism of the reaction with the structures of
all intermediates involved in the formation of the final product.
C2H5OH NaOH, H2O
(a) (b)
Br SN1 SN1
Br
Br
Cl KOH, H2O
(c) NaOH, H2O
(d)
SN1 SN1
C8H17
MeOH AgNO3
(e) (f) EtOH-H2O
Br
TsO
9-5 Write a reasonable mechanism for each of the following reactions.

O O O O
OEt CF3CO2H OEt FSO3H

(a) CH2Cl2
(b) SbF5
HO OH
SO2
The foregoing discussion tacitly assumes that carbocation rearrangements lead to the
more stable cation as the product, and this is generally the case. It is not, however, always
the case, as has been illustrated by Nishizawa on the rearrangement of cations generated
from certain tertiary alcohols (e.g., Example 9.11).38 In this work, Nishizawa has observed
38. Nishizawa, M.; Asai, Y.; Imagawa, H. Org. Lett. 2006, 8, 5793.

that the counterion is critical to determining the product of the rearrangement, because
the counterion affects the conformation of the rearranging carbocation. The rearranging
group must fulfill a stereoelectronic requirement that permits the type of activated com-
plex shown in Figure 9.6 to be formed (i.e., the σ bond to the migrating group must be able
to achieve coplanarity with the empty 2p orbital on the cation carbon). Therefore, any-
thing that restricts the conformation of the cation will affect the outcome of the reaction.
Cl
TiCl4
(9.11) OH (9.12)
-78°C
BF3 (9.13)
+
Transannular Rearrangements
Transannular rearrangements are rearrangements from one position of a reactive inter-
mediate to a remote position of the same intermediate by transfer of a group across a
medium-sized ring. Thus, in carbocations where the cation carbon is part of a medium-
sized ring, we find that the cation may be isomerized by rearrangement of the hydrogen
from one side of the ring to the other. This type of rearrangement is facilitated by the fact
that there is severe steric crowding of one side of the medium-sized ring by the other,
bringing the groups on opposite sides of the ring into van der Waals contact with each
other in many cases. This same steric crowding is why (1) medium-sized rings are difficult
to make by most cyclization methods and why (2) the ring strain in medium-sized rings
rises to a maximum before falling as the ring size gets larger.
One example of this is provided by the reaction of the alcohol in Example 9.14,39 where
the hexacyclic compound (Example 9.16), that one would predict to be the major product
of the reaction, formed by cyclization of the initial carbocation (Example 9.15), was not.
Instead, the carbocation underwent a 1,4- (transannular) rearrangement of hydrogen from
the other benzylic position to give a tertiary carbocation (Example 9.17) that lost a proton
to give the observed product (Example 9.18). Note the proximity of the migrating hydro-
gen to the largest lobe of the LUMO of the cation in Example 9.15.
39. Lansbury, P.T. Acc. Chem. Res. 1969, 2, 210.

Problem
9-6 The following reaction has been used as part of a synthesis of a precursor to
1-deoxypaclitaxel. Suggest a mechanism for the reaction. The workup of the reac-
tion involved the sequential addition of methanol and then sodium potassium
tartrate solution. Suggest a mechanism for the reaction and give reasons why the
reaction should occur at all.
Ar
O O OTBS HO O OTBS
H H
Et2AlCl/CH2Cl2
H H Ar = OMe
-78°C — r.t
HO HO
O OAc HO OAc
Reaction Synopses
Carbocation Rearrangements
R R R R R R
R R
R R R R R X R X
X: OH, OR, NR 2, SR, etc.

Regiochemistry: more stable carbocation almost always predominates
Transannular rearrangements: can occur in medium-sized (8- to 12-membered)
cyclic carbocations
9.3 Neighboring Group Participation
The carbocations that we have discussed so far are classical carbocations, where the
positive charge is formally localized on a single carbon or delocalized by conjugation
(π-type overlap of the empty p orbital with an adjacent π bond or lone pair) or hyper-
conjugation (π-type overlap of the empty p orbital with a σ bond on the adjacent atom).
However, in the late 1950s, American chemist Saul Winstein40 noted that certain alkyl
halides and similar compounds with good leaving groups underwent SN1 reactions sev-
eral hundred times more rapidly than would be predicted on the basis of the structures
of the carbocations that should form as intermediates, whereas other structurally simi-
lar compounds reacted at the rates one would predict. The one common structural fea-
ture of these species was the presence of a nearby group that had an available electron
pair—either a π bond or a lone pair—to assist the heterolysis of the carbon-leaving
group bond. This group was not in the position to participate in hyperconjugation or
conjugation with the cation center. Winstein proposed that the heterolytic step of the
rapid SN1 reactions was assisted by this nearby group in a process known as neighboring
group participation and introduced the term anchimeric assistance to describe the
40. Saul Winstein (1912–1969) was born in Montreal, and educated at the University of California, Los
Angeles (UCLA) (AB, MA) and the California Institute of Technology (PhD, 1938). After a postdoctoral fellow-
ship at Harvard, Winstein began his career at the Illinois Institute of Technology in Chicago; he moved to
UCLA in 1941. He was embroiled in an often vitriolic controversy with H.C. Brown over the non-classical
carbocation that lasted the rest of his life. For more biographical details, see: Young, W.G.; Cram, D.J. Int.
J. Chem. Kinetics 1970, 2, 167.

δ+ Figure 9.7 Neighboring
nX nX n group participation in the
δ+ R X product (9.19) heterolysis of a carbon-
Y
R
R Yδ− R R R leaving group bond by a
heteronium nearby heteroatom
ion
phenomenon.41 It is generally observed that anchimeric assistance occurs only when

absolutely needed (either the carbocation being formed is relatively high energy, or the
leaving group is poor). It is seldom found to occur when the starting compound is ter-
tiary, for example. This phenomenon has been described this phenomenon in terms of a
tool of increasing electron demand.42
The net result of neighboring group participation by atoms with lone pairs is to form a
transient intermediate heteronium ion, where the positive charge is localized on the het-
eroatom (Figure 9.7). It is important to remember that the slow step of these reactions is
still the unimolecular ionization of the alkyl halide or sulfonate, so the reaction is still an
SN1 reaction. However, reactions involving heteronium ions occur much more rapidly
than similar reactions where anchimeric assistance does not occur.
The intermediacy of a heteronium ion in such reactions has been inferred from the
stereochemistry of the SN1 reactions of the two stereoisomers of 3-bromo-2-butanol,43
which give different stereoisomers of the dibromide. In some cases,44 the heteronium ion
has been intercepted, and a salt of one has been isolated. When anchimeric assistance
occurs during an SN1 reaction, the stereochemical outcome also differs from what is ob-
served in unassisted reactions: the product is no longer racemic but is formed with reten-
tion of configuration at the reacting carbon.
Me Br Br Me Br
HBr
H H H H H H (9.20)
HO Me Me Me Br Me
Me Br Br Me Br
HBr
H H H H H H (±) (9.21)45
HO Me Me Me Br Me
O Me H O Me
CH3CO2H O 46
Me (±) (9.22)
O O
OTs O O
H
O Me
O Me H H
EtOH O EtOH O CH3
45, 46
O Me (9.23)
O O OEt
OTs H
H
41. (a) Winstein, S. Bull. Soc. Chim. France 1951, 18, C55. (b) Streitwieser, A., Jr. Chem. Rev. 1956, 56, 675. (c) Capon,
B. Quart. Rev. Chem. Soc. 1964, 18, 45. (d) Gould, E.S. Mechanism and Structure in Organic Chemistry (Holt, Rinehart,
and Winston: New York, 1959), ch. 14. (e) Isaacs, N.S. Physical Organic Chemistry (Longman Scientific & Technical:Burnt
Mill, Harlow, 1987), pp. 589–595. (f) Allred, E.L.; Winstein, S. J. Am. Chem. Soc. 1967, 89, 3991, 3998. (g) Winstein, S.;
Allred, E.; Heck, R.; Glick, R. Tetrahedron 1968, 3, 1. (h) Winstein, S.; Grunwald, E. J. Am. Chem. Soc. 1948, 70, 828.
(i) Capon, B.; McManus, S.P. Neighboring Group Participation (Plenum: New York, 1976).
42. Lambert, J.B.; Mark, H.W.; Holcomb, A.G.; Magyar, E.S. Acc. Chem. Res. 1979, 12, 317.
43. Winstein, S.; Lucas, H.J. J. Am. Chem. Soc. 1939, 61, 1576.
44. (a) Winstein, S.; Grunwald, E.; Buckles, R.E.; Hanson, C. J. Am. Chem. Soc. 1948, 70, 816. (b) Winstein,
S.; Hanson, C.; Grunwald, F. J. Am. Chem. Soc. 1948, 70, 812. (c) Winstein, S.; Hess, H.V.; Buckles, R.V. J. Am.
Chem. Soc. 1942, 64, 2796.
45. Winstein, S.; Buckles, R.E. J. Am. Chem. Soc. 1942, 64, 2780, 2787; 1943, 65, 613, 2196.
46. Winstein, S.; Anderson, C.B.; Friedrich, E.C. Tetrahedron Lett. 1963, 2037.

Figure 9.8 SN1 substitutions threo meso

of stereoisomeric (2S*,3S*)
3-bromo-2-butanols Me Br
Me Br Me Br Br
H H H H H H H H (9.24)
HO Me H2O Me Me Me Br Me
(±)
H Br
erythro (±)
(2S*,3R*)
Me Br Me Br Br Me Br
H H H H H H H H (9.25)
HO Me H2O Me Me Me Br Me
meso
H Br
This stereochemical outcome is a result of two inversions (Figure 9.8). The first inversion
occurs during the ionization of the alkyl halide: the lone pair on the assisting atom attacks the
developing carbocation from the back side as the leaving group departs. In the second step,
this is reversed: as the bond to the assisting atom is broken, the nucleophile attacks the incipi-
ent carbocation from the back side, leading to net retention of configuration at the reacting
carbon atom—the second inversion reverses the first. Retention of configuration, especially
when coupled with the evidence of the rate law and solvent effects, and so on, is usually suffi-
cient to indicate that anchimeric assistance takes place during a reaction. It is also noteworthy
that both enantiomers of threo-3-bromo-2-butanol (Example 9.24) gave racemic product,
strongly implying that meso stereochemistry of the intermediate bromonium ion is meso.
Worked Problem
9-2 The two optically active sulfonates below undergo solvolysis in acetic acid to give
the outcomes shown. Provide a reasonable rationalization for this observation.
OTs OAc OTs OAc
MeO MeO MeO MeO

this enantiomer (±) this enantiomer this enantiomer
§Answer below.

In both reactions, the ionization of the sulfonate is assisted by the participation of the π electrons of the
electron-rich aryl group to give a bridged benzenonium in the first step of the reaction. This participation in the
solvolysis leads to inversion of configuration at the carbon carrying the leaving group, so the stereochemistry
of the benzenonium ion will reflect the stereochemistry of the starting sulfonate:
Me OTs Me OTs
H Me H Me
Me Me
Me Me
MeO H MeO H
MeO MeO
chiral: this enantiomer only achiral: meso
In the second step, the attack of the acetate anion on the benzenonium ion leads to the racemic product when
the benzenonium ion is meso, and it returns an optically active product with overall retention of configuration
when the benzenonium ion is chiral.

Problems
9-7 What will be the major product(s) outcome of each of the following reactions?
Where more than one product may form, indicate which is expected to be the
major product. Assuming that each chiral compound is used as the enantiomer
shown, what will be the stereochemistry of the final product(s)?
D
D H2O, Me2CO O AcOH
(a) (b) OTs
Br (SN1) (SN1)
OMe
Br H2O, Me2CO S AcOH

(c) (SN1)
(d) (SN1)
OMe Br
9-8 Is neighboring group assistance involved in the following reaction? Support your
answer with a mechanism.
O 1) TiCl4
MeO O OR ROH
2) H2O
9-9 Write a reasonable mechanism for the transformations below:
O O OMOM OMOM
O O
K2CO3, Me2CO-H2O
(a) H H
sealed tube, 80°C
H OH H O
OTs
H H
TsOH, PhH
(b) H Me 80°C, 2 h H
HO H Me
H
OH
Reaction Synopses
Neighboring Group Participation (Anchimeric Assistance)
R X R R R Y
R H R H R H
R Z R
Z Z
Z: OH, OR, OCOR, RCONR’, SR, RCO, etc.

Stereochemistry: always results in retention of configuration at carbon with leav-
ing group
Reaction speed: usually much faster than similar unassisted reactions
9.4 Nonclassical Carbocations
The question of modes of stabilization of carbocations arose in the late 1940s when Win-
stein and Trifan noted that the solvolysis of exo-2-norbornyl sulfonates (Example 9.26) in
acetic acid occurred some 350 times faster than the same solvolysis of the endo isomers
(Example 9.27) or of the corresponding cyclohexyl compounds.47 In addition, they
observed that the same product—exclusively the exo acetate—was obtained regardless of
47. Winstein, S.; Trifan, D.S. J. Am. Chem. Soc. 1949, 79, 2953.

which diastereoisomer of the starting sulfonate ester was used—and that the product from
optically active starting sulfonates was completely racemized.
AcOH (±)-
X OAc (9.26)
rel. rate = 350
H H
AcOH
H (±)- OAc (9.27)
rel. rate = 1
X H
X = OTs, OBs
These observations were rationalized in terms of a mechanism involving participation
by the electrons of the σ bond anti to the carbon-leaving group bond to give a bridged
carbocation that was Cs-symmetric. In 1951, Roberts48 first used the term non-classical to
describe these σ-bridged carbocations. The non-classical carbocation concept ignited a
firestorm of controversy in organic chemistry,49 involving the research groups of Brown50
and Winstein, and, after Winstein’s death, of Olah.51
The question is still not completely resolved, but when the neighboring group that
participates in the heterolysis step is a non-adjacent C—C σ or π bond, the cation formed
is today generally (but not universally) accepted as being non-classical. In a non-classical
cation, the charge is delocalized by σ-type overlap of the empty p orbital on the charged
carbon atom with a σ bond or with π bond that is not adjacent to it. Clearly, this stabili-
zation mechanism has rather stringent structural requirements, so it may not be unrea-
sonable to view this type of stabilization as a last resort—usually a bridged cation will not
form unless there is no alternative. This typically restricts non-classical carbocations to
primary or secondary cations. Most tertiary carbocations are sufficiently stabilized by
hyperconjugation that they do not require stabilization by bridging; tertiary cations are
classical.
48. (a) Roberts, J.D.; Mazur, R.H. J. Am. Chem. Soc. 1951, 73, 3542. (b) Roberts, J.D.; Lee, C.C. J. Am. Chem.
Soc. 1951, 73, 5009.
49. For leading papers and monographs, see: (a) Winstein, S.; Clippinger, E.; Howe, R.; Vogelfanger, E. J. Am.
Chem. Soc. 1965, 87, 376. (b) Colter, A.; Friedrich, E.C.; Holness, N.J.; Winstein, S. J. Am. Chem. Soc. 1965, 87,
378. (c) Winstein, S. J. Am. Chem. Soc. 1965, 87, 379, 381. (d) Brown, H.C. Pure Appl. Chem. 1982, 54, 1783.
(e) Sargent, G.D. In Olah, G.A.; Schleyer, P.v.R., Eds. Carbonium Ions, vol. 3 (John Wiley: New York, 1972), ch.
24. (f) Bartlett, P.D. Non-Classical Ions: Reprints and Commentary (Benjamin: New York, 1965). (g) Olah, G.A.;
Jewett, C.L.; Kelley, D.P.; Porter, R.D. J. Am. Chem. Soc. 1972, 94, 147. (h) Berson, J.A. In DeMayo, P., Ed. Molec-
ular Rearrangements, Part One (Wiley: New York, 1963). (i) Brown, H.C. The Non-Classical Ion Problem
(Plenum: New York, 1977). (j) Sargent, G.D. Quart. Rev. Chem. Soc. 1966, 20, 301. (k) Saltzmann, M.D.; Wilson,
C.L. J. Chem. Educ. 1980, 57, 289.
50. Herbert Charles Brown (1912–2004) was born in London, and educated at the University of Chicago
(PhD, 1938), where he stayed as a postdoctoral researcher and instructor. He moved to Wayne State in 1943, and
to Purdue in 1947. His development of hydroboration as a synthetic method revolutionized synthetic organic
chemistry. Brown shared the 1979 Nobel Prize in Chemistry. For more biographical details, see the Nobel
Foundation website.
51. George Andrew Olah (1927–) was educated at the Budapest Technical University (PhD, 1949), where he
remained until 1954. In 1954 he became Associate Director of the Central Research Institute of the Hungarian
Academy of Sciences and head of the organic chemistry laboratory. In 1956, he fled to Canada, and he moved to
Case Western Reserve University in 1965 and to the University of Southern California in 1977. He received the
1994 Nobel Prize in Chemistry for his work in carbocation chemistry. For more biographical details, see Olah’s
autobiography: Olah, G.A. A Life Of Magic Chemistry: Autobiographical Reflections of a Nobel Prize Winner.
(Wiley-Interscience: New York, 2000).

Figure 9.9 The norbornyl

cation is the prototypical
non-classical carbocation.
non-classical (9.28) classical (9.29)
non-classical (9.30) Figure 9.10 The homoallyl

classical (9.31) carbocation
H
H H H H
H H
H H
cyclopropyl
-carbinyl homoallyl cyclobutyl
(9.32) (9.33) (9.34)
The most famous non-classical cation is the norbornyl cation, about which hundreds of
research articles have been written.52 The structure of the norbornyl cation can be written
as a bridged non-classical cation, as a pair of rapidly equilibrating classical ions, or as a π
complex of a primary cation and an alkene π bond (Figure 9.9). By 1990, sufficient experi-
mental evidence53 had accumulated to convince the vast majority of organic chemists that
the non-classical cation is legitimate but not before more than three decades of (often ran-
corous54) debate. Even so, the question still draws attention today,55 but the low-temperature
X-ray crystal structure determination of the tetrabromoaluminate salt in 201356 clearly re-
veals that the non-classical structure is correct.
Another group of cations that are, in a formal sense, at least, non-classical are the ho-
moallyl cation57 (Figure 9.10) and the structurally similar homoaromatic carbocations. In
the homoallyl cation, there is involvement of the π bond through space to allow delocal-
ization of the positive charge over more atoms in the ion. This delocalization is different
from classical conjugation because the delocalization is actually σ delocalization rather
than π delocalization. In homoaromatic carbocations, the same situation applies: the
formal cyclic conjugated π electron system is interrupted by at least one sp3 hybridized
carbon, and the electron delocalization has at least some σ character.
All the precursors that would lead to non-classical cations react unusually rapidly in
SN1 reactions, and unusually fast reactions are often interpreted as experimental evidence
that a nonclassical carbocation may be involved as a reaction intermediate in SN1 reac-
tions. In addition, modern computations at a relatively high level of sophistication predict
that primary carbocations also have a σ-bridged structure that leads to electron delocal-
ization. These structures are, therefore, entirely analogous to the structure of the non-
classical norbornyl cation shown in Figure 9.9, so primary carbocations, also, may
reasonably be designated as nonclassical carbocations. A similar situation holds true for
many secondary, cyclic carbocations (e.g., the cyclopentyl carbocation).
52. For historical perspectives on this most famous of questions, see: (a) Davenport, D.A. Aldrichimica Acta
1987, 20, 25. (b) Weininger, S.J. Bull. Hist. Chem. 2000, 25, 123.
53. The key evidence came from 13C NMR spectroscopy, which showed that the two interconverting classical
carbocations could not be separated by a barrier of more than 0.2 kcal mol−1, based on classical rate theory:
Yannoni, C.S.; Macho, V.; Myhre, P.C. J. Am. Chem. Soc. 1982, 104, 7380.
54. Commentary from an “innocent bystander”: Walling, C. Acc. Chem. Res. 1983, 16, 448
55. (a) Werstiuk, N.H.; Muchall, H.M. J. Mol. Struct. (Theochem.) 1999, 463, 225. (b) Werstiuk. N.H.; Muchall,
H.M. J. Phys. Chem. A 2000, 104, 2054. (c) Smith, K.; Pan, H.; Hondrogiannis, G.; Mamantov, A.; Pagni, R.M.
ARKIVOC 2009, 68.
56. Scholz, F.; Himmel, D.; Heinemann, F.W.; Schleyer, P.v.R.; Meyer, K.; Krossing, I. Science 2013, 341, 62.
57. Roberts, J.D.; Mazur, R.H. J. Am. Chem. Soc. 1951, 73, 3542.

Problems
9-10 The solvolysis in acetic acid of exo-2-norbornyl-2,3-14C2 p-bromo-benzenesulfonate

(below) gives the labeling pattern shown (the heavy dots indicate the labeled posi-
tions, although the label does not occur at positions 1 and 4 simultaneously). What
does this pattern of labeling in the product tell you about the structure and dynam-
ics of the cation intermediate in the solvolysis? [J. Am. Chem. Soc. 1954, 76, 4501].
AcOH
OBs 45°C OAc OAc OAc OAc
30 min
H H H H H
31.5 : 20.1 : 28.1 : 18.5
9-11 SN1 nucleophilic substitution of the enantiomerically pure bromides below by

water is expected to occur unusually rapidly due to probable anchimeric assis-
tance. Write a mechanism that shows the structure of the intermediate hetero-
nium ions that would be formed if the oxygen atom participates in the reaction.
Are any of these heteronium ions further stabilized by resonance? What is the
stereochemistry of the final product of each reaction?
H3C
H3CO CH3 H2O O CH3 CH3CO2H
(a) H
H (b) O H H
H3C Br H3C Br
9-12 When the two regioisomeric alkyl tosylates below are solvolyzed in aqueous etha-
nol, the same mixture of alcohols is obtained. Draw the structures of the ex-
pected products and rationalize their formation.
(a) MeO OTs (b) MeO OTs
9-13 One of the two halides below is expected to react much faster than the other in an
SN1 solvolysis in 80% aqueous ethanol to give an alcohol product. Which isomer
is expected to react faster—and why?
(a) (b)
Br OCH3 Br OCH3
9-14 When cyclohexane is treated with HBr-AlBr3, methylcyclopentane is formed; the

reaction is accelerated by a catalytic amount of cyclohexene. Write a mechanism
for this transformation and show how non-classical carbocations may be involved
in the process.
9-15 The formation of 1,2-diols from alkenes is an important oxidation reaction.
Osmium tetroxide gives the cis-1,2-diol where the reagent has attacked the alkene
from the less-hindered side. R. B. Woodward developed a method for the synthe-
sis of the same product where the two OH groups are added to the more hindered
face of the double bond (e.g., giving a diol where there is a 1,3-diaxial interaction
with the methyl group in the example shown). The reaction involves the addition
of an acyl hypoiodite to an alkene in moist acetic acid. Suggest a reasonable
mechanism for this reaction.
OH
H 1) AgOAc (2 eq), I2 (1 eq), HOAc-H2O H
2) KOH, MeOH OH
H H
O O

9.5 Methods for Generating Carbocations
Methods for the generation of carbocations from non-ionic precursors can be subdivided
into four major classes. The first two of these are the most widely used, and they consist of
(1) addition of an electrophile to a π bond (Example 9.35) and (2) heterolysis of a bond to a
leaving group (Example 9.36). Strong Lewis acids such as aluminum chloride can—formally,
at least—abstract a hydride anion from alkanes to generate carbocations (Example 9.37).
A final method, based on one-electron oxidation of a neutral precursor, is of less general
utility (Example 9.38).
E (9.35)
E
X (9.36)
MXn
H (9.37)
–e (9.38)
X
X•
The loss of a leaving group from a cation precursor is by far the most common method
for preparing carbocations. Leaving groups in general may be categorized as good or poor,
with groups such as the diazonium ion or trifluoromethanesulfonate ester (triflate, OTf)
being excellent leaving groups in most solvents. Vinyl triflates, for example, can serve as
precursors to the otherwise difficult-to-form vinyl cations. At the other end of the leaving
group spectrum are groups such as fluoride, which is a poor leaving group under normal
conditions, and groups such as hydroxide, which acts as leaving group only under excep-
tional circumstances. In recent years, there has been an effort to quantify the ability of a
leaving group to leave, and this has included the development of approximate scales of
intrinsic nucleofugality in the gas phase.58 An approximate ranking of leaving group abil-
ity derived from solution-phase reactions is given in Table 9.5.
The one feature of the data in Table 9.5 is that the best leaving groups are those that
leave as the weakest bases, so that any method that will increase the strength of the conju-
gate acid of the leaving group should also lead to an improvement in the ability of the
group to function as a leaving group. This is observed. We can see this from the experi-
mental rate data in Table 9.5. These data show that trifluoroacetate esters solvolyze more
rapidly than do acetates by several orders of magnitude and that p-nitrobenzoate esters
solvolyze some four times faster than the acetate. These values are in accord with the pKa
values of the conjugate acids of the leaving groups (−0.25 to 0.3, depending on the source
of the data; 3.44; 4.76, respectively).
The logical conclusion that one can draw from the data in Table 9.5 is that decreasing
the basicity of the leaving group increases the effectiveness of the leaving group. The sim-
plest method for doing this is to conjugate the leaving group with a strong Lewis acid, and
H+, BF3, ZnCl2, and TiCl4 have all been used for this purpose. This concept has been taken
to its limit by Olah, who showed that one can convert a modest leaving group into a pow-
erful leaving group by complexation with SbF5 (one of the few Lewis acids strong enough
to have a bridging fluorine atom in the solid phase). Using SbF5, Olah was able to generate
carbocations from alkyl chlorides and fluorides under conditions where they could be
studied spectroscopically. The SbF5X− ion is non-nucleophilic, and so the carbocations
were not intercepted, as is usually the case in solvolysis reactions.
58. Jaramillo, P.; Domingo, L.R.; Pérez, P. Chem. Phys. Lett. 2006, 420, 92–99.

Table 9.5 Leaving Groups in Approximate Decreasing Order of Ability to Leave at sp3 Carbon
Conjugate Base of
Substrate Leaving Group Relative Rate Constant for Solvolysis Ref.
R—N2+ N2
R—OTf CF3SO2− 1.4 × 108 59
R—OSO2F FSO3−
R—OSO2R′ R′SO3− 3.0 × 104 (R′ = Me); 43

3.7 × 104 (R′ = p-C6H4Me)
R—I I− 91 43
R—Br Br − 14 43
R—OH + H 2O
2
R—OCOCF3 CF3CO2− 2.1 43

R—Cl Cl− 1.0 43
R—O(R′)H+ R′OH
R—OPO3H H3PO4
R—SR′2+ R′2S
R—NR′3+ R′3N
R—F F− 9 × 10−6 43
R—OCOR′ R′CO −
2
1.4 × 10 (R′ = Me);
−6 43
5.5 × 10−6 (R′=p-C6H4NO2)
Another method for increasing the effectiveness of a leaving group is to incorporate it

into a small ring (Example 9.39). Thus, although ethers are protonated only under strongly
acidic conditions, epoxides are protonated by dilute aqueous acids, and the three-
membered oxonium ions react as carbocations in solution. A similar situation occurs with
the aziridines (where X=NR).59
H
(9.39)
X X X
H H
The generation of carbocations by addition of electrophiles to alkenes is an important
step in the overall addition of electrophilic reagents to alkenes, and this underlies the basis
for the fact that Markovnikov regiochemistry predominates in such reactions. The stron-
ger the acid, the more favorable the protonation, and this has led to the development and
use of superacids (acids whose H0 values are more negative than concentrated H2SO4). The
strongest acid known is hexafluoroantimonic acid, HSbF6, which is formed by dissolving
SbF5 in HF. Olah developed “magic acid” (HSO3F/SbF5) for the study of carbocations. Both
these acids are strong enough to protonate even saturated hydrocarbons to give onium
ions that lose molecular hydrogen to give trivalent carbocations.60 Some idea of the types
of reactions that occur when alkanes are teated with “magic acid” can be gained from
Figure 9.11. In addition to the alkane reactions, once alkenes are formed, the cations can
add to the alkenes to generate larger, more complex carbocations. The reaction between
59. Solvolysis of PhCHXMe in 80% EtOH at 75°C: Noyce, D.S.; Virgilio, J.A. J. Org. Chem. 1972, 37, 2643.
60. Olah, G.A.; Schlosberg, R.H. J. Am. Chem. Soc. 1968, 90, 2726.

H2 Figure 9.11 The reaction

between methane and other
FSO3H saturated hydrocarbons and
CH4 CH5 CH3 “magic acid.” (Adapted from
SbF5
Olah, G.A. A Life of Magic
Chemistry: Autobiographical
CH4 Reflections of a Nobel Prize
H2 H Winner. (Wiley-Interscience:
FSO3H New York, 2000.)
C2H6 C2H7
SbF5 C2H5 C2H4
H
CH4
H H2
C3H8 C3H9 C3H7
alkenes and strong acids in a strongly ionizing solvent such as liquid sulfur dioxide gives
carbocations under conditions that allow them to be studied by NMR, for example. In a
similar vein, the treatment of alkanes with strong Lewis acids such as aluminum b romide
results in carbocation formation (ostensibly by hydride abstraction from the alkane), with
concomitant formation of an anionic “ate” complex from the Lewis acid. The resultant
cations may rearrange before reacting with the hydride “ate” complex to regenerate a rear-
ranged alkane, as illustrated by the synthesis of adamantane from the tricyclic precursor,
tricyclo[5.2.1.02,6]decane (Example 9.40).61
AlCl3
HAlCl3
150-180°C (9.40)
The remaining methods for the generation of carbocations are not suited for their
large-scale generation. Carbocations can be formed by ionization of neutral molecules,
either by electron impact or by radioactive decay. In the mass spectrometer, for example,
the impact of a high-energy electron on a neutral molecule in the gas phase gives rise to
a radical cation, which is an odd-electron species. The excess energy in the radical cation
from the electron impact leads to fragmentation to give a more stable even-electron
species (a simple cation). Based on the potential at which various ions are formed (the
appearance potential of the ion), one can deduce a number of parameters about the
molecule undergoing ionization, including, among other things, bond strengths in the
molecule.
The final method for the generation of a carbocation comes from the use of tritiated com-
pounds as precursors to the cation. In this case, the radioactive β decay of the tritium atom
leads to a species bearing a positive charge, with what is formally, at least, a carbon-helium
bond to the helium-3 atom generated by the nuclear reaction. This immediately loses a helium
atom to give the free cation. Of course, because tritiated compounds are used in a tracer
mode, this method is of very limited applicability.
e 3
He
3 3
H R He R R (9.41)
61. Schleyer, P.v.R.; Donaldson, M.M.; Nicholas, R.D.; Cupas, C. Org. Syn. 1973, Coll. Vol. 5, 16.

Reaction Synopses
Forming Cations by Heterolysis or Solvolysis
solvent
R X R X
X: N > OTf > I > OTs ≈ OMs ≈ Br > OH > Cl ≈ OTFA > F ≈ NR 3+ > OR
+
2
+
2
Solvent: EtOH-H2O; AcOH; HCO2H; CF3CO2H; H2O-dioxane; etc.
Forming Cations by Heterolysis Assisted by Lewis Acids
MYn
R X R X MYn
solvent
X: Cl, F, OH, OR
MYn: BF3; BBr3; AlCl3; AlBr3; Me3SiI; SnCl4; TiCl4; ZnCl2; SbF5; etc.
Solvent: usually an alkane or CH2Cl2
Forming Cations with Superacids
HY
R X R X H Y
solvent
X: OH, OR
HY: H2SO4; FSO3H; HF-SbF5; etc.
Solvent: usually FSO3H, SO2 or similar strongly ionizing solvent
Forming Cations from Alkenes
R R HX R R
H
solvent
R R R R
X: Cl, Br, I, OSO3H, ClO4; BF4; etc.
Regiochemistry: Markovnikov addition usually occurs
Forming Cations by Hydride Abstraction
MYn
R H R H MYn
solvent
MYn: AlBr3; SbF5; etc.
Chapter Summary
This chapter introduced the carbocations, one of the oldest known classes of reactive in-
termediates that participate in organic reactions. Carbocations possess a tricoordinate
carbon atom carrying a formal positive charge. They can be generated by heterolysis, elec-
trophilic addition, radiolysis, or electron impact, with the first two methods being the
most common.
Carbocations are stabilized by any mechanism that leads to delocalization of the charge
from carbon. There are three such mechanisms. In descending order of effectiveness, they
are conjugation with the lone pair on a heteroatom, conjugation with a C—C π bond, and
hyperconjugation. One manifestation of hyperconjugation is the Baker-Nathan effect. The
13
NMR spectroscopy of carbocations generated in superacid medium has been discussed.
Stabilization of a carbocation by a lone pair on a heteroatom located where it can
form a cyclic heteronium ion is known as neighboring group participation or anchimeric
assistance. Anchimeric assistance leads to retention of configuration in SN1 reactions, for
example. Stabilization of carbocations by non-adjacent σ or π bonds gives rise to

non-classical carbocations. Primary and secondary carbocations are almost always

non-classical, but tertiary carbocations are stabilized enough by hyperconjugation that
bridging is unnecessary.
The characteristic reaction of carbocations is the Wagner (Vagner)-Meerwein rear-
rangement, which is a 1,2-rearrangement of hydrogen or alkyl. During the Wagner-
Meerwein rearrangement, the migrating alkyl group retains its configuration.
Key Terms
anchimeric assistance classical carbocation solvolysis

Baker-Nathan effect non-classical cation superacid
carbenium ion heteronium ion Wagner-Meerwein
carbocation neighboring group rearrangement
carbonium ion participation
Additional Problems
9-16 The homoallyl cation seldom rearranges to the allyl cation, even though the
latter is stabilized by resonance. What inferences can you make from this
observation—beyond the obvious one that the activation energy for this rear-
rangement must be too high to permit rapid rearrangement?
9-17 The closure of the tetracyclic carbon skeleton of steroids involves a cascade of
carbocation reactions that is initiated by protonation of the epoxide oxygen of
squalene epoxide. The starting epoxide is shown, along with the intermediate
tetracyclic carbocation, and the final product, lanosterol.
H
HO H
H
H
H
HO
H
H
(a) Write a mechanism that accounts for the formation of the tetracyclic interme-
diate carbocation.
(b) Does any part of the mechanism of formation of the tetracyclic carbocation
involve an unusual stereochemical or regiochemical outcome?

(c) The final tetracyclic product is formed by the rearrangement of several

groups. Where it is possible to deduce the stereochemistry of the reaction and
what is the stereochemistry of each rearrangement?
9-18 1-Adamantyl halides and sulfonates are bridgehead compounds that react under
solvolytic conditions to give substitution products, and the bicyclo[2.2.1]hept-1-yl
halides and sulfonates are resistant to both solvolysis and bimolecular nucleop-
hilic substitution. Rationalize the difference in the reactivity of these two
systems.
X
X
9-19 The reaction of the amine shown with nitrous acid gives a diazonium ion. This
ion loses nitrogen to give a carbocation that gives compounds (e.g., the alcohol
shown) based on the tricyclic skeleton shown as the major products of the reac-
tion. Give the structure of this cation intermediate, and rationalize the formation
of this product from it.
HONO HO
NH2
9-20 How many mechanistically different ways are there, potentially, to generate the
2-norbornyl cation? If all these methods give a product with the same 1H and 13C
NMR spectra, regardless of the origin of the cation, what deductions can one
make about the cation structure? The 1H NMR spectrum of the 2-norbornyl
cation in SbF5-FSO2Cl-SO2F2 solution at −100°C and −158°C is summarized in
the table.
Temp δ (area) δ (area) δ (area) δ (area) δ (area)
− 100°C 4.92 (4H) 2.82 (1H) 1.93 (6H)
−158°C 6.75 (2H) 3.17 (2H) 2.82 (1H) 2.13 (4H) 1.37 (2H)
9-21 When the alcohol shown is heated with triphenylphosphine in carbon tetrachlo-
ride, chloroiceane, a molecule with a carbon skeleton that mimics the structure of
ice, is formed. The oxophosphonium ion is an intermediate in this reaction. Sug-
gest a mechanism for the formation of the iceane skeleton.
OH O PPh3
H H Cl
Ph3P Cl
CCl4

9-22 Predict the major carbocation formed when each of the following alkenes is pro-
tonated. If the major cation formed is not the first cation formed, provide a reason.
Me H
(a) (i) X=Ph; (ii) X=Me; (iii) X=OMe; (iv) X=NMe2; (v) X=SiMe3; (vi) X=SPh
X Me
OMe
(b) SnMe3 (c) (d)
MeO
9-23 The alcohol shown undergoes facile SN1 substitution, catalyzed by acid. The 13C
NMR spectrum of the cation intermediate formed in this reaction shows that it
possesses an alkene double bond. What is the structure of the cation, and why
does it form? What is the mechanism of the second step of the SN1 reaction?
N
Me HO
9-24 In the reaction shown, the Grignard reagent does not open the epoxide by the
expected nucleophilic attack to give the tertiary alcohol. Instead, the product
shown is formed. Write a reasonable mechanism for this reaction and provide a
reasonable explanation for why the reaction proceeds as observed.
O o-MeC6H4MgI
OTBDPS HO
Et2O, ∆
OTBDPS
9-25 How does the reaction shown occur? How would you expect changing the solvent
from toluene to DMF to affect the product ratio?
OMe
OMe MeO
N N
N
1) SOCl2, solvent, 36 h
2) HBr, H2O, ∆ Me H +
Me H N Boc O H
N Boc
HO H Me
Me

Chapter TEN
Organic Reactions II
Synthesis Using Carbocations to Form C—C Bonds
10.1 Introduction
In the last chapter, we focused our attention on the preparation, structure, and properties
of carbocations. In this chapter, we will shift the focus to reactions where those carboca-
tions are key participants. The most important types of these reactions are addition to
alkene π bonds as well as electrophilic substitution in alkenes and arenes.
As we have seen, carbocations can be stabilized by three different mechanisms:
(1) hyperconjugation, (2) conjugation with a carbon-carbon π bond or an aromatic
ring (Example 10.1), and (3) conjugation with an atom bearing a lone pair of electrons
(Example 10.2). All three types of carbocations are key intermediates in synthetically
useful C—C bond-forming reactions. Simple carbocations stabilized by hyperconju-
gation or conjugation with a C—C π bond are important in the Friedel-Crafts alkyla-
tion and Mukaiyama alkylation reactions. Carbocations stabilized by an adjacent
oxygen or nitrogen are important in the Friedel-Crafts acylation and its derivative
reactions, as well as the Mukaiyama aldol addition, the Mannich reaction, and the
Prins reaction.
It is worthwhile noting that both classes of electrophiles are represented in variants of
the Friedel-Crafts and Mukaiyama reactions.
R R R R R
R (10.1)
R R R R R
hyperconjugation conjugation
XR XR
R R
R R (10.2)
X=N, O, S. etc.
R X R X
The relative strength of electrophilic reagents can be approximated by examining the

rates of their reactions with aromatic compounds. The strongest electrophiles (e.g.,
nitronium ions) react with all aromatic compounds, whereas less reactive electrophiles
(e.g., alkyl cations) react with aromatic compounds provided that they do not carry any
strongly electron-withdrawing substituents. The weakest electrophiles (carbenes and
arenediazonium ions) react only with the most electron-rich aromatic compounds.
347

348 Advanced Organic Chemistry | Chapter TEN
10.2 Friedel-Crafts Reactions
While studying the effects of metallic aluminum on alkyl halides in benzene, French chem-
ist Charles Friedel1 and his American student James Mason Crafts2 observed that (1) copious
quantities of hydrogen chloride were evolved after a brief induction period and that (2) the
benzene was converted to a mixture of alkylbenzenes.3 Later they found that aluminum
chloride was actually the catalyst of the reaction. Subsequently, they found that this reaction
will also work with acid chlorides to give ketones, and that it is, in fact, quite a general reac-
tion when a halide is treated with an aromatic compound in the presence of a Lewis acid.
Since the pioneering efforts of Friedel and Crafts, a plethora of analogous reactions has been
discovered, but all are variations on the same theme: the reaction between a carbocation (or
stabilized carbocation) electrophile with an aromatic ring to give a substitution product.
This reaction is quite general and adaptable to most alkyl halides that will undergo SN1
or SN2 reactions. It is now known as the Friedel-Crafts alkylation,4 and it is a very import-
ant method for the formation of carbon-carbon bonds between an aromatic ring and an
alkyl group.
The reaction between an aromatic hydrocarbon and an acid chloride or anhydride5
(especially a mixed trifluoroacetic, phosphoric, or trifluoromethanesulfonic anhydride) in
the presence of a Lewis acid or a strong Lowry-Brønsted acid produces an aromatic ketone.
The mechanism of the reaction involves either a Lewis acid complex of the acid derivative,
or an acylium ion. The reaction, which is known as Friedel-Crafts acylation, is viewed as
being more useful than the alkylation reaction for two reasons: (1) it gives the product of
monosubstitution only and (2) it gives a product with a functional group in the side chain.
The first step in these electrophilic aromatic substitutions is always the same: the addi-
tion of the electrophile to the conjugated π bond system of the aromatic ring (Figure 10.1).
Thus, there are two major factors that control the outcome of any substitution of this type:
(1) the nature of the electrophile, which may be a simple alkyl cation or its equivalent
(10.3), an oxonium or iminium ion (10.4), or an acylium or nitrilium ion (10.5) and (2) the
nature of the arene. We will now examine these in turn.
The Electrophile: Generating Carbocation Electrophiles

Simple carbocation electrophiles can be formed by the heterolysis of carbon-halogen
bonds (Examples 10.6 and 10.7), promoted by strong Lewis acids such as AlCl3, AlBr3,
TiCl4, FeBr3 or SnCl4. Allylic carbocations can be formed by heterolysis of halides in the
presence of silver ions. The conversion of alcohols to carbocations (Example 10.8) can be
accomplished in one step by means of strong acids—the poor nucleophilicity of their con-
jugate bases has made polyphosphoric acid and trifluoroacetic acid popular for this;
1. Charles Friedel (1832–1899) entered Wurtz’ laboratory in 1854 (Dr ès-sc, 1859) and rose through the École
des Mines from conservator in 1856 to Professor of Mineralogy in 1876. He became Director of the Paris Acad-
emy in 1878 and succeeded Wurtz as Professor of Organic Chemistry at the Sorbonne (1884). For more bi-
ographical details, see: Willemart, A. J. Chem. Educ. 1949, 26, 3.
2. James Mason Crafts (1839–1917) was educated at Harvard (SB, 1858) and then traveled to Europe where he
studied under Bunsen and Wurtz. In Paris, he met Charles Friedel, with whom he collaborated for most of the
next three decades (1860–1867; 1874–1891). He was Professor at Cornell (1867–1871) and MIT (1871–1874). He re-
turned to the United States permanently in 1891—as Professor (1891–1898) and President (1898–1900) at the Mas-
sachusetts Institute of Technology. For more biographical details, see: Ashdown, A.A. J. Chem. Educ. 1928, 5, 911.
3. Friedel, C.; Crafts, J.M. Comptes Rend. 1877, 84, 1392, 1450.
4. (a) Olah, G.A.; Krishnamurti, R.; Prakash, G.K.S. In Comprehensive Organic Synthesis; Trost, B. M., Flem-
ing, I., Eds. (Pergamon Press: Oxford, 1991) Vol. 3, Chapter 1.8, p 293. (b) Roberts, R.M.; Khalaf, A.A. Friedel-
Crafts Alkylation Chemistry (Marcel Dekker: New York, 1984). (c) Olah, G. A., Ed. Friedel-Crafts Chemistry
(Wiley: New York, 1973). (d) Olah, G. A., Ed. Friedel-Crafts and Related Reactions (Wiley-Interscience: New
York, 1963–65); Vols. 1–4.
5. Review: Berliner, E. Org. React. 1949, 5, 229.

Organic Reactions II 349
Figure 10.1 The first step in

R X R R the Friedel-Crafts class of
H electrophilic aromatic
(10.3) substitutions
X = OH2, Cl—AlCl3, Cl—TiCl4, N2,etc.
major minor
R R R X
C X C X
R H
R R
(10.4)
X = OH, OR, O—AlCl3, O—BF3, etc;

NH, NR, N—BF3, etc.
major minor
R X
R C X R C X
H
(10.5)
X = OH, OR, O—AlCl3, O—BF3, etc;

NH, NR, N—BF3, etc.
sulfuric acid tends to give higher amounts of tarry by-products and so is less frequently
used. Primary alkylamines react with nitrous acid to give alkyldiazonium ions that rap-
idly lose molecular nitrogen to give a “hot” carbocation (Example 10.9).
MXn
R X R X MXn R (10.6)
M = Al, Ti, Fe, Sn, etc. X = Cl, Br
O MXn O
R R R C O (10.7)
X X MXn
M = Al, Ti, Fe, Sn, etc. X = Cl, OCOR, etc.
H X
R OH R OH2 R (10.8)
X = HSO4, H2PO4, ClO4, CF3CO2, CF3SO3, etc.
HNO2
R NH2 R N2 R (10.9)
FORMING CARBOCATIONS BY HETEROLYSIS OF σ BONDS

Protonation of π-bonded Lewis bases also provides a convenient route to carbocation

electrophiles: alkenes add protons and Lewis acids to give carbocations (Example 10.10),
and the oxygen atom of carbonyl compounds is readily protonated by Lowry-Brønsted
acids, or complexed by Lewis acids to give a resonance-stabilized oxonium ion (Examples
10.11 and 10.12). This is the preferred process for generating carbocation equivalents from
acids and their derivatives. A similar reaction occurs with the nitrogen atom of nitriles to
give resonance-stabilized nitrilium cations (Example 10.13) or their more complex equiv-
alents (Example 10.14). Less commonly used methods for generating carbocations include
the oxidation of carboxylic acids by lead tetraacetate in the presence of pyridine6 and the
electrochemical oxidation of free radicals.
R R H X R R
H (10.10)
R R R R
X = HSO4, H2PO4, F, CF3CO2, CF3SO3 etc.
O MXn O MXn O MXn

R R R
(10.11)
G G G
M = Al, Ti, Fe, Sn, etc.; X = Cl, Br; G = H, R, OR, NR2, etc
O H X O H O H
R R R (10.12)
G G G
X = HSO4, F, CF3CO2, CF3SO3 etc.; G = H, R, OH, OR, NR2, etc.
H X
R C N R C NH R C NH (10.13)
X = HSO4, F, CF3CO2, CF3SO3 etc.
MXn
R C N R C N MXn R C N MXn (10.14)
M = B, Al, Ti, Fe, Sn, etc.; X = F, Cl, Br
FORMING CARBOCATIONS BY REACTIONS WITH LEWIS ACIDS
The Electrophile: Strength and Reactivity

The electrophile in the Friedel-Crafts alkylation using an alkyl chloride and aluminum
chloride, for example, may be viewed as either the Lewis acid complex of the alkyl halide
for halides that do not react well by the SN1 mechanism7 and as the carbocation for halides
that do. The reacting species is therefore determined by the equilibrium constant of the
dissociation reaction in Example 10.6. In acylation reactions, using acid chlorides and
aluminum chloride, for example, the electrophile may also be either a Lewis acid complex
of the acyl halide (Example 10.15) or the free acylium ion (Example 10.16).
6. (a) Sheldon, R.A.; Kochi, J.K. Org. React. 1970, 19, 279. (b) Kochi, J.K. J. Am. Chem. Soc. 1965, 87, 3609.
(c) Corey, E.J.; Casanova, J., Jr. J. Am. Chem. Soc. 1963, 85, 165, 169. (d) Gream, G.E.; Wege, D. Tetrahedron Lett.
1967, 503. (e) Theine, A.; Traynham, J.G. J. Org. Chem. 1974, 39, 153.
7. Brown, H.C.; Grayson, M. J. Am. Chem. Soc. 1953, 75, 6285.

Figure 10.2 Competing SN2

and SN1 pathways for the
Cl
AlCl3 (SN2) Friedel-Crafts alkylation of
Cl benzene with 1-chlropropane
AlCl3 H
AlCl3 H
Cl (SN1)
Cl
AlCl3
H
R C O
AlCl3 AlCl3
O O
R Cl R Cl
R C O
Lewis acid complex
acylium ion
(10.15)
(10.16)
Depending on whether the active electrophile is the free alkyl carbocation or the Lewis
acid–Lewis base complex of the alkyl halide, the Friedel-Crafts alkylation reaction can be
viewed in two ways. It may be considered either an SN2 reaction, with the arene acting as
the nucleophile to displace the halide ion complex of the Lewis acid or an SN1 reaction,
with the leaving group being lost first, followed by trapping of the carbocation with the
arene, which again functions as the nucleophile (Figure 10.2).
Benzene and alkylbenzenes react with n-propyl chloride in the presence of aluminum chlo-
ride to give mainly the n-propylarene at low temperature, where little of the free carbocation is
formed (Example 10.17) and mainly the isopropylarene at high temperatures, where the forma-
tion of the free carbocation from the complex is more favored (Example 10.18).8 The reaction of
isobutyl chloride and benzene catalyzed by aluminum chloride (Example 10.19) gives only
t-butyl-benzene.9 The amount of the rearranged alkylbenzene is higher when less reactive
arenes are used, consistent with a competition between the dissociation of the Lewis acid com-
plex of the halide (the SN1 pathway) and the direct displacement by the arene (the SN2 pathway).
Cl
(10.17)
AlCl3, 25°C
Cl
(10.18)
AlCl3, 25°C
Cl
(10.19)
AlCl3, –5°C
8. (a) Ipatieff, V.N.; Pines, H.; Schmerling, L. J. Org. Chem. 1940, 5, 253. (b) Roberts, R.M.; Shienthong, D. J.
Am. Chem. Soc. 1960, 82, 2851. However, it has also been reported that 1-chloropropane gives predominantly
isopropylbenzene, even at low temperatures: (c) Roberts, R.M.; Shienthong, D. J. Am. Chem. Soc. 1960, 82, 732.
(d) Marsi, K.L.; Wilen, S.H. J. Chem. Educ. 1963, 40, 214.
9. Konovalov, M.I. J. Russ. Phys.-Chem. Soc. 1895, 27,156. (b) Konowaloff, M.I. Bull. Soc. Chim. France 1896, 16, 864.

Worked Problem
10-1 Why should the dissociation of the Lewis acid complex with an alkyl halide be
less favored at lower temperatures, so that the products alkylation without rear-
rangement are observed?
§Answer below.
The active electrophile can also be generated by the reaction between alkenes or alco-
hols with strong Lowry-Brønsted acids. The reactions of carbonyl compounds with strong
Lewis acids or strong Lowry-Brønsted acids give stabilized carbocations. Cations from
conjugated carbonyl compounds react through the β carbon to give saturated ketones, as
illustrated by the reaction (Example 10.20) between mesityl oxide and benzene.10 An ex-
ample of the reaction of a saturated ketone with an arene is the synthesis of bisphenol A
from phenol and acetone (Example 10.21).
AlCl3 (1.5 eq)

PhH, 10°C, 3 h (10.20)
O
(86%) O
H
O
H AlCl3
O O
AlCl3 AlCl3
Me2C=O
(10.21)
ZnCl2
HO
HO OH
The Arene: Reactivity and Orientation

The Friedel-Crafts reaction requires an aromatic ring that is not excessively deactivated
toward electrophilic substitution: arenes carrying m-directing groups do not react, so ni-
trobenzene and o-dichlorobenzene can be used as solvents for the reaction. Generally
speaking, aromatic compounds react more rapidly as the electron density in the ring in-
creases. Thus, five-membered heterocyclic compounds (furan, pyrrole, indole, and thio-
phene) all react more rapidly than benzene with electrophiles, because the average electron
density in the ring is 1.2 π electrons per position.
As with simple benzenoid aromatics, the orientation of substitution in these hetero-
cycles can be predicted on the basis of resonance theory. Thus, furan, pyrrole, and
10. Koelsch, C.F.; LeClaire, C.D. J. Org. Chem. 1941, 6, 516.

In the complex, all atoms have complete valence shell octets, but in the simple alkyl carbocation, the charged
carbon atom does not. Thus, the ∆Hreact for dissociation is positive. The dissociation of the complex, on the
other hand, converts a single particle into two, so the ∆Sreact for dissociation is also positive. Thus, we find that
at low temperature, where enthalpy dominates, the non-dissociated complex is favored, and at higher tempera-
tures, where entropy becomes more important, the free carbocation becomes more favored.

thiophene all react with electrophiles to give substitution at the 2-position of the ring
(Example 10.22). The major canonical form of the intermediate onium ion in these reac-
tions is an ion with linear conjugation in the conjugated system and three major canon-
ical forms. Substitution at the 3-position gives a cross-conjugated intermediate cation
(Example 10.23) with only two major canonical forms. In indoles, on the other hand, the
major product of electrophilic substitution is at the 3-position. In this case, only one
(Example 10.24) of the two major isomeric cations (Examples 10.24 and 10.25) that have
an iminium ion structure, only 10.24 retains the benzenoid sextet (the Clar sextet 11 that
we discussed in C hapter 7), so this predicts that the major product will be the 3-substi-
tuted indole.
E
H
(10.22) E E H (10.23)
X X X X E
cross-conjugation linear conjugation

one additional X = O, N, S two additional
canonical form canonical forms
E H E
(10.24) NH NH
HN E (10.25)
E NH
H
one Clar sextet no Clar sextets
preserved preserved
A similar situation occurs in fused aromatic hydrocarbons. Attack of the electrophile

at position 1 of a naphthalene ring system gives a carbocation in which there are two con-
tributing structures (Examples 10.26 and 10.27) that retain the Clar sextet. Attack at posi-
tion 2, on the other hand, gives a carbocation (Example 10.28) with only one such structure.
We predict that electrophilic aromatic substitution in naphthalene under kinetic condi-
tions will give the 1-substituted naphthalene as the major product. It does; electrophilic
aromatic substitution of naphthalene at low temperatures gives the 1-substituted naphtha-
lene (Example 10.29). The reaction is reversible, however, and the same reaction under
thermodynamic conditions gives the much less sterically hindered 2-substituted naphtha-
lene (Example 10.30). Likewise, Friedel-Crafts acylation of 1-substituted naphthalenes
leads to substitution at the 4-position.12 2-substituted derivatives give products where the
substitution has occurred at the 8-position,13 unless the electrophile is hindered, in which
case the 2,6-disubstituted naphthalene may be obtained as the major product. The effects
can be fairly subtle, as illustrated by Example 10.31, where the product formed is the ki-
netic 1-alkyl product, and Example 10.32,14 where the product formed is the thermody-
namic product. All five-membered heterocycles and all fused-ring aromatic hydrocarbons
react more rapidly with electrophiles than benzene does—the approximate order of re-
activity is pyrrole > furan > thiophene > a nthracene > naphthalene > benzene—and all
will react with weaker electrophiles than does benzene. By contrast, the six-membered
11. (a) Clar, E. Aromatische Kohlenwasserstoffe, 2nd ed. (Springer: Berlin, 1952). (b) Clar, E. Polycyclic Hydro-
carbons (Academic: London, 1964). (c) Clar, E. The Aromatic Sextet (John Wiley: London, 1972.).
12. Jacobs, T.L.; Winstein, S.; Ralls, J.W.; Robson, J.H. J. Org. Chem. 1945, 11, 27.
13. (a) Leonard, N.J.; Hyson, A.M. J. Org. Chem. 1947, 13, 164. (b) Winstein, S.; Jacobs, T.L.; Day, B.F. J. Org.
Chem. 1947, 13, 171.
14. For an example, see: Arai, K.; Ohara, Y.; Iizumi, T.; Takakuwa, Y. Tetrahedron Lett. 1983, 24, 1531.

nitrogen heterocycles, pyridine, quinoline, and isoquinoline are all electron-deficient, and
they are resistant to electrophilic attack by carbon electrophiles.
E H
H
E
(10.26) (10.28)
two canonical forms one canonical form

with one Clar sextet with one Clar sextet
preserved preserved
E H
(10.27)
O R
RCOCl, AlCl3, low T (10.29)
RCOCl, AlCl3, ∆ R
(10.30)
EtS CO2Et
SEt
Cl CO2Et MeO
(10.31)
SnCl4, CH2Cl2, r.t.
MeO
SEt
Cl CO2Et MeO
Me
CO2Et (10.32)
SnCl4, CH2Cl2, r.t.
(72%) SEt
N
N N
pyridine quinoline isoquinoline
Problems
10-1 Predict the major product of the acylation of anthracene and phenanthrene under
kinetic conditions (CH3COCl, AlCl3, CS2, 0°C).
anthracene phenanthrene
10-2 Provide a rational explanation for the differences in the reactions leading to the
products shown in 10.31 and 10.32. Note that the reaction conditions are the
same.

Complicating Factors in Alkylation: Dealkylation, Disproportionation,

and Rearrangement of Products
The intermediate in the Friedel-Crafts alkylation is a benzenonium cation, which usually
loses proton to reestablish aromaticity in the ring. Other than proton loss, there are two
major reactions that these cations exhibit: (1) rearrangement (e.g., Example 10.33), which
changes the isomer distribution; and (2) dealkylation (e.g., Example 10.34), where an alkyl
cation is lost or transferred to another molecule of arene rather than a proton.15 In an ex-
tensive study of the alkylation of anisole and toluene, Olah showed that anisole and tolu-
ene give predominantly o,p substitution under kinetic conditions, but rearrangement of
the kinetic product occurs under thermodynamic conditions.16 Although these reactions
are often undesirable in laboratory syntheses, the dealkylation reaction is important in the
disproportionation of toluene into benzene and xylene,17 both of which have much more
commercial value.
H (10.33)
R1 R1 H
R2
R2
H H
H R1
R1 R1 R1 R2
R2 +
H
H (10.34)
H
R2
R2
Acylation
In solution, alkylation by the Friedel-Crafts method often leads to polyalkylation due to a
combination of factors, including the greater reactivity of the alkylbenzenes than benzene
itself toward the electrophile. For this reason, Friedel-Crafts acylation has frequently been
preferred over alkylation, because the product does not undergo further substitution.
“Greening” the Friedel-Crafts Acylation

The use of traditional metal halide catalysts for the Friedel-Crafts acylation (e.g., AlCl3,
TiCl4, SnCl4, FeBr3) requires the use of more than one equivalent of the catalyst, because
the formation of a strong complex between the Lewis acid and the ketone product removes
one equivalent of the catalyst from the reaction mixture. This complex must then be hy-
drolyzed during isolation of the product; therefore, the catalyst cannot be reused and a
large quantity of hazardous waste is generated.
Reduction of hazardous wastes is one of the core principles of “green” chemistry, and
the Friedel-Crafts acylation, which generates large quantities of hazardous wastes, is a
prime candidate for testing new, “greener” methods of synthesis. One of the earliest ways
to reduce the amount of hazardous waste was developed for the Hoechst-Celanese
synthesis of p-isobutylacetophenone by using anhydrous hydrogen fluoride as the acid
15. (a) Nightingale, D.F. Chem. Rev. 1393, 25, 329. (b) Nightingale, D.; Smith, L.I. J. Am. Chem. Soc. 1939, 61,
101. (c) Nightingale, D.; Carton, B., Jr. J. Am. Chem. Soc. 1940, 62, 280.
16. Olah, G.A.; Olah, J.A.; Ohyama, T. J. Am. Chem. Soc. 1984, 106, 5284.
17. E.g., see: Kaeding, W.W.; Chu, C.; Young, L.B.; Butter, S.A. J. Catal. 1981, 69, 392.

Table 10.1 Effects of Substrate and Catalyst on Friedel-Crafts catalyst (Example 10.35).18 Unlike metal salts, this
Acylation catalyst can be recycled and reused, which makes HF—
OMe CO2H OMe despite being highly toxic and corrosive—a “green” cata-
O lyst for the reaction.
O
MeO O O MeO O O
Ac2O, HF
(10.35)
Reagent Yield
(1) (COCl)2; (2) AlCl3 (3 eq.), CH2Cl2, r.t. 31 Other approaches to “greening” this reaction have
focused on using scandium,19 lanthanide,20 gallium,21 or
(1) (COCl)2; (2) Sc(OTf)3 (1 eq.), CH2Cl2, r.t. 46
bismuth 22 triflates as catalysts. A catalyst composed of
(1) (COCl)2; (2) Sc(OTF)3 (1 eq.), TfOH (1 eq), CH2Cl2, r.t. 64 hafnium (IV) triflate and lithium perchlorate in nitro-
(1) (CF3CO)2O; (2) Sc(OTf)3 (1 eq.), CH2Cl2, 40°C 0
methane has proved to be a highly efficient catalyst for
alkylation and acylation reactions,23 and a recent report
(1) (CF3CO)2O; (2) ZnCl2 (1 eq.), HOAC, 60°C 0 has added samarium (II) iodide to the list of catalysts
HF, –78°C to r.t. 36 useful in the Friedel-Crafts acylation.24 As part of the
“green revolution” in synthetic organic chemistry, recent
Sc(OTf)3 (1 eq.), MeNO2, 60°C 0
efforts have been focused on the development and use of
Sc(OTf)3 (1 eq.), LiClO4 (5 eq.), MeNO2, 60°C 79 ecocompatible catalysts—solid catalysts in particular25—
in Friedel-Crafts reactions. The effects of a variety of
catalyst and reactant combinations on a vinylogous intramolecular F riedel-Crafts acy-
lation are shown in Table 10.1.26 Note how in the reaction in Table 10.1, the electrophile
attacks the alkene π bond that is conjugated with the methoxy substituent on the aro-
matic ring. The attack of an acylium ion on an alkene is not an uncommon reaction,
especially when the carbocation formed is tertiary. An example is provided by the spon-
taneous cyclization (Example 10.36) of the acid chloride from Corey’s synthesis of a
dolabellane diterpene.27
ClOC CHCl3, r.t. O
(10.36)
Cl
Worked Problem
10-2 What is the product of each of the reactions below?
Cl
PhCOCl, AlCl3 OH H3PO4, ∆
(a) CS2, 45-50°C
(b)
Cl
(continues)
18. Lindley, D.D.; Curtis, D.A.; Ryan, T.R.; de la Garza, E.M.; Hilton, C.B.; Kenesson, T.M. U.S. Patent No.
5,068,448 [Nov. 26, 1991].
19. Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett 1994, 545.
20. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W.W.-L. Chem. Rev. 2002, 102, 2227.
21. Kobayashi, S.; Komoto, I.; Matsuo, J. Adv. Synth. Catal. 2001, 343, 71.
22. (a)Desmurs, J.-R.; Labrouillère, M.; Le Roux, C.; Gaspard, H.; Laporterie, A.; Dubac, J. Tetrahedron Lett.
1997, 38,8871. (b) Répichet, S.; Le Roux, C.; Dubac, J.; Desmurs, J.-R. Eur. J. Org. Chem. 1998, 2743.
23. Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem. Soc. Japan 1995, 68, 2053.
24. Soueidan, M.; Collin, J.; Gil, R. Tetrahedron Lett. 2006, 47, 5467.
25. Sartori, G.; Maggi, R. Chem. Rev. 2006, 106, 1077.
26. Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 2003, 125 3090.
27. Corey, E.J.; Kania, R.S. J. Am. Chem. Soc. 1996, 118, 1229.

CO2Et O
MeCOCl, AlCl3 C6H6, AlCl3
(c) CS2
(d) O
N Me
H O
§Answers below.
Asymmetric Friedel-Crafts Alkylation

The rather severe conditions of the traditional Friedel-Crafts reaction tends to raise diffi-
culties in carrying out such a reaction under asymmetric conditions. However, if the
strong metallic Lewis acids are replaced by a proton from a modestly strong acid, one can
successfully generate a chiral product in reasonable enantiomeric excess.
The two major successful approaches to inducing asymmetry in the Friedel-Crafts
reaction have involved a C2-symmetric catalyst to generate a chiral electrophile that then
is then selectively attacked on one face of the alkene. In reactions involving proton trans-
fer to generate the electrophile, polyphosphoric acid has been an especially popular re-
agent, because sulfuric acid often leads to undesired tar and resin formation and
polyphosphoric acid does not present the hazards of anhydrous hydrogen fluoride. In an
extension of this reaction, chiral phosphoric acid derivatives28 such as Example 10.37
have been developed as catalysts for the (formal) asymmetric Friedel-Crafts alkylation of
electron-rich arenes.29 The common structural features of most of these chiral phos-
phoric acids are a 1,1'-binaphthyl core with sterically large hydrophobic groups (e.g., the
9-anthryl groups in the example shown) flanking the phosphate ester groups. This type
of reaction is restricted to substitution in electron-rich arenes (e.g., pyrroles, as in Exam-
ple 10.38, and indoles, as in Example 10.39). It has been proposed that the activated com-
plex of the reaction is organized by means of specific hydrogen bonding (Figure 10.3).
Although these reactions could equally well be described as conjugate addition of a nuc-
leophilic arene to the Michael acceptor, it has become standard practice to refer to them
28. For reviews, see: (a) Schreiner, P.R. Chem. Soc. Rev. 2003, 32, 289. (b) Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719. (c) Pihko, P.M. Angew. Chem. Int. Ed. 2004, 43, 2062. (d) Taylor, M.S.; Jacobsen, E.N. Angew.
Chem. Int. Ed. 2006, 45, 1520.
29. (a) Cai, Q.; Zhao, Z.-A.; You, S.-L. Angew. Chem. Int. Ed. 2009, 48, 7428. (b) Sheng, Y.-F.; Gu, Q.; Zhang,
A.-J.; You, S.-L. J. Org. Chem. 2009, 74, 6899.
§ Answers to Worked Problem:

Cl Cl
PhCOCl, AlCl3 OH H3PO4, ∆

(a) CS2, 45-50°C (b)
Cl Cl
O Ph
O O
CO2Et CO2Et
MeCOCl, AlCl3 C6H6, AlCl3
(c) CS2
Me (d) O
Me N Me
N CO2H
H O H
O
(a) In this reaction, the solvent is non-polar and the reaction temperature is relatively low; these are kinetic
conditions. We expect that the major product will be the 4-benzoyl compound. (b) The phosphoric acid will
protonate the alcohol to give the oxonium ion, which can then attack the aromatic ring to give a benzenonium
ion with a six-membered ring fused to it, so the product is tetralin. Note how this intramolecular reaction
allows the SN2-like pathway to dominate the reaction. (c) This pyrrole has available 2- and 3-positions; electro-
philic attack is favored at the 2-position, so the product will be the 5-acetylpyrrole. (d) Here the electrophile is
generated from an anhydride; this Friedel-Crafts acylation will give the ketoacid shown.

as Friedel-Crafts alkylations because a new C—C bond is formed by substitution of a

hydrogen atom on the aromatic ring. The stereochemistry of these additions is such that
the S phosphoric acid catalyst leads to addition to the re face of the E alkene (where the
group R 2 is assigned the highest priority), and the R enantiomer of the catalyst leads to
addition to the si face.
O
O P OH (10.37)
O
NO2 NO2
O N
30
N O (10.38)
CH2Cl2, PhH, 4Å MS H H
H
(S)-10.37
(91%; e.r.95.5:4.5)
O 2 O
R R 2 OH H R OH
31
R (10.39)
N FeCl3, PhH, 4Å MS
H (R)-10.37 N
H
(91%; e.r. 95.5:4.5)
Cl
m-ClC6H4CH=CHCHO CHO
32
THF-i-PrOH (1:1), -25°C
N (10.40)
Me S Me
N •TFA
Ph N
N Me
H
The use of a chiral catalyst has also been extended to using a chiral imidazolidinone
derivative to form chiral iminium ion electrophiles that then attack the electron-rich
arene.33 A recent report (Example 10.40) shows the use of the conjugate acid of an imidaz-
olidinethione as a catalyst for the chiral alkylation of indoles by cinnamaldehydes. In
Example 10.40, the S catalyst leads to addition to the si face of the alkene π bond of
E-m-chlorocinnamaldehyde. It is worthwhile noting that the face selectivity of the two
catalytic systems (the chiral phosphoric acids and the chiral imidazolidinethiones) is
opposite for the same configuration in the catalyst.
30. For reviews, see: (a) Schreiner, P.R. Chem. Soc. Rev. 2003, 32, 289. (b) Seayad, J.; List, B. Org. Biomol.
Chem. 2005, 3, 719. (c) Pihko, P.M. Angew. Chem. Int. Ed. 2004, 43, 2062. (d) Taylor, M.S.; Jacobsen, E.N. Angew.
Chem. Int. Ed. 2006, 45, 1520.
31. Yang, L.; Zhu, Q.; Guo, S.; Qian, B.; Xia, C.; Huang, H. Chem. Eur. J. 2010, 16, 1638.
32. Liang, X.; Li, S.; Su, W. Tetrahedron Lett. 2012, 53, 289.
33. Paras, N.A.; MacMillan, D.W.C. J. Am. Chem. Soc. 2001, 123, 4370.

Ar Figure 10.3 Hydrogen
R1
bonding organizes the
O O H N activated complex of a
P H Friedel-Crafts alkylation
O R2 catalyzed by a chiral
O O H O N
H phosphoric acid derivative.
Ar
O
H
O O O N
P H
O
O HH
N
R
A variety of chiral C2-symmetric bis-oxazoline (“box”) ligands, which share the gen-
eral structure 10.41, have been used to chelate metal triflates as well as to provide effective
chiral catalysts for the addition of electron-rich aromatic compounds to electron-deficient
alkenes based on metals that include scandium,34 copper (II),35 and zinc.36 Palomo and
coworkers have used the copper (II) triflate complex (10.42) shown in Figure 10.4 for the
alkylation of electron-rich aromatic compounds with α'-hydroxyenones; the reaction is
proposed to proceed via chelated electrophile such as 10.43.37 In this square planar copper
chelate, the tert-butyl group of one of the oxazoline rings blocks the si face of the β carbon
of the enone, so the reaction occurs through the re face.
O O
N N (10.41)
R2 R1 R1 R2
Figure 10.4 Use of a chiral

O O O O copper (II) triflate “box”
chelate to catalyze the
N N N N
M Cu asymmetric Friedel-Crafts
O OH alkylation
M = Cu(OTf)2
R
(10.42) (10.43)
O Ph O
N Me
OH OH
CH2Cl2, 25°C, cat.
N
Ph (86%, 92% ee) Me
(10.44)
34. (a) Evans, D.A.; Fandrick, K.R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (b) Evans, D.A.; Scheidt,
K.A.; Fandrick, K.R.; Lam, H.W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780.
35. (a) Palomo, C.; Oiarbide, M.; Kardak, B.G.; García, J.M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154.
(b) Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69, 1309.
Review: (c) Poulsen, T.B.; Jørgensen, K.A. Chem. Rev. 2008, 108, 2903.
36. Lu, S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115.
37. Palomo, C.; Oiarbide, M.; Kardak, B.G.; García, J.M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154.

Figure 10.5 Use of a chiral

scandium (III) triflate
complex to catalyze the N
asymmetric Friedel-Crafts O O N
H N M N H O O
alkylation
N Sc N
H H
N O
N
R
M = Sc(OTf)3 Me
(10.45) (10.46)
N
N
N
Me O
N N
Me O Me
MeCN, 4 Å MS, cat, 0°C
(78%, 94% ee)
N
(10.47) Me
Evans has used 2-acylimidazoles as substrates in similar alkylations of indoles cata-

lyzed by a chiral (pybox)scandium (III) triflate complex (10.45, Figure 10.5)38 and sees
similar high levels of enantioselectivity in the reaction. In this reaction, the stereochemi-
cal outcome can be rationalized in terms of the s-cis conformation of the enone in the
scandium chelate, 10.46. The electrophiles in the reactions in Figures 10.4 and 10.5 share
two structural features: (1) a group that restricts the conformation of the enone system to
the s-cis conformation and (2) a group at the α' position that permits the formation of a
chelate with the metal atom in the catalyst.
The Role of Solvent

It is reasonable that a reaction in which there are ionic intermediates should be facilitated
by a polar solvent. For this reason, there has been a significant amount of activity investi-
gating the effects of solvent on the Friedel-Crafts and similar electrophilic aromatic sub-
stitutions.39 For example, using Cu(OTf)2 as the catalyst in the ionic liquid [bmim][BF4]
permitted the benzoylation of a range of electron-rich aromatic hydrocarbons (e.g., Exam-
ple 10.48, 2-methoxynaphthalene).40 Most interestingly, this reaction system permitted
the synthesis of the kinetic product from 2-methoxynaphthalene rather than the thermo-
dynamic product (6-methoxy-2-naphthyl phenyl ketone) obtained in conventional sol-
vents. Similar acceleration of the reaction has been observed using indoles (e.g., Example
10.49) and the ionic liquid [emim][Cl]–AlCl3 to promote the reaction.41 One useful ad-
vance in the use of ionic liquids has been the development of inter- (Example 10.50) and
intramolecular (Example 10.51) alkenylation reactions of arenes by alkynes, using metal
triflate catalysts.42 In this reaction, the ionic liquid is proposed to stabilize the highly reac-
tive vinyl cation, thus lowering the activation energy of the reaction. However, the
38. (a) Evans, D.A.; Fandrick, K.R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942. (b) Evans, D.A.; Scheidt,
K.A.; Fandrick, K.R.; Lam, H.W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780.
39. Review: Earle, M.J.; Seddon, K.R. Pure Appl. Chem. 2000, 72, 1391.
40. Ross, J.; Xiao, J. Green Chem. 2002, 4, 129.
41. Yeung, K.-S.; Farkas, M.E.; Qiu, Z.; Yang, Z. Tetrahedron Lett. 2002, 43, 5793.
42. Song, C.E.; Jung, D.-a.; Choung, S.Y.; Roh, E.J.; Lee, S.-g. Angew. Chem. Int. Ed. 2004, 43, 6183.

i ntermolecular reaction is neither stereospecific nor regiospecific. Mixtures of (o,p‑) regio-

isomers and (E/Z) stereoisomers are obtained in the alkenylation of anisole and chloro-
benzene by 1-phenylpropyne, which limits its intermolecular applications.
OMe OMe
PhCOCl, Cu(OTf)2 COPh

[bmim][BF4], 80°C, 16 h (10.48)
(72%)
OMe
N MeO COCl N
(10.49)
[emim][Cl]-(0.75) AlCl3 HN
HN
(79%)
O
PhC CMe, Sc(OTf)3 (0.1 eq) Ph

[bmim][SbF6], 4 h, r.t. (10.50)
Ph Me
(91%)
O O
Ph
HN HN Ph
Hf(OTf)4, (0.1 eq)
(10.51)
[bmim][SbF6]/c-C6H11Me (1:5)
85°C, 9 h
O O (72%) O O
Houben-Hoesch Acylation
The reaction analogous to the Friedel-Crafts acylation using a nitrile instead of an acid
chloride or anhydride is known as the Houben-Hoesch reaction.43 Although the electro-
phile may be viewed—formally, at least—as the resonance-stabilized nitrilium ion, re-
search has shown that the mechanism is almost certainly more complex.44 Evidence has
been obtained that the actual electrophile may be the diprotonated form of the sym-
triazene (10.52) formed by cyclotrimerization of the nitrile.45 A mechanism involving this
species in the acylation of benzene is shown in Figure 10.6; the final step of the reaction,
which is not shown explicitly, is the acid-catalyzed hydrolysis of the imine. A modified
Houben-Hoesch reaction (Example 10.57), in which an N-alkylnitrilium ion is generated
in situ, proved superior to alternative methods of acylation in the synthesis of O-methyl-
sterigmatocystin. When the electrophile can be generated in an intramolecular manner
(as in Example 10.58), the Houben-Hoesch reaction provides a convenient method for the
formation of nitrogen heterocycles.
43. (a) Hoesch, K. Ber. dtsch. chem. Ges. 1915, 48, 1122. (b) Houben, J. Ber. dtsch. chem. Ges. 1926, 59, 2878.
(c) Arkhipov, V.V.; Smirnov, M.N.; Khilya, V.P. Chem. Heterocycl. Compd. 1997, 33, 515. (d) Kawecki, R.;
Mazurek, A.P.; Kozerski, L.; Maurin, J.K. Synthesis 1999, 751. Review.
44. Reviews: (a) Ruske, W. In Olah, G.A., Ed. Friedel-Crafts and Related Reactions; (Wiley-Interscience: New
York, 1964), Vol. 3, Part I, Ch 32. (b) Spoerri, P.E.; DuBois, A.S. Org. React. 1949, 5, 387.
45. Amer, M.I.; Booth, B.L.; Noori, G.F.M.; Proença, M.F.R.P. J. Chem. Soc. Perkin Trans. 1 1983, 1075.

Figure 10.6 A mechanism for R R

the Houben-Hoesch R C NH
H H H H
acylation reaction N N N N
R C N R
R N R N R
R C NH H
(10.52)
(10.53)
H
R
R CN R CN R
H H H
N N N H H
N N
R Ph R Ph R
N R
H Ph
(10.56) (10.55)
(10.54)
OH
1) Me2CHCl (7.5 eq)
NC F SbF5 (1.4 eq) CO2Me
CH2Cl2, r.t., 2 h MeO
OH (10.57) 46
MeO OH
N
F
2) MeO CO2Me
MeO
OH
(92%)
OMe
OMe
O H2SO4-HOAc O
O (9:10) (10.58) 47
O
NC 60°C, 1 h Me N
O
O (30%)
O Me Me
Me
OMe OMe
MeO MeO
Drill Problem
What will be the major organic product from the reaction of each of the com-
pounds in the first list with each of the reagents in the second? Assume one
equivalent of each reactant.
Compounds:
Me O
OH N
(a) (b) N (c) (d)

MeO N
H
Reagents:
(A) MeCOCl, AlCl3, CS2. (B) Me3CCl, TiCl4, CH2Cl2, –78°C
(C) Me2C=CH-COCH3, AlCl3. (D) c-C6H11OH, H3PO4, ∆
(continues)
46. Casillas, L.K.; Townsend, C.A. J. Org. Chem. 1999, 64, 4050.
47. Deguchi, J.; Hirahara, T.; Oshimi, S.; Hirasawa, Y.; Ekasari, W.; Shirota, O.; Honda, T.; Morita, H. Org.
Lett. 2011, 13, 4344.

(E) PhCN, AlCl3. (F) 1-methylcyclohexene, CF3SO3H

(F) R-10.37, E-PhCH=CHNO2, PhH, 4Å MS
Reaction Synopses
Friedel-Crafts Alkylation
RX, cat.
Ar H Ar R
Reagents:
RX:RCl, RBr, ROH, ROTf, etc.
or R 2C=CHR, RCH=CHCOR, RCH=CHNO2, etc.
Catalyst: AlCl3, AlBr3, BF3, ZnCl2, TiCl4, etc.
or Sc(OTf)3, Cu(OTf)2, Hf(OTf)4, etc.
or H3PO4, CF3CO2H, CF3SO3H, H2SO4, HF, etc.
ArH: must not be more deactivated toward electrophilic aromatic substi-
tution than chlorobenzene
Solvent: kinetic selectivity enhanced by nonpolar solvents; thermodynamic
product favored by nitromethane or nitrobenzene. Ionic liquids en-
hance rate and kinetic selectivity.
Friedel-Crafts Acylation
O
RCOX, cat.
Ar H Ar
R
Reagents:
RCOX: RCOCl, (RCO)2O, RCO-O-SO2R', RCO2COCF3, etc.
Catalyst: AlCl3, AlBr3, HF, BF3, ZnCl2, TiCl4, etc. or
Sc(OTf)3, Cu(OTf)2, Hf(OTf)4, etc. or
H3PO4, CF3CO2H, CF3SO3H, H2SO4, HF, etc.
ArH: must not be more deactivated towards electrophilic aromatic substi-
tution than chlorobenzene
Solvent: kinetic selectivity enhanced by nonpolar solvents; thermodynamic
product favored by nitromethane or nitrobenzene. Ionic liquids as
solvents enhance rate and kinetic selectivity.
Asymmetric Friedel-Crafts Alkylation
O
X R O
R Y X
Ar H chiral cat.
Ar Y
X = C, N, S; Y = O, CMe2OH, 2-imidazolyl, etc.

Catalysts:
Ar
O G O Z Me
O N
O
P N N R1 R
OH M
O R R R2 N R
R' R' H
Ar chiral box complex chiral imidazoline derivative
chiral Brønsted acid
Ar = 9-anthryl, 9-phenanthryl, 3,5-dimesitylphenyl, etc.;
M = Sc(OTf)3, Cu(OTf)2, Zn(OTf)2, Hf(OTf)4, etc.
(continues)

R, R' = H, tert-butyl, etc.
R 1, R 2 = H, alkyl, etc.; R 3 = Me, (CH2)n, etc.
ArH: pyrrole, indole, furan, thiophene, etc. The reaction generally fails
with benzene and simple substituted benzenes.
Houben-Hoesch Acylation
O
Ar H Ar
R
Reagents: RCN, H2SO4; RCN, AlCl3; RCN, TiCl4; etc. or
(1) RCN, i-PrCl, SbF5; (2) H2SO4, H2O, ∆; etc.
Reaction: may be used to form imines or nitrogen heterocycles
Problem
10-3 What is the major organic product of each of the following reactions?
O H3PO4, HCO2H
(a) HN OMe
MeO OH
PPA, 60°C
(b) 43 h
MeO N
OMe BF3•Et2O
(c) MeO
OMe CH2Cl2
N
MeO Me O
NO2
Ph
(d)
N CH2Cl2, PhH, 4Å MS
H
(S)-phosphoric acid catalyst 10.37
References: (a) J. Am. Chem. Soc. 1968, 90, 1647. (b) J. Org. Chem. 1996, 60, 115. (c) J. Am. Chem. Soc.
1978, 100, 1548. (d) J. Org. Chem. 2009, 74, 6899.
10.3 Formylation
Acylation is usually used to describe the formation of ketones, with the corresponding
reactions to form aldehydes being known as formylation. Although they are formally
analogous to acylation reactions, formyl chloride (H—COCl) decomposes to HCl and CO
above –60°C, so one cannot carry out the reaction by treating an aromatic compound with
formyl chloride and a Lewis acid.48 Consequently, surrogates for this unstable compound
are needed, and the search for such surrogates has given us a number of useful formylation
reactions. The simplest surrogate is (obviously?) a mixture of hydrogen chloride and
carbon monoxide, which is used in the presence of a strong Lewis acid; this is the basis
of the Gattermann-Koch formylation.49 Replacement of the carbon monoxide in this
48. Ferguson, L.N. Chem. Rev. 1946, 38, 227.

49. For a review of formylations with carbon monoxide, see: Willemse, J.A. M.Sc. Dissertation, Rand
frikaans University, Johannesburg, 2003.
A

mixture by a metal cyanide gives the Gattermann aldehyde synthesis. The use of a substi-
tuted iminium ion as the surrogate provides the basis of the Vilsmeier-Haack and Duff
formylations. We will examine each of these reactions in turn.
Gattermann, Gattermann-Koch, and Gattermann-Olah Formylations

Formyl chloride is not stable, but subjecting the aromatic compound to a mixture of
carbon monoxide and hydrogen chloride in the presence of aluminum chloride will give
the aldehyde; this reaction is known as the Gattermann-Koch reaction. Treating the
aromatic compound with hydrogen cyanide and hydrogen chloride is known as the
Gattermann aldehyde synthesis.50 The Gattermann-Koch reaction generally proceeds
well only under high pressures of carbon monoxide, so it has largely been supplanted by
the Gattermann synthesis, which does not require high temperatures. The Gattermann
synthesis itself was improved by Adams,51 who replaced the hydrogen cyanide with zinc
cyanide; a small quantity of potassium chloride is usually needed in this version of the
reaction, also.
In the Gattermann-Koch reaction, the reactive electrophile may be viewed, in a formal
sense, as the formyl cation, [H–C≡O]+, although the need for a Cu (I) cocatalyst (e.g.,
Example 10.5952) suggests that the formation of the active electrophile may involve a tran-
sient copper carbonyl or formyl copper species. In the Gattermann reaction (Examples
10.60 and 10.61), the active electrophile may be viewed as the conjugate acid of hydrogen
cyanide, [H–C≡N–H]+, although this, too, is almost certainly an oversimplification. A
study of the reaction in acidic media using trimethylsilyl cyanide as the cyanide source53
has found that the rate of product formation is directly related to the acidity of the reaction
medium. The authors proposed that the diprotonated form of HCN, [H–C=NH22+], is the
active electrophile. The final step of the Gattermann reaction is hydrolysis of an iminium
ion to give the aldehyde.
CO, HCl, CuCl CHO

(10.59)
Me AlCl3
Me
CHO
Zn(CN)2 (2 eq)
MeO OH HCl (g) MeO OH
54
(10.60)
Et2O, r.t., 2 h
MeO MeO
OMe (69%) OMe
50. (a) Gattermann, L.; Koch, J.A. Ber. dtsch. chem. Ges. 1897, 30, 1622.
Reviews: (b) Crouse, N.N. Org. React. 1949, 5, 290. (c) Olah, G. A. Friedel-Crafts and Related Reactions
(Wiley- Interscience: New York, 1964) Vol.3, 1153. (d) Truce, W.E. Org. React. 1957, 9, 37. (e) Olah, G.A,; Ohan-
nesian, L.; Arvanaghi, M. Chem. Rev. 1987, 87, 671.
Friedrich August Ludwig Gattermann (1860–1920) was educated at Göttingen (PhD 1885) under Victor
Meyer, whom he followed to Heidelberg in 1889. He concluded his career at Freiburg 1899. For more biograph-
ical detail, see: Jacobson, P. Ber. dtsch. chem,. Ges. 1921, 54, A115.
Julius Arnold Koch (1864–1956) was an American chemist born in Germany. He graduated from the Pitts-
burgh College of Pharmacy in 1884 and spent seven years in the drug business. He became Chair of Pharmacy
and was Dean at his alma mater in 1891. He remained there until 1932. In 1896 he traveled to Germany to study
with Baeyer at Munich and with Gattermann and Victor Meyer in Heidelberg. Koch became Professor of Or-
ganic Chemistry at Pittsburgh in 1900. He was President of the American Pharmaceutical Association in 1923.
51. (a) Adams, R.; Levine, I. J. Am. Chem. Soc. 1923, 45, 2373. (b) Adams, R.; Montgomery, E. J. Am. Chem.
Soc. 1924, 46, 1518.
52. Coleman, G.H.; Craig, D. Org. Synth. 1943, Coll. Vol. 2, 583; Org. Synth. 1932, 12, 80.
53. Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 691.
54. Burke, J.M.; Stevenson, R. J. Nat. Prod. 1986, 49, 522.

OAc OAc
Zn(CN)2 (1.7 eq), HCl (g) 55
(10.61)
O KCl (0.2 eq), Et2O, –5°C O CHO
(50%)
In 1960,56 Olah showed that formyl fluoride, the most stable of the formyl halides,
could form a stable complex with boron trifluoride that would formylate benzene and
more electron-rich aromatic hydrocarbons. The reaction is occasionally referred to as the
Olah formylation, or the Gattermann-Olah reaction. The actual electrophile does not
appear to the formyl cation but a boron trifluoride complex of the formyl fluoride (e.g.,
Example 10.62).
BF3 BF3
O O
(10.62)
H F H F
Vilsmeier-Haack Formylation
The reaction between dimethylformamide (DMF) and phosphoryl chloride gives an imin-
ium ion (Example 10.63) that is electrophilic enough to attack electron-rich aromatic spe-
cies such as furans, pyrroles, indoles, and thiophenes (e.g., Examples 10.64 and 10.65), as
well as polycyclic hydrocarbons and simple benzenes with an electron-releasing substitu-
ent. This reaction is known as the Vilsmeier-Haack formylation after the two chemists
who first reported it.57 Hydrolysis of the initial product during the workup procedure then
gives the aromatic aldehyde.
O
PCl2 Cl2PO2
O O Cl
POCl3 Cl
(10.63)
H NMe2 H NMe2 H NMe2
POCl3, DMF, 0°C CHO 58

(10.64)
(84%)
N N
H H
55. Wong, H.N.C.; Niu, C.R.; Yang, Z.; Hon, P.M.; Chang, H.M.; Lee, C.M. Tetrahedron 1992, 43, 10339
56. Olah, G.A.; Kuhn, S.J. J. Am. Chem. Soc. 1960, 82, 2380.
57. Vilsmeier, A.; Haack, A. Ber. dtsch. chem. Ges. 1927, 60, 119. This paper refers to an earlier report of the
reaction between N-methylacetanilide and phosphoryl chloride: Fischer, O.; Müller, A.; Vilsmeier, A. J. Prakt.
Chem. 1925, 109, 69.
Anton Vilsmeier (1894–1962) graduated from Regensburg in 1914 and entered the German army. In 1920, he
resumed his education and took his PhD at Erlangen under Otto Fischer. He remained at Erlangen as an Assistant
until 1927, when he moved to I.G. Farbenindustrie (later BASF) as a dye chemist. He retired from BASF in 1959.
Albrecht Haack (1898–1976) received his PhD at Erlangen in 1926 under Fischer and Vilsmeier. From 1928–
1941 he worked as an industrial chemist at “Milk Central” in Karlsruhe/Baden. After military service (1941–1945),
he left chemistry and entered government service. He retired in 1969.
58. Kuttruff, C.A.; Zipse, H.; Trauner, D. Angew. Chem. Int. Ed. 2011, 50, 1402.

Me Me
POCl3, DMF, 0°C
(96%) (10.65)59
Me O Me O CHO
The Vilsmeier-Haack reaction is a popular reaction because it avoids the use of strongly
acidic reagents and is thus suitable for use with compounds carrying sensitive functional-
ity. This reagent has been modified by replacing the phosphoryl chloride with oxalyl chlo-
ride, and this reagent has been reported60 to give higher yields with sensitive compounds
such as the electron-rich N-vinylpyrrole in Example 10.66, which gave only 28% yield of
the aldehyde when phosphoryl chloride was used.61
1) (COCl)2 (1.1 eq), DMF (1.1 eq)

CH2Cl2, r.t., 40 min (10.66)
N N CHO
2) NaOAc (1.1 M, 5 eq), H2O
(48%)
Duff Formylation Reaction

The Duff formylation, first described in a series of four papers by Duff and Bills,62 is a re-
action between an electron-rich aromatic compound and hexamethylenetetramine in
acetic acid at elevated temperature. The reaction proceeds by way of an intermediate
Figure 10.7 The mechanism

H H H H of the Duff formylation
N N N reaction
CH2
N N N N N N
N N N
(10.67) (10.68) (10.69)
H H
H2N H
H N N
N N N N
N N N N
N
(10.72) (10.71) (10.70)
H2N H H
N N O
N
Me
(10.73)
59. Martin, S.F.; Gluchowski, C.; Campbell, C.L.; Chapman, R.C. J. Org. Chem. 1984, 49, 2512.
60. Mikhaleva, A.I.; Ivanov, A.V.; Skital’tseva, E.V.; Ushakov, I.A.; Vasil’tsov, A.M.; Trofimov, B.A. Synthesis 2009, 587.
61. Mikhaleva, A.I.; Zaitsev, A.B.; Ivanov, A.V.; Schmidt, E. Yu.; Vasil’tsov, A.M.; Trofimov, B.A. Tetrahedron
Lett. 2006, 47, 3693.
62. Duff, J.C.; Bills, E.J. J. Chem. Soc. 1932, 1987; 1934, 1305; 1941, 547; 1945, 276.

iminium ion (10.68) that attacks the aromatic ring to give a benzylamine derivative (10.69,
Figure 10.7). If the reaction is carried out at low temperature, the product obtained is, in
fact, a benzylamine, but at high temperature, the intermediate undergoes an assisted in-
tramolecular 1,5-rearrangement of hydrogen to give an isomeric iminium ion (10.73) that
can then be hydrolyzed to give the aromatic aldehyde. An alternative intermolecular hy-
drogen transfer has also been proposed as part of the mechanism.63 It is worthwhile noting
that the closely related Sommelet reaction,64 which is a formal oxidation of a benzyl halide
to a benzaldehyde by hexamethylenetetramine and water, as in Example 10.74,65 almost
certainly follows the same general mechanism as the Duff reaction.
Br CHO
1) C6H12N4, CHCl3, ∆
(10.74)
2) H2O, ∆
S S
(54-72%)
Like the Vilsmeier-Haack reaction, the Duff reaction is restricted to electron-rich aro-
matic compounds such as phenols. The reaction is not widely used in its original form
because of the reaction conditions, but it has been used for the synthesis of simple phenolic
aldehydes (e.g., Example 10.75).66 The replacement of acetic acid by trifluoroacetic acid
allows the reaction to be carried out under much less forcing conditions and allows a
larger range of aromatic hydrocarbons—including benzene itself—to be formylated by the
reagent.67
OH OH
Me Me 1) C6H12N4, CF3CO2H Me Me
∆, 12 h (10.75)
2) H2O
(95%) CHO
Reaction Synopses
Gattermann-Koch, Gattermann, and Gattermann-Olah Reactions
Ar H Ar CHO
Reagents:
CO, HCl, CuCl, AlCl3 (Gattermann-Koch); or
HCN, HCl, AlCl3 (Gattermann); or
Zn(CN)2, HCl, KCl, Et2O (Adams modification); or
HCOF, BF3 (Gattermann-Olah)
ArH: must be at least as reactive as benzene toward electrophilic aromatic
substitution
Vilsmeier-Haack formylation
Ar H Ar CHO
Reagents:
DMF, POCl3; PhN(Me)CHO, POCl3; etc. or
(COCl)2, DMF; etc.
(continues)
63. Ogata, Y.; Sugiura, F. Tetrahedron 1968, 24, 5001.

64. Sommelet, M. Compt. Rend. 1913, 157, 852.
65. Campaigne, E.; Bourgeois, R.C.; McCarthy, W.C. Org. Synth. 1963, Coll. Vol. 4, 918; 1953, 33, 93.
66. (a) Larrow, J.F.; Jacobsen, E.N. Org. Synth. 2004, Coll. Vol. 10, 96; 1998, 75, 1. (b) Allen, C.H.F.; Leubner,
G.W. Org. Synth. 1963, Coll. Vol. 4, 866; 1951, 31, 92.
67. Smith, W.E. J. Org. Chem. 1972, 37, 3972.

ArH: must be more reactive than benzene toward electrophilic aromatic

substitution
Duff Reaction
Ar H Ar CHO
Reagents:
C6H12N4, HOAc, H2O, ∆; or
(1) C6H12N4, CF3CO2H, ∆; (2) H2O ∆; etc.
ArH: must be more reactive than benzene toward electrophilic aromatic
substitution; if CF3CO2H is used, benzene will react.
Worked Problem
10-3 What is the major monosubstitution product expected from each of the following
reactions? Account for the regiochemistry of the reactions.
Ph
N CHO, POCl3
Cl Me 1) DMF, POCl3
(a) Fe (b)
2) H2O
§Answers below.

Ph
N CHO, POCl3
Cl Me Cl
(a) Fe Fe
CHO
In this reaction, the ferrocene derivative has two aromatic rings, one substituted with chlorine (which is
electron-withdrawing), and one unsubstituted. Because the unsubstituted ring is more electron-rich, it will be
formylated first. Note how in this example, N-methylformanilide is used in place of DMF. This reagent occa-
sionally provides advantages over DMF itself.
1) DMF, POCl3 H2O

(b) (hydrolysis)
2) H2O
X CHO X
Me2N
N
Me Me X = Cl or OP(O)Cl2
H
etc.
X X X
Me2N Me2N Me2N
In this reaction, the electrophile attacks the five-membered ring because this leads to an aromatic tropylium
ion contributor to the resonance hybrid of the intermediate carbocation. Attack on the seven-membered ring
leads to complete loss of aromaticity of the azulene. Loss of the proton and hydrolysis of the initial product
complete the reaction.
References: (a) J. Am. Chem. Soc. 1957, 79, 3416. (b) Angew. Chem. 1957, 69, 533.

Drill Problem
What are the products expected when each of the arenes below is treated with
each of the reagents in the list below them?
Me O
OH N
(a) (b) N (c) (d)

MeO N
H
Reagents:
(A) Zn(CN)2, HCl. (B) 1) PhN(Me)CHO, POCl3; 2) H2O
(C) 1) Cl2CHOMe, AlCl3; 2) H2O. (D) C6H12N4, CF3CO2H, ∆
Problems
10-4 Supply the structure of the major organic product of each of the following
reactions.
OH
H
Zn(CN)2 (1.5 eq) HO C6H12N4, AcOH
(a) (b) O
HCl (g), Et2O, r.t. 110°C, 48 h
MeO O H
POCl3
(c) MeO N DMF, 0-35°C
OMe Me
References: (a) J. Org. Chem. 1990, 55, 2913. (b) J. Am. Chem. Soc. 2005, 127, 11958. (c) J. Am. Chem.
Soc. 1999, 121, 6771.
10-5 A reaction similar to the Vilsmeier-Haack formylation is the Reiche-Gross

formylation [Chem. Ber. 1960, 93, 88; Org. Synth. 1973, Coll. Vol. 5, 49], which in-
volves treating an aromatic compound that is more electron-rich than benzene
with methoxydichloromethane and a Lewis acid. Using the example below, give a
reasonable mechanism for this reaction.
OAc Cl2CHOMe (5 eq)

SnCl4 (5 eq)
N CH2Cl2, 19 h
SO2Ph –78 to –10°C
Reference: J. Am. Chem. Soc. 2011, 133, 2864.
10.4 Addition of Stabilized Carbocations: The Prins, Mannich,

and Mukaiyama Reactions
Up to now, our discussion of the use of carbocation electrophiles in synthesis has been
confined to their use in electrophilic aromatic substitution reactions. However, the overall
usefulness of electrophilic addition reactions also extends to addition reactions, especially
when a stabilized carbocation and an alkene carrying a substituent with a lone pair are
involved. The addition of stabilized carbocations (oxonium ions) to alkenes is known as

H Figure 10.8 The mechanism

H O of the acid-catalyzed Prins
R reaction
R R
OH OH
OH
H H (10.76) H
H
R OH
O R
H2C=O
O H OH
H
(10.78) (10.77)
the Prins reaction, after the Dutch chemist68 who discovered it. The similar addition of
iminium ions to enols is known as the Mannich reaction, after its discoverer, German
chemist Carl Mannich.69 The use of alkenes that can form stabilized carbocations is exem-
plified by the Mukaiyama reactions.70
The Prins Reaction71

In the Prins reaction, the conjugate acid of formaldehyde adds to an alkene to form a new
carbon-carbon σ bond. This addition leads to an intermediate carbocation that is believed
to be stabilized as a protonated oxetane by neighboring group participation of the lone
pair of electrons on the oxygen (10.76). Trapping of the cation by a water molecule com-
pletes the addition reaction. The overall stereochemistry of the addition is usually anti,
and this is what one would expect if the intermediate cation were stabilized by the neigh-
boring group. The course of the Prins reaction is actually quite complex (there are numer-
ous side reactions), but the formation of the major product of the reaction (10.77) may be
rationalized as shown in Figure 10.8 for the sulfuric acid–catalyzed addition of formalde-
hyde to a 1-alkylcyclohexene. As expected on the basis of this mechanism, the overall ad-
dition occurs with Markovnikov regiochemistry. A major by-product of the reaction,
especially in the presence of excess formaldehyde, is the 1,3-dioxane (10.78). The course of
the reaction can be controlled to some degree by the solvent; when the solvent is bulky, or
68. Hendrik Jacobus Prins (1889–1958) was educated at the University of Delft (Dr Ir, 1912). He joined the
N.V. Polak & Schwartz Essencefabrieken, in Hilversum immediately after his graduation, then, in 1925, he
joined Nederlandse Thermochemische Fabrieken, being appointed Director in 1932. In 1951, he was made an
Officer of the Order of Orange-Nassau. Prins continued his research into the reactions of cations and alkenes
through World War II, although publication of his work, which was always in Dutch journals, was interrupted
by the war.
69. Carl Mannich (1887–1947) was educated at Marburg and Berlin, where he graduated with a degree in
pharmacy in 1900. He then studied at Berlin (PhD, 1903); his career took place in Berlin (1903), Göttingen (1911),
and Frankfurt (1919). For more biographical details, see: Priesner, C. Neue Deutsche Biographie (Duncker &
Humblot: Berlin, 1990), vol. 16, p. 71.
70. Teruaki Mukaiyama (1927–) graduated from Tokyo Institute of Technology in 1948. In 1952, he joined
the faculty of Gakushuin University as Assistant Professor of Chemistry. He continued research toward his
graduate degree, and in 1956, he was awarded the DSc degree from the University of Tokyo. In 1962, he moved
to Tokyo Institute of Technology as Professor of Chemistry, and in 1974, he moved to the University of Tokyo
in the same capacity. For more biographical detail, see: Kobayashi, S. Chem. Asian J. 2008, 3, 148.
71. (a) Prins, H.J. Chem. Weekblad 1917, 14, 627, 932; 1919, 16, 64, 1072, 1510. Reviews: (b) Arundale, E.; Mike-
ska, L.A. Chem. Rev. 1952, 51, 505.

OH OH OH
OH OH2
OH HO O O
H
(10.79) (10.80) (10.81)
O
H H
H O OH OH O
H H
O O
O O O H
(10.82)
(10.84) (10.83)
(10.85)
pinacol rearrangement Prins reaction
Figure 10.9 The pinacol-terminated Prins reaction
significantly less nucleophilic than water, the cation intermediate may undergo deproton-
ation to yield an unsaturated alcohol.
In addition to proton acids, Lewis acids such as SnCl4, AlCl3, Me2AlCl, and EtAlCl2
can also be used as catalysts in the Prins reaction. When diethylaluminum chloride is
used as the catalyst, the Prins reaction can also be extended to other aldehydes, although
the yields are generally not as good as with formaldehyde.
One of the more useful applications of the Prins reaction in synthesis has been the
pinacol-terminated Prins cyclization reaction (Figure 10.9), discovered by Mousset,72 and
extended into a useful synthetic method for the synthesis of cyclic ethers by Overman.73
The reaction consists of an initial addition to give the oxonium ion 10.80, followed by de-
hydration to form the oxonium ion 10.82—strictly analogous to forming a cyclic ketal.
This is followed by an intramolecular Prins reaction to give a β-hydroxy-carbocation
(10.83) that then undergoes a pinacol rearrangement to give the carbonyl product (in this
case, the aldehyde 10.84). The original Mousset example is shown in Figure 10.9. As the
mechanism implies, at should be possible to apply this reaction to 1,3-dioxolanes (e.g.,
10.85). One can, and tetrahydrofurans are obtained as the major reaction products (e.g.,
Examples 10.86 and 10.87).
72. (a) Martinet, P.; Mousset, G.; Michel, M. C. R. Acad. Sci. Paris, Ser. C 1969, 268, 1303. (b) Martinet, P.; Mousset,
G. Bull. Soc. Chim. Fr. 1970, 1071. (c) Martinet, P.; Mousset, G. Bull. Soc. Chim. Fr. 1971, 4093. (d) Mousset, G. Bull.
Soc. Chim. Fr. 1971, 4097. (e) Chambenois, D.; Mousset, G. C. R. Acad. Sci. Paris, Ser. C 1972, 274, 715. (f) Chambenois,
D.; Mousset, G. C. R. Acad. Sci. Paris, Ser. C 1972, 274, 2088. (g) Chambenois, D.; Mousset, G. Bull. Soc. Chim. Fr.
1974, 2969. (h) Malardeau, C.; Mousset, G. Bull. Soc. Chim. Fr. 1977, 988.
73. (a) Hopkins, M.H.; Overman, L.E. J. Am. Chem. Soc. 1987, 109, 4748. (b) Hopkins, M.H.; Overman, L.E.;
Rishton, G.M. J. Am. Chem. Soc. 1991, 113, 5354; 1992, 114, 10093. (c) Gasparski, C.M.; Herrinton, P.M.; Over-
man, L.E.; Wolfe, J.P. Tetrahedron Lett. 2000, 41, 9431. (d) Cohen, F.; MacMillan, D.W.C.; Overman, L.E.;
Romero, A. Org. Lett. 2001, 3, 1225. (e) Herrinton, P.M.; Hopkins, M.H.; Mishra, P.; Brown, M.J.; Overman, L.E.
J. Org. Chem. 1987, 52, 3711. (f) Brown, M.J.; Harrison, T.; Herrinton, P.M.; Hopkins, M.H.; Hutchinson, K.D.;
Mishra, P.; Overman, L.E. J. Am. Chem. Soc. 1991, 113, 5365. (g) Overman, L.E.; Rishton, G.M. Org. Synth. 1998,
Coll. Vol. 9, 4. (h) Cloninger, M.J.; Overman, L.E. J. Am. Chem. Soc. 1999, 121, 1092. (i) MacMillan, D.W.C.;
Overman, L.E.; Pennington, L.D. J. Am. Chem. Soc. 2001, 123, 9033. (j) Overman, L.E.; Pennington, L.D. J. Org.
Chem. 2003, 68, 7143.

O
O O
SnCl4, MeNO2
O (10.86) 74
–23°C to r.t.
EtO2CN (90%)
EtO2CN
SiMe2Ph
O
SnCl4, CH2Cl2 75
O (10.87)
–78°C SiMe2Ph
O O
(89%)
TBDPSO
OTBDPS
Although the intermolecular Prins reaction does not proceed as well with alde-
hydes other than formaldehyde, the intramolecular cyclization of aldehydes and ke-
tones and their conjugated counterparts onto alkenes is a facile reaction. In an extensive
study,76 Snider investigated the use of alkylaluminum chlorides to promote an intra-
molecular Prins-type addition to alkenes. The final product of the reaction was found
to be determined by the amount of the Lewis acid catalyst used in the reaction, a result
that was not expected. With one equivalent or less, the reaction followed the expected
course and gave the alkene with the isopropenyl group (Example 10.88). With two
equivalents of the Lewis acid, however, the initial cyclization was followed by an un-
precedented series of Wagner-Meerwein rearrangements to give the enone product
(Example 10.89).
H H
MeAlCl2 (1 eq), CH2Cl2
–40°C to r.t., 20 h (10.88)
O (85%) O
H
H H
–65 to –10°C, 3 h (10.89)
O (70%) O
When the Prins reaction with aldehydes is applied to homoallylic alcohols, the
product is a 4-hydroxytetrahydropyran with substituents at the 2- and 6-positions. In
the product, all the substituents in the tetrahydropyran ring are equatorial. Example
10.90 77 illustrates this highly diastereoselective Prins reaction under “green” condi-
tions, using a heteropolymolybdic acid catalyst in aqueous solution. A similar reaction
to give a 4-chlorotetrahydropyran (Example 10.91) with all groups equatorial by means
of an electrophilic ionic liquid as the solvent was earlier reported by the same research
group.78
74. Overman, L.E.; Rishton, G.M. Org. Synth. 1998, Coll. Vol. 9, 4.
75. Nemoto, H.; Ishibashi, H.; Nagamochi, M.; Fukumoto, K. J. Org. Chem. 1992, 57, 1707.
76. Snider, B.B.; Rodini, D.J.; van Straten J. J. Am. Chem. Soc. 1980, 102, 5872.
77. Yadav, J.S.; Reddy, B.V.S.; Kumar, G.G.K.S.N.; Aravind, S. Synthesis, 2008, 395.
78. Yadav, J.S.; Reddy, B.V.S.; Reddy, M.S.; Niranjan, N.; Prasad, A.R. Eur. J. Org. Chem. 2003, 1779.

PhCHO OH
(10.90)
H3PMo12O40 (0.4 eq) Ph O Ph
H2O, r.t., 8 h
OH
(88%)
Ph
Cl
PhCHO
Ph O Ph (10.91)
[bmim]Cl, xAlCl3, 5 min
(95%)
The addition of a carbocation to an alkene occurs fairly readily, but the process is often
not especially regiospecific. This can be addressed by using an allylsilane in place of the simple
alkene acceptor. The C—Si bond is much more efficient than a C—C or C—H bond at stabi-
lizing the adjacent cation center by hyperconjugation, so additions become regiospecific, and,
critically, the desilylation of the intermediate carbocation allows the regiospecific generation
of an alkene double bond. It is an important feature of silane chemistry that silanes can over-
ride the Zaitsev regiochemical preference for elimination from a carbocation. A good example
of the regiospecific addition of a carbocation to an allylsilane, and subsequent desilylation is
provided by the key cyclization step from the synthesis of the hydroazulene species in Exam-
ple 10.92.79 This reaction illustrates the directing effect of the silicon: in the absence of the
silane directing group, the product would have been an endocyclic alkene.
Et2AlCl (2 eq)
PhMe
–10°C to r.t., 1 h
(10.92)
(70-85%)
O O
Me3Si
Aza-Prins Reactions
In an intramolecular reaction, the protonated carbonyl group of the Prins reaction can be
replaced by an iminium ion (Example 10.93). Markovnikov addition of the iminium ion to
the alkene gives a cation (Example 10.94) that then deprotonates to give an allylic amine
(Example 10.95) or reacts with a nucleophile to give the addition product (Example 10.96).
The electrophile is even more effective when the nitrogen atom is acylated. The resultant
aza-Prins reaction is a useful carbon-carbon bond-forming reaction.
R R R R
O R'2NH NR'2
R acid R H
(10.93)
R X R R
R'2N R'2N R'2N R
R R
R R R
and/or
(10.96) (10.95) (10.94)
Br
SnBr4, CH2Cl2 H
AcO (10.97) 80
–78°C, 10 min H
N N
(78%) Boc
Boc CO2Me CO2Me

79. Majetich, G.; Song, J.-S.; Leigh, A.J.; Condon, S.M. J. Org. Chem. 1993, 58, 1030.
80. Hanessian, S.; Tremblay, M.; Petersen, J.F.W. J, Am. Chem. Soc. 2004, 126, 6064.

TBSO TBSO
OMEM H
H
Me2NH, ZnBr2
O (10.98) 81
MeCN, 50°C
40 min
AcO CHO AcO NMe2
AcO OAc
Drill Problem
(i) What will be the major organic product from the reaction of each of the com-
pounds in the first list with each of the reagents in the second? You may assume
one equivalent of the reagent (how would the product differ if an excess of the
reagent were available?).
Compounds:
SiMe3
OH OMe
(a) (b) (c) (d)
S
Reagents:
(A) (H2CO)n, H2SO4. (B) PhCHO, EtAlCl2. (C) Me2NH, (CH2O)n, CF3CO2H
(ii) What will be the major organic product from the reaction of each of the com-
pounds below with a strong Lewis acid or a strong protic acid?
(a) N (b) O
Reaction Synopses
Prins and Aza-Prins Reactions
H R'
XH OH
R R' X HX O
R R and/or
acid R' R
R R
R R'
R
R
R: alkyl, aryl, H; R': H, alkyl, aryl; X=O, N;

Acid: H2SO4, Me2AlCl, EtAlCl2, BF3, ZnBr2, SnBr4, TiCl4, etc.
The reaction can be carried out under “green” conditions, using H3PMo12O40 in
water, or the electrophilic ionic solvent, [bmim]Cl•xAlCl3.
The regiochemistry of the reaction can be controlled using an allylsilane as the
alkene partner.
(continues)
81. Lee, H.M.; Nieto-Oberhuber, C.; Shair, M.D. J. Am. Chem. Soc. 2008, 130, 16864.

Figure 10.10 Mechanism of (10.99) (10.100)

the Mannich reaction H
O O
HOAc
R R O
R R R
R R R R
(10.102)
H HNR'2 H R' R' NR'2
O N
HOAc
R' R' R'
(10.101)
Pinacol-Terminated Prins Reaction.
H R'
R' H
HO R O R
R' O R'
R R
R acid
OH R R
R O
Reagents: SnCl4, MeNO2, –20°C; SnCl4, CH2Cl2, –78°C; etc.

Relative stereochemistry of the product: can be predicted on the basis of a
cyclohexane-like activated complex for the Prins step
Mannich Reaction: An Iminium Equivalent of the Aldol Addition

Few reactions have seen the rise to prominence that the Mannich reaction82 has under-
gone since the last decade of the 20th century. In large part, this is due to the emergence of
chiral secondary amines as catalysts in carbon-carbon bond-forming reactions involving
aldehydes, in particular, through chiral iminium ions. In a formal sense, the Mannich
reaction is an aza-aldol reaction in which the neutral carbonyl electrophile is replaced by
a more electrophilic iminium ion (10.101). Because the reaction is carried out in the pres-
ence of a weak acid catalyst (typically acetic acid), the nucleophilic participant in the reac-
tion is the thermodynamic enol of the second carbonyl component (10.100, Figure 10.10).
The iminium ion is most reactive when derived from formaldehyde, or an aldehyde rather
than a ketone. In the first step, the amine condenses with the reactive carbonyl compound in
the presence of the acid catalyst to form an iminium ion, and the acid also catalyzes the con-
version of some of the ketone to its enol form. The enol then adds to the iminium ion to gen-
erate an intermediate oxonium that loses a proton to give the Mannich base. An intramolecular
Mannich reaction (Example 10.103) was the final step in Evans’ synthesis of luciduline.83
Me Me
HN (CH2O)n N
Me Me
(10.103)
Me2CHCH2OH
∆, 20 h
O O
The same kinds of advances that have much increased the synthetic utility of the aldol
addition reaction have also made the Mannich reaction even more useful in synthesis. It is
now possible to preform the iminium ion (an example is Eschenmoser’s salt, [H2C=NMe2]I,
formally derived from formaldehyde and dimethylamine (e.g., Example 10.104).84 Iminium
82. (a) Mannich, C.; Krösche, W. Arch. Pharm. 1912, 250, 647. Review: (b) Blicke, F.F. Org. React. 1942, 1, 303.
83. Scott, W.L.; Evans, D.A. J. Am. Chem. Soc. 1972, 74, 4779.
84. Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew. Chem. Int. Ed. Engl. 1971, 10, 330.

ions can also be formed by protonation of enamines at carbon (Example 10.105). In addi-
tion, enol trimethylsilyl ethers have now made kinetic enolate surrogates readily available,
so that one is no longer restricted to the thermodynamic enol as the reactant.
TESO TESO
CHO CHO
O O
[H2C=NMe2]I
(10.104) 85
Et3N, CH2Cl2
O O
O (97%) O
TIPSO O TIPSO O
O
O
H (CF3CO)2O 86
(10.105)
Br CF3CO2H, ∆, 14 h
Br N
N (67%)
MeO2C
CO2Me
A creative way to generate the enol is illustrated by an early step in the Woodward
synthesis of vitamin B12, where the acid-catalyzed hydration of a homopropargyl imine
(Example 10.106) provides an intermediate (Example 10.107) containing both the enol and
the iminium ion moieties.87
OMe OMe OMe
BF3•Et2O, HgO
N MeOH N BF
3 NH
HO
O
H
(10.106) (10.107) (10.108)
Enantioselective Mannich Reactions

As implied in the introductory paragraph of this section, the Mannich reaction can be adapted
to asymmetric synthesis by appropriate choice of chiral catalysts. The reaction has generally
been most effective when the imine is derived from a glyoxylate ester.88 In a 2005 report,89
(S)-2-(5-tetrazolyl)pyrrolidine (as in Example 10.109) was shown to be an efficient chiral cata-
lyst for the syn-selective, highly enantioselective Mannich reaction between aldehydes or ke-
tones and the p-methoxyphenyl imine of ethyl glyoxylate. Branching at the β carbon reduces
both the diastereoselectivity and the enantioselectivity of the reaction. Three years later,90 a
85. Wender, P.A.; Badham, N.F.; Conway, S.P.; Floreancig, P.E.; Glass, T.E.; Houze, J.B.; Krauss, N.E.; Lee, D.;
Marquess, D.G.; McGrane, P.L.; Meng, W.; Natchus, M.G.; Shuker, A.J.; Sutton, J.C.; Taylor, R.E. J. Am. Chem.
Soc. 1997, 119, 2757.
86. Becker, M.H.; Chua, P.; Downham, R.; Douglas, C.J.; Garg, N.K.; Hiebert, S.; Jaroch, S.; Matsuoka, R.T.;
Middleton, J.A.; Ng, F.W.; Overman, L.E. J. Am. Chem. Soc. 2007, 129, 11987.
87. Woodward, R.B. Pure Appl. Chem. 1968, 17, 519.
88. (a) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548 (Ag-catalyzed). (b) Hagi-
wara, E.; Fujii, A.; Sodeoka, M. J. Am. Chem. Soc. 1998, 120, 2474. (c) List, B. J. Am. Chem. Soc. 2000, 122, 9336.
(d) Juhl, K.; Gathergood, N.; Jorgensen, K.A. Angew. Chem., Int. Ed. 2001, 40, 2995. (e) Kobayashi, S.; Matsubara, R.;
Kitagawa, H. Org. Lett. 2002, 4, 143. (f) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J.M.; Barbas, C.F. J. Am. Chem.
Soc. 2002, 124, 1842. (g) Nakamura, Y.; Matsubara, R.; Kiyohara, H.; Kobayashi, S. Org. Lett. 2003, 5, 2481–2484.
89. Cobb, A.J.A.; Shaw, D.M.; Longbottom, D.A.; Gold, J.B.; Ley, S.V. Org. Biomol. Chem. 2005, 3, 84.
90. Zhang, H.; Mitsumori, S.; Utsumi, N.; Imia, M.; Garcia-Delgado, N.; Mifsud, M.; Albertshofer, K.;
Cheong, P.H.–Y.; Houk, K.N.; Tanaka, F.; Barbas, C.F., III J. Am. Chem. Soc. 2008, 130, 875.

similar, anti-selective reaction between an aldehyde and the same imine, catalyzed by chiral
pyrrolidine-3-carboxylic acid derivatives (as in Example 10.110), was reported.
PMP
O PMP-N=CHCO2Et O HN
CH2Cl2, r.t, 2h
(10.109)
CO2Et
NN
H
N N N (5 mol %)
H H
(65%; dr > 19:1; ee >99%)
PMP
PMP-N=CHCO2Et NH
CHO
Me2SO, r.t, 48h
CHO (10.110)
Me EtO2C
CO2H (10 mol %)
HN
(57%; anti/syn 86/14; ee 77%)
This reaction is also susceptible to steric effects in the form of β-branching in the alde-
hyde: straight-chain aldehydes routinely give anti/syn ratios of 93:7 or higher and ee’s
above 95%. Other hydrogen-bonding catalysts based on the thiourea skeleton have also
been developed as efficient chiral catalysts for the anti-selective asymmetric Mannich re-
action of nitroalkanes with imines, as in Example 10.111,91 although a model for predicting
the stereochemistry in these reactions has not been proposed.
Boc
PrNO2 (5 eq), MeCN, 4 Å MS, –20°C Boc NH
N (10.111)
S Ph Ph NO2
Ph Ph (10 mol %)
N
H N C H (CF3)2 (94%)
NMe2 H S 6 3 (d.r. 99:1, ee 99%)
O2
Reaction Synopses
Mannich Reaction
O O NR'2
R R R R
Reagents:
R'2NH, CH2O, AcOH, ∆; etc. or
(1) LDA, THF, –78°C; (2) [R'2N=CH2]I; etc.
Asymmetric Mannich Reaction
Ar N—Y X HN Y
X catalyst
R R Ar
X: CHO, COR, NO2Y = CO2R, Boc, etc.

Catalysts:
CO2H S Ph
N Ph
N N N N
R N H H
H HN N NMe2 HN
H SO2Ar
syn anti anti
Absolute configuration of product: can be predicted with pyrrolidine-3-carboxylic

acid derivatives as catalysts.
91. Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. J. Am. Chem. Soc. 2008, 130, 8606.

Worked Problem
10-4 Complete the following reactions.
(CH2O)n (6 eq)
(a) dioxane, 75°C, 12 h
S OBF2
t-Bu t-Bu
(10 mol %)
1) p-MeOC6H4NH2 (1.1 eq) HN OMe

L-proline (0.1 eq), NMP, 2 h
(b) ? 2) PrCHO, –20°C, 20 h
3) NaBH4, MeOH, 0°C, 30 min OH
§Answers below.
Drill Problem
What is the major organic product from each of the following reactions?
Compounds:
CHO
(a) (b) N (c)

MeO
(continues)

O
O
(CH2O)n (6 eq)
(a) dioxane, 75°C, 12 h
S OBF2
t-Bu t-Bu S
(10 mol %)
This is a Prins reaction catalyzed by a hindered Lewis acid. As is common, acids where the acidic site is sterically
hindered by large, hydrophobic alkyl groups tend to be more effective acid catalysts. The large excess of formalde-
hyde used in this reaction strongly suggests that the final product will be the 1,3-dioxane rather than the 1,3-diol.
CHO
H
N N
O
(b) O
O
N H O NH
CHO
MeO
OH
CHO
HN OMe
NaBH4
NH NH
OH
The missing reactant is benzaldehyde. The final product of this reaction sequence is a 3-aminoalcohol, and
the most likely source of the primary alcohol functional group is an aldehyde. Thus, this reaction is a Mannich
reaction, because the intermediate compound would be a β-aminoaldehyde. The two substituent groups other
than the amine group at the β carbon are the two groups bonded to the carbonyl group of the missing reactant.
The stereochemistry can be predicted on the basis of a model where a hydrogen bond formed between the aldi-
mine and the proline enamine organizes the activated complex.
References: (a) Synthesis 2002, 2521. (b) Angew. Chem. Int. Ed. 2003, 42, 3677.

(Drill Problem continued)
Reagents:
(A) (CH2O)n, H2SO4. (B) EtO2CCH=NPh,
(C) PhCHO, Me2AlCl.
Problems
10-6 Provide the major organic product expected from each of the following reactions.
SO2Ph Zn(OTf)2 (3 eq)
(a) ClCH2CH2Cl
N
96°C, 16 h
OTBS
MeO Br
O
MeO
Me2Si H
MeO
(b) O C18H25BrO4
Bf3•Et2O (1 eq)
CH2Cl2, -78°C
OAc
O BF3•Et2O (1.2 eq)

(c) HOAc-hexanes, 0°C
C29H42O4Si
OTBDPS
Me
References: (a) J. Am. Chem. Soc. 2008, 130, 9238. (b) Org. Biomol. Chem. 2006, 4, 4118. (c) Org. Lett.
2000, 2, 1217.
10-7 Provide a reasonable mechanism that explains the regiochemistry of the reaction
below.
O O
OMe OMe
H
(CH2O)n, H2O Ph
Ph N
MeO2C O NH2 Yb(OTf)3, 4 Å MS O Ph
MeO2C ClCH2CH2Cl, 70°C MeO2C CO Me
Ph 2
O
OMe
BUT NOT Ph N
MeO2C O Ph
MeO2C
Reference: Org. Lett. 2009, 11, 777.
Electron-Rich Alkenes: Surrogates of Enolate Anions

for Reactions with Carbocations
The nucleophilic partner of the electrophile in the Mannich and Mukaiyama reactions is
an enol or the surrogate of an enolate anion. We will discuss the chemistry of enolate
anions in much more detail in Chapter 12. At this point in time, one need only know that
they are strong nucleophiles and strong bases (the pKa values of the carbonyl compounds
that one deprotonates to give the enolate anions are typically around 26), which makes

them basically incompatible with carbocation electrophiles, or their analogous oxonium

or iminium cations.
One defining structural feature of a useful enolate equivalent is a double bond–
bearing substituent with a lone pair (Example 10.112). One effect of such substituents is
to make the alkene π bond more susceptible to the addition of electrophiles because the
intermediate carbocation formed during these additions can be stabilized by conjuga-
tion of the positive charge with the lone pair. In resonance terms, these alkenes have a
minor canonical form in which the β carbon carries a formal negative charge (Example
10.113). Such alkenes react readily with carbocations to give products containing a new
carbon-carbon σ bond. Depending on the substituent, the second step of the addition
may resemble the second step of the SN1 reaction, where the positive charge on carbon is
neutralized by σ bond formation to the nucleophile, or it may resemble the second step
of the E1 reaction, where the positive charge on carbon is neutralized by π bond
formation.
R X R X
E (10.112)
E
R R R R
X = O, N, S, etc.
R R
R R
X X (10.113)
R R
major minor
Enamines
One of the first enolate surrogates to be widely used was the enamine, shown as Example
10.114, which is formed by condensing a carbonyl compound with a secondary amine. The
resultant compound has the nitrogen directly bonded to one of the sp2-hybridized carbons
of the alkene. Enamines are not widely used in reactions with carbocations, so we will
reserve our discussion of these enolate surrogates to Chapter 12.
N N (10.114)
major minor
Enol Silyl Ethers

One of the most useful alkenes of this type is the enol trimethylsilyl ether (Example
10.115).92 An enol trimethylsilyl ether reacts with both unstabilized alkyl carbocations and
stabilized carbocations such as those used in the Prins reaction to give an intermediate
carbocation stabilized by the oxygen (Example 10.116). Attack of the nucleophile in the
second step of the addition usually occurs at the silicon atom to give a carbonyl compound
(Example 10.117) as the ultimate product. An enol trimethylsilyl ether reacts with an alkyl
halide in the presence of a Lewis acid (a way of generating an alkyl cation equivalent) to
give a carbonyl compound as the final product.
92. For reviews, see: (a) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16, 817; Org. React. 1982, 28, 203.
(b) Rasmussen, J.K. Synthesis 1977, 91. (c) Brownbridge, P. Synthesis 1983, l, 85. (d) For a general method of
preparing enol trimethylsilyl ethers, see: Walshe, N.D.A.; Goodwin, G.B.T.; Smith, G.C.; Woodward, F.E. Org.
Synth. 1986, 62, 1.

R OSiMe3 R O SiMe3 R O
R R
R R E R E R
E (10.116) (10.117)
(10.115)
The first general solution to the long-standing problem of α-tert-alkylation of ke-
tones was obtained by using the enol trimethylsilyl ether and a Lewis acid catalyst in
place of the enolate anion.93 Examples 10.118 and 10.119, where the enol trimethylsilyl
ether of a ketone is alkylated with a tert-alkyl chloride or an allylic chloride in the pres-
ence of titanium tetrachloride as a Lewis acid catalyst, are typical of this type of reac-
tion. In both reactions, the titanium tetrachloride serves to generate the carbocation
from the alkyl chloride.
OSiMe3 EtCMe2Cl (1.1 eq) O
TiCl4 (1 eq) (10.118)94
CH2Cl2, –50°C
(60-62%)
OSiMe3 O
95
Me2C=CHCH2Cl (10.119)
TiCl4
CN (70%) CN
The reaction of silyl enol ethers with allylic halides where the allyl cation is not sym-
metrical (e.g., the prenyl halides), give regioisomeric products, and the ratio of the prod-
ucts depends on a number of factors, including the structure of the halide, the identity of
the Lewis acid, and the solvent (Table 10.2).
Enol trimethylsilyl ethers also react with aldehydes and ketones under acid catalysis in
what is formally a Prins-type reaction. The reaction also corresponds to an acid-catalyzed
Table 10.2 Regiochemistry of Prenylation of 1-Trimethylsilyloxycyclopentene
OSiMe3 O O
Me2C=CHCH2Cl (A) or
H2C=CHC(Me)2Cl (B)
and/or
Lewis acid, solvent, 0°C
P T
Halide Lewis Acid Solvent P:T Ratio Yield (crude)
B ZnCl2 MeNO2 60:40 100%

A ZnCl2 MeNO2 60:40 95%
A CuI CH2Cl2 88:12 85%
A ZnCl2 none 80:20 >85%
93. (a) Chan, T.H.; Paterson, I.; Pinnsonnault, J. Tetrahedron Lett. 1977, 4183. (b) Reetz, M.T.; Maier, W.F.
Angew. Chem. Int. Ed. Engl. 1978, 17, 48. (c) Reetz, M.T. Angew. Chem. Int. Ed. Engl. 1982, 21, 96. (d) Reetz, M.T.;
Maier, W.F.; Heimbach, H.; Giannis, A.; Anastassiou, G. Chem. Ber. 1980, 113, 3734. (e) Reetz, M.T.; Hüttenhain,
S.; Waltz, P.; Löwe, U. Tetrahedron Lett. 1979, 4971. (f) Paterson, I. Tetrahedron Lett. 1979, 1519.
94. Reetz, M.T.; Chatziiosifidis, I.; Hübner, F.; Heimbach, H. Org. Synth. 1984, 6, 95.
95. Kraus, G.A.; Kirihara, M. Tetrahedron Lett. 1992, 33, 7727.

version of the aldol condensation. When a protic acid is used to catalyze this reaction, the
product is almost always the conjugated carbonyl compound derived by dehydration of
the resultant β‑hydroxycarbonyl compound. However, when a Lewis acid such as tita-
nium tetrachloride is used, the β-hydroxycarbonyl compound can often be isolated. The
reaction, which was developed into a useful synthetic reaction largely as a result of the
work of Japanese chemist Teruaki Mukaiyama, is now known as the Mukaiyama aldol
reaction.96 Unlike many aldol addition reactions, the Mukaiyama aldol addition is not
always highly stereoselective, but the fact that it does not need to be carried out under
basic conditions and its high level of chemoselectivity still render it a valuable reaction.
For example, it can be used to prepare the aldol 10.120,97 which reverts to acetophenone
and acetone under the “normal” aldol addition conditions, from the enol trimethylsilyl
ether. The stereoselectivity of the reaction has been improved by the use of “super silyl”
groups, Si(SiMe3)3, which are very large, and allow facile silyl transfer reactions; their re-
activity has permitted the assembly of molecules with arrays of stereocenters, as in Exam-
ple 10.121.98 In addition, the reaction can also be used with ketals and acetals. In these
reactions, the Lewis acid converts the acetal or ketal into an oxonium ion that then adds
to the silyl ether. This reaction is exemplified by the closure of the bridged 8-membered
ring of the taxane skeleton (Example 10.122).99
1) Me3SiCl (1.3 eq), Et3N (1.3 eq)
O NaI (1.3 eq), MeCN, 30-40°C O
(91%)
(10.120)
2) Me2CO (1.1 eq), TiCl4 (1.0 eq)
CH2Cl2, 0°C OH
(70-74%)
1) H2C-CH-OSi(SiMe3)3
HNTf2 (5 mol %)
CHO Ph (10.121)
2) OSi(SiMe3)3 OR OR O
Ph
(78%, dr 94:5:<1:<1) R = Si(SiMe3)3
OTIPS O
Me Me
Me O Me O
B SPh Cl2Ti(O-i-Pr)2 (6 eq) B
O O SPh (10.122)
CH2Cl2, –78° to 0°C
O (>59%) H
O O
Ph Ph Ph
Enol silyl ethers, including silyloxyfurans, can also be used for Michael additions to
conjugated carbonyl acceptors and the acetals and ketals of α,β-unsaturated carbonyl
compounds.100 α-Silyloxyfurans give a vinylogous Michael addition with enones, as shown
in Example 10.123.101
96. Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. (b) Mukaiyama,T.; Banno, K.; Narasaka,
K. J. Am. Chem. Soc. 1974, 96, 7503.
97. Mukaiyama, T.; Narasaka, K. Org. Synth. 1986, 62, 6.
98. Boxer, M.B.; Yamamoto, H. J. Am. Chem. Soc. 2007, 129, 2762.
99. Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Hajime Kashima, H.; Nakamura, N.; Morihira, K.;
Kuwajima, I. J. Am. Chem. Soc. 2000, 122, 3811.
100. (a) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223. (b) Narasaka, K.; Soai, K.; Aikawa, Y.;
Mukaiyama, T. Bull. Chem. Soc. Japan 1976, 49, 779.
101. Chabaud, L.; Jousseaume, T.; Retailleau, P.; Guillou, C. Eur, J. Org. Chem. 2010, 5471.

O O
Me3SiO O
O Me H
O (10.123)
SnCl4 (10 mol %)
Me CH2Cl2, –78°C H
(95%, d.r. 76:24)
Allylboranes and Allylborinates

Boranes are Lewis acids that complex well to carbonyl groups to generate oxonium ions. What
is especially interesting about the interaction of allylboranes with carbonyl groups is that the
complexation of the carbonyl oxygen serves two purposes: (1) it makes the carbonyl carbon
significantly more electron-deficient; and (2) it makes the allylic group attached to boron signifi-
cantly more nucleophilic. This sets up a reaction that can be described as an analog of an intra-
molecular Prins reaction, proceeding through a cyclic transition state (e.g., Example 10.124).
‡
R'
O (10.124)
R
BR2
The addition reaction occurs with allylic rearrangement through a six-membered cyclic
transition state, which allows two new chiral centers to be incorporated stereoselectively into
the product. By the use of diisopinocampheylborane derivatives, these allylborane additions
can also be made enantioselective (e.g., Example 10.125). The required allylboranes are conve-
niently prepared from alkenes by deprotonation with “LICKOR” (effectively butylpotassium;
we will discuss this reagent in much more detail in Chapter 11), followed by treatment with a
methoxydialkylborane, as illustrated in Example 10.126. This borane was subsequently used
in an allylation reaction as part of the total synthesis of archazolid A and B.102
CHO OH
N (-)-Ipc N
B
(-)-Ipc
S S (10.125)
O Et2O-PhMe, –78°C O
O (65%, dr > 20:1) O
MeHN MeHN
B(Ipc)2
Me
1) LICKOR, PhMe, –50°C
2) (Ipc)2BOMe, Et2O, –78°C (10.126)
Me 3) BF3•OEt2
Me
The addition of allylboranes to aldehydes is highly stereoselective, and the relative

stereochemistry of the reaction can be predicted on the basis of a chairlike transition state.
The observed stereochemistry is that the E borane gives the anti alcohol, whereas the Z
borane gives the syn alcohol. The Z allylboron reagent is consistently more stereoselective
than the E isomer. The absolute configuration of the major product can be predicted for
simple allylboronates derived from tartrate esters using the model in Example 10.127,103
which predicts that the simple allylboronate derived from dialkyl (2S,3S)-tartrates will
add to the si face of the aldehyde. Roush has shown that the chirality of the boron reagent
dominates the enantioselectivity of the reaction.104 In 10.128, for example, the enantiomer
shown of the syn isomer accounts for 95% of the product mixture.105
102. Mensche, D.; Hassfeld, J.; Li, J.; Mayer, K.; Rudolph, S. J. Org. Chem. 2009, 74, 7220.
103. Roush, W.R.; Hoong, L.K.; Palmer, M.A.J.; Park, J.C. J. Org. Chem. 1990, 55, 4109.
104. Roush, W.R.; Palkowitz, A.D.; Palmer, M.J. J. Org. Chem. 1987, 52, 316.
105. (a) Roush, W.R.; Adam, M.A.; Walts, A.E.; Harris, D.J. J. Am. Chem. Soc. 1986, 108, 3422. (b) Huckins,
J.R.; de Vicente, J.; Rychnovsky, S.D. Org. Lett. 2007, 9, 4757.

O O
H H (10.127)
B O B O
O O
R R
O CO2-i-Pr
B
O O CO2-i-Pr H O
OHC (10.128)
O PhMe, 4Å MS, –78°C O
(56%) HO
Worked Problem
10-5 What reagent or sequence of reagents should be used to effect the following
transformations? Give your reasoning.
O O O O
(a) (b) OH
§Answers below.
Reaction Synopses
Alkylation of Enol Silyl Ethers
O OSiR3 O
R'
R R R
R R R
Reagents: (1) Me3SiCl, Et3N; (2) R'Cl, TiCl4, CH2Cl2, –78°C; or

(1) LDA, THF, –78°C; (2) R'Cl, TiCl4, CH2Cl2, –78°C; etc,
Best method for incorporating a tertiary alkyl group α- to a carbonyl group
(continues)

(a) This product may be prepared by alkylation of the trimethylsilyl enol ether, which should work well in
this instance since the alkyl group is tertiary.
O OSiMe3 O
Cl
1) LDA, THF, –78°C
2) Me3SiCl TiCl4, CH2Cl2, –78°C
(b) Because the involvement of a carbocation is required, the Muikaiyama aldol addition should be used to
prepare this product.
O O
O
Br2, HOAc Br 1) Zn, Et2O
OH
2)
O

Mukaiyama-Directed Aldol Addition
O OSiR3 O OH
R R R R'
R'
R R R
Reagents: (1) Me3SiCl, Et3N; (2) R'2CO, TiCl4, CH2Cl2, –78°C; or
(1) LDA, THF, –78°C; (2) Me3SiCl; (3) R'2CO, TiCl4, CH2Cl2, –78°C; etc.
Conditions: permit the isolation of labile aldol addition products
Addition of Allylboron Electrophiles: Allylation
O OH
RCH=CHCH2BX2
R H R
R'
X = R, OR, F, etc.
Reagents: RCH=CHCH2BX 2 CH2Cl2, –78°C; etc.
Diastereoselectivity: determined by geometry of allylboron reagent: Z gives mainly
syn product; E gives mainly anti product. Stereoselectivity of Z
allylboron reagents are higher (often much higher).
Enantioselectivity: fixed by chirality of the allylboronate in cyclic derivatives of
dialkyl tartrates. Enantioselectivity is often high.
Chapter Summary
This chapter has introduced major carbon-carbon bond-forming reactions that involve
carbocations as key intermediates. These reactions include the Friedel-Crafts alkylation
and acylation reactions, as well as the related formylations that include the Gattermann,
Gattermann-Koch, Houben-Hoesch, Vilsmeier-Haack, Duff, and Reiche-Gross reactions.
The dealkylation and rearrangements occurring during Friedel-Crafts alkylation, and the
asymmetric form of that reaction have been discussed. Reactions involving carbocations
stabilized by an adjacent lone pair–bearing heteroatom include the Prins, aza-Prins, and
Mannich reactions, as well as the Mukaiyama alkylation and aldol reactions. Enamines
and enol ethers have been introduced as enolate surrogates; enol trimethylsilyl ethers have
been introduced as nucleophilic partners in the Mukaiyama and related reactions, and the
use of allylboranes for the formation of new carbon-carbon bonds by a form of intramo-
lecular Prins reaction has been discussed.
Key Terms
allylboron allylation Gattermann-Koch Pinacol-terminated Prins

aza-Prins reaction formylation reaction
dealkylation Gattermann-Olah Prins reaction
Duff reaction formylation Reich-Gross formylation
enamines Houben-Hoesch acylation silyl enol ether
formylation Mannich reaction Vilsmeier-Haack
Friedel-Crafts acylation Mukaiyama aldol addition formylation
Friedel-Crafts alkylation Mukaiyama alkylation
Gattermann formylation

Additional Problems
10-8 What is the structure of the major organic product of each of the following
reactions?
CO2Me
HO [Org. Lett. 2006, 8,
(a) MeCOCl, AlCl3, CH2Cl2
831]
This reaction fails to work with the methoxy
compound. Why?
Boc
N
H Ph
[J. Am. Chem. Soc.
(b) MeO O catalyst
Mes OPO Mes
ClCH2CH2Cl 2004, 126, 11804]
HO O
Mes Mes
catalyst
Br
1) (COCl)2, Et2O, 20 h [J. Am. Chem. Soc.

(c)
N 2) MeOH 2007, 129, 13794]
H
AcCl, [emim][Cl]-(0.67)AlCl3
0°C, 5 min
[Chem. Commun.
(d) 1998, 2097]
AcCl, [emim][Cl]-(0.67)AlCl3
0°C, 5 min
HO OH
MeOCH2CN, HCl [J. Med. Chem.
(e) Me ZnCl2, Et2O 1998, 41, 2333]
Me
O COCl SnCl4, CH2Cl2 [J. Am. Chem. Soc.

(f) O –78°C, 2 h 1989, 111, 2302]
O O
EtO OEt
P P
MeO EtO O OEt [Tetrahedron Lett.
(g)
CH2Cl2, ∆, 5 h 2012, 53, 373]
MeO CO2H
O H HCl [J. Org. Chem. 1977,

(h) C19H24O
MeO H
42, 3214]
NC
1) CF3SO3H, 140 h
O [Org. Lett. 2001, 3,
(i) O 2) 75% H2SO4, 140°C, 24 h
2337]
CN
Me
Zn(CN)2 (1.5 eq), HCl (g) [Heterocycles 1999,
(j) Et2O, –5 to 0°C, 3-5 h
N
51, 2163]
H OH

CO2H
Me
Me (CF3CO)2O [Tetrahedron 2001,
(k)
OH CH2Cl2, r.t. 57, 6935]
O
Cl O
N CO2CH2CCl3 [Tetrahedron 2002,
(l)
TfOH, ClCH2CH2Cl 58, 8475]
0°C to r.t.
10-9 Give the structure of the major organic product expected from each of the follow-
ing reactions.
OH
TIPSO CHO [J. Am. Chem. Soc.

(a) OH SiMe3 BF3•Et2O 1995, 117, 10391]
(CH2O)n [J. Org. Chem. 1993,

(b) EtAlCl2 58, 1030]
O
O
TsOH, PhH, r.t. [J. Am. Chem. Soc.,
(c)
2005, 127, 8398]
N
O
H2C=CHCH2SiMe3 (1.5 eq) [J. Am. Chem. Soc.
(d) TiCl4 (1.2 eq), CH2Cl2, –78°C 1984, 106, 721]
Br
OTBS
(3 eq)
H OBut [J. Am. Chem. Soc.
(e)
O TiCl4 (1.2 eq), CH2Cl2 1981, 103, 4136]
–78°C to r.t.
MeO2C
OSiMe3
1) (CH2O)3, (1.2 eq), TiCl4 (3.6 eq)
OMe CH2Cl2, –78 to –45°C [J. Am. Chem. Soc.
(f)
OMe 2) MeOH, r.t. 1988, 110, 649]
O N O H2C=CHCH2SiMe3 (3 eq) [Tetrahedron Lett.

(g) TiCl4 (3 eq), CH2Cl2, 50°C 1999, 40, 739]
H
Me 1) Me3SiO OSiMe3 (5 eq)
OMe [J. Org. Chem.
(h) CHO TiCl4 (2 eq), CH2Cl2, –78°C
2002, 67, 5969]
2) H2O
O O 1) Me3Si SiMe3 (2 eq)

TiCl4 (1.4 eq), CH2Cl2, –72°C [J. Am. Chem. Soc.
(i) O
2) MeOH 2004, 126, 12432]
OTBS
SiMe2Ph
CHO CO2Me (1.3 eq)
1) [Org. Lett. 2004, 6,
(j) TiCl4 (1.3 eq), CH2Cl2, –50°C
Ph 3533]
O 2) H2O

O
H 1) LDA, Me3SiCl, THF, –78°C [J. Am. Chem. Soc.
(k) 2) H2CO, Yb(OTf)3, H2O-THF
OTIPS 3) DBU, CH2Cl2
2002, 124, 14546]
PMBO
What is the reason for using the DBU?
TBSO
Ph O Ph OMe
O [Chem. Eur. J. 1999,
(l) TBSO
CHO MgBr2•OEt2, PhMe 5, 121]
OPMB –15°C
CHO
Me3Si
TBSO [Angew. Chem. Int.
(m) BF3•OEt2, TBAT
Ed. 2009, 48, 9315]
TBSO CO2Me
O B[(+)-(Ipc)2] [J. Am. Chem. Soc.

(n) OH
OTBS
2004, 126, 998]
OTBS
B[(+)-(Ipc)2]
[Org. Lett. 2004, 6,
(o)
O OH 3245]
Ph Ph
O CO2-i-Pr
B
CHO O [Org. Lett. 2004, 6,
(p) Ph
CO2-i-Pr
3533]
O
Br
Ph Ph
MeO CHO [Tetrahedron Lett.
(q) O NCbz
Cu(OTf)2 (8 mol %) 2012, 53, 380]
CH2Cl2, r.t.
TBSO
10-10 Suggest a reasonable mechanism for each of the reactions below, all of which have
been used a key steps in the total synthesis of natural products.
Me Me
N NEt2 C6H12N4, HOAc, ∆ N [J. Org. Chem.

(a) N HN N NH
2008, 73, 5989]
O O
What light does this reaction shed on the mechanism
of the Duff reaction?
OTIPS (3 eq)
N CHO
H
[J. Am. Chem.
N N
(b) Ts O
H
H
BCl3 (4 eq),CH2Cl2, r.t., 15 h;
Ts
H
Soc. 2007, 129,
N then H2O HO N 11987].
H O (85%) H O
O O
What is the function of the 2,6-di-tert-butyl-

4-methylpyridine?
Br
Ph
MeO2C O
OSiMe3
N 1)
OMe, –78°C
N
Ph [J. Org. Chem.
(c)
2) BrCH2COCl, –78 to 0°C 2010, 75, 3529]
3) CF3CO2H, 0°C to r.t.
N N
4) NH3, H2O
Boc Boc
(78%)

AcO
AcO
H
OSiMe3 (5 eq) O
H MeO
O [Org. Lett. 2003, 5,
(d) MeO ZnCl2 (4 eq), –78°C to r.t. Me OPMB
CH2Cl2-Et2O (1:4)
O 5035]
Me OPMB
O (85%) H O
AcO
O R N R [Chem. Eur. J.
(e) O
N MgI2, THF, 80°C 2006, 12, 8208]
CH2Ph N
CH2Ph
Me3SiO OSiMe3
Me
CHO OMe
HO
Me
O [J. Am. Chem.
CO2Me
(f) H TiCl4, CH2Cl2, –78°C; H
Soc. 2005, 127,
then H2O
(75%)
11616]
10-11 The bromide shown reacts with trimethylsilyl cyanide to give the nitrile shown.
Because this halide is a tertiary bridgehead halide, it cannot react by the SN2
mechanism, and it should not react by a simple SN1 mechanism. Suggest a mecha-
nism for the reaction (Hint: trimethylsilyl cyanide is an oxophilic Lewis acid.)
O O
Me3SiCN
Br CN
10-12 Account for the regiochemistry of the C—C bond formation in following reac-
tion. [J. Am. Chem. Soc. 2003, 125, 2400; Aust. J. Chem. 2010, 63, 742].
O
MeO OMe O
CO2H add acetone solution dropwise
HO CO2H HO2C OMe
to 60% v/v H2SO4-H2O
but not
0-5°C
(80%)
OMe OMe OMe
10-13 Write mechanisms that will account for the formation of products 10.88 and
10.89 in the reactions below. Your mechanism should address why the two reac-
tions give different products, because both reactions involve the same starting
compound and the same reagent.
H H
–40°C to r.t., 20 h (10.88)
O (85%) O
H
H H
–65 to –10°C, 3 h (10.89)
O (70%) O

Chapter eleven
Reactive Intermediates II
Carbanions and Their Reactivity
11.1 Carbanions: Introduction and Overview
Carbanions are species where a formally trivalent carbon carries a lone pair and a formal
negative charge.1 As a consequence of this, a carbanion is isoelectronic with the corre-
sponding amine, and one can draw conclusions about carbanion structure by analogy
with the amines. Thus, we expect that simple saturated alkyl anions (11.1) will be pyrami-
dal, with the carbanion carbon sp3 hybridized. Also, placing a double or triple bond or an
aromatic ring in a position that allows conjugation should change the shape to trigonal
planar and the hybridization of the anion carbon to sp2 (11.2) by analogy with the enam-
ines and anilines.
The simplest example of this type of nucleophilic carbon compound is the metal alkyl,
where the compound contains a metal-carbon bond and reacts as a Lewis base. Metal
alkyls occupy a central position in the development of chemistry. It was the discovery of
the zinc alkyls by English chemist Sir Edward Frankland2 in 1849 that led to his publica-
tion in 18523 of the theory that all elements have a “saturation capacity” (i.e., they are
limited in the number of bonds that they can form) and to the development of the concept
of valence.
R R
R
(11.1) (11.2)
Free alkyl and alkenyl carbanions, where the carbon atom carries a full negative
charge, are actually quite rare and occur only when the metal is very electropositive.
Group IA salts of these anions are typical ionic compounds: they have ionic lattices and
they react as strong nucleophiles with alkyl halides. For example, CH3K has the same
1. Monographs: (a) Buncel, E.; Durst, T. Comprehensive Carbanion Chemistry, Parts A, B, C (Elsevier: New York,
1980–1987). (b) Stowell, J.C. Carbanions in Organic Synthesis (Wiley: New York, 1979). (c) Ogle, C.A. Carbanion
Chemistry (Springer: New York, 1987). (d) Cram, D.J. Fundamentals of Carbanion Chemistry (Academic Press: New
York, 1965). (e) Bates, R.B.; Ogle, C.A. Carbanion Chemistry (Springer-Verlag: Berlin, 1983). (f) Gronert, M. In Moss,
R.A.; Platz, M.S.; Jones, M., Jr. Reactive Intermediate Chemistry (John Wiley & Sons: New York, 2004), Part 1, p. 69.
2. Sir Edward Frankland (1825–1899) was apprenticed to a pharmacist before extending his education in
London and Marburg (PhD, 1849). He served as Professor of Chemistry at Owens College in Manchester, then
at the Royal College of Chemistry, in London, where he provided regular reports on the pollution levels of the
water (novel in the 1860s but very topical today). Frankland was knighted in 1897. For more biographical details,
see: Tilden, W.A. Famous Chemists. The Men and Their Work (George Routledge & Sons: London; and E.P.
Dutton & Co: New York, 1921; ), p. 216.
3. (a) Frankland, E. Ann. Chem. Pharm. 1849, 71, 213. (b) Frankland, E. J. Chem. Soc. 1849, 2, 297.
(c) Frankland, E. Phil. Trans. Roy. Soc. 1852, 142, 417. (d) Frankland, E. Ann. Chem. Pharm. 1853, 85, 329.
391

392 Advanced Organic Chemistry | Chapter eleven
crystal lattice as NiAs, with alternating sheets of K+ and CH3– ions in the lattice,4 and
methylsodium reacts with alkyl chlorides as an anionic reagent5 (although its reactions
with alkyl bromides and iodides are complicated by metal-halogen exchange reactions6).
Butylpotassium can be prepared by a metathesis reaction between potassium tert-butoxide
and butyllithium at low temperature, a mixture known as “LICKOR.” This has found use
as an especially powerful base, and we will discuss its use in more detail in Chapter 12. The
only other “free” carbanions are alkynide anions, and here the stability is a result of the sp
hybridization of the anion carbon.
The C—M bond in most metal alkyls is best described in terms of resonance (Example
11.3), where the major contributor to the hybrid has a non-polar covalent bond, and the
minor contributor has an ionic bond between carbon and the metal. As the polarity of the
C—M bond decreases, the tendency to form aggregates also decreases. Alkyllithiums (Ex-
ample 11.4) occur as tetramers and hexamers, depending on the alkyl group and the sol-
vent, and Grignard reagents Example (11.5)7 occur as dimers; on the other hand, dialkylzinc
reagents (e.g., Example 11.6), where the C—M bond is even less polar, occur as discrete
molecules (dimethylzinc is a linear molecule). When the metal in a metal alkyl lacks a
complete octet, the structure is often an aggregate with bridging alkyl groups (e.g., Exam-
ples 11.7 and 11.8). Trimethylaluminum, for example, occurs as a dimer with bridging
methyl groups,8 and dimethylberyllium as extended chains with all the methyl groups as
bridging ligands.9 Organometallic compounds based on practically every metal in the pe-
riodic table are now known. A completely accurate description of the bonding in many
(most?) organometallic compounds requires delocalized, multicenter bonds (e.g., the
three-center, two-electron bonds of the bridging alkyl groups in alkylmetal aggregates—
Examples 11.4, 11.5, 11.7, and 11.8).
R M R: M (11.3)
major minor
R'2O X
OR'2 R R
Li R (11.4) Mg Mg (11.5)
R Li Et2O X OEt2
R Li
Li R OR'2
R R R
R'2O
Al Al (11.7)
R R R
R Zn R (11.6)
R R R R R
Be Be Be Be Be Be (11.8)
R R R R R
Fortunately, organometallic compounds of electropositive metals such as lithium and
magnesium react as if the compound were ionic, so we generally introduce a negligible
error into our discussion if we treat these compounds as the ionic (minor) contributor to
4. (a) Weiss, G.; Sauerman, G. Angew. Chem. Int. Ed. Engl. 1968, 7, 133. (b) Weiss, E.; Sauerman, G. Chem. Ber.
1970, 103, 265.
5. (a) Bergmann, E. Helv. Chim.Acta 1937, 20, 590. (b) Letsinger, R.T. J. Am. Chem. Soc., 1948, 70, 406.
(c) Letsinger, R.L.; Maury, L.G.; Burwell, R.G., Jr. J. Am. Chem. Soc., 1951, 73, 2373.
6. Brink, N.G.; Lane, J.F.; Wallis, E.S. J. Am. Chem. Soc. 1943, 65, 943.
7. Structure: Spek, A.L.; Voorbergen, P.; Schat, G.; Blomberg, C.; Bickelhaupt, F. J. Organomet. Chem. 1974,
77, 147.
8. Vranka, R.G.; Amma, E.L. J. Am. Chem. Soc. 1967, 89, 3121.
9. Snow, A.I.; Rundle, R.E. Acta Crystallogr. 1951, 4, 348.

Reactive Intermediates II 393
the resonance hybrid. Of course, in doing so, we must rec- Table 11.1 Percent Ionic Character in Metal-Carbon σ Bonds*
ognize that free carbanions actually do not exist in solution
% Ionic % Ionic
in the presence of metal ions. One should also bear in mind
Metal Character Metal Character
that this simplification may not be insubstantial. There is
evidence from 7Li and 13C nuclear magnetic resonance K† 35 Cu 15
(NMR) spectroscopy of alkyllithiums that the partial nega- Na 33 Ni 15
tive charge on the carbon may not be as large as would be
predicted on the basis of this simple model.10 Li 32 Sn 14
The variation in reactivity of the organometallic com- Mg 26 Hg 13
pounds is mainly due to the polarity of the carbon-metal
Ti 21 Mo 9
bond. As the electronegativity of the metal increases, the
percent ionic character of the bond decreases, and the po- Al 20 Pd 8
larity of the carbon-metal bond decreases. The amount of Zn 20 Ru 8
ionic character in a polar covalent bond is approximated by:
Cd 19 W 5
Ionic character = 1 = e ∙ ∙ (Eq. 11.1)
−0.25 x A − xB
*Values are calculated using Equation 11.1 and a value of 2.55 for xC.
†
Shaded regions are ionic metal alkyls.
where xA and xB are the electronegativities of the two atoms
at the ends of the bond.11 The values given by this relation-
ship are very approximate only, and they tend to overesti- Table 11.2 Relative Importance of Ionic Forms of Metal Alkyls
mate the percent ionic character in molecules such as
hydrogen fluoride. Nevertheless, the values obtained are still R M R: M
useful in a qualitative sense; the approximate percent ionic
M=Na, K negligible dominant
character of several carbon-metal bonds of importance in
organic chemistry are given in Table 11.1. M=Mg, Zn, Al major minor, but substantial
The more polar the metal-carbon bond, the more im-
portant the ionic contributor to the resonance hybrid be- M=Cu, Pd major minor
comes. When the ionic character rises above 32%—the
shaded region of Table 11.1—the compound is best described M=Hg dominant negligible
as ionic, but in all other metal alkyls, the compound is best
described as polar covalent, with the carbon atom is at the
negative end of the dipole. The qualitative importance of the ionic contributor to the reso-
nance hybrid is given in Table 11.2. As the importance of the ionic resonance contributor
increases, the metal alkyl becomes both a stronger base and a more reactive nucleophile.
Many metal alkyls function as good Lewis bases and also as good carbon nucleophiles. For
this reason they have long held a place of importance in synthetic organic chemistry, es-
pecially because it is possible to modulate the reactivity of the metal alkyl by appropriately
choosing the metal. Alkyllithiums react explosively with water and add to even the least
reactive carbonyl group, dialkylmercury compounds dissolve in water and react with only
the most reactive carbonyl compounds under forcing conditions, and many reactions
based on palladium or ruthenium catalysts can be carried out in water.
The hybridization of the carbon atom can also play a role in determining the ionic
character of the carbon-metal bond. The relative acidities of C—H bonds increase as the
hybridization (and hence, the electronegativity) of carbon changes from sp3 (pKa ≈ 40–50)
to sp2 (pKa ≈ 35–40) to sp (pKa ≈ 25–30). As the s character of the orbital carrying the lone
pair on the anion increases, the ionic character of the organometallic compound increases,
also. Thus, the carbon-metal bond in metal alkynides is more ionic than corresponding
10. (a) McKeever, L.D.; Waack, R. J. Chem. Soc. D, Chem. Commun. 1969, 750. (b) Review of NMR methods
for strudying carbanions: O'Brien, D.H. in Buncel, E.; Durst, T., Eds. Comprehensive Carbanion Chemistry,
Part A. Structure and Reactivity (Elsevier: Amsterdam, 1980), p. 271.
11. Pauling, L. The Nature of the Chemical Bond 3rd ed. (Cornell University Press: Ithaca, N.Y., 1960), section
3–9, pp. 97–102.

metal-carbon bonds in the corresponding metal aryls and metal alkyls—sodium alkynides
are easily prepared by the reaction between sodium hydride and the alkyne.
The simple valence-bond view of the alkyl anion provides a good first approximation
for discussing the bonding in metal alkyls. Thus, even in aggregates involving multicenter
bonding, the carbon atom of the carbon-metal bond in saturated metal alkyls is sp3 hy-
bridized with the electron pair formally in an sp3 hybrid orbital (e.g., 11.1). However, if
there is a π bond adjacent to this carbon atom (e.g., the allyl anion), the anion becomes
delocalized and the carbon atom becomes sp2 hybridized (e.g., 11.2).
Stabilization of Carbanions: Comparison and Contrast with Cations

The Pauling electronegativity of carbon is 2.5, so carbon does not support a negative
charge as well as later non-metals in the second row of the periodic table. Species where
carbon carries a localized negative charge are high-energy, like those where carbon carries
a localized positive charge, and mechanisms for stabilizing the ion are important in deter-
mining reactivity—even more important than for carbocations. Like cations, anions are
stabilized by delocalization of the charge; the more effective the delocalization, the more
stable the anion.
Stabilization of Carbanions
In contrast to carbocations, where the field effect lowers the energy of the cation and, along
with hyperconjugation, is a stabilizing influence, the field effect of simple alkyl groups
raises the energy of the anion, with the result that the stability of simple saturated carban-
ions (as measured by solution-phase reactions) follows the order shown in Figure 11.1. In the
gas phase, competitive proton transfer reactions have been used to measure relative acidi-
ties of simple hydrocarbons.12 These experiments give a slightly different order for carban-
ion energies:
C2H5– > (CH3)2CH− > CH3− > (CH3)3C−

strongest base weakest base
Unlike carbocations, most simple, saturated carbanions do not rearrange—the driv-

ing force for rearrangements in carbocations comes from the need to disperse the region
of electron deficiency; carbanions are not electron-deficient, so this does not apply to
anions. This is not, of course, a totally exclusionary statement, and some anions do give
rise to synthetically useful rearrangements.13
Stabilization by Third-Row and Higher Heteroatoms

Simple alkyl carbanions can be stabilized by third- and fourth-row heteroatoms14 but not
by electronegative second-row heteroatoms. The electron affinity of these anions is nega-
tive, which makes their generation in the gas phase problematic.15 Carbanions stabilized
12. (a) DePuy, C.H.; Bierbaum, V.M.; Damrauer, R. J. Am. Chem. Soc. 1984, 106, 4051. (b) DePuy, C.H.;
Gronert, S.; Barlow, S.E.; Bierbaum, V.M.; Damrauer, R. J. Am. Chem. Soc. 1989, 111, 1968.
13. For example, the [1,2]-Wittig rearrangement: (a) Marshall, J.A. In Trost, B.M.; Fleming, I, Eds. Compre-
hensive Organic Synthesis (Pergamon: London, 1991), vol. 3, p. 975. (b) Tomooka, K.; Yamamoto, H.; Nakai, T.
Liebigs Ann./Receuil 1977, 1275. Also, the [2,3]-Wittig rearrangement: (c) Nakai, T.; Mikami, K. Chem. Rev.
1986, 86, 885. (d) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105.
14. Stabilization by silicon, phosphorus and sulfur: (a) Peterson, D.J. J. Organomet. Chem. 1967, 9, 373. (b) Magnus,
P. Aldrichimica Acta 1980, 13, 43. (c) Ager, D.; Cookson, R.C. Tetrahedron Lett. 1980, 21, 1677. (d) Mathey, F.; Mercier,
F. J. Organomet. Chem. 1979, 17, 255.
15. Downard, K.M.; Sheldon, J.C.; Bowie, J.H.; Lewis, D.E.; Hayes, R.N. J. Am. Chem. Soc. 1989, 111, 8112.

least reactive most reactive Figure 11.1 The effects of

H H R R alkyl substitution on the
H R R R reactivity of carbocations
H H H R and carbanions are opposite.
H H R R
H R R R
H H H R
most reactive least reactive
by phosphorus are the key reagents in the Wittig,16 Wadsworth-Emmons,17 and Horner18
reactions. Carbanions stabilized by adjacent sulfur (sulfoxide or sulfonyl groups, and
dithianes) and silicon are also important synthetic intermediates.
The stabilization of carbanions by third-row elements, in particular, is often attributed
to the presence of dπ − pπ bonding (e.g., Example 11.9) between the carbanion carbon and
the heteroatom.19 There is some support for this view when one observes that third-row
elements (which would use 3d orbitals) stabilize carbanions better than the corresponding
fourth-row elements (which would use 4d orbitals). The operation of dπ − pπ bonding is
not, however, universally accepted, and other mechanisms for stabilization of anions by
heteroatoms are possible, including “inverse hyperconjugation” and stabilization arising
from the polarizability of the third-row element.20
(11.9)
R R (11.10) R R
R O R O
R O (11.11) R O
N N
R O R O
R (11.12) R
C N C N
R R
minor major
The most efficient stabilization of anions occurs by conjugation of the lone pair with a π
bond to an electronegative element (e.g., Examples 11.10 to 11.12), which allows the delocaliza-
tion of the negative charge onto the most electronegative element. This leads to the formation
of an extended π bonding system, giving resonance-stabilized anions that are much better
16. Reviews: (a) Maercker, A. Org. React. 1965, 14, 270. (b) Schlosser, M. Top. Stereochem. 1970, 5, 1.
(c) Bestmann, H.J.; Vostrowsky, O. Top. Curr. Chem. 1983, 109, 85. (d) Murphy, P.J.; Brennan, J. Chem. Soc. Rev.
1988, 17, 1. (e) Maryanoff, B.E.; Reitz, A.B. Chem. Rev. 1989, 89, 863.
17. Reviews: (a) Wadsworth, W.S., Jr. Org. React. 1977, 25, 73. (b) Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87.
18. (a) Horner, L.; Hoffmann, H.; Wippel, H.G. Chem. Ber. 1958, 91, 61–63. (b) Horner, L.; Hoffmann, H.;
Wippel, H.G.; Klahre, G. Chem. Ber. 1959, 92, 2499–2505.
19. (a) Kwart, H.; King, K. d-Orbitals in the Chemistry of Silicon, Phosphorus, and Sulfur (Springer: New York,
1977). (b) Wolfe, S.; LaJohn, L.A.; Bernardi, F.; Mangini, A.; Tonachini, D. Tetrahedron Lett. 1983, 24, 3789.
(c) Wolfe, S.; Stolow, A.; LaJohn, L.A. Tetrahedron Lett. 1983, 24, 4071.
20. (a) Bernardi, F.; Csizmadia, I.G.; Mangini, A.,; Schlegel, H.B.; Whangbo, M.; Wolfe, S. J. Am. Chem. Soc. 1975,
97, 2209. (b) Lehn, J.M.; Wipff, G. J. Am. Chem. Soc. 1976, 98, 7498. (c) Borden, W.T.; Davidson, E.R.; Andersen,
N.H.; Denniston, A.D.; Epiotis, N.D. J. Am. Chem. Soc. 1978, 100, 1604. (d) Bernardi, F.; Bottoni, A.; Venturini, A.;
Mangini, A. J. Am. Chem. Soc. 1986, 108, 8171. (e) Bernasconi, C.F.; Kittredge, K.W. J. Org. Chem. 1998, 63, 1944.

Table 11.3 Effects of Solvent and Cation on Fluorenide Salts in described as enolate-type anions. As is common with
Solution* resonance-stabilized species where the two canonical forms
Mol % do not contribute equally to the resonance hybrid, the minor
Cation Solvent [R–]solv[M+]solv contributing form (the carbanion form) is the best predictor
of reactivity. The stabilization of carbanions in solution by
Li+ Dimethoxyethane (DME) 100 functional groups is in the following order:
Na +
DME 95
NO2 > CHO > RCO > CO2R > SO2 > CN ≈ CONR 2 > X
K+ DME ≈10
>H>R
Cs+ DME 0
Generally speaking, the negatively charged carbon of
Li+
PhMe 0
conjugated carbanions is sp2 hybridized, and that of
Li+ Dioxane 0 simple, non-conjugated carbanions, including those sta-
Li+
Tetrahydrofuran 80 bilized by sulfur or phosphorus, is sp3 hybridized.
The reactivity of carbanions is dramatically affected
Li+ Pyridine 100
by the identity of the counterion. This can be illustrated
Li+ Me2SO 100 using the 9-fluorenyl anion, which is stable enough to
exist in solution in ethers as the solvated ion [R–]solv. In
*Data taken from Bernardi F., Csizmadia I.G., Mangin, A., Schlegel H.B., ethereal solvents, the fluorenyl anion exists mainly as a
Whangbo M., Wolfe S. J. Am. Chem. Soc. 1975, 97, 2209.
solvent-separated ion pair, [R–]solv[M+]solv (Example 11.13),
when the cation is lithium, and as a contact ion pair, [R–][M+] (Example 11.14), when the
cation is cesium (Table 11.3).21 This has been interpreted as reflecting the competition be-
tween solvent and the anion for the cation. Because the ion-dipole interaction energy is
inversely proportional to the square of the distance between the ion and the dipole, and the
ion-ion interaction energy is inversely proportional to the distance between the ions, the
ion-ion energy becomes more important than the ion-dipole energy as the ion becomes
larger. In other words, solvation of the cation becomes more important as the cation
changes from cesium to lithium, so the solvent-separated ion pair becomes favored.
M solv M
solv
solvent-separated ion pair contact ion pair
(11.13) (11.14)
Problem
11-1 Ylides are compounds having the general structure below. Ylides of third- and
higher-row elements (X=P, S) are stable, useful nucleophiles. Ylides based on
second-row elements (e.g., X=N) are not. Suggest a reason why this is so.
R
X
R
21. (a) Hogen-Esch, T.E.; Smid, J. J. Am. Chem. Soc. 1966, 88, 307. (b) Smid, J. In Szwarc, M., Ed. Ions and Ion
Pairs in Organic Reactions (Wiley-Interscience: New York, 1971), vol. 1, ch. 3, p. 86. (c) Hogen-Esch, T.E.; Smid,
J. J. Am. Chem. Soc. 1972, 94, 9240. (d) Smid, J. J. Poly. Sci., Part A: Polymer Chem. 2004, 42, 3655.
Review: (d) Hogen-Esch, T.E. Adv. Phys. Org. Chem. 1977, 15, 153.

11.2 Metal Alkyls22
There are three major methods for the formation of metal alkyls:
1. Direct synthesis or oxidative addition—the reaction of the metal with an alkyl halide
(Equation 11.2)
2. Transmetalation—the metathesis reaction of an organometallic reagent with a metal
halide or an alkyl halide. This can be either metal-halogen exchange (Equation 11.3)
or metal-metal exchange (Equations 11.4 and 11.5).
3. Metalation of hydrocarbons (Equation 11.6)
R–X + 2 M → R–M + M–X (Eq. 11.2)

R–X + R'–M → R–M + R'–X (Eq. 11.3)
R–M + R'–M' → R–M' + R'–M (Eq. 11.4)
R–M + M' → R–M' + M (Eq. 11.5)
R–H + R–M → R–M + R'–H (Eq. 11.6)
Direct Synthesis
The formation of metal alkyls by direct combination of an alkyl halide with a metal in-
volves the two-electron reduction of the carbon-halogen bond, or oxidative addition of the
carbon-halogen bond to the metal. There is strong experimental evidence that this reac-
tion occurs in two steps with an alkyl free radical formed as an intermediate,23 although
more recent work has evidence that no freely diffusing radicals are detectable during the
formation of arylmagnesium halides.24 Simple alkyl free radicals are sp2-hybridized—they
are not chiral. Therefore, a chiral alkyl halide usually gives the organometallic compound in
which the configuration of the chiral center is lost (e.g., Example 11.15). NMR studies of
Grignard reagents have shown that the carbon-magnesium bond is sufficiently ionic in
nature to render it configurationally labile.25
R1 Mg, Et2O R1
X H 2 MgX (11.15)
H 2 (X=Cl, Br, I)
R R
The direct synthesis of metal alkyls from the elemental metal is restricted to the more
active metals such as the alkali metals, magnesium, aluminum, and zinc, although metal
alkyls of less reactive metals can be formed readily from the alkyl halide with an alloy of
the less electropositive metal and an alkali metal. Historically, the dialkylzinc reagents
were prepared first, and despite the greater reactivity of similar organomagnesium re-
agents, organozinc reagents long overshadowed these compounds in synthesis. Useful
syntheses based on the addition of alkylzinc reagents to carbonyl compounds were devel-
oped over three decades by the chemists of Kazan University in Russia: Butlerov, Zaitsev,
Wagner, and Reformatskii.26 It was problems with the preparation of certain organozinc
22. Monographs: (a) Stowell, J.C. Carbanions in Organic Synthesis (John Wiley & Sons: New York, 1979).
(b) Bates, R.B.; Ogle, C.A. Carbanion Chemistry (Springer-Verlag: Brelion, 1983).
23. Ashby, E.C. Quart. Rev. Chem. Soc. 1967, 21, 259.
24. Walter, R.I. J. Org. Chem. 2000, 65, 5014.
25. (a) Whitesides, G.M.; Roberts, J.D. J. Am. Chem. Soc. 1965, 87, 4878. (b) Fraenkel, G.; Dix, D.T. J. Am.
Chem. Soc. 1966, 88, 979. (c) Fraenkle, G.; Dix, D.T.; Adams, D.G. Tetrahedron Lett. 1964, 3155.
26. For a synopsis of the work of these chemists, see Lewis, D.E. Early Russian Organic Chemists and Their
Legacy (Springer: Heidelberg, 2012), pp. 32. 47, 75, 95 and 101, and references therein.

reagents that led French chemist Philippe Antoine Barbier27 and his student Victor Gri-
gnard28 to explore replacing the zinc with the more reactive magnesium. The Grignard
reagent revolutionized organic synthesis by making organomagnesium nucleophiles
easily and widely available for the first time. The importance of Grignard's contribution
was quickly recognized; his reaction had been used in more than 800 published papers by
the time he shared the Nobel Prize for Chemistry in 1912 with Paul Sabatier. Many organ-
olithium compounds and Grignard reagents are now commercially available, making
their use in the organic chemistry laboratory routine.
The use of transition metals other than zinc in organic chemistry is of more recent
origin. Organocopper reagents, for example, were first prepared by Henry Gilman in
1936,29 but their extensive exploitation as reagents in organic synthesis really dates from
the 1960s and 1970s.30
Metathesis Between Alkyl Halides and Metal Alkyls

Metal-halogen exchange reactions are, in a formal sense, at least, displacement reactions
of the alkyl anion from an alkyl halide by a nucleophile. The only nucleophiles powerful
enough to do this are the alkyllithiums, which are very strong Lewis bases. The products
of these reactions, which are reversible, are also alkyllithiums. The exchange reaction be-
haves, in some ways, as an acid-base reaction: the major products of the equilibrium reac-
tion are usually the less basic metal alkyl and the alkyl halide derived from the more basic
of the two alkyl anions.31 The relative acidities of C—H bonds increase with increasing
s character of the hybrid orbitals on carbon: sp3 (pKa ≈ 40–50)32 to sp2 (pKa ≈ 35–40)33 to sp
(pKa ≈ 25–30).34 Thus, alkyllithiums react with aromatic halides and vinyl halides to give
aryllithiums and vinyllithiums.
27. Philippe Antoine Barbier (1848–1922) destroyed all records of his life's work shortly before he died, so
this brief biography will be longer than most. He was born in Luzy, Nièvre, and in 1869 he moved to Paris,
where he studied under Berthelot at the Collège de France. On graduating with his Dr-ès-sc in, he was ap-
pointed to teach mineralogy in the pharmacy college, and in 1878 he moved to Lyon as “Maître des Con-
férences” in the faculty of science. In 1879, he moved to Besançon as a junior faculty member in applied
chemistry, moving back to Lyon in 1880 as Professor of Chemistry and Director of the Agronomy Station. At
Lyon he discovered that the zinc used in the Zaitsev-Vagner synthesis of alcohols could be replaced by magne-
sium, thus introducing the use of magnesium intermediates into organic synthesis. The method proved to be
unreliable, however, and he did not pursue it further personally. At Lyon, Barbier was responsible for the edu-
cation of several influential chemists of the next generation, including Louis Bouveault and Victor Grignard
(whose project with organomagnesium reagents he suggested and supervised). His student, Grignard, had
planned to write the biography of his mentor, but never found the time to do the necessary research.
28. François Auguste Victor Grignard (1871–1935) was educated at Lyon (PhD, 1901). At the suggestion of
his doctoral mentor, Barbier, he prepared the organomagnesium reagents that now bear his name. He shared
the Nobel Prize in Chemistry for 1912 with Paul Sabatier (incidentally, Grignard often made the point that his
mentor, Barbier, should have shared the Prize). Grignard served as Professor of Chemistry at Nancy, then at
Lyon. For more biographical information, see the Nobel Foundation web site.
29. Gilman, H.; Straley, J.M. Rec. Trav. Chim. Pays-Bas 1936, 55, 821.
30. Reviews: (a) Posner, G.H. Org. React. 1972, 19, 1; 1975, 22, 253. (b) Normant, J.F. Synthesis 1972, 63.
(c) Normant, J.F. Pure Appl. Chem. 1978, 50, 709. (d) Jukes, A.E. Adv. Organomet. Chem. 1974, 12, 215.
(e) Kaufmann, T. Angew. Chem. Int. Ed. Engl. 1974, 13, 291. (f) Posner, G.H. An Introduction to Synthesis Using
Organocopper Reagents (Wiley: New York, 1980).
31. (a) Parham, W.E.; Bradshher, C.K. Acc. Chem. Res. 1982, 15, 300. (b) Bailey, W.F.; Punzalan, E.R. J. Org.
Chem. 1990, 55, 5404. (c) Negishi, E.; Swanson, D.R.; Rousset, C.J. J. Org. Chem. 1990, 55, 5406. (d) Neumann,
H.; Seebach, D. Chem. Ber. 1978, 111, 2785. (e) Milller, R.B.; McGarvey, G. Synth. Commun. 1979, 9, 831.
32. (a) Streitwieser, A., Jr.; Caldwell, R.A.; Young, W.R. J. Am. Chem. Soc. 1969, 91, 529. (b) Streitwieser, A.,
Jr.; Young, W.R.; Caldwell, R.A. J. Am. Chem. Soc. 1969, 91, 527. (c) Streitwieser, A., Jr.; Taylor, D.R. J. Chem. Soc.
D 1970, 1248. (d) Jaun, B.; Schwarz, J.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 5741.
33. (a) Streitwieser, A., Jr.; Scannon, P.J.; Niemeyer, H.M. J. Am. Chem. Soc. 1972, 94, 7936. (b) Maskornick,
M.J.; Streitwieser, A., Jr. Tetrahedron Lett. 1972, 1625.
34. (a) Wooding, N.S.; Higginson, W.E.C. J. Chem. Soc. 1952, 774. (b) Streitwieser, A., Jr.; Reuben, D.M.E. J.
Am. Chem. Soc. 1971, 93, 1794. (c) Matthews, W.S.; Bares, J.E.; Bartmess, J.E.; Bordwell, F.G.; Cornforth, F.J.;
Drucker, G.E.; Margolin, Z.; McCallum, R.J.; McCollum, G.J.; Vanier, N.R. J. Am. Chem. Soc. 1975, 97, 7006.

The available experimental data indicate that, despite its superficial resemblance to an
SN2 displacement of alkyl from the halogen, there is at least one single electron transfer
step in the mechanism of the reaction.35 Some typical examples of metal-halogen exchange
reactions are given as Examples 11.16 to 11.18.
Br Li 36
BuLi (11.16)
50°C
(95%)
Br Li
37
BuLi (11.17)
S -70°C S
78%)
H Br H Li
BuLi 38
(11.18)
-76°C
Ph Ph Ph Ph
(82%)
Metathesis Between Metal Halides and Metal Alkyls

Exchange reactions where the metal alkyl of a more electropositive metal is allowed to
react with the halide of a less electropositive metal constitute the most common method
by which organometallic compounds can be prepared. In this way, one can prepare alkyl-
copper, alkylcadmium, and alkyltin (stannane) reagents, for example. In fact, the reaction
of alkyllithium reagents or Grignard reagents with cuprous salts is the major method for
the production of alkylcopper nucleophiles.
Whenever metal alkyls are formed from alkyllithium or Grignard reagents, the alkyl
halide to be converted to the organometallic reagents is still subject to the same limitations
as a halide that will be converted to a Grignard reagent—even though the product metal
alkyls may react quite slowly with hydroxyl groups and other functional groups. In general,
the functional groups permitted on an organometallic reagent are restricted to those compat-
ible with the most reactive organometallic reagent used in its preparation, as illustrated in
Examples 11.19 and 11.20. However, at sufficiently low temperatures, the problem caused by
the reactivity of the metal alkyl can be alleviated, as shown by Examples 11.21 and 11.22;
this still does not, of course, work for more reactive functional groups (e.g., aldehydes).
Br Me
(11.19)
BuLi Li Me
Br CHO
Li CHO
(11.20)
BuLi
Br CHO OLi
Br
Bu
35. (a) Ward, H.R.; Lawler, R.G.; Loken, H.Y. J. Am. Chem. Soc. 1968, 90, 7359. (b) Ward, H.R.; Lawler, R.G.;
Cooper, R.A. J. Am. Chem. Soc. 1969, 91, 746. (c) Lepley, A.R.; Landau, R.L. J. Am. Chem. Soc. 1969, 91, 748.
(d) Ashby, E.C.; Pham, T.N. J. Org. Chem. 1987, 52, 1291. (e) Bailey, W.F.; Patricia, J.J. J. Organomet. Chem. 1988, 352, 1.
36. Trepka, W.J.; Sonnenfeld, R.J. J. Organomet. Chem. 1969, 16, 317.
37. Moses, P.; Gronowitz, S. Arkiv. Kemi 1962, 18, 119.
38. Köbrich, G.; Stöber, I. Chem. Ber. 1970, 103, 2744.

Br Li
BuLi
(11.21)39
THF, –100°C CN
CN
(83%)
Br Li
BuLi
(11.22)40
THF, –100°C NO2
NO2
(97%)
Metathesis Between Metal Alkyls

One major problem in the synthesis of lithium alkyls by the direct synthesis method is the
tendency of the reaction with reactive halides such as allyl and benzyl halides to give prod-
ucts of Wurtz coupling41 and for the tendency of other halides (e.g., vinyl bromide) to
undergo metal- halogen exchange too slowly for practical use. This can be avoided by
generating the alkyllithium from a stannane reagent,42 which is, available, in turn, by hy-
drostannylation of an alkyne (e.g., Example 11.23), or from the alkyl halide by reaction
with a stannane (e.g., Example 11.24).43
OEt OEt OEt
Bu3SnH BuLi 43b,c
(11.23)
AIBN
SnBu3 Li
O O
PhSCu(SnMe3)Li
I SnMe3
(11.24) 43e
LDA, R3SiCl
OSiR3 OSiR3
BuLi
Li SnMe3
Exchange reactions where the metal alkyl of a more electronegative (i.e., less elec-
tropositive) metal is reduced by a less electronegative (i.e., more electropositive) metal are
not widely used in the synthesis of metal alkyls except in reactions used to form the more
nucleophilic metal alkyl under “halide-free” conditions. The most common type of this
reaction involves the reduction of alkylmercury and alkyltin reagents with an alkali metal
(e.g., Example 11.25).44 Because the reduction reactions are typically slow and reversible, it
39. Gilman, H.; Melstrom, D.S. J. Am. Chem. Soc. 1948, 70, 4177.
40. Köbrich, G.; Buck, P. Chem.Ber. 1970, 103, 1412.
41. (a) Wurtz, A. Ann. Chim. Phys. [3] 1855, 44, 275. (b) Wurtz, A. Ann. Chem. Pharm. 1855, 96, 364.
(c) Kosolapoff, G.M. Org. React. 1951, 6, 326. (c) Lampman, G.M.; Aumiller, J.C. Org. Syn., Coll. Vol. 6 1988, 133.
(d) Pincock, R.E.; Torupka, E.J. J. Am. Chem.Soc. 1969, 91, 4593.
42. (a) Seyferth, D.; Weiner, M.A. J. Am. Chem. Soc. 1961, 83, 3583; J. Org. Chem. 1961, 26, 4797. (b) Seyferth, D.;
Jula, T.F. J. Orgamomet. Chem. 1974, 66, 195. (c) Seyferth, D.; Mammarella, R.E. J. Organomet. Chem. 1979 , 177, 53.
43. (a) Corey, E.J.; Williams, D.R. Tetrahedron Lett. 1977, 3847. (b) Wollenberg, R.H.; Albizati, K.F.; Peries,
R. J. Am. Chem. Soc. 1977, 99, 7365. (c) Wollenberg, R.H. Tetrahedron Lett. 1978, 717. (d) Chen, S.L.; Schaub,
R.E.; Grudzinkas, C.V. J. Org. Chem. 1978, 43, 3450. (e) Piers, E.; Morton, H.E. J. Org. Chem. 1979, 44, 3437.
44. (a) Fraenkel, G.; Dix, D.T.; Carlson, M. Tetrahedron Lett. 1968, 579. (b) O'Brien, D.H.; Russell, C.R.; Hart,
A.J. J. Am. Chem. Soc. 1979, 101, 633. (c) Barluenga, J.; Fañanás, F.; Yus, M. J. Org. Chem. 1979, 44, 4798.
(d) Barluenga, J.; Fañanás, F.J.; Yus, M. J. Org. Chem. 1981, 46, 1281.

1) Hg(OAc)2
Nu Nu
H—Nu M
R HgBr M (11.25)44c,d
2) KBr R R
Nu = NR2, OR
is usually important that the reducing metal be substantially more electropositive than the
metal of the starting organometallic compound.45
Sample Problem
Br
Li, Et2O Mg, Et2O

(a) Br (b)
Br
K, THF 1) Li, THF

(c) Hg (d)
2) CdCl2
Bu
Bu Bu
1) Li, THF Sn Li, THF, –78°C
(e) Br
2) Me3SiCl
(f)
H
§Answers below.
Metalation of Hydrocarbons
The conjugate bases of simple hydrocarbons are usually too strongly basic to allow
them to be generated by deprotonation. For this reason, direct metalation of hydrocar-
bons by either the reaction between the hydrocarbon and a reactive metal or by the
deprotonation of a hydrocarbon by a metal alkyl (typically an alkyllithium or Grignard
reagent) is generally restricted to the most acidic hydrocarbons. By far the most useful
of these are the terminal alkynes, which are readily deprotonated by strong bases—
sodium hydride, alkyllithiums or Grignard reagents—to give the corresponding metal
45. (a) Coates, G.E.; Wade, K. Organometallic Compounds, 1, The Main Group Elements (Methuen: London,
1967). (b) Makarova, L.G.; Nesmeyanov, A.N. Methods of Elemento-Organic Chemistry (North-Holland:
A msterdam, 1967), vol. 4.
MgBr
(a) Li (b) (c) K (d) Cd

2
Li
(e) SiMe3 (f)
H
Reactions (a) and (b) are examples of direct synthesis of the metal alkyl from an alkyl halide; reactions
(c) and (f) are examples of metal-metal exchange between an active metal and the metal alkyl of a less reactive
metal; and reactions (d) and (e) are examples of the synthesis of the metal alkyl of a less reactive metal by
metal-halogen exchange.

alkynides. These reagents are extremely useful nucleophiles that can be used in a vari-
ety of reactions.
An interesting reaction that involves the generation of carbanions is known as the
“acetylene zipper” reaction (Examples 11.25 and 11.26). This reaction involves the treat-
ment of an unbranched internal alkyne with strong base (usually potassium 3-aminopro-
panamide, or “KAPA”) and results in the rapid migration of the triple bond to the terminal
position by means of a series of acid-base equilibria. The generation of the alkynide anion
terminates the reaction series.46 The driving force for this reaction appears to be the irre-
versible formation of the alkynide anion in the final step of the isomerization. With bases
that are not strong enough to deprotonate the terminal alkyne (e.g., hydroxide anion or
metal alkoxides), the equilibrium favors the internal alkynes and allenes rather than the
terminal alkyne.
1) KAPA, H2N(CH2)3NH2, 20°C

(11.26)
2) HCl, H2O
(100%)
1) KAPA, H2N(CH2)3NH2, 20°C

(11.27)
2) HCl, H2O
(94%)
With bases that are not strong enough to completely deprotonate the terminal alkyne
(e.g., hydroxide anion or metal alkoxides), the equilibrium favors the internal alkynes and
allenes rather than the terminal alkyne. This reaction almost always results in a mixture
of regioisomers, but anchoring the alkoxy anion at one location in the molecule tends to
improve regioselectivity and permits the isomerization of acetylenic alcohols to allenic
alcohols by bases such as butyllithium at low temperature, as illustrated in Examples 11.28
and 11.29.47 These reactions go through the lithium alkoxides, of course.
HO
OH OH
BuLi, TMEDA
+ (11.28)
THF, –78°C
(38%) (<2%)
BuLi, TMEDA
OH OH + OH (11.29)
THF,–78°C
(42%) (9%)
A second class of simple metal alkyls that can be easily prepared from the hydrocarbon
is that in which the carbanion formed is strongly stabilized by resonance. The two repre-
sentative types of these anions are the deep red triphenylmethide anion (Example 11.30),
46. (a) Bushby, R.A. Quart. Rev. 1970, 24, 585. (b) Brown, C.A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891.
(c) Brown, C.A.; Yamashita, A. J. Chem. Soc. Chem. Commun. 1976, 959. (d) Macaulay, S.R. J. Org. Chem. 1980,
45, 734. (e) Abrams, S.R. Can. J. Chem. 1984, 62, 1333.
47. Enomoto, M.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 4599.

which is readily available by deprotonation of triphenylmethane with strong base, and

widely used as an indicator in titrations of alkyllithium reagents. The stability of the cyclo-
pentadienide anion (Example 11.31) is due to its aromaticity. Both these anions can be
formed by treatment of the hydrocarbon with an alkyllithium or sodium hydride. Cyclo-
pentadienide anion may also be formed by the reaction between cyclopentadiene and
sodium metal.
H Ph
NaH, THF Na (11.30)
Ph Ph Ph Ph
Ph
Na, THF Na (11.31)
Reactivity of Metal Alkyls

One can modulate the reactivity of metal alkyls by choosing the metal appropriately. The re-
activity of the metal alkyl as a base and a nucleophile can be predicted on the basis of the
electronegativity of the metal—the less electronegative the metal, the more reactive the metal
alkyl. Recall that the approximate percent ionic character of a number of carbon-metal σ
bonds was given in Table 11.1.
Metal alkyls (other than sodium and potassium) are best described as polar covalent
compounds with the carbon atom at the negative end of the polar carbon-metal bond. The
variation in reactivity of the metal alkyls is mainly due to the variation in the polarity of
the carbon-metal bond, and the more polar the carbon-metal bond, the more reactive the
nucleophile. This can be illustrated using the examples in Table 11.4, where the addition of
metal alkyls to carbonyl groups of gradually increasing reactivity is gathered.
Alkyllithiums are the only metal alkyls that will add to carboxylate anions to give the
dialkoxide of the gem-diol. Grignard reagents add to carbon dioxide to give carboxylic
acids, but dialkylzinc reagents do not (in fact, carbon dioxide was used as an inert atmo-
sphere for the early work with these nucleophiles). Dialkylzinc reagents do react with al-
dehydes and ketones, but the less reactive dialkylcadmiums (just like the lithium
dialkylcuprates) require an acid chloride as the carbonyl partner before reacting. Only
alkyllithiums and Grignard reagents add to the cyano group of nitriles.
Effects of Overall Charge on Nucleophilicity

Unlike the metal alkyls of the alkali and alkaline earth metals, the transition metals may
form both neutral and anionic metal-based species. Generically, it is found that the more
negative the charge on a nucleophile, the stronger the nucleophile. This facet of nucleop-
hile reactivity is nicely illustrated by the reactions of organozinc and organocopper nucle-
ophiles with carbonyl electrophiles. Sodium trimethylzincate, NaZnMe3, was first
prepared by Wanklyn, who treated dimethylzinc with sodium metal48—based on its reac-
tivity, he thought he had prepared sodium methyl. The resulting reagent reacted with
carbon dioxide to give acetic acid: the first synthesis of a carboxylic acid by carbonation.49
Because the Butlerov and Zaitsev syntheses of alcohols (dialkylzincs and alkylzinc iodides
with acid chlorides) can be carried out under an atmosphere of carbon dioxide, the an-
ionic ate complex is clearly a much stronger nucleophile.
48. Wanklyn, J.A. Ann. Chem. Pharm. 1858, 108, 67.

49. Wanklyn, J.A. Ann. Chem. Pharm. 1858, 107, 125; 1859, 111, 234.

Table 11.4 Reactivity of Metal Alkyls with Carbonyl Compounds
Substrate R'Li R MgX R'2Zn R'2Cd R'Cu
O O
R R – – – –
O R'
O O O
C R R' – – –
O R' OH
O O O
R R R – – –
NR2 R' R'
O OH OH
R R R' R R' – – –
OR R' R'
O OH OH OH
R R R R – –
H R' R' R'
O OH OH OH
R R R' R R' R R' – –
R R' R' R'
O OH OH O
R R R' R R' R – –
OCOR R' R' R'
O OH OH OH O
R R R' R R' R R' R –
Cl R' R' R' R'
N O O
C R R – – –
R R' R'
O OH OH OH
– –
H R' R' R'
O OH OH OH
R' R' R' – –
R R R R
The behavior of organocopper nucleophiles illustrates this variation of nucleophilicity

even better. The reaction of one equivalent of an alkyllithium with cuprous chloride yields
an alkylcopper reagent (RCu)—a reagent that is relatively unreactive unless catalyzed by a
Lewis acid50 (RCu/BF3 is a widely used reagent). The addition of a second equivalent of the
alkyllithium converts this initial copper alkyl into a lithium dialkylcuprate, or Gilman
reagent, (R 2CuLi), which is named for American chemist Henry Gilman51 and which is a
50. (a) Williams, D.R.; Nold, A.L.; Mullins, R.J. J. Org. Chem. 2004, 69, 5374. (b) Yamamoto, Y. Angew. Chem.
Int. Ed. Engl. 1986, 25, 947.
51. Henry Gilman (1893–1986) was educated at Harvard University (PhD, 1918), and joined Iowa State Uni-
versity in 1919; he spent his entire career there. Gilman published more than 1,000 papers in organometallic
chemistry—more than half after he had become legally blind. For more biographical details, see: (a) Earborn,
C. Biogr. Mem. Fellows Roy. Soc. 1990, 36, 153. (b) Roberts, J.D. Org. Synth. 1987, 66, xiii.

much stronger nucleophile capable of adding to acid chlorides and conjugated carbonyl
compounds. Gilman reagents are the preferred reagents for carrying out conjugate addi-
tions to α,β-unsaturated esters and ketones, but they are less effective when the conju-
gated system is β,β-disubstituted. Gilman reagents also tend to react poorly with
secondary halides (see Example 11.32)52 or epoxides. When the alkyllithium is added to
cuprous cyanide, an especially reactive cuprate reagent, the Lipshutz cuprate53 is formed.
This nucleophile is capable of adding to a β,β-disubstituted-α,β-unsaturated carbonyl
compound and reacting well with epoxides and secondary bromides.
Bu2CuLi
Et2O
I
(11.32)
Bu2Cu(CN)Li2
Et2O
The structures of several copper alkyl reagents show these compounds to be oligo-
mers based on a planar or bent square array of copper atoms bridged by alkyl ligands.
The structure of a Gilman reagent (Example 11.34) is analogous to the alkylcopper
structure (Example 11.33), except that two copper atoms on opposite sides of the array
are replaced by lithium. The copper and lithium atoms in this structure are still bridged
by alkyl groups.
R Cu R R Li R
Cu Cu Cu Cu
R Cu R R Li R
(11.33) (11.34)
The structure of the Lipshutz “higher order” cuprates was the subject of intense debate
during the last decades of the 20th century.54 The structures of two “higher order” cyano-
cuprates were finally determined, and it was revealed that the cyanide anions bridge a pair
of lithium, not copper, atoms. These structures may be seen as the consequence of cyanide
ion disrupting the structure of the Gilman reagent by inserting between the lithium ions
(11.35). In one case (11.36),55 the structure consists of a zigzag arrangement of alternating
‑R–Cu–R- and -Li–C ≡ N–Li- chains. In the other case (11.37),56 the structure consists of
linear R 2Cu– and [LiCNLi]+ ions (the logical extreme of the zigzag structure as the lithium
ions become solvated by donor solvents such as tetrahydrofuran (THF). The enhanced
reactivity of these reagents compared to traditional Gilman reagents may be due to the
closer resemblance of the Lipshutz cuprates to the free R 2Cu– ion.
52. (a) Corey, E.J.; Posner, G.H. J. Am. Chem. Soc. 1968, 90, 5615. (b) Lipshutz, B.H.; Wilhelm, R.S.; Floyd,
D.M. J. Am. Chem. Soc. 1981, 103, 7672.
53. Lipshutz, B.H.; Wilhelm, R.S.; Kozlowski, J.A.; Parker, D. J. Org. Chem. 1984, 49, 3928.
Bruce H. Lipshutz (1951–) was educated at Yale (PhD, 1977), and joined the University of California, Santa
Barbara after postdoctoral study with Corey at Harvard. Lipshutz is known for his organocopper chemistry; he
received a Presidential Green Chemistry Award in 2011. More biographical detail is available at Lipshutz' web site:
http://web.chem.ucsb.edu/~lipshutzgroup/bio/index.shtml
54. Leading references to this debate: (a) Lipshutz, B.H.; James, B. J. Org. Chem. 1994, 59, 7585. (b) Bertz,
S.H.; Miao, G.; Eriksson, M. J. Chem. Soc., Chem. Commun. 1996, 815.
55. Kronenburg, C.M.P.; Jastrzebski, J.T.B.H.; Spek, A.L.; van Koten, G. J. Am. Chem. Soc. 1998, 120, 9688.
56. Boche, G.; Bosold, F.; Marsch, M.; Harms, K. Angew. Chem. Int. Ed. Engl. 1998, 37, 1684.

R
R Li R R Li
Li
C R C C
Cu Cu Cu
N Li N N
Li Cu
R Li R R Li
R n
(11.35) (11.37)
(11.36)
Copper-based organometallic reagents are important intermediates in a wide range of
reactions leading to the formation of new carbon-carbon σ bonds.57 Among these reac-
tions is the reaction of lithium dialkylcuprates with alkyl halides, which proceeds well
with primary alkyl bromides and iodides, but which seldom occurs in satisfactory yield
with secondary halides; with chlorides, it only proceeds well with primary chlorides, and
only in THF.58 The reaction proceeds much better with the Lipshutz cuprates, which react
well with secondary bromides to give hydrocarbon products with almost complete inver-
sion of configuration (e.g., Example 11.38).
Br
Et2Cu(CN)Li2
(11.38) 58
THF, 0°C
(72%)
Epoxides, also, react with Lipshutz cuprates to give alcohols (e.g., Example 11.39) in
higher yield than the Gilman reagents themselves.59 It is important to note that although
the reaction between a cuprate and an alkyl halide bears a superficial resemblance to the
SN2 reaction, it almost certainly involves single electron transfer steps and free radical
intermediates.
O HO
"RCu"
(11.39) 59
"RCu" = Pr2CuLi: 15-30%
"RCu" = Pr2Cu(CN)Li2: 86%
Unlike the coupling of organocuprates with saturated alkyl halides and epoxides, the
coupling of organocuprates with vinyl halides occurs with predominant retention of con-
figuration (e.g., Examples 11.40 and 11.41).60 The formally similar coupling of aryl halides
in the presence of a copper catalyst (the Ullmann reaction) likely proceeds through an
arylcopper intermediate.61
Br Ph2CuLi Ph Ph
+ (11.40)
4h
Ph Ph Ph
90% <2%
Br Ph2CuLi Ph Ph
(11.41)
4h
Ph Ph Ph
<1% 73%
57. Monograph: (a) Posner, G.H. An Introduction to Synthesis Using Organocopper Reagents (Wiley-
Interscience: New York, 1980). Reviews: (b) Posner, G.H. Org. React. 1975, 22, 253. (c) Normant, J.F. Synthesis
1972, 63. (d) Jukes, A.E. Adv. Organomet. Chem. 1974, 12, 215.
58. Whitesides, G.M.; Fischer, W.F., Jr.; San Filipo, J., Jr.; Bashe, R.W.; House, H.O. J. Am. Chem. Soc. 1969, 91, 4871.
59. (a) Lipshutz, B.H.; Kozlowski, J.; Wilhelm, R.S. J. Am. Chem. Soc. 1982, 104, 2305. (b) Lipshutz, B.H.;
Kotsuki, H.; Lew, W. Tetrahedron Lett. 1986, 27, 4825.
60. House, H.O. Acc. Chem. Res. 1976, 9, 59.
61. Reviews: (a) Bacon, R.G.R.; Hill, H.A.O. Quart. Rev. 1965, 19, 95. (b) Fanta, P.E. Synthesis 1974, 9.

Sample Problem
11-2 What reagent or reagents are needed to complete the following transformations?
Br OH
O
(a) H H (b)
O HO O O
(c) (d)
COMe
COMe EtO2C
O EtO2C
(e) COCl
(f)
CHO
HO
§Answers below.
Acid-Base Chemistry of Metal Alkyls—A Limitation on Their Use

Formally, metal alkyls are the conjugate bases of hydrocarbons, so they are strong bases.
This leads to their strong tendency to react with protic compounds by simple proton
transfer, a tendency that increases with the ionic character of the carbon-metal bond.
Thus, alkali metal and alkaline earth metal organometallic compounds all react vigor-
ously with water to generate the corresponding hydrocarbon, as do dialkylzinc reagents.
Alkylcopper reagents, including lithium dialkylcuprates (but not the Lipshutz cuprates),
react relatively slowly with water and alcohols to give hydrocarbons, whereas dialkylmer-
cury reagents do not react appreciably with water at all (which is one reason for their bi-
ological toxicity).
Because proton transfers are among the most rapid reactions known, this places a
limitation on the generation and use of metal alkyls in synthesis—one cannot use a metal
alkyl in a reaction where there is an acidic proton capable of quenching it. Likewise, one
must use a solvent that will not react with the more reactive organometallic compound
when making a less reactive organometallic reagent by a metathesis reaction.
As a rule of thumb, alkali metal alkyls will react with ammonia and amines (pKas ≈
33–36) at temperatures near 0°C to give the corresponding amide salts (for example, lith-
ium diisopropylamide [LDA], a very popular hindered base, is made by the reaction be-
tween butyllithium and diisopropylamine between –30°C and 0°C). Grignard reagents are
slowly protonated by amines to give the magnesium amide salts—and alkylzinc reagents
even more slowly. Organocopper reagents are not protonated by amines. Changing the
proton source to water or an alcohol (pKas ≈ 15–18) results in Grignard reagents and or-
ganozinc reagents being quenched rapidly. Gilman reagents are still not rapidly quenched
by water or alcohols—although the more reactive Lipshutz cuprates are. The rapid quench-
ing of less reactive metal alkyls usually requires ammonium ions or strong acids. The rel-
ative rates for protonolysis of some typical metal alkyls are shown in Table 11.5.

(a) This reaction involves the stereospecific replacement of the halogen of a vinyl halide by an alkyl group, so
a cuprate should be used: Et 2CuLi, THF. (b) This is the ring opening of an epoxide, which can be accomplished
with any organometallic reagent of high nucleophilicity: i-BuLi, THF or i-BuMgBr, Et 2O or i-Bu 2CuLi, or
i-Bu 2Cu(CN)Li 2, THF. (c) This involves the attack on the carbonyl group of an α,β-unsaturated ketone and
requires a more reactive nucleophile: MeLi, THF (preferred) or MeMgBr, Et 2O. (d) This involves the attack on
the conjugated alkene π bond of an α,β-unsaturated ketone, so a cuprate must be used: Et 2CuLi, THF. (e) This
requires a nucleophile that will react with an acid chloride but not with a ketone: i-Pr2Cd or i-Pr2CuLi. (f) This
requires a nucleophile that will react with an aldehyde but not an ester: Me2Zn.

Table 11.5 Effects of Bond Polarity on the Ease of Protonolysis of Metal Alkyls
R 2NH ROH NH4Cl (aq) HCl (aq)
R–Li Fast Fast Fast Fast

R–MgX Slow Fast Fast Fast
R 2Zn Slow Moderate Fast Fast
R 2Cu(CN)Li2 — Moderate Fast Fast
R 2CuLi — Slow Fast Fast
RPdX — — Slow Slow
Some Final Words on the Reactivity of Simple Metal Alkyls

Generally speaking, the more ionic a metal alkyl, the more likely it is to react well with alkyl
halides to give the products of carbon-carbon bond formation. Alkali metal alkynides,
which are ionic metal alkyls, react well with alkyl halides by the SN2 mechanism to give in-
ternal alkynes, but Grignard reagents, in general, do not (Example 11.42). The treatment of
an alkyl halide with sodium metal or a sodium-potassium alloy usually gives the product of
Wurtz coupling. This reaction, which is generally agreed to proceed through sodium alkyls,
does not involve a simple SN2 displacement of the halide ion, but appears, instead, to involve
free radicals at some point in the reaction.62 This may be a general occurrence when metal
alkyls react with alkyl halides.
R1
R2
H RCCNa X RMgX R1
R2
H H (11.42)
R2
R1 R
R
The ionic character of the carbon-metal bond is also revealed in characteristic reactiv-
ity patterns with carbonyl compounds (especially α,β-unsaturated carbonyl compounds;
Example 11.43). Ionic metal alkyls are strong bases that deprotonate the carbonyl com-
pound to give an enolate anion. Ionic metal alkynides, which are much weaker bases, add
to the carbonyl group to give allylic carbinols. The covalent metal alkyls react as nucleop-
hiles rather than bases, so addition dominates their reactions. As the C—M bond becomes
less polar, the nucleophile becomes softer and shows a greater tendency to add at the β
carbon of α,β-unsaturated carbonyl compounds—alkyllithiums give the products of
1,2-addition only, Grignard reagents give mainly 1,2-addition but some 1,4-addition, and
cuprates react to give products of 1,4-addition only.
R OH O O
(11.43)
R
62. Garst, J.F.; Cox, R.H. J. Am. Chem. Soc. 1970, 92, 6389.
Afterword: Considering the reactivity of organolithiums and Grignard reagents, it might seem inconceiv-
able that metal alkyls could exist within the cells of a living being. And yet vitamin B12, which was discovered
in 1926, is an organocobalt compound that is essential for the normal maturation of erythrocytes; the
cobalt-carbon bond is critical for the activity of the vitamin.
Not all metal alkyls are as benign as vitamin B12, however. For decades, tetraethyllead was used as an anti-knock
additive to improve the octane rating of gasoline. Its use in gasoline was banned in the 1970s but not before it had
been implicated as a major causative factor in raising the blood lead levels in children. Similarly, for many decades,
certain organomercury compounds had been used as topical antiseptics, and it was believed that organomercury
compounds were not a serious health hazard (in contrast to inorganic mercury compounds, whose toxicity had
been well established). However, an outbreak of a mysterious, crippling disease in Minamata, Japan, during the
early 1950s was subsequently traced to the large quantities of fish in the diet and to the high levels of mercury in the
fish in Minamata Bay. Organomercury antiseptics are no longer freely available in the United States.

Reaction Synopses
Direct Synthesis of Organometallic Reagents
M
R X R M
solvent
M = Li, Mg, Zn, Al, etc.;
X = Cl, Br, I
Reagents: Li, Et2O, Li, THF; Mg, Et2O; Zn, Et2O, ∆; etc.
Stereochemistry: Chiral alkyl halides give partially or totally racemic organo-
metallic reagents. The method works only for very electropos-
itive metals.
Transmetalation
(a) Metal-halogen exchange
R' M
R X R M
solvent
Reagents: BuLi, THF, –78°C; t–BuLi, THF, –100°C; etc.

Any halide may be used, including aryl and vinyl halides. The
organometallic reagent (R'—M) may not be methyllithium.
(b) Metal-metal exchange
R M'
M X R M
solvent
M': Li; Mg; etc. M: Cu; Cd; Hg; etc.
Reagents:
R–M': RLi, RMgX; R 2Zn, R 3Al; etc.
M–X: CuCl, CuBr, CuI, CuCN; CdCl2, CdBr2; SiCl4, R 3SiCl; SnCl4,
R 3SnCl; MnCl2, ZnCl2, HgCl2, etc.
M is always less electropositive than M'.
Metalation of Hydrocarbons (especially alkynes)
R' M R' M or R2N

R H R M R H R M
solvent solvent
Reagents: BuLi, NaH, KH, LDA, RMgX, etc.

Hydrocarbon usually needs to have a pKa value below 28.
R—C ≡ C—M can be formed with transition metals: Mn+, NH3, H2O (M=Cu, Ag, etc).
Acetylene Zipper
KAPA
R (CH2)nCH3 R (CH2)(n+1) K
H2N(CH2)3NH2
Reagents: (1) KNH(CH2)3NH2 (KAPA); (2) H3O+

Note: the chain may not be branched; when the chain is branched, a mixture of
acetylenes results.
(continues)

Organocuprate Coupling
O R OH
R X R R'
R R R' R
RX: Not 3° alkyl; reaction is slow with 2° alkyl;
Epoxide: ring opening occurs at less substituted ring carbon.
Reagents: R 2CuLi; R 2Cu(CN)Li2; etc.
Stereochemistry:
Inversion of configuration with alkyl bromides
Retention of configuration with vinyl halides
Inversion of configuration with epoxides
Drill Problems
(a) What is the major organic product formed when each of the compounds
below is treated with the reagent specified?
(A) 3-pentanone (B) 2-methylpropanal
(C) cyclohexanone (D) acetophenone
(E) 2-cyclohexenone (F) cinnamonitrile
(F) methyl crotonate (G) (S)-2-ethyloxirane
(H) (R)-2-bromo-1-phenylethane
(I) (R)-2-octyl p-toluenesulfonate
MgBr, Et2O Li, THF

(a) (b)
Na , THF Na , THF
(c) (d)
LiCuEt2, THF
(e)
(b) Draw the structure of the major organic product that will be formed when the
each of the alkynes below reacts with each of the following sequences of reagents.
Reagents:
(a) (1) NaNH2, NH3; (2) BrCH2CH=CH2, THF
(b) (1) LDA, THF, −78°C; (2) CO2; 3) HCl, H2O
(c) (1) EtMgBr, Et2O, ∆; (2) cycloheptanone; (3) NH4Cl, H2O
(d) (1) BuLi, THF, −78°C; (2) ClCO2Et, THF, −78°C; (3) NH4Cl, H2O
(e) (1) KNH2, NH3; (2) cyclopentene oxide; (3) HCl, H2O
(f) (1) KNH2, NH3; (2) Me(CH2)4Br, THF; (3) KAPA, THF; (4) NH4Cl, H2O.
Compounds:
(A) 1-pentyne (B) 1-octyne
(C) phenylacetylene (D) 3-ethyl-1-pentyne
(E) 3,3-dimethyl-1-butyne (F) 1-ethynylcyclopentanol
(G) 3-methoxy-3-methyl-1-butyne

Problems
11-2 When one needs to prepare allylmagnesium bromide according to the reaction
below, it is important to use highly activated magnesium to prevent the formation
of a major by-product whose molecular formula is C6H10. Draw the structure of
this compound and propose a reasonable mechanism for its formation.
Br Mg/Et2O MgBr
11-3 What is the final product of each of the following reactions or sequences of
reactions?
H
Br
1) Mg, Et2O Br 1) Li, THF
(a) (b)
2) DCl, D2O 2) CuCN
3) PhCH2Br
Br
1) Li, Et2O Na, THF, 25°C
(c) (d) Br
MeO 2) D2O
Br
Br
1) Li, Et2O 1) Li, Et2O
(e) (f)
2) D2O 2) CuBr
OMe
3) Me2CHCH2Br
Br Br 1) Li, Et2O
(g) H Me
Et2CuLi (h)
THF 2) CuBr
D Br H 3) Me2CHCH2Br
11.3 Carbanions Stabilized by Heteroatoms
A carbanion center may be stabilized by an adjacent heteroatom provided that the hetero-
atom occurs in the third row of the periodic table or lower. Second-row heteroatoms do
not usually stabilize carbanions well (in fact such anions are not even detectable in the gas
phase63), and when anions are formed adjacent to a second-row heteroatom, the resultant
anion almost always rearranges by a homolytic mechanism, as occurs in the Wittig rear-
rangement of ethers.64
Stabilization by the adjacent heteroatom is, however, an important part of the stabiliza-
tion of anions next to sulfur, phosphorus, selenium, and silicon. There are two mechanisms
by which this stabilization can occur (Figure 11.2). In the first, the stabilization of the nega-
tive charge is attributed to delocalization of the negative charge into the empty d orbitals of
the heteroatom by dπ − pπ back-bonding, resulting in formation of a carbon-heteroatom π
bond.65 In the alternative view, which is particularly applicable to the carbon-phosphorus
bond of phosphoranes, the extra electron density on carbon is delocalized into the
63. Downard, K.M.; Sheldon, J.C.; Bowie, J.H.; Lewis, D.E.; Hayes, R.N. J. Am. Chem. Soc. 1989, 111, 8112.
64. (a) Wittig, G.; Lohman, L.; Happe, W. Ann. 1942, 550, 260. (b) Wittig, G.; Lohman, L.; Happe, W. Ann.
1947, 557, 205. (c) Hauser, C.R.; Kantor, S.W. J. Am. Chem. Soc. 1951, 73, 1437. (d) Baldwin, J.E.; Patrick, J.E. J.
Am. Chem. Soc. 1971, 93, 3556. (e) Felkin, H.; Frajerman, C. Tetrahedron Lett. 1977, 3485. (f) Chérest, M.; Felkin,
H.; Frajerman, C. Tetrahedron Lett. 1977, 3489.
65. (a) Wolfe, S.; LaJohn, L.A.; Bernardi, F.; Mangini, A.; Tonachini, G. Tetrahedron Lett. 1983, 24, 3789.
(b) Wolfe, S.; Stolow, A.; LaJohn, L.A. Tetrahedron Lett. 1983, 24, 4071.

Figure 11.2 The models of the

C—X bond in heteroatom-
stabilized carbanions based
on dπ − pπ back-bonding
(left), and delocalization of
the excess electron density
into low-energy antibonding
orbitals (right).
Figure 11.3 Bond lengths in 1.888 Å

1.928 Å 1.873 Å
stabilized anions. The bond
between the carbanion 1.873 Å 1.757 Å
Me Me Me Me Me
carbon and the heteroatom is
considerably shorter than the Me Si Me P S S CH2
Me CH2
bond between a neutral Me Me Me Me O
carbon and the heteroatom in 1.792 Å 1.693 Å 1.726 Å
the same molecule. The P–C 1.768 Å
bond length in dimethyl 1.864 Å
methylphosphonate is 1.810 Å.
S S
Me 1.871 Å
Me P CH2
O
1.882 Å 1.816 Å
1.723 Å
MeO Me Me
MeO P CH2 S CH2 Me S CH2
O Me O
1.691 Å 1.665 Å 1.639 Å
relatively low-energy antibonding orbitals of the adjacent carbon-heteroatom bond.66 In

either case, the electron density on carbon is delocalized in part onto the electronegative
heteroatom, thus stabilizing the anion, and increasing the bond order (reducing the bond
length) of the carbon-heteroatom bond. The values of the bond lengths computed for a
number of carbanions stabilized by heteroatoms, calculated at the B3LYP/6-31+G* level, are
gathered given in Figure 11.3. They reveal the same general trend: removing a proton from
the carbon atom shortens the bond.
The enhanced stability of carbanions adjacent to heteroatoms is reflected in strength
of the base required to generate the carbanion. This, in turn, depends on the stabilizing
group: anions stabilized by just a single heteroatom usually require butyllithium or a sim-
ilar base. As the stabilizing group becomes more electron withdrawing, or as the number
of these groups attached to the carbon atom carrying the acidic proton increases, the sta-
bility of the anion increases, and a weaker base can be used for the deprotonation step.
Some typical ranges of pKas for a range of precursors to silicon-, phosphorus- and
66. (a) Bernardi, F.; Csizmadia, I.G.; Mangini, A.; Schlegel, H.B.; Whangbo, M.; Wolfe, S. J. Am. Chem. Soc.
1975, 97, 2209. (b) Lehn, J.M.; Wipff, G. J. Am. Chem. Soc. 1976, 98, 7498. (c) Borden, W.T.; Davidson, E.R.;
Andersen, N.H.; Denniston, A.D.; Epiotis, N.D. J. Am. Chem. Soc. 1978, 100, 1604. (d) Bernardi, F.; Bottoni, A.;
Venturini, A.; Mangini, A. J. Am. Chem. Soc. 1986, 108, 8171.

Table 11.6 Typical pKas for Silicon, Phosphorus, and Sulfur Compounds
Compound pKa Compound pKa
R
R Si S R >30 (R=alkyl, aryl)
22–23 (R=fluorenyl) R'
R R 17-20 (R=acyl, CN)
S
R 29–30 (R=alkyl) S R 16–18
19–21 (R=acyl, CN) R'
S R'
O O
S R 29–35 S R ≈18
R' R'
R'
Ph O
P R 17–23 (R=alkyl, aryl) P R ≈25 (R=alkyl, SR)
Ph 6–9 (R=acyl, CN) Ph ≈17 (R=CN)
Ph Ph
O
P R 27–30 (R=alkyl)
EtO 16–18 (R=acyl, CN)
OEt
s ulfur-stabilized anions are collected in Table 11.6.67 Compounds with pKa values below 25
can typically be deprotonated with sodium hydride or LDA; compounds with pKa values
above 30 usually require butyllithium for effective deprotonation.
Ylides
The ylides differ from the simple unstabilized carbanions by having a group that could
function as a leaving group bonded directly to the carbanion carbon. This positively
charged group helps to stabilize the carbanion center by simple polar effects. When the
heteroatom is in the third row or lower, stabilization also occurs by π-type delocalization
of the electron density from carbon onto the heteroatom. Because of this π-type delocal-
ization of the electron density of the carbanion, ylides can be represented by the resonance
contributors shown at in Example 11.44.
R R
X X (11.44)
R R
X = NR3, SR2, X = SR2, PR3,

PR3, AsR3 AsR3
The two types of ylides most frequently used in modern organic synthesis are the
phosphorus ylides, or phosphoranes, and the sulfur ylides, or sulfuranes. These ylides are
67. These and many other acidity constants can be found in the following compilations: (a) Bordwell, F.G.
Acc. Chem. Res. 1988, 21, 456. (b) Bordwell, F.G.; Matthews, W.S. J. Am. Chem. Soc. 1974, 96, 2116. (c) Matthews,
W.S.; Bares, J.E.; Bartmess, J.E.; Bordwell, F.G.; Cornforth, F.J.; Drucker, G.E.; Margolin, Z.; McCallum, R.J.;
McCollum, G.J.; Vanier, N.R. J. Am. Chem. Soc. 1975, 97, 7006. (d) Bordwelll, F.G.; Fried, H.E. J. Org. Chem.
1981, 46, 4327. (e) Smith, M.B.; March, J. March's Advanced Organic Chemistry. Reactions, Mechansims, and
Structure, 5th ed. (Wiley: New York, 2001), ch. 8, pp. 329–331, and references therein. (f) Isaacs, N.S. Physical
Organic Chemistry (Longman Scientific & Technical: London, 1987), ch. 6, contains several useful tables of
acidity constants.

formed from the corresponding phosphonium or sulfonium ions by reaction with a strong
base such as sodium hydride or butyllithium. The sulfonium and phosphonium ions are
themselves formed by SN2 displacement reactions of the neutral sulfides or phosphines, as
shown in Examples 11.45 and 11.46.
phosphine phosphonium phosphorane

salt
R R
R R R R
P P R R
R R R R
H R' P P (11.45)
R'
X R' R'
X B
sulfide sulfonium sulfurane

salt
R R R R
S S
R R R R
H R' S S (11.46)
R'
X R' R'
X B:
Phosphorus Ylides
Because the formation of a carbon-heteroatom π bond involves the overlap of a 2p orbital
on carbon with a 3p or a 3d orbital on the heteroatom, the formation of the π bond is less
efficient than the formation of a π bond between carbon and elements of the second row.
In addition, the contribution from the dipolar canonical form in a carbon-phosphorus π
bond of a phosphorane is higher than in a carbon-nitrogen π bond. The effect of having to
overlap orbitals from different electron shells to form a bond is even more pronounced in
π bond formation than in σ bond formation. Stable compounds with carbon-silicon π
bonds are unknown, despite much effort to prepare one. Unlike the π bonds between
carbon and the second-row elements, π bonds between carbon and third-row elements are
much weaker than the corresponding σ bonds, so elimination from gem-disubstituted
alkane derivatives is seldom favorable.
The X-ray crystal structures of those phosphorus ylides whose structures have been
determined strongly suggest that the non-polar, double-bonded canonical form is the
dominant contributor to the resonance hybrid. The P=C bond in methylenetriphenyl-
phosphorane (Example 11.47) has a length of 1.661 Å,68 which corresponds to an approxi-
mate bond order of 2.0, similar to values from electron diffraction of trimethyl(methylene)
phosphorane in the gas phase.69 The bond lengths of the P=C bond in stabilized ylides
vary between 1.7 and 1.74 Å, corresponding to bond orders between 1.5 and 1.7, with a con-
comitant reduction in the C—C bond length. The carbon atom in Ph3P=CH2 is very close
to planar, consistent with sp2 hybridization. Thus, there is solid evidence that there is sub-
stantial π bonding between phosphorus and carbon in phosphonium ylides. Non-
stabilized ylides have a bond close to a full double bond, with minimal dipolar character,
whereas stabilized ylides have a lower carbon-phosphorus bond order and a correspond-
ingly higher contribution from the dipolar canonical form.
68. Bart, J.C.J. J. Chem. Soc. (B) 1969, 350.

69. Ebsworth, E.A.V.; Fraser, T.E.; Rankin, D.W.H. Chem. Ber. 1977, 110, 3494.

The most recognized reaction of phosphorus ylides is probably the Wittig reaction70 to
give alkenes. Simple phosphorus ylides react with aldehydes to give Z-alkenes as the major
product (Example 11.48). As the anion is stabilized by groups in addition to the phospho-
rus, the proportion of the E alkane rises.
CO2Et CO2Et
THF
CHO (11.48)
71
(69%)
PPh3
(8-cis:8-trans 94:6)
Sulfur Ylides
Deprotonating trialkylsulfonium salts or trialkylsulfoxonium salts gives sulfur ylides.
Computations at relatively high level of theory show that, as with the phosphorus ylides,
the bond order of the carbon-sulfur bond in the sulfonium ylides (11.49) is close to 2.0 and
that the ylide carbon is planar, indicating that the non-polar, double-bonded contributor
dominates the resonance hybrid. In the sulfoxonium ylides (11.50), on the other hand, the
C—S bond order is closer to 1.7, and the ylide carbon is now pyramidal, indicating that the
dipolar form contributes significantly to the resonance hybrid (Figure 11.4). Sulfonium
ylides are more strongly basic and more strongly nucleophilic than the sulfoxonium ylides.
Sulfonium ylides seldom add reversibly to a carbonyl group, and their reactions are gener-
ally under kinetic control, whereas reactions of sulfoxonium ylides are often under ther-
modynamic control. This can have useful consequences, synthetically. Both types of ylides
Figure 11.4 Formation and

structures of sulfur ylides at
the B3LYP/6-311**G(2df,2p)
level of theory
70. Reviews (Wittig reaction): (a) Maercker, A. Org. React. 1965, 14, 270. (b) Schlosser, M. Top. Stereochem.
1970, 5, 1. (c) Bestmann, H.J.; Vostrowsky, O. Top. Curr. Chem. 1983, 109, 85. (d) Murphy, P.J.; Brennan, J. Chem.
Soc. Rev. 1988, 17, 1. (e) Maryanoff, B.E.; Reitz, A.B. Chem. Rev. 1989, 89, 863.
71. Anderson, R.J.; Henrick, C.A. J. Am. Chem. Soc. 1975, 97, 4327.

react with saturated carbonyl compounds to give epoxides (Example 11.51). In contrast,
sulfoxonium ylides react with α,β-unsaturated carbonyl compounds to give cyclopro-
panes (Example 11.52).72
O
O
Me S
Me CH2
+ O
O (kinetic) (11.51) O Me S O
CH2 H
Me
(11.52)
O Me2SO
(64%) (13%)
Me S (89%)
Me CH2
(thermodynamic) (99%)
Dithiane Anions
With two sulfur atoms on the same carbon atom, the anions of thioacetals are readily
prepared. The most widely used thioacetal carbanions are derived from 1,3-dithianes
(Example 11.53). The synthetic utility of dithiane anions arises from the fact that the nu-
cleophilic carbon in the dithiane anion was originally a carbonyl carbon, so that the
dithiane anion corresponds in a formal sense to an acyl anion. You will recall that the
carbon atom of a carbonyl group is electrophilic, not nucleophilic, so one cannot prepare
acyl anions directly from carbonyl compounds. Dithiane anions are important umpoled
synthons,73 a term derived from the German umpolung, denoting reversal of the normal
electrophilic or nucleophilic character of a carbon atom. Dithiane anions react rapidly
with alkyl halides by the SN2 mechanism, as shown, where the anion of the dithiane 11.54
reacts with the alkyl halide to give the dithiane 11.55.74 They also add rapidly to aldehydes
and ketones at low temperatures to give alcohols. On hydrolysis of the dithiane, the car-
bonyl group is recovered, as illustrated by the mercury-assisted hydrolysis of Examples
11.55 to 11.56.
S S
R
(11.53)
1) n-BuLi, -40°C HgCl2, CdCO3

S S S S H2O, Me2CO
2) O
(59%)
Br
(11.54) (51%) (11.55) (11.56)
Alkylsulfinyl Anions, Phosphonate Anions, and Anions from Phosphine Oxides

The sulfoxides, sulfones, phosphine oxides, and phosphonate esters share a common
structural feature: highly polar bonds to oxygen that are best represented by the hybrid
of non-polar and polar canonical forms (Example 11.57). In both types of compounds,
the polar canonical form makes a significant contribution to the resonance hybrid, lead-
ing to X—C bond orders close to 1.5 and a pyramidal anion carbon atom. Not surpris-
ingly, the conjugate bases of these compounds share some of the reactivity of the
corresponding ylides.
72. Corey, E.J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
73. (a) Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239. (b) Gröbel, B.T.; Seebach, D. Synthesis 1977, 357.
(c) Seebach, D.; Corey, E.J. J. Org. Chem. 1975, 40, 231.
74. Reece, C.A.; Rodin, J.O.; Brownlee, R.G.; Duncan, W.G.; Silverstein, R.M. Tetrahedron 1968, 24, 4249.

O O O
S R S R S R
R R R
O O O
S R S+2 R S+2 R
R R R (11.57)
O O O
O O O
P R P R P R
X X X
X X X
X=R, OR
Sulfoxides are converted to their conjugate bases by treatment with strong bases.
imethyl sulfoxide, for example, is converted into its conjugate base, the dimsyl anion
D
(CH3SOCH2–), by heating to 70°C with sodium hydride.75 Sulfoxide anions are both good
nucleophiles and strong bases. They react with esters to give β-ketosulfoxides. The
β-ketosulfoxides may be prepared by the nucleophilic acyl substitution of esters by sulfox-
ide anion nucleophiles. Because of its ability to stabilize an adjacent carbanion, the sulfox-
ide group has achieved popularity as an activating group for the regioselective formation of
enolate anions. Strong bases such as LDA or the dimsyl anion deprotonate β-ketosulfoxides
to give the enolate anion adjacent to sulfur.
These enolate anions participate readily in SN2 reactions to give alkylated sulfoxides
that may then be reduced to the hydrocarbon by active metals. Like the sulfinyl group, the
phosphoryl group also confers enhanced acidity on the hydrogens α to it. Phosphine
oxides and phosphonate esters can both be converted to their conjugate bases with sodium
hydride or butyllithium or lithium amide bases, and these conjugate bases are important
nucleophiles that react with aldehydes and ketones to give alkenes. The reactivity of phos-
phoryl anions was explored by Horner76 as well as by Wadsworth and Emmons.77 The
reaction between a phosphoryl anion and an aldehyde or ketone is generally known today
as the Horner-Wadsworth-Emmons (HWE) reaction. The α-anions of phosphonate esters
are the critical nucleophiles in the most widely used version of the reaction. In contrast to
the Wittig reaction with unstabilized ylides, the HWE reaction favors the formation of the
E isomer, as illustrated by Example 11.58.
76. (a) Horner, L.; Hoffmann, H.; Wippel, H.G. Chem. Ber. 1958, 91, 61–63. (b) Horner, L.; Hoffmann, H.;
Wippel, H.G.; Klahre, G. Chem. Ber. 1959, 92, 2499–2505.
Leopold Horner (1911–2005) was educated at Munich (PhD, 1937) and began his independent career in 1942
at the Plastics Research Institute in Frankfurt am Main. In 1952, he moved to Mainz as Professor. Horner's work
in organophosphorus chemistry led to his enduring fame. For more biographical details, see: Kuntz, H. Angew.
Chem. Int. Ed. 2005, 44, 7664.
77. Reviews: (a) Wadsworth, W.S., Jr. Org. React. 1977, 25, 73. (b) Boutagy, J.; Thomas, R. Chem. Rev. 1974,
74, 87.
William S. Wadsworth, Jr. (1927–). Because there is no published biography of Wadsworth, this biograph-
ical note will be somewhat longer than most in this book. Wadsworth was born in Farmington, Connecticut,
to a long-established New England family, and was educated at Trinity College (site of the Wadsworth
Library) and at Pennsylvania State University, where he received his PhD in 1956. He then joined the Rohm
and Haas Company, and it was while in Emmons' group there that Wadsworth discovered the reaction that
bears their joint names. His project had been to prepare new acrylate monomers containing a phosphonate
group—such compounds had been proposed as potential flame retardants in synthetic fibers—and he set
about preparing them by the condensation of α-phosphonoacetonitrile with formaldehyde. To his chagrin,
the major product was an insoluble polymer that was totally devoid of phosphorus; by continued work, how-
ever, he was able to determine that the polymer was poly(acrylonitrile) formed by polymerization of the initial
product. In 1963, Wadsworth joined the faculty of South Dakota State University, where he remained until his
retirement in 1991.
William David Emmons (1924–2001) was educated at the Minnesota and Illinois (PhD, 1951). He joined the
Rohm & Haas Company, where he became Director of Pioneering Research in 1973. From 1961–1969 he was an
editor of Organic Syntheses. For more biographical details, see; Freeman, J.P. Org. Synth. 2003, 80, xxvi.

O
P(OEt)2
1)LDA, THF-HMPA (1:2), –78°C
(11.58)78
2)
CO2Me CHO
CO2Me
(78%; 99% isomer shown)
Silane Anions: The Peterson Olefination

Carbanions stabilized by silicon are useful nucleophiles that participate in typical nucleo-
philic reactions: they react with alkyl halides to give products of SN2 reactions, and they add
to carbonyl compounds to give alcohols. When treated with acid or base, the adducts of
silicon-stabilized anions and carbonyl compounds undergo a facile elimination to give
alkenes (Example 11.59). This two-step reaction converting a carbonyl compound to an
alkene is known as the Peterson olefination.79 When the β-hydroxyalkylsilane is treated
with strong base in the second step of the Peterson olefination, the elimination occurs with
syn stereochemistry; when acid is used in the second step, the elimination occurs with anti
stereochemistry.
O HO SiMe3 CH2
Me3SiCH2MgBr NaH, THF (11.59)

Et2O
(50% overall)
The Peterson olefination is less affected by steric hindrance than the Wittig reaction,
so it offers a useful alternative to the Wittig reaction in reactions of hindered ketones. For
example, the formation of the exocyclic methylene double bond in gorgonene was accom-
plished as shown in Example 11.60 using a Peterson reaction; the Wittig reaction led to
epimerization at the bridgehead carbon in this particular case.80
OLi
O Me3Si
Me3SiCH2Li AcOH, H2O
(11.60)
THF, ∆, 18 h
gorgonene
Reaction Synopses
Wittig Reaction
R3
PPh3
R' R' R3
R2
O
base
R R R2
Base: NaH, Me2SO; BuLi; NaH, THF; LDA, THF; etc.

Stereochemistry: R=alkyl, predominantly Z
R= COR, CO2R, CHO, CN, Ph, etc, predominantly E
78. Wadsworth, W.S., Jr. Org. React. 1977, 25, 73.

79. (a) Peterson, D.J. J. Org. Chem. 1968, 33, 780. Reviews: (b) Chan, T.H. Acc. Chem. Res. 1977, 10, 442.
(c) Birkofer, L.; Stiehl, O. Top. Curr. Chem. 1980, 88, 58. (d) Ager, D. J. Synthesis 1984, 384; Org. React. 1990, 38, 1.
Donald John Peterson (1935–) received his graduate education at Iowa State University (PhD, 1962, under
Gilman), and immediately joined the Procter and Gamble Company, where he rose to become Director of the
Corporate Technology Division. Peterson's independent work with heteroatom-stabilized carbanions dates to
his early years at P&G; his seminal publication appeared in 1968. In what may presage the future, information
about Peterson is most conveniently found on the Facebook page devoted to his reaction:
D.J.Peterson,PhD/the Peterson Olefination Reaction (https://www.facebook.com/groups/209574029106964/)
80. Boeckmann, R.K., Jr.; Silver, S.M. J. Org. Chem. 1975, 40, 1755.

Horner-Wadsworth-Emmons Reaction
R3 O
P X
R' R' R3
R2 X
O
base
R R R2

X = alkyl, Ph (Horner reaction); X = alkoxy
(Wadsworth-Emmons)
Stereochemistry: predominantly E
Peterson Olefination
R3
2
R SiMe3
R'
M R' R3 acid or R' R3
O R R2 base
R HO SiMe3 R R2
M = Li, Mg, etc.

Stereochemistry: elimination by base is syn; elimination by acid is anti.
Epoxide Synthesis Using Sulfonium Ylides
R3
SR2
R' R2 R' R3
O base
R R O R2
Base: NaH, Me2SO; LDA, THF; etc.

Reagents: Me3SI, NaH, Me2SO; RCH2SPh2Br, NaH, THF; etc.
Reaction with sulfonium ylide is under kinetic control; reaction with sulfoxo-
nium ylide is under thermodynamic control.
Cyclopropanation Using Sulfoxonium Ylides
R3 O
R' SR2 R'
R O R2 R O
base
R R R R
Base: NaH, Me2SO; LDA, THF; etc.

Reagents: Me3S(O)I, NaH, Me2SO; RCH2S(O)Ph2Br, NaH, THF; etc.
Umpolung and Dithiane Anions
S base S RX (SN2) S Hg2+
Li R R CHO
S S S
:CHO
Base: BuLi, THF, –78°C; etc.

11.4 Formation of Enolate Anions
Enolate anions formed by deprotonation of carbonyl compounds have been extremely im-
portant nucleophiles for more than a century, so it is well worth knowing the approximate
pKas of some simple representative examples (Table 11.7). The pKas of the α hydrogens of
simple monofunctional aldehydes, ketones, and nitriles are usually in the range of 20 to 31,
depending on the solvent. All are considerably weaker acids than water (pKa 15.5), but stron-
ger acids than ammonia and amines (pKa 32–35).81 As is apparent from the values in Table 11.7,
the effects of multiple carbonyl or cyano groups are cumulative: β‑dicarbonyl and α-
cyanocarbonyl compounds as well as α‑cyanonitriles are all stronger acids than water. Nitro
groups have an even larger effect on the acidity of the α hydrogens, so nitromethane is ap-
proximately as strong an acid as pentane-2,4-dione.
Structure and Bonding in Enolate Anions and Nitrile α-Anions

The removal of an α-hydrogen from a carbonyl compound or a nitrile gives a resonance-
stabilized carbanion with an extended π electron system. As shown in Example 11.61, the
major contributor to the resonance hybrid of these anions is the one with the negative
charge on the heteroatom.
O
major C N
(11.61)
O
minor C N
The effects of resonance stabilization of the anion can be viewed in terms of the reaction
coordinate diagrams for the deprotonation reactions of an alkane and a carbonyl compound
(Figure 11.5). Both reactions involve the cleavage of a
Table 11.7 Typical pKa Values of Carbonyl Compounds, Nitriles,
carbon-hydrogen bond. Because neither the hydrocarbon
and Common Bases
nor its conjugate base is delocalized, the alkane provides a
Compound pKa (H2O) pKa (Me2SO) baseline energy profile that the deprotonation of the car-
bonyl compound can be compared against. In contrast to
R–CH(COR')2 ≈9 ≈ 13
the hydrocarbon, the carbonyl compound is slightly stabi-
R–CH(CN)2 ≈ 11–12 ≈ 11–12 lized by resonance, although much less so than the enolate
H 2O 15.74 31.4 anion due to the charge separation in the minor canonical
form. Thus, compared to the ∆H for the deprotonation of
ROH 15–19 29–32
the hydrocarbon, which gives a localized anion, the ∆H for
R–CH2–COR' 19–20 24–27 deprotonation of the carbonyl compound is less positive:
the carbonyl compound is more acidic.
R–CH2–CN ≈ 25 ≈ 31
Because the major contributor to the resonance
NH3 32.5 ≈ 35 hybrid for these anions is the one in which the hetero-
RNH2, R 2NH ≈ 33–43 ≈ 35–40 atom carries the negative charge, one would predict that
structure of these anions should resemble an alkene,
81. For compilations of acidity constants, see (a) Bordwell, F.G. Acc. Chem. Res. 1988, 21, 456. (b) Bordwell,
F.G.; Matthews, W.S. J. Am. Chem. Soc. 1974, 96, 2116. (c) Matthews, W.S.; Bares, J.E.; Bartmess, J.E.; Bordwell,
F.G.; Cornforth, F.J.; Drucker, G.E.; Margolin, Z.; McCallum, R.J.; McCollum, G.J.; Vanier, N.R. J. Am. Chem.
Soc. 1975, 97, 7006. (d) Bordwell, F.G.; Fried, H.E. J. Org. Chem. 1981, 46, 4327. (e) Smith, M.B.; March, J. March's
Advanced Organic Chemistry. Reactions, Mechansims, and Structure, 5th ed. (Wiley: New York, 2001), ch. 8, pp.
329–331, and references therein. (f) Isaacs, N.S. Physical Organic Chemistry (Longman Scientific & Technical:
London, 1987), ch. 6, contains several useful tables of acidity constants.

Figure 11.5 Reaction
coordinate diagrams for
∆Hreaction for deprotonation of a
hydrocarbon hydrocarbon (dashed line)
and a carbonyl compound
Energy
additional stabilization of (solid line)
anion due to resonance
∆Hreaction for carbonyl

compound or nitrile
additional stabilization of
carbonyl compound or
nitrile due to resonance
Reaction coordinate
with a C=C double bond and a C—O single bond. The X-ray crystal structures of several
metal enolates have shown that this is the case (Figure 11.5 gives the most widely cited
example). The X-ray structures have also shown that the lithium enolates are aggregates
of two or more enolate anions with their lithium counterions. The enolate oxygen atom
in these aggregates is simultaneously coordinated to more than one lithium atom, and
each lithium is coordinated by four oxygens. For example, in the lithium enolate in
Figure 11.6, the enolate is tetrameric based on a Li4O4 scaffold, and each lithium atom is
coordinated to three enolate oxygens and one oxygen atom from the solvent.82
Enolate anions can exhibit geometric (E/Z) isomerism like all other alkenes. For exam-
ple, if we take the enolate anion derived from 3-pentanone, there are two isomeric enolates
possible. Just like any other alkene, the stereochemistry of the enolate anions can be as-
signed as either E or Z by using the Cahn-Ingold-Prelog sequence rules. This can, however,
pose problems when one is comparing the stereochemical outcome from reactions of geo-
metrically identical enolates with differing metals, as shown by the two ester enolates in
Example 11.62. Although the spatial disposition of the four groups around the enolate
double bond is the same in terms of the chemical nature of the groups, its E/Z configura-
tion changes with the identity of the metal bonded to oxygen. To circumvent this problem,
the E/Z system for enolates is modified to give the atom bound to the metal the higher
priority, regardless of what the other substituent at this position is (Example 11.63). This
Figure 11.6 The structure of the lithium enolate of 3,3-dimethyl-2-butanone

(pinacolone) shows clearly that (1) the carbon-carbon bond is a double bond
(a carbon-carbon single bond would be 1.54 Å long) and that (2) the carbon-
oxygen bond is a single bond (a double bond would be 1.21 Å long).
82. (a) Seebach, D. Angew. Chem. Int. Ed. Engl. 1988, 27, 1624. (b) Williard, P.G.; Liu, Q.-Y. J. Am. Chem. Soc.
1993, 115, 3380.

allows the reaction stereochemistry of enolates of ketones, esters, amides, and thioesters,
for example, to be compared directly. Enolate configurations assigned in this way are des-
ignated E(O) and Z(O) configurations.83
OM
OM
Z E
(11.62)
OLi OZnX
OMe OMe
E Z
OM
OM
R Z(O) X E(O)
(11.63)
X
R
X = NR2, OR, SR, etc.
M = Li, Na, Mg, Zn, etc.
The generation of a specific enolate anion involves two separate tasks: controlling the re-
giochemistry of enolate formation (in ketones) and controlling the stereochemistry of the eno-
late double bond. Both of these enolate properties—regiochemistry and stereochemistry—have
important consequences in their reactions, so it is important to have methods that can repro-
ducibly generate the specific enolate anion of choice.
Controlling Regiochemistry During Formation of Ketone Enolates

Aldehydes, nitriles, and derivatives of carboxylic acids (e.g., Example 11.64) have only one
α position and are therefore unable to form more than one regioisomeric enolate. How-
ever, ketones with hydrogen atoms at the α and α' positions are capable of forming two
regioisomeric enolates. In the case of unsymmetrical ketones, which enolate is formed is
decided by the reaction conditions—whether the ketone is deprotonated under kinetic or
thermodynamic control (Example 11.65).
R1 R1
X base X
R2 R2 (11.64)
O OM
X=OR, SR, NR2, Ar, etc.
R1
base
R1 (thermo.) R2 R3
OM
R2 R3 1 (11.65)
R
O
base
(kinetic) R2 R3
OM
The stability of an alkene increases as the substitution of the carbon-carbon double
bond increases. The same is true for enolates, and generating a metal enolate under
83. Masamune, S.; Choy, W. Aldrichimica Acta 1982, 15, 47.

equilibrium conditions will lead to the formation of the more substituted enolate as the
major product. However, the kinetic acidity of most α hydrogens decreases in the order
CH3 > CH2 > CH, so that methyl ketones are almost invariably deprotonated at the
methyl group to give the less substituted enolate under conditions of kinetic control.84
In similar fashion, the kinetic deprotonation of an α,β-unsaturated ketone (Example
11.66) occurs preferentially at the sp3-hybridized α' carbon85 rather than at the γ carbon,
despite the latter reaction giving the more stable enolate86 (the thermodynamic enolate
of an α,β-unsaturated carbonyl compound is, indeed, formed by deprotonation at the γ
carbon).
R R R
base
and/or (11.66)
O R' MO R' MO R'
(thermo.) (kinetic)
There are four experimental parameters that can affect the regiochemistry of enolate anion
formation over which the chemist has control: the counterion, the solvent, the reaction tem-
perature, and the reaction time. Because enolate anions undergo equilibration at room tem-
perature and equilibration can occur over time even at low temperature, kinetic deprotonation
is almost always carried out at low temperature and over short reaction times. The presence of
a protic solvent provides a means for the enolate anion to equilibrate, so thermodynamic con-
trol of enolate regiochemistry is often provided by adding a proton source such as tert-butyl
alcohol to the deprotonation reaction, as in Example 11.67. Kinetic deprotonation is usually
carried out by treating the carbonyl compound with a strong, hindered base containing a co-
ordinating cation (e.g., Li+), in an aprotic solvent and at low temperature. The bases that are
most widely used are amide anion bases, shown as their lithium (“L”) forms in Example 11.68.
The bases shown are lithium diisopropylamide (LDA),87 lithium 2,2,6,6-tetramethylpiperidide
(LTMP),88 lithium isopropylcyclohexylamide (LICA), and lithium (or sodium or potassium)
hexamethyldisilazides (LHDS or LHMDS; and thus NaHDS or NaHMDS, and KHDS or
KHMDS).89 These bases exist in solution as aggregates (often dimers),90 so they are even more
hindered than their monomeric structures would suggest. All these bases can be formed by the
reaction between the amine and butyllithium or a metal hydride, and most are commercially
available. All are soluble in organic solvents such as THF, which is a distinct advantage over
strong bases such as potassium hydride and sodium amide, which are not, because it allows the
84. (a) House, H.O.; Trost, B.M. J. Org. Chem. 1965, 30, 1341. (b) House, H.O.; Czuba, L.J.; Gall, M.;
Olmstead,H.D. J. Org. Chem. 1969, 34, 2324. (c) House, H.O.; Gall, M.; Olmstead, H.D. J. Org. Chem. 1971, 36, 2361.
(d) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944. (e) Reich, H.J.; Renga, J.M.; Reich, I.L. J. Am. Chem.Soc. 1975, 97,
5434. (f) Clark, R.D.; Heathcock, C.H. J. Org. Chem. 1976, 41, 1396. (g) Brown, C.A. J. Org. Chem. 1974, 39, 3913.
Reviews & monographs: (h) D’Angelo, J. Tetrahedron 1976, 32, 2979. (i) Stowell, J.C. Carbanions in Organic
Synthesis (Wiley-Interscience: New York, 1979), pp. 127–216.
85. Lee, R.A.; McAndrews, C.; Patel, K.M.; Reusch, W. Tetrahedron Lett. 1973, 965.
86. Büchi, G.; Wuest, H. J. Am. Chem. Soc. 1974, 96, 7573.
87. (a) Hammell, M.; Levine, R. J. Org. Chem. 1950, 15, 162. (b) Albarella, J.P. J. Org. Chem. 1977, 42, 2009.
(c) Sasson, I.; Labovitz, J. J. Org. Chem. 1975, 40, 3670.
88. Olofson, R.A.; Dougherty, C.M. J. Am. Chem. Soc. 1973, 95, 581.
89. Amonoo-Neizer, E.H.; Shaw, R.A.; Skokvlin, D.O.; Smith, B.C. J. Chem. Soc. 1965, 2997.
90. LHDS: Lucht, B.L.; Collum, D.B. Acc. Chem. Res. 1999, 32, 1035.
LDA: (a) Jackman, L.M.; DeBrosse, C.W. J. Am. Chem. Soc. 1983, 105, 4177. (b) Bauer, W.; Seebach, D. Helv.
Chim. Acta 1984, 67, 1972. (c) Williard, P.G.; Salvino, J.M. J. Org. Chem. 1993, 58, 1. (d) Galiano-Roth, A.S.;
Collum, D.B. J. Am. Chem. Soc. 1989, 111, 6772.
LICA: (a) DePue, J.S.; Collum, D.B. J. Am. Chem. Soc. 1988, 110, 5518. (b) DePue, J.S.; Collum, D.B. J. Am.
Chem. Soc. 1988, 110, 5524.

deprotonation reaction to occur in solution instead of just at the surface of the undissolved
solid. (Despite their base strength, the hydride bases give the thermodynamic enolate due to
rapid proton transfer between the enolate and the excess carbonyl compound during the kinet-
ically slow deprotonation step.) All of these amide bases will deprotonate a carbonyl compound
or nitrile at temperatures well below 0°C.
t-BuOH
O OLi (trace) OLi
LDA/THF (11.67)
-78°C
Me Me
Me Me
Si Si (11.68)
N N N Me N Me
Li Li Li Li
LDA LTMP LICA LHMDS
The regiochemistry of the enolate anion is also influenced by the conformation of the
α hydrogen. Before the hydrogen atom can be abstracted by the base, the σ orbital of the
C—H bond must be coplanar with one lobe of the π* orbital of the carbonyl group. In
other words, the carbon-hydrogen bond and the carbonyl group must be in an orienta-
tion that allows the most effective hyperconjugation. In cyclohexanones, for example, the
axial α hydrogens are removed much faster than the corresponding equatorial hydrogens
(Figure 11.7).
Deprotonation of Conjugated Systems

The deprotonation of α,β-unsaturated ketones such as 2-cyclohexenone can occur at two
sites: the α' carbon and the γ carbon (Figure 11.8). The deprotonation at the α' carbon leads
to a cross conjugated enolate anion, which is a 2-substituted-1,3-butadiene. This is a pro-
cess that is favored under kinetic control.91 The deprotonation at the γ carbon is slower, but
it gives an enolate anion that has linear conjugation, a 1-substituted-1,3-butadiene. This
dienolate anion is more stable (lower energy) than the cross-conjugated isomer. Forma-
tion of this enolate anion is favored under thermodynamic control.92 Interestingly, this
preference for kinetic deprotonation at the α' carbon is still present, even when the α'
carbon already carries an alkyl substituent and the γ carbon does not.
Figure 11.7 The axial hydrogens of cyclohexanones are more acidic than the
equatorial hydrogens due to more efficient overlap of the C‑H σ orbital with the
π* orbital of the carbonyl group.
91. (a) Grieco, P.A.; Ferrino, S.; Oguri, T. J. Org. Chem. 1979, 44, 2593. (b) Stork, G.; Danheiser, R.L. J. Org.
Chem. 1973, 38, 1775.
92. Lee, R.A.; McAndrews, C.; Patel, K.M.; Reusch, W. Tetrahedron Lett. 1973, 965.

Figure 11.8 The
deprotonation of
2-cyclohexenone under
conditions of kinetic and
thermodynamic control
Energy
KINETIC O
PRODUCT
α' α
THERMODYNAMIC
β PRODUCT
γ
extent of reaction extent of reaction
Problems
11-4 Draw the geometric isomers of the major contributor to the resonance hybrid of
the conjugate base of each of the following compounds. Label each isomer either
E or Z according to the Cahn-Ingold-Prelog sequence rules. For ester and amide
enolates, use the Z(O) and E(O) variant of this system.
(a) 3-pentanone (b) propanal
(c) 2,2-dimethyl-3-hexanone (d) 2-methylpentanal
(e) ethyl butanoate (f) N,N-dimethylbutanamide
N-propanoylpyrrolidine
(g) (h) cyclohexyl propanoate
11-5 What is the structure of the enolate anion expected to be major product of each
of the following reactions? Indicate whether each is formed under kinetic or ther-
modynamic control.
O
O O
LDA KOBut LDA
(a) (b) (c)
O
KOBut LDA O KOBut
(d) (e) O (f)
t-BuOH THF, –78°C t-BuOH
O O O
H
KOMe LDA KOBut
(g) (h) (i)
MeOH THF, –78°C t-BuOH
Me
OTHP OTHP
O
KOBut LDA O KOBut
(j) (k) O (l)
t-BuOH THF, –78°C t-BuOH
(continues)

O
O
O
H
(m) LICA KOBut

(n) H H
THF, –78°C t-BuOH
OMe O
The π molecular orbitals of a ketone enolate anion are shown in Figure 11.9. In this
anion, the lowest energy unoccupied molecular orbital is the antibonding π orbital ψ3 and
the highest energy occupied molecular orbital (HOMO) is the non-bonding π molecular
orbital ψ2. Because the terminal atoms of the HOMO of an enolate anion are not the same,
electrophiles may react at carbon or at oxygen. Nucleophiles with two different nucleop-
hilic sites are called ambident nucleophiles, from the Latin words ambo (both) and dens
(tooth)—the nucleophile can “bite” in two places. The reaction between an enolate anion
and a proton illustrates the ambident nature of the nucleophile. When the proton reacts at
the carbon atom, the product possesses a carbonyl group—we call this product the keto
form of the compound. When the proton reacts at the oxygen atom, the product possesses
an olefinic double bond bearing a hydroxyl group—we call this isomer the enol form of
the compound (hence the term enolate anion—the conjugate base of an enol). In general,
protonation at oxygen is the kinetically favored process.
The keto and enol forms of carbonyl compounds are isomers that are in equilibrium
(e.g., Example 11.69) and are related to each other by interchanging the positions of a hy-
drogen atom and a π bond. Such isomers are known as tautomers, and the equilibrium
reaction interconverting them is known as tautomerization. In the keto tautomer, the
hydrogen is bonded to the α carbon, and the π bond is between carbon and oxygen. In the
enol tautomer, the hydrogen is bonded to oxygen, and the π bond is between the two
carbon atoms. The interconversion of tautomers is catalyzed by either acid or base.
R O R OH
H (11.69)
R R R R
keto enol
Deuterium Exchange and Epimerization

Enolate anions are powerful nucleophiles, and they readily participate in typical reactions of
nucleophiles, especially SN2 reactions and nucleophilic additions. Because of its ambident
nature, an enolate anion can react with an electrophile at either oxygen or carbon; which site
is more reactive depends on the electrophilic reagent—hard or soft. The oxyanion contributor
Figure 11.9 The π molecular Increasing Energy

orbitals of a ketone enolate
anion. There are two
different non-bonding
orbitals that may function as
the highest energy occupied
molecular orbital: the lone O O O
pairs on oxygen and the non- R R R R R R
bonding electron pair in the
R R R
π molecular orbital ψ2.
ψ1 ψ2 ψ3
bonding non-bonding antibonding

to the resonance hybrid is reasonably viewed as a hard base or hard nucleophile, and hard
electrophiles tend to react with enolate anions at oxygen. Protonation of an enolate anion
occurs most rapidly at oxygen to give the enol (Example 11.71): the hard electrophile (the
proton) reacts most rapidly at the hard location of the enolate (the oxygen atom). Despite
protonation at oxygen being kinetically favored over protonation at carbon, the keto-enol
equilibrium in simple aldehydes, ketones, nitriles, and esters strongly favors the keto tau-
tomer (Example 11.70), and the enol content of these compounds is quite small (Table 11.8).
The keto tautomer does not dominate the equilibrium mixture for all carbonyl compounds,
however. In compounds where there are two carbonyl groups bonded to the same carbon
atom (β-dicarbonyl compounds), the amount of enol present at equilibrium can be quite sub-
stantial. Note that the enol content of aldehydes tends to be higher than the enol content of
structurally similar ketones.
attack at carbon (slower)
R O R O
H keto (11.70)
H
R R R R
R O H R OH
enol (11.71)
R R R R
attack at oxygen (faster)
Table 11.8 Enol Content of Some Carbonyl Compounds in Protic Solvents*
Carbonyl Compound % Enol at 25°C Carbonyl Compound % Enol at 25°C
O
O
2 × 10−4
5 × 10−4
Me H 3.9 × 10−5
O
O
6.3 × 10−6
1.2 × 10−2
H 1.7 × 10−6
O
CHO
2 × 10−5
1.4 × 10−2
Me 1.2 × 10−6
O O
6.3 × 10−6
2 × 10−5
Me Me 6 × 10−7 Et
O O
O 3.6 × 10−6 ≈ 95
5 × 10−7
O O
3.7 × 10−6 N 0.25
C
1.6 × 10−6 OEt
O O O O
18.7 0.16
Me OEt EtO OEt
*The enol content of simple esters and nitriles is usually too low to measure (i.e., < 10−7%).

Recall that diastereoisomers that are identical except for the configuration of one chiral
center are called epimers, and the interconversion of such stereoisomers by the inversion of a
single chiral center is called epimerization. The treatment of a carbonyl compound or a nitrile
with a chiral α carbon leads to loss of stereochemical integrity at that position—epimerization
occurs (e.g., Example 11.72). When the carbonyl compound or nitrile is treated with deuterium
oxide or a deuterated alcohol in the presence of a catalytic amount of base (e.g., Example 11.73),
the α hydrogens are gradually replaced by deuterium. When the α carbon is chiral, as in
(S)-2-methyl-1-phenyl-1-butanone, the product is racemic. When there is more than one chiral
center in the molecule undergoing the hydrogen exchange reaction, a mixture of stereoisomers
is often obtained, with the most stable stereoisomer being the major one isolated.
CHO H
OO H OO CHO
KOH (11.72)
MeOH
O O
O KOD O
D2O
H Me
S only
O O
(11.73)
D Me Me D
equal amounts
Exchange in conjugated ketones is rather more complex. When we examine the con-
tributors to the resonance hybrid of the two regioisomeric anions from a conjugated enone,
we see that exchange can, in principle, occur at the α position, the α' position, and the γ
position. In practice, we see exchange at all the possible positions in a conjugated system.
The contributors to the resonance hybrid of the dienolate anions from an α,β-unsaturated
carbonyl system are shown in Figure 11.10. Protonation of a dienolate anion may occur at
any atom that bears a negative charge in one of the contributing structures.
Figure 11.10 Enolate anions

in conjugated carbonyl H O H O H O
compounds H R H H R H
R R H R R R H R R R H R R
(11.74)
H O H O H O
H R R H R H
R R H R R H HR R R H R R
(11.75)
α-deprotonation
(11.76) H O
R H
R H R R
γ-deprotonation
(11.77)

An especially illustrative example of this is provided by the naturally occurring com-

pound mitchelladione (Example 11.78), in which fully ten hydrogens are replaced by deu-
terium after treatment with sodium ethoxide in deuterated ethanol (ethanol-O-d).93
D D
D
D
NaOEt, EtOD D
OD D (11.78)
O D
(repeat 3x)
O O
D D
Problems
11-6 Draw the enolate anion that can be formed from each of the following com-
pounds. Where more than one enolate may form, draw both and indicate which
one is the more stable.
O CHO CN CN
(a) (b) (c) (d) (e)

O
O O
O CN O
(f) (g) O (h) (i) (j)
CN
O
H O
(k) (l) (m) (n)
O H H
O
11-7 The enol content of the aldehydes MeCHO, EtCHO, and Me2CHCHO increases
from 5 × 10−4 to 0.16 at 25°C. Explain this trend.
Reaction Synopses
Formation of Enolate Anions
O R O R
base
R R R R
Base: KOBut, ButOH; NaH, Me2SO; NaH, THF; LDA, THF;

LHMDS, THF; NaHMDS, THF; LiTMPP, THF; etc.
Kinetic deprotonation with strong amide bases at low
temperature
Thermodynamic deprotonation with oxyanion bases and
NaH, THF
Regiochemistry: kinetic deprotonation favors less substituted enolate; thermo-
dynamic deprotonation favors more substituted enolate;
kinetic deprotonation of α,β-unsaturated ketones occurs at
α'-carbon; thermodynamic deprotonation of α,β-unsaturated
ketones occurs at γ-carbon.
(continues)
93. Lewis, D.E.; Massy-Westropp, R.A.; Ingham, C.F.; Wells, R.J. Aust. J. Chem. 1982, 35, 809.

Epimerization and α-Exchange

O R1 O R
H base H
R R2 ROH R R
Base: KOBut, But OH; NaOEt, EtOH; K 2CO3, MeOH; etc.

Stereochemistry: racemization of compounds with one chiral center; most stable
diastereoisomer predominates in product mixture from compound with more
than one chiral center.
11.5 Rearrangements of Carbanions
Rearrangements of carbanions are much less common than rearrangements of carboca-

tions because carbanions lack an electron-deficient center to provide the driving force for
rearrangements: every atom in a carbanion possesses a complete octet. Nevertheless, car-
banions where the carbanion center is adjacent to a second-row heteroatom (especially
oxygen and nitrogen) do undergo rearrangements. In these cases, the major driving force
for the rearrangement appears to come from the transfer of the formal negative charge to
the more electronegative element.
The two major classes of these rearrangements differ in mechanism and in the struc-
tural requirements of their substrates (see Example 11.79). In [1,2]-rearrangements (which
are structurally analogous to the rearrangement of carbocations), the only structural re-
quirement is the heteroatom adjacent to the carbanion carbon. In [2,3]-rearrangements,
however, one of the alkyl groups attached to the heteroatom is an allyl or benzyl group,
and the rearrangement also involves the rearrangement of the π bond in the allyl group.
R1
[1,2]
R1
X R2 X R2
(11.79)
R2
X R2 [2,3] R1
X
R1
X=NR, O, S, NR2, SR, etc.
By far the most widely studied of these reactions are the [1,2]- and [2,3]-Wittig rear-
rangements of ethers,94 and the [2,3]-Wittig rearrangement of allyl ethers has become a
useful reaction in stereoselective synthesis. Both reactions are initiated by the treatment of
an ether with a strong base (typically an amide or alkyllithium base or a mixture of butyl-
lithium and potassium tert-butoxide). At lower temperatures (below about –30°C), the
[1,2]-rearrangement is slow, and one can use these strong bases in ether solvents. However,
at higher temperatures (around 0°C), the [1,2]-Wittig rearrangement becomes competitive
with the [2,3]-rearrangement.
The [1,2]-Wittig rearrangement (Example 11.80) occurs through a radical pair
mechanism,95 constrained largely within the solvent cage. Support for this mechanism
comes from a number of lines of evidence. One, the migratory aptitudes of substituents
94. Reviews, [1,2]-Wittig rearrangement: (a) Marshall, J.A. In Trost, B.M.; Fleming, I, Eds. Compregensive
Organic Synthesis (Pergamon: London, 1991), vol. 3, p. 975. (b) Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs
Ann./Receuil 1977, 1275. Reviews, [2,3]-Wittig rearrangement: (c) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86,
885. (d) Nakai, T.; Mikami, K. Org. React. 1994, 46, 105.
95. Review: Schöllkopf, U. Angew. Chem. Int. Ed. Engl. 1970, 9, 763.

(allyl ≈ benzyl > ethyl > methyl > phenyl)96 reflect the stability of the free radicals, not
of the carbanions.97 Two, the migrating alkyl group largely retains its configuration.98
Three, crossover products, which can only come from a dissociative mechanism, have
been detected in the reaction.99
R1
[1,2]
R1
O R2 O R2
(11.80)
R1 R1
O R2 O R2
The analogous [1,2]-rearrangement of a nitrogen ylide (e.g., Example 11.81) is known as

the Stevens rearrangement.100 1H NMR evidence (chemically induced dynamic nuclear
polarization [CIDNP], a technique used to determine whether radicals are involved in a
reaction) indicates that it, too, proceeds through a radical pair mechanism.101 There is also
CIDNP evidence for the involvement of radicals in the Stevens rearrangement of sulfur
ylides.102
Ph
Ph OH Ph
N Ph NMe2 (11.81)
O Me Me O
By contrast, the [2,3]-Wittig rearrangement of ethers (11.82) is a concerted rearrange-

ment occurring through a cyclic transition state with concomitant rearrangement of a π
bond—this is a [2,3]-sigmatropic rearrangement (Figure 11.11). The reaction is very stereo-
selective, and it is believed to occur through an envelope-type transition state with the
large groups preferentially in the pseudoequatorial positions of the five-membered ring.
The rearrangement is suprafacial with respect to the allyl group. Analogous sigmatropic
rearrangements of allylic ammonium ylides (11.83) and allylic sulfur ylides (11.84) are also
known. The [2,3]-sigmatropic rearrangements of benzyl ammonium ylides include the
Sommelet (or Sommelet-Hauser) rearrangement (11.85),103 which provides a method for
the synthesis of tertiary o-methylbenzylamines. Some examples of the use of these
[2,3]-sigmatropic rearrangements in synthesis are gathered in Table 11.9.
96. (a) Wittig, G. Angew. Chem. 1954, 66, 10. (b) Slov’yanov, A.A.; Ahmed, E.A.A.; Beletskaya, I.P.; Reutov,
O.A. J. Chem. Soc., Chem. Commun. 1987, 23, 1232.
97. Lansbury, P.T.; Pattison, V.A.; Sidler, J.D.; Bieber, J.B. J. Amn. Chem. Soc. 1966, 88, 78. (b) Schöfer, H.;
Schöllkopf, U. Tetrahedron Lett. 1968, 2809.
98. (a) Schöllkopf, U.; Schöfer, H. Liebigs Ann. Chem. 1963, 663, 62. (b) Felkin, H.; Frajerman, C. Tetrahedron
Lett. 1977, 3485. (c) Hebert, E.; Welvart, Z. J. Chem. Soc., Chem. Commun. 1980, 1035. (d) Hebert, E.; Welvart,
Z. Nouv. J. Chim. 1981, 5, 327.
99. (a) Lansbury, P.T.; Pattison, V.A. J. Org. Chem. 1962, 27, 1933. (b) Lansbury, P.T.; Pattison, V.A. J. Am.
Chem. Soc. 1962, 84, 4295.
100. (a) Stevens, T.S.; Creighton, E.M.; Gordon, A.B.; MacNicol, M. J. Chem. Soc. 1928, 3193. (b) Stevens, T.S.
J. Chem. Soc. 1930, 2107. (c) Stevens, T.S.; Snedden, W.W.; Stiller, E.T.; Thomson, T. J. Chem. Soc. 1930, 2119. (d)
Thomson, T.; Stevens, T.S. J. Chem. Soc. 1932, 55. (e) Dunn, J.L.; Stevens, T.S. J. Chem. Soc. 1932, 1926. (f) Thom-
son, T.; Stevens, T.S. J. Chem. Soc. 1932, 1932. (f) Brewster, J.H.; Kline, M.W. J. Am. Chem. Soc. 1952, 74, 5179. (g)
Fenney, E.F.; Druey, J. Angew. Chem. Int. Ed. Engl. 1962, 1, 155. (h) Review: Pine, S.H. Org. React. 1970, 18, 403.
101. (a) Schöllkopf, U.; Ludwig, U.; Ostermann, G.; Patsch, M. Tetrahedron Lett. 1969, 3415. (b) Dolling, U.H.;
Closs, G.L.; Cohen, A.H.; Ollis, W.D. J. Chem. Soc., Chem. Commun. 1975, 545.
102. Iwamura, H.; Iwamura, M.; Nishida, T.; Yoshida, M.; Nakayama, J. Tetrahedron Lett. 1971, 63.
103. (a) Sommelet, M. Comptes Rend. 1927, 205, 56. (b) Kantor, S.W.; Hauser, C.R. J. Am. Chem. Soc. 1951, 73,
4122. (c) Hauser, C.R.; van Eenam, D.N. J. Am. Chem. Soc. 1956, 78, 5698. (d) Bunnett, J.F. Quart. Rev. 1958, 12,
15. (e) Huisgen, R. Angew. Chem. 1960, 72, 3572.

Figure 11.11 The variations ‡

R3 R2 R3 R2
on the theme of 4 R2 R1
R R4
[2,3]-sigmatropic A of O O δ− R 3
O (11.82)
carbanions all occur through 5 1 δ− 6
R R R5
a five-membered transition R6 R1 R4 R5 R
R6
state.
‡
R3 R2 R3 R2
R2 R1
R4 δ+
R4 NR2
NR2 R3 NR2 (11.83)
5 1 δ−
R R R5 6 R4 R6
R6 R R1 R5
‡
R3 R2 R3 R2
R2 R1
R 4 δ+
SR R4 SR 3
R SR (11.84)
δ−
R5 R1 R5 6 R6
R6 R1 R4 R5
R
CH2
NMe2
CH2 NMe2 NMe2
H (11.85)
B
Me
NMe2
Table 11.9 Representative [2,3]-Sigmatropic Rearrangements in Synthesis
BuLi, hexanes (11.86)104

H H OH
SnMe3 0°C
O
SPh Ph Cl Cl
S
Cl SPh
KOBut (11.87)105
Cl
CHCl3 (d.r. = 97:3)
106
BuLi, pentane S
S (11.88)
–78°C
S
S
104. Crimmins, M.T.; Gould, L.D. J. Am. Chem. Soc. 1987, 109, 6199.
105. Andrews, G.; Evans, D.A. Tetrahedron Lett. 1972, 5121.
106. Corey, E.J.; Walinsky, S.W. J. Am. Chem. Soc. 1972, 94, 8932.

Reaction Synopses
[1,2]-Wittig Rearrangement
R2
base
R1 O R2 R1 O R2 R1 O
Base: BuLi; BuLi, KOBut; BuLi; TMEDA; etc.

Stereochemistry: mainly retention at migrating center; mainly inversion at ter-
minal center
Stevens Rearrangement
R2
base
R1 N R2 R1 N R2 R1 NR2
R R R R
Base: Na2CO3; KOH; NaOEt; etc.

Reaction facilitated by R 1=acyl
[2,3]-Wittig Rearrangement
R2
R2
base OH
R1 O R3 R1
R3
R 1=alkyl, phenyl; R 2=alkyl; R 3=alkyl, acyl, etc.
Base: KOEt, KOBut, etc. (R 3=alkyl); K 2CO3, KOH, etc. (R 3=acyl)
Stereochemistry: product alkene is mainly E; reaction occurs with suprafacial
stereochemistry.
Stevens Rearrangement
R2
R2
base NR2
R1 N R3 R1
R R R3
R 1=alkyl, phenyl; R 2=alkyl; R 3=alkyl, acyl, etc.
Base: KOEt, KOBut, etc. (R 3=alkyl); K 2CO3, KOH, etc. (R 3=acyl)
Stereochemistry: product alkene is mainly E; reaction occurs with suprafacial
stereochemistry.
Sommelet or Sommelet-Hauser Rearrangement
NMe3 Me
BuLi
X X
NMe2

Chapter Summary
This chapter has focused on the carbanions. Free carbanions are actually rare, and the
bonding in most metal alkyls is best described by means of multicenter, two-electron
bonds. Metal alkyls of reactive metals (e.g., Mg) can be formed by direct synthesis from
the metal and an alkyl halide; others are accessible by metathesis reactions between a
metal alkyl of an electropositive element and either a metal halide or metal alkyl of the less
electropositive metal. The nucleophilicity and base strength of the metal alkyl increases
with increasing polarity of the C—M bond. The effect of substitution by alkyl groups of
hydrogen on the carbanion carbon is approximately the reverse of that in carbocations.
Delocalization of the charge by conjugation with an adjacent π bond is an important
mechanism for carbanion stabilization, especially if the π bond is electron-deficient (e.g.,
a carbonyl, cyano or nitro group). These enolate anions are important synthetic interme-
diates and can exhibit stereoisomerism. They may be formed by kinetic or thermody-
namic deprotonation of the carbonyl compound, and regioisomeric enolates can result
from ketones. Epimerization can occur on deprotonation of a chiral α-carbon of a car-
bonyl compound. The carbanion can also be stabilized by an adjacent heteroatom from
the lower rows of the main group (e.g., Si, P, S, Sn); carbanions stabilized by this mecha-
nism are important nucleophiles. One subset of this type of carbanion comprises the
phosphorus and sulfur ylides. Dithiane anions represent an umpoled carbonyl group and
are equivalent to a carbonyl anion. Carbanions do not rearrange as readily as carboca-
tions, but the conjugate bases of allylic ethers, amines, sulfonium ions and ammonium
ions do (the Wittig, Stevens, or Sommelet-Hauser rearrangement). The Wittig rearrange-
ment of ethers may be either [1,2] or [2,3]. The [1,2]-Wittig rearrangement proceeds through
free radical intermediates, and the [2,3]-Wittig rearrangement is a pericyclic reaction.
Key Terms
alkynide anion Horner-Wadsworth- Stevens rearrangement

“ate” complexes Emmons (HWE) reaction transmetalation
dimsyl anion Lipshutz cuprate umpolung
dithiane Peterson olefination Wittig reaction
Gilman reagent Sommelet-Hauser Wittig rearrangement
rearrangement ylide
Additional Problems
11-8 Consider the carbonyl compounds in Table 11.8. Rank these compounds in de-
scending order of the expected rates of their exchange reactions with NaOD in
D2O. Is there any caveat when answering this question?
11-9 Alkyllithium solutions often contain lithium alkoxides and undissolved lithium
hydride. The butyllithium content can be determined by titration using triph-
enylmethane as an indicator.
(a) What species is formed by the indicator? Why is it formed?
(b) What does this reaction tell you about the acidity of the hydrogen in the
indicator?
11-10 The reaction of cis-2-bromo-1-methylcyclopropane with isopropyllithium in mixed
ether-pentane at –70°C gives the corresponding 3-methylcyclopropyllithium. When

this compound is trapped at –70°C with carbon dioxide, only cis-2-methylcyclopro-

panecarboxylic acid is obtained. When molecular bromine is used as the trapping
agent, the stereochemistry of the product is scrambled.
(a) Are these results consistent with the cyclopropyllithium being configura-
tionally stable at –70°C or not? Give your reasons.
(b) Provide a rationalization for the different stereochemical outcomes from
using the two trapping reagents (CO2 and Br2).
11-11 In an experiment to generate and trap an optically active alkyllithium
(–)-2-iodooctane was added over 20 minutes to a fourfold excess of 1.04 M s-
butyllithium in petroleum ether (hexanes) and 25 mL of ether at –70°C, and the
product formed was trapped with carbon dioxide. The product, 2-methyloctanoic
acid, exhibited the following rotations:
Wait Before
Iodide Rotation Temperature Quenching Acid Rotation
–44.36° –70°C 1 minute –1.18°

–41.00° –70°C 60 minutes –0.96°
–39.86° –70°C→E0°C 20 minutes 0°
–45.86° –70°C 2 minutes –0.78°*
*The iodide was added over 2 hours at –70°C.
If the absolute configurations of the acid and the halide are the same, what de-
ductions can you make about the stereochemistry of the reactions involved?
11-12 Cyclopentadiene has a pKa of 16, and triphenyl-methane has a pKa of 31. The two
compounds shown have structural features of both. Provide a rationalization for
the pKa values for cyclopentadiene, triphenylmethane, and the two compounds.
pKa = 18.5 pKa = 11
11-13 (a) Carbon-to-carbon rearrangements of carbanions are rare, but they have been
observed, as exemplified by the reaction shown [J. Am. Chem. Soc. 1961, 83,
412, 2537]. When lithium is used as the metal, the rearrangement takes place
only above 0°C. Provide a reasonable rationalization for the formation of the
product in this reaction.
Ph Ph K
Ph K
Ph Cl –66°C Ph Ph
(b) When the corresponding anion is generated from the methylated analog
shown, preferential migration of the phenyl group is observed. How does this
modify your answer to part (a)?
Ph Ph
Ph 1) K, THF
HO2C
Me Hg 2) CO2 Me Ph
2

(c) The Grignard reagent, the alkyllithium, and the alkylpotassium with the
same alkyl group as in part (b) show very different propensities to rearrange:
the Grignard reagent does not rearrange, even in refluxing dioxane, the al-
kyllithium is stable at 0°C but rearranges at 40°C, and the alkylpotassium
rearranges rapidly at room temperature. What does this tell you about the
species actually rearranging? [J. Am. Chem. Soc. 1961, 83, 1196]
11-14 What is the final product of the sequence of reactions shown? Rationalize the re-
giochemistry and stereochemistry of the reaction. [J. Org. Chem., 1973, 38, 2915].
1) pyrrolidine
2) ClCH2CN
3) KOBut
Br
11-15 Sulfur ylides can be formed by the reaction between a sulfide and a diazoalkane,
catalyzed by rhodium (II) acetate. Write a mechanism to account for the trans-
formation pictured [Org. Lett. 2006, 8, 2511]. The product shown is the major
product of the reaction.
N2
N N EtO2C CO2Et EtO2C N N CO2Et

S O S Rh2(OAc)4 EtO2C O CO2Et
xylenes, ∆ S S
In the analogous reaction, shown below, the regiochemistry of the rearrangement

changes, and the isomeric cyclophane is formed [Org. Lett. 2000, 2, 3785]. Provide
a reasonable explanation for the change in regiochemistry caused by the struc-
tural changes in the starting compound.
N2
N N EtO2C CO2Et N N
S O S S O S
Rh2(OAc)4
xylenes, ∆ EtO2C CO2Et
EtO2C CO2Et
11-16 Identify which of the of the compounds in each pair shown will undergo H/D
exchange more rapidly with a base such as KOBut, But OH? Give reasons for your
answers.
O2N O2N
(a) and
D D
O
O2N
(b) and
O D O D
11-17 The bases typically favored for carrying out the Stevens rearrangement are strong
amide bases such as NaNH2, NH3, LDA, THF rather than alkoxide bases such as
potassium tert-butoxide or alkyllithium reagents. Why might this be the case?
(Hint: think about the anion that will be formed.)

11-18 When an internal alkyne (e.g., 4-octyne) is treated with potassium tert-butoxide,
it is largely isomerized to an allene. When the same internal alkyne is treated
with KAPA, the product is the potassium salt of the terminal alkyne. Account
for the difference in the outcomes of these two reactions.
11-19 The effective base strength of n-butyllithium is greatly enhanced if a mixture of
potassium tert-butoxide and n-butyllithium in THF is used: the n-butyllithium
behaves as a superbase. A similar enhancement of base strength in n-butyllith-
ium is observed when N, N'-tetramethylethylenediamine (TMEDA) is added to
the solution of the butyllithium. Suggest reasons why these effects are observed
in these two different cases.
NMe2
Me2N
TMEDA
11-20 The control of regiochemistry of reactions of allylic anions is often problematic.

The transformation shown is a tandem Michael addition-ring closure that in-
volves the sulfone anion as the initiating nucleophile. What does the fact that the
product shown is the only regioisomer of the product obtained, tell you about the
initiating nucleophile? [Pure Appl. Chem. 2000, 72, 1671.]
CO2Et O
O R S
S Br Ph O
Ph LDA/THF
O
R CO2Et

Chapter twelve
Organic Reactions III

Synthetic Reactions of Carbon Nucleophiles:
Substitution and Addition
12.1 Carbon-Carbon Bond Formation: Carbon

Nucleophiles and Electrophiles
Methods for the formation of carbon-carbon bonds are of pivotal importance in organic
synthesis. In Chapter 6, we discussed the formation of carbon-carbon bonds using pericy-
clic reactions, and in Chapter 10, we discussed C—C bond-forming reactions involving
carbocations as important intermediates. In this chapter, we will discuss the formation of
C—C bonds by means of reactions involving carbon nucleophiles. Between them, reac-
tions between a carbanion nucleophile and a carbon electrophile account for the vast ma-
jority of C—C bond-forming reactions in organic synthesis. These reactants can be
classified as strong or weak, as summarized in Table 12.1.
Combinations of these reagents give rise to a multitude of synthetic organic reactions,
as we have already seen for the reactions of carbocation electrophiles. It is important to
remember that reactions between strong nucleophiles and strong electrophiles are usually
precluded because the reaction conditions required to generate one of the reacting species
are almost always incompatible with the other. It is also quite unusual—but not i mpossible—
to find a productive reaction between a weak nucleophile and a weak electrophile. Such
reactions often have an impossibly high activation barrier to overcome. The one common
exception to this generalization involves cycloaddition reactions, especially of carbenes to
alkenes. We will discuss this reaction further in Chapter 13. By far the most common
bond-forming reactions of this type are between a strong nucleophile and a weak electro-
phile, or a weak nucleophile and a strong electrophile.
12.2 Substitution and Addition with Metal Alkyl

Reagents Having C—M 𝛔 Bonds
Since the 1970s, no area of organic synthesis has expanded as rapidly as the preparation and
use of organotransition metal compounds. These compounds now form the basis for a wide
range of catalytic reactions, and they have revolutionized the formation of carbon-carbon
bonds in compounds and the control of absolute configuration. Compounds of the Group
VIIIB (Groups 8–10) metals (Fe, Co, Ni, Pd, Pt, Ru, Rh, and Ir, in particular) have become
mainstays of modern organic synthesis. The preeminent position of these compounds in
modern synthesis may be gauged by noting that two Nobel prizes in chemistry have been
awarded to chemists who have developed methods for C—C bond formation using transi-
tion metal catalysts. This area is so important that we will devote Chapter 17 to a (too brief)
introductory discussion of these reactions.
In Chapter 11, we discussed the metal alkyls, which occur in two different classes
(Example 12.1): simple metal alkyls, where the alkyl nucleophile is bonded to a metal bear-
ing a formal positive charge, and “ate” complexes, where the alkyl group is attached to a
439

440 Advanced Organic Chemistry | Chapter twelve
Table 12.1 Classifying Carbon Nucleophiles and Carbon Electrophiles
Nucleophile Electrophile
Strong metal alkyl acylium ions

R M R M metal alkynide R C X nitrilium ions
M = Li, Mg, Zn, Cu, etc. X = O, NR
R R
oxonium ions
X iminium ions
R
stabilized carbanion R
G (including ylides)
R X = O, NR, S, etc.
G = SiR3, SR, SR2, PR3, etc.

alkyl cation
R R X Lewis acid complex
X R X = ClAlCl3, ClTiCl4, BrFeBr3, etc.

enolate anions and
equivalents
G R
X = O, S, NR, =N
G = R, OR, NR2, etc.
Medium strength X
β-dicarbonyl anions, etc. R X heteronium ions
Y
X = OR2, NR3, SR2, etc.
X, Y = CHO, COR, CO2R, CN, NO2, etc.
X cyclic heteronium ions

R
X = OH, NH2, NHR, SH, SR, Cl, Br, I etc.
Weak R R R X alkyl halide, sulfonate, etc.

alkenes, including
enol ethers, enamines, etc. X = halogen, OSO2R, etc.
X R
X = R, Ar, OSiR3, NR2, etc
X epoxides, aziridines, etc.
R
X X = O, NH, NR, S, etc.
Y arenes
X = OR, NR2, etc. R'

carbonyl compounds
Y = O, NR, S, etc. X R' C N imines, nitriles etc.
R
R' = alkyl, aryl, C=C, C≡C, OR, NR2, Cl, etc
X = O, NR, S, etc.
R'
carbenes
R

Organic Reactions III 441
metal bearing a formal negative charge. The “ate” complexes are usually prepared by the
addition of a metal alkyl of a group IA metal or group IIA metal to a metal alkyl of another
metal (e.g., aluminum, zinc, or copper).
R M R M R
(12.1)
metal "ate"
alkyl complex
As strong nucleophiles, simple metal alkyls will react with weak carbon electrophiles
to generate new carbon-carbon bonds. The types of reactions that these species enter into
depend to some degree on the hardness or softness of the nucleophile. Generally speaking,
more ionic (harder) nucleophiles are better for use in SN2 reactions with alkyl halides.
Alkali metal alkynides, cyanide anion, and lithium dialkylcuprates or trialkylzincates
react with alkyl halides with inversion of configuration, as do anions stabilized by hetero-
atoms, such as dithiane, α-silylalkyl, and sulfoxide α-anions. Depending on the carbon
nucleophile and its electrophilic partner, carbon-carbon σ bond formation in allylic sys-
tems can take place by simple SN2 (Example 12.2) or SN2' (Example 12.3) displacement of
the leaving group, with softer nucleophiles tending to favor the SN2' route. In general, nu-
cleophiles with more ionic character are preferred for SN2 substitutions, and nucleophiles
with less ionic character are preferred for addition to carbonyl groups. Carbanion nucleo-
philes also add to electrophilic π bonds, as in carbonyl compounds and their conjugated
analogues (Examples 12.4 to 12.8). As we saw in the Chapter 11, the more ionic the
metal-carbon bond, the greater the propensity of the metal alkyl to add in the 1,2- mode to
conjugated carbonyl compounds.
R' R" R'

R" (12.2)
R X R
R' X R'
R" R" (12.3)
R Y R Y
R' R'
R" (12.4)
R"
R X R X
R' X R' X
(12.5)
R Y R Y
R"
R"
R' X R' X
R" R" (12.6)
R Y R Y
R' X R' X
R" R" (12.7)
R Y R Y
X X
Y R" Y (12.8)
R"
R
R

Nucleophilicity and basicity tend to be complementary characteristics of metal alkyls, with

the result that it is often possible to modulate both forms of reactivity by judiciously choosing
the structural features of the compound. More ionic nucleophiles are harder bases and tend to
react more frequently as bases. The nucleophilicity of a metal alkyl is modulated by three fac-
tors: (1) the electronegativity of the metal, (2) the formal charge on the metal, and (3) the hy-
bridization of the carbon atom. The more electronegative (less electropositive) the metal, the
softer the nucleophile and the less basic the metal alkyl; the higher the formal negative charge
on the metal, the stronger the nucleophile and the more strongly basic the compound; and the
higher the s character of the hybrid orbitals on the carbon bonded to the metal, the more likely
the compound is to be ionic and the harder and more powerful the nucleophile.
Using Metal Alkyls as Bases

Group IA and IIA metal alkyls react with organic compounds with pKa values below about
30, especially alcohols, which limits the usefulness of these reagents in synthesis. However,
these metal alkyls generally do not deprotonate simple hydrocarbons other than alkynes. As
we discussed in Chapter 11, there is a clear-cut division of reactivity among alkali metal
alkyls because alkyllithiums are aggregates of a polar covalent species, the metal alkyls of the
higher alkali metals are effectively ionic salts with a free carbanion.1 The reactivity of alkyl-
lithiums can be modulated by additives and by changing the structure of the alkyl groups. If
we assume n-butyllithium as the standard, we find that branching the alkyl group increases
the tendency of the alkyllithium to act as a base. This is probably due, in part, to steric hin-
drance preventing the close approach required for it to act as a nucleophile and to the inher-
ent increase in base strength with branching. Likewise, adding ligands that can disrupt the
aggregation state of the alkyllithium also increases its tendency to act as a base. N,N,N',N'-
tetramethylethylenediamine (TMEDA; Example 12.9) is very widely used for this purpose.2
NMe2
(12.9)
NMe2
Alkylsodium or alkylpotassium reagents react with alkenes only by proton abstraction
or hydrogen-metal exchange to give the allylmetal products.3 Butylpotassium deproton-
ates alkenes at allyl and vinyl positions at the same time.4 Branched alkyllithium reagents
such as sec- and tert-butyl-lithium add to unactivated alkenes such as propene.5 Depro-
tonation as the sole reaction also occurs with the 1:1 mixture of butyllithium and potas-
sium tert-butoxide, a reagent known as Schlosser’s reagent6 or “LICKOR,” which metallates
alkenes preferentially at the allylic position, before deprotonating at an available vinyl
1. Leading references: (a) Finnegan, R.A. Tetrahedron Lett. 1963, 429. (b) Schade, C.; Bauer, W.; Schleyer,
P.v.R. J. Organomet. Chem. 1985, 295, C25. (c) Pi, R.; Bauer, W.; Brix, B.; Schade, C.; Schleyer, P.v.R. J. Or-
ganomet. Chem. 1986, 306, C1.
2. (a) Eberhardt, G.G.; Butte, W.A. J. Org. Chem. 1964, 29, 2928. (b) Klein, J.; Medlik, A. J. Chem. Soc., Chem.
Commun. 1973, 275. (c) Akiyama, S.; Hooz, J. Tetrahedron Lett. 1973, 4115. (d) Bates, R.B.; Beavers, W.A. J. Am.
Chem. Soc. 1974, 96, 5001.
3. Reviews: (a) Schlosser, M. Angew. Chem. 1964, 76, 124, 258; Angew. Chem. Int. Ed. Engl. 1964, 3, 287, 362.
(b) Ebel, H.F. in Müller, E., Ed. Houben WeyI : Methoden der organischen Chemie (G. Thieme Verlag: Stuttgart
1970); vol. 13/1, 261. (c) Schlosser, M.; Struktur und Reaktivität polarer OrganometalIe (Springer Verlag: Berlin,
1973). (d) Schlosser, M. Mod. Synth. Methods 1992, 6, 227. (e) Schlosser, M.; Faigl, F.; Franzini, L.; Geneste, H.;
Katsoulos, G.; Zhong, G. Pure Appl. Chem. 1994, 66, 1439.
4. (a) Broaddus, C.D.; Logan, T.J.; Flautt, T.J. J. Org. Chem. 1963, 28, 1174. (b) Broaddus, C.D. J. Org. Chem.
1964, 29, 2689.
5. Bartlett, P.D.; Friedman, S.; Stiles, M. J. Am. Chem. Soc. 1953, 75, 1771.
6. (a) Schlosser, M. J. Organomet. Chem. 1967, 8, 9. (b) Schlosser, M.; Hartmann, J. Angew. Chem. 1973, 85,
544; Angew. Chem. Int. Ed. Engl. 1973, 92, 439; Angew. Chem. 1974, 86, 751; Angew. Chem. Int. Ed. Engl. 1974,
13, 701. (c) Schlosser, M. Pure Appl. Chem. 1988, 60, 1627.

position. Despite the presence of both metals (lithium and potassium), the metal alkyl
product contains not lithium, but potassium.7 This has been interpreted as support for the
view of the reagent as the complex 12.10.
Pr
CH2 K
(12.10)
Li O
The allylmetal compounds obtained in this way are powerful nucleophiles in SN2 reac-
tions and can be alkylated to give new carbon-carbon bonds. Schlosser has reported a
strong stereochemical bias in the allylpotassium products of “LICKOR” deprotonation of
alkenes: the deprotonation to give the endo metal alkyl (Example 12.11) is favored over the
exo metal alkyl (Example 12.12) by at least 15:1—and more often by a much higher ratio.
R
(12.11)
R 50
LICKOR
R
(12.12)
Alkylation with Metal Alkyls

Alkali Metal Alkyls and Alkynides
The Schlosser allylmetals and the metal alkynides are basically ionic nucleophiles that
participate readily in nucleophilic displacement reactions. For example, trapping the
Schlosser allyl-metal nucleophile from 2-methyl-2-butene with an alkyl halide gives a tri-
substituted alkene with well-defined stereochemistry (Example 12.13).8 The usefulness of
these anionic nucleophiles is illustrated by Examples 12.14 and 12.15.
9
1) LICKOR, THF, –75°C (12.13)
2)
Br (64% overall)
1) LICKOR, –78°C
2) X (CH2)n OTHP (CH2)nOTHP
(12.14)10
X=Br, n=3; 62%
X=I, n=4; 74%
X=I, n=5; 76%
Me 1) LICKOR, hexane, 25°C

2) MeI, –75°C
3) LICKOR, hexane, 25°C
CO2H (12.15)11
4) Me2CHBr, –25°C
5) LICKOR, hexane, 60°C
Me 6) CO2 (52% overall; 1 pot)
7. Boche, G.; Etzrodt, H. Tetrahedron Lett. 1983, 24, 5477.

8. Review: Schlosser, M.; Desponds, O.; Lehman, R.; Moret, E.; Rauchschwalbe, G. Tetrahedron 1993, 49, 10175.
9. Schlosser, M.; Zhong, G.-f. Tetrahedron Lett. 1993, 34, 5441.
10. Revell, J.D.; Ganesan, A. J. Org. Chem. 2002, 67, 6250.
11. Faigl, F.; Schlosser, M. Tetrahedron Lett. 1991, 32, 3369.

In contrast to the higher alkali metal alkyls, lithium and magnesium alkyls do not
react well with alkyl halides and sulfonates unless the halide is allylic or benzylic, al-
though vinyllithium reagents (where the carbon is now sp2 hybridized) will react with
primary alkyl iodides, as shown in Example 12.16.12
t-BuLi CH3(CH2)7I
Li (12.16)
O THF, –40°C O Me(CH2)7 O
The alkyne carbon atom is sp-hybridized, and terminal alkynes are easily deproton-
ated by metal hydrides or alkyls to give the metal alkynide (Example 12.17). Alkali metal
alkynides react essentially as free carbanion nucleophiles with a wide range of electro-
philic partners, including alkyl halides, alkyl sulfonates, epoxides, and carbonyl com-
pounds. With alkyl halides, the reaction is restricted to primary halides (preferably
bromides) that are not branched at the β carbon (i.e., RCH2CH2X).13 This restriction may
be traced to the fact that the alkynide anion is still a strong base and that there is compet-
ing E2 elimination. It is interesting that the use of allyl halides leads to the formation of
compounds consistent with polyalkylation. In nucleophilic substitution reactions,
alkynide anions react by the SN2 mechanism.
M
H KH, THF; or
NaNH2, NH3; or
(12.17)
RLi, THF; or
R RMgX, Et2O R
Electrophiles with functional groups containing oxygen atoms capable of functioning as
ligands for a metal ion will react well with metal alkyls derived from lithium and magnesium.
In these reactions, there is evidence that the oxygen atom of the functional group displaces a
molecule of solvent to form a complex with the metal ion that serves both to increase the
electrophilicity of the carbon and to anchor the nucleophile in a position conducive to group
transfer (e.g., Example 12.18). Thus, although alkyl halides and sulfonates do not react well
with alkyllithiums and Grignard reagents, carbonyl compounds and epoxides do.
R R
M M M M
R1 O O R R
R1 R1 O R1 O
R R R R
R R R R
(12.18)
The reactions between an epoxide and alkylmetal nucleophiles give the products of
anti ring opening with the metal alkyl attacking the less substituted carbon. The reaction
may therefore be considered as an SN2 epoxide ring opening. In certain cases (e.g., Exam-
ple 12.19) the reaction is facilitated by the addition of a Lewis acid other than the alkyllith-
ium to complex the epoxide oxygen.
OH
H MeO Li, THF NBn2
O NBn2 (12.19)14
BF3•Et2O, –78°C
(69%)
OMe
12. Hedenström, E.; Högberg, H.-E. Tetrahedron 1994, 50, 5225.

13. Jacobs, T.L. Org. React. 1949, 5, 1.
14. Mena, M.; Valls, N.; Borregán, M.; Bonjoch, J. Tetrahedron 2006, 62, 9166.

Worked Problems
12-1 Trapping of an alkylpotassium reagent with a borate ester provides a useful entry
into boronic acids that can be oxidized to alcohols. What is the major product of
the reaction below? Provide a rationalization of the stereochemistry.
1) LICKOR, THF, –78°C

2) FB(OMe)2•OEt2
3) H2O2
(46%)
§Answer below.
12-2 What is (are) the major product(s) of the following reaction sequence?
1) LICKOR
SiMe3
2) n-C8H17I
§§Answer below.
Drill Problems
What are the products of the treatment of the compounds in list A with each of
the reagents in list B?
List A:
(1) (2) (3) (4)

H
List B:
(i) t-BuLi, THF-HMPA, –78°C
(ii) KAPA, H2N(CH2)3NH2
1) LICKOR, THF, –78°C

2) FB(OMe)2•OEt2
HO
3) H2O2
(46%)
The deprotonation of this alkene occurs to give mainly the endo allylpotassium reagent. Trapping of this
reagent with the boronic acid fluoride gives the Z borane that reacts with hydrogen peroxide to give the alcohol.
[Tetrahedron Lett 1993, 34, 5441] The second step is identical to the oxidation step of the hydroboration-
oxidation reaction and proceeds with retention of configuration at carbon.
§§ Answer to Worked Problem:
1) LICKOR SiMe3
SiMe3 C8H17 SiMe3 +
2) n-C8H17I C8H17
86 : 14
The deprotonation of the alkene gives an allylpotassium reagent that reacts preferentially through the less
substituted end of the anion. [Tetrahedron Lett. 1984, 25, 717]

(iii) KOBut, THF

(iv) (1) LICKOR, hexane, –70°C; (2) EtI, THF, –70°C
(v) (1) LICKOR, hexane, –70°C; (2) S-2-iodobutane, THF, –70°C
Reaction Synopses
Deprotonation of Hydrocarbons
R'M
R H R' H
Reagents:
RH = alkyne: NaNH2, NH3; LDA, THF; RMgX, Et2O; RLi, THF; etc.
RH = alkene: t-BuLi, TMEDA; n-BuLi, KOBut, –78°C; etc.
Alkenes deprotonated at allylic position if hydrocarbon only; deprotonated
adjacent to heteroatom in vinyl ethers, sulfides
Alkylation with Metal Alkyls
R'X
R M R R'
Reagents: RM, Et2O or THF, R'X (R' must be 1° or 2°)

Mechanism: SN2 (M = Na, K), or SN2' (M = Cu)
Stereochemistry: usually inversion at carbon; stereochemistry at carbanion
carbon may not be retained
M = Na, K: X = OTs, Cl, Br, I; etc.
M = Li: X = OTs, epoxide; Br, I (R = vinyl, aryl); etc.
M = Mg: X = epoxide, etc.
M = Zn, Cu: X = OTs, Br, I, etc.
Problem
12-1 What is the major organic product in each of the following reactions or reaction
sequences?
OTIPS
1) t-BuLi, THF-HMPA, –78°C
SS
(a) O
O O
OMe PMB H O O
H
2)
I
O
SiEt2iPr
1) s-BuLi, TMEDA, THF, 0°C

(b)
TIPSO O Br
2) Br
(excess)
(Why is the order of addition of reagents—what is added to what and when—

important in this reaction?)
OTBS 1) Cs2CO3, NaI, CuI, DMF

(c)
2) CO2Me
Br
References: (a) J. Am. Chem. Soc. 2003, 125, 350. (b) J. Am. Chem. Soc. 1996, 118, 3299. (c) Tetrahedron
2003, 59, 7787.

Addition to Carbonyl Compounds Table 12.2 Addition Products with Carbonyl Compounds
Carbonyl and similar electrophiles react with most simple O
R R'M
metal alkyls by addition. Recall, however—alkylsodium and
X
alkylpotassium reagents derived from saturated alkyl halides X Product X Product
are such strong bases that competing deprotonation becomes
the dominant reaction. For this reason, they are generally in- R" R"
ferior to the corresponding lithium reagents. A similar situa- H H OH OR" R" OH
R R
tion often occurs in the reactions of ketones with strongly
basic nucleophiles such as simple (unstabilized) phos- R" R'
phoranes, where acid-base reactions often occur to give
15 R" R" OH NR"2 O
R R
competing or concomitant epimerization at the α carbon,
especially when the phosphorane is generated in dimethyl R" R'
Cl R" OH MeON O
sulfoxide (DMSO).16 R Me R
The course of the reaction between saturated carbonyl
compounds and organolithium compounds or Grignard
reagents (Table 12.2) is generally straightforward. Aldehydes and ketones give alcohols;
esters and more reactive carboxylic acid derivatives give tertiary alcohols carrying two
identical alkyl groups by an addition-elimination-addition sequence; and amides and ni-
triles give ketones (the adduct of the amide cannot eliminate a leaving group, so only one
addition step occurs). Weinreb amides,17 in particular, have been popular species for the
formation of ketones from acyl derivatives (e.g., 2-acyloxy-4,6-dimethoxy-1,3,5-triazines,
as in Example 12.20).
OMe
N
1) Cl N , NMM, THF
CO2H N
OMe 17
O (12.20)
N 2) MeNHOMe•HCl
Cbz N
3) EtMgBr, THF Cbz
(67%)
Conjugation of the carbonyl group adds a regiochemical component to the nucleop-
hilic addition reaction with metal alkyls, as summarized in Table 12.3, with the result that
one can prepare compounds by 1,2-addition or 1,4-addition to the conjugated system by
choosing the nucleophilic and electrophilic species appropriately. In general, conjugated
aldehydes and acid chlorides react with nucleophiles by the 1,2-addition pathway, whereas
conjugated esters and amides usually react preferentially by the 1,4-addition pathway (es-
pecially if the nucleophile can add reversibly). In contrast, conjugated ketones may react
by either pathway or both. Conjugate addition of carbon nucleophiles to nitriles has long
been known as a more difficult task than conjugate additions to other carboxylic acid de-
rivatives, with the result that this methodology is rather less developed than additions to
conjugated carbonyl compounds.18 In additions to conjugated carbonyl systems, harder
nucleophiles such as alkyllithium reagents or alkali metal alkynides tend to react with
1,2- regiochemistry. In general, additions to carbonyl groups are best carried out using
nucleophiles of intermediate hardness, and conjugate additions are favored by soft nucle-
ophiles. Alkyllithiums and alkali metal alkynides usually give 1,2-addition to conjugated
carbonyl compounds, Grignard reagents tend to give a mixture of 1,2- and 1,4-addition
15. Adlerkreutz, P.; Magnusson, G. Acta Chem. Scand. B 1980, 34, 647.
16. Early examples: (a) Soffer, M.D.; Burk, L.A. Tetrahedron Lett. 1971, 211. (b) Marshall, J.A.; Pike, M.T.;
Carroll, R.D. J. Org. Chem. 1966, 31, 2933. (c) Heathcock, C.H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 73, 1746.
17. Nahm, S.; Weinreb, S.M. Tetrahedron Lett. 1981, 22, 3815.
18. Fleming, F.F.; Wang, Q. Chem. Rev. 2003, 103, 2035.

Table 12.3 Products of Nucleophilic Addition to products, and organocuprates and organozincates give exclusive
Conjugated Carbonyl Compounds 1,4-addition. Thus, as the metal-carbon bond becomes more co-
valent (i.e., the nucleophile becomes softer), the proportion of
R' O O HO R'
R'M R'M conjugate addition rises. In a recent report, Knochel has shown
R R R R R R
that the lanthanide-lithium chloride complex LnCl3•2LiCl can
R R R
dramatically improve the yield of 1,2-additions of Grignard re-
agents to conjugated, hindered, and readily enolizable ketones,
R'M (1:4) R'M (1:2)
while at the same time suppressing reduction of the ketone by
RLi the Grignard reagent.19
RC ≡ CM
Alkylcopper, Alkylzinc, and Alkylaluminum Reagents
RMgX RMgX Although copper and zinc are transition metals, their organo-
R 2CuLi, etc. metallic compounds tend to react more like those of the main
group metals. The neutral organometallic derivatives of copper,
R 3ZnLi, etc. R 2Zn
zinc, and aluminum are usually non-nucleophilic or modest nu-
cleophiles that can be induced to react with carbonyl compounds
but that do not react with alkyl halides. Dialkylzinc reagents, for example, will add to acid
chlorides, aldehydes, and ketones to give alcohols, as will alkylzinc halides.20 However,
these reagents will not attack carbon dioxide or conjugated ketones, and the reactions of
dialkylzinc reagents where the alkyl group is larger than ethyl often lead to reduction
rather than addition in their reactions with ketones (see Example 12.21).
(RCH2)2Zn OH
R R
O (R=H, Me)
R'
(12.21)
R' Cl (RCH2)2Zn OH
R
(R=Pr, Bu...)
R'
Zinc holds a central place in the history of organic synthesis, because dialkylzinc re-
agents were the first simple organometallic compounds prepared21 (although Bunsen’s
“cacodyl,” Me2As—AsMe2,22 was the first organometallic compound prepared if one in-
cludes the metalloids). The first general syntheses of secondary and tertiary alcohols were
accomplished by the addition of alkylzinc nucleophiles to acid chlorides and aldehydes,
and the first synthesis of a carboxylic acid was accomplished by carbonation of sodium
triethylzincate (mistaken at the time for ethylsodium) with carbon dioxide. This reaction
also nicely illustrates the difference in reactivity between a metal alkyl and an ate complex:
the additions of dialkylzinc or alkylzinc halides to aldehydes and acid chlorides can, in
fact, be carried out under carbon dioxide as an inert atmosphere.
The pioneering work of Noyori in the 1990s showed that additions of dialkylzinc re-
agents to aldehydes are catalyzed by (especially chiral) β-aminoalcohol ligands;23 this work
resurrected the importance of organozinc nucleophiles. From this early work, it became
apparent that the nucleophilicity of the alkylzinc reagent is highly dependent on the hy-
bridization of zinc. Simple dialkylzinc reagents, where the zinc atom is sp hybridized, are
relatively poor nucleophiles that require quite reactive electrophilic partners (e.g., acid
19. Krasovskiy, A.; Kopp, F.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 497.
20. These reactions of organozinc nucleophiles are of long standing: (a) Butlerow, A. Bull. Soc. Chim. Paris 1863,
5, 582; 1864, 2, 106.; Jahresb. 1863, 475; 1864, 496; Ann. Chem. Pharm. 1867, 144, 132. (b) Saytzeff, A. Ann. Chem.
Pharm. 1875, 175, 351, 374; 1877, 185, 148, 151, 175;. J. prakt. Chem. 1885, 31, 319. (c) Vagner, E.E. Zh. Russ. Khim.
Obshch. Fiz. Obshch. 1876, 8, 290, Zh. Russ. Fiz.-Khim. Obshch. 1884, 16, 283. (d) Wagner, G. Ann. Chem. Pharm.
1875, 175, 351; 179, 302, 313; Ber. dtsch. chem. Ges. 1894, 27, 2436.
21. Frankland, E. Quart. J. Chem. Soc. 1850, 2, 297.
22. Bunsen, R.W. Ann. Pharm. 1839, 31, 175;. 1841, 37, 1; 1842, 42, 14; 1843, 46, 1.
23. Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M.; Oguni, N.; Hayashi, M.; Kaneko, T.; Matsuda, Y.
J. Organomet. Chem. 1990, 382, 19.

chlorides) for the reaction to occur. However, when the zinc atom is complexed by a hard
donor ligand, the hybridization of zinc changes, and the p character of the orbitals in-
creases; the resultant dialkylzinc complexes are much stronger nucleophiles. These obser-
vations have led to a resurgence of organozinc chemistry, as illustrated by the number of
review articles in this area since 1990.24
One of the earliest generally useful reaction of organozinc nucleophiles is the Refor-
matsky (Reformatskii) reaction (Example 12.22),25 discovered in 1887.26 In this reaction, an
α-halocarbonyl compound (originally an α-haloester) reacts with zinc to give an organoz-
inc halide, and this then adds to the carbonyl group of an aldehyde or ketone to give a
β-hydroxycarbonyl product. What is important about the reaction is that it allows the
construction of highly hindered β-hydroxycarbonyl compounds, which can be difficult to
obtain by other methods. The crystal structures of two Reformatsky reagents (Figure 12.1)
show that the zinc atom is approximately sp3 hybridized, with the carbonyl oxygen of the
ester and an oxygen atom from solvent coordinated to the metal.27 In the two examples
shown, the reagent is dimeric with an eight-membered ring that adopts either a chairlike
(12.23) or tublike (12.24) conformation.
CO2Et CO2Et
Zn/Me2CO
(12.22)
Br
HO
Figure 12.1 Crystal
conformations (structures)
of two Reformatskii reagents
24. Selected reviews: (a) Noyori, R.; Kitamura, M. Angew. Chem. Int. Ed. 1991, 30, 49. (b) Soai, K.; Niwa, S.
Chem. Rev. 1992, 92, 833. (c) Knochel, P.; Singer, R.D. Chem. Rev. 1993, 93, 2117. (d) Knochel, P.; Jones, P., Eds.,
Organozinc Reagents: A Practical Approach, (Oxford University Press: Oxford,1999). (e) Knochel, P.; Vettel, S.;
Eisenberg, C. Appl. Organomet. Chem. 1995, 9, 175. (f) Knochel, P.; Almena, J.; Jones, P. Tetrahedron 1998, 54,
8275. (g) Erdik, E. Organozinc Reagents in Organic Synthesis (CRC Press: Boca Raton, FL, 1996). (h) Soai, K.
Enantiomer 1999, 4, 591. (i) Frantz, D.E.; Faessler, R.; Tomooka, C.S.; Carreira, E.M. Acc. Chem. Res. 2000, 33,
373. (j) Boudier, A.; Bromm, L.O.; Lotz, M.; Knochel, P. Angew. Chem. Int. Ed. 2000, 39, 4414. (k) Pu, L.; Yu,
H.-B. Chem. Rev. 2001, 101, 757. (l) Knochel, P.; Millot, N.; Rodriguez, A.L.; Tucker, C.A. Org. React. 2001, 58,
417. (m) Knochel, P. Science of Synthesis (Georg Thieme Verlag: Stuttgart, 2004), 3, 5.
25. Reviews: (a) Shriner, R.L. Org. React. 1942, 1, 1. (b) Diaper, D.G.M.; Kukis, A. Chem. Rev. 1959, 59, 89.
(c) Rathke, M.W. Org. React. 1975, 22, 423. (d) Ocampo, R.; Dolbier, W.R., Jr. Tetrahedron 2004, 60, 9325.
26. Reformatsky, S. Ber. dtsch. chem. Ges. 1887, 20, 1210.
Sergei Nikolaevich Reformatskii (1860–1934) graduated from the Kostroma Spiritual Seminary, then stud-
ied under Zaitsev at Kazan University (Dr Chem, 1890, Warsaw). After a year of study under Meyer and Ost-
wald, he returned to Russia in 1891 and was appointed Professor of Chemistry at the Kiev University, a post he
held until his retirement. For more information, see: Lewis, D.E. Early Russian Organic Chemists and Their
Legacy (Springer: Heidelberg, 2012), p. 101.
27. (a) Dekker, J.; Budzelaar, P.H.M.; Boersma, J.; Van der Kerk, G.; Spek, A. J. Organometallics 1984, 9, 1403.
(b) Miki, S.; Nakamoto, K.; Kawakami, J.; Handa, S.; Nuwa, S. Synthesis 2008, 409.

Alkylcopper reagents are generally unreactive toward electrophiles, but when coupled
with boron trifluoride, they will add to enones to give products of conjugate addition, as
shown by a key step (Example 12.25) of an early total synthesis of the interesting sesqui
terpene modhephene.28 The active reagent is not known, but it may be formed by transfer
of the alkyl group from copper to boron to give a copper (I) alkyltrifluoroborate.
O O
MeCu•BF3
(12.25)
With “Ate” Complexes

The lack of success when most simple metal alkyls are treated with alkyl halides and
sulfonates contrasts starkly with the success in the substitution reactions when “ate”
complexes are used as the nucleophiles. Recall that an “ate” complex is an anionic
complex of a transition metal alkyl in which the metal atom is coordinated to one or
more alkyl groups more than the neutral metal alkyl.29 This is most commonly accom-
plished by treating the metal alkyl with an alkyllithium or Grignard reagent (e.g.,
E xample 12.26). Converting the simple metal alkyls of copper, zinc and aluminum into
anionic “ate” complexes transforms them into much stronger nucleophiles that can
displace the halide anion from primary and secondary halides (e.g., Examples 12.27
and 12.28).
RCu + RLi R2CuLi
R2Zn + RLi R3ZnLi (12.26)
R3Al + RLi R4AlLi
Br
[t-BuCuSPh]Li
30
(12.27)
N THF, –18°C
N
Boc CO2But (54%)
Boc CO2But
MeO2C
AlMe3 Li
MeO2C OTf (12.28)

31
TBSO hexane, –40°C TBSO

(51%)
Nucleophilic Substitution with Cuprates

The discovery of cuprate complexes (also known as Gilman reagents) provided the or-
ganic chemist with a particularly useful and versatile nucleophile for use in organic
28. Karpf, M.; Dreiding, A.S. Tetrahedron Lett. 1980, 21, 4569.
29. (a) Wittig, G. Quart. Rev. 1966, 191. (b) Tochtermann, W. Angew. Chem., Int. Ed. Engl. 1966, 5, 351.
30. Koskinen, A.M.P.; Helaja, J.; Kumpulainen, E.T.T.; Koivisto, J.; Mansikkamäki, H.; Rissanen, K. J. Org.
Chem. 2005, 70, 6447.
31. Hoye, T.R.; Tennakoon, M.A. M.A. Org. Lett. 2002, 2, 1481.

synthesis.32 Their impact on the development of modern synthesis may be gauged by the
fact that among the four Organic Reactions reviews published between 1971 and 1992,
more than 2200 references are cited.33 A more recent review shows the continuing
versatility of these reagents in controlling both regiochemistry and stereochemistry of
the product.34
It was observed fairly early on that when homoleptic Gilman reagents (i.e., Gilman
reagents where both the alkyl groups bound to copper are identical, such as Example 12.29)
react with electrophiles, only one of the two alkyl groups is transferred from copper to
carbon. Thus, when working with cuprate reagents, especially if the ligand to be trans-
ferred is costly or complex, it is frequently desirable to use a heteroleptic reagent that
contains a “non-transferring” ligand (designated by “L” in Example 12.30). Typical
non-transferring ligands are alkynide anions, cyanide anion, and thiolate anions, all of
which form exceptionally strong bonds to copper.35
R Cu R L Cu R
Li Li Li Li
R Cu R R Cu L
homoleptic heteroleptic
(12.29) (12.30)
Although the stereochemical result of these reactions is inversion of configuration, the
mechanism is more complex than a simple SN2 displacement.36 After more than a decade
of debate about a possible Cu (III) intermediate,37 1H nuclear magnetic resonance evidence
revealing the presence of a Cu(III) complex during an alkylation settled the question in
2007.38 A very simplified mechanistic model is shown as Example 12.31.
R Li R R S
R' X
CuI CuI R' CuIII X Li
solvent
(S) S S
R Li R R S
(12.31)
R R' + R CuI + LiX

Just as the reactivity of alkylcopper reagents can be modified by the addition of
Lewis acids to the reagent, so we find that cuprates become more useful nucleophiles
32. Monograph: Posner, G.H. An Introduction to Synthesis Using Organocopper Reagents (Wiley-Interscience:
New York, 1980).
33. (a) Posner, G.H. Org. React. 1971, 19, 1; 1975, 22, 253. (b) Chapdelaine, M.J.; Hulce, M. Org. React. 1990,
38, 225. (c) Lipshutz, B.H.; Sengupta, S. Org. React. 1992, 41, 135.
34. Breit, B.; Schmidt, Y. Chem. Rev. 2008, 108, 2928.
35. (a) Corey, E.J.; Beames, D.J. J. Am. Chem. Soc. 1972, 94, 7210 and references therein. (b) Mandeville, W.H.;
Whitesides, G.M. J. Org. Chem. 1974, 39, 400.
36. Review: Yoshikai, N.; Nakamura, E. Chem. Rev. 2012, 112, 2339.
37. (a) Dorigo, A.E.; Wanner, J.; Schleyer, P.v.R. Angew. Chem. Int. Ed. Engl. 1995, 34, 476. (b) Snyder, J.P. J.
Am. Chem. Soc. 1995, 117, 11025. (c) Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc. 1998, 120, 8273.
(d) Nakamura, E.; Mori, S. Angew. Chem. Int. Ed. 2000, 39, 3751. (e) Mori, S.; Hirai, A.; Nakamura, M.;
Nakamura, E. Tetrahedron 2000, 56, 2805. (f) Mori, S.; Nakamura, E. Tetrahedron Lett. 1999, 40, 5319.
(g) Nakamura, E.; Yamanaka, M.; Yoshikai, N.; Mori, S. Angew. Chem. Int. Ed. 2001, 40, 1935. (h) James. P.F.;
O'Hair, R.A. J. Org. Lett. 2004, 6, 2761.
38. (a) Gärtner, T.; Henze, W.; Gschwind, R.M. J. Am. Chem. Soc. 2007, 129, 11362. (b) Bertz, S.H.; Cope, S.;
Murphy, M.; Taylor, B.J. J. Am. Chem.Soc. 2007, 129, 7208. (c) Hu, H.; Snyder, J.P. J. Am. Chem. Soc. 2007,
129, 7210.

when complexed with Lewis acids such as boron trifluoride. Thus, lithium or magnesium
dialkylcuprates complexed with boron trifluoride are very useful nucleophiles for carrying
out SN2' displacements of allylic halides and acetates (e.g., Example 12.32).39
Br
Me2CuLi Me2CuLi
BF3
Ph Ph Ph Ph
only 30 : 70
(12.32)
Since 1984, when Lipshutz reported the synthesis and applications of what he termed
“higher order” cuprate reagents from copper (I) cyanide,40 the use of Lipshutz cuprates has
been widespread. These Lipshutz cuprates are characterized by greater reactivity than the
simple Gilman reagents, and the origins of this reactivity sparked a long polemical debate
in the literature, as discussed in Chapter 11. From the viewpoint of using them in organic
synthesis, the fact that these reagents are more reactive nucleophiles than the simple
Gilman cuprates, makes them useful in displacements of bromides or secondary alkyl
iodides, as well as ring opening of epoxides and aziridines. The reactions of Lipshutz cu-
prates with bromides and epoxides proceed with inversion of configuration, whereas the
reactions with alkyl iodides proceed with almost complete racemization. These results are
consistent with free radicals being involved in the reactions with secondary alkyl iodides.41
A study of reactions of Lipshutz cuprates with vinylaziridines, where both the SN2 and SN2'
pathways are available (e.g., Example 12.33), revealed a strong preference for the SN2'
pathway.42
Bu2Cu(CN)Li2
(12.33)
THF, –78°C to r.t.
N Ts
81%; SN2':SN2 19:1
NHTs
E:Z 13.7:1
The reactions of organocuprate nucleophiles with vinyl halides constitute a useful
method for the formation of carbon-carbon σ bonds. The reaction with vinyl iodides and
bromides proceeds with retention of configuration, as illustrated by the formation of
Z-1-phenylpropene from Z-2-bromo-1-phenylethene (Example 12.34).43
Br Me
Me2CuLi
(12.34)
Et2O
39. Maruyama, K.; Yamamoto, Y. J. Am. Chem. Soc. 1977, 99, 8068.
40. (a) Lipshutz, B.H.; Wilhelm, R.S.; Kozlowski, J.A.; Parker, D. J. Org. Chem. 1984, 49, 3928. (b) Lipshutz,
B.H.; Wilhelm, R.S.; Kozlowski, J.A. J. Org. Chem. 1984, 49, 3938. (c) Lipshutz, B.H.; Kozlowski, J.A.; Wilhelm,
R.S. J. Org. Chem. 1984, 49, 3943.
41. Ashby, E.C.; DePriest, R.N.; Tuncay, A.; Srivastava, S. Tetrahedron Lett. 1982, 23, 5251.
42. Cunha, R.L.O.R.; Diego, D.G.; Simonelli, F.; Comasseto, J.V. Tetrahedron Lett. 2005, 46, 2539.
43. Corey, E.J.; Posner, G.H. J. Am. Chem. Soc. 1967, 89, 3911.

Conjugate Addition with Cuprates

Gilman reagents do not add to ketone or ester carbonyl groups but do add to reactive
carbonyl compounds such as acid chlorides44 and thioesters,45 with which they give
the saturated ketone as the major product (e.g., Example 12.35, from the synthesis of
myodesmone46).
O O
O i-Bu2CuLi O
(12.35)
SMe
In contrast to their lack of reactivity toward most saturated carbonyl compounds by

the 1,2-addition mode, Gilman reagents do react with conjugated carbonyl compounds to
give 1,4-addition products, although the reaction is susceptible to steric effects and tends
to be sluggish when the β carbon is disubstituted. In fact, copper is one of the few elements
whose metal alkyls consistently add in the 1,4-mode to conjugated carbonyl compounds.
However, its toxicity has proved to be a major stumbling block to its use in industrial ap-
plications. For this reason, considerable effort has been expended in developing reactions
based on less toxic organometallic compounds, such as organozinc compounds, and using
copper in catalytic amounts. The success of these reactions depends on copper’s propen-
sity to undergo metal-metal exchange (transmetallation) reactions with metal alkyls of
less electronegative metals (e.g., zirconium and zinc, as in Example 12.36.47).
H 1) Et2Zn O
2) 4CuI•3Me2S Me
ZrCpCl (12.36)
O
H Me
(67%)
The competition between conjugate addition and substitution in thioesters is nicely
illustrated by Example 12.37. In the starting thioester, where the β position is monosubsti-
tuted, the propensity for alkylcuprate reagents is still for 1,4-addition to dominate, as
shown by the copper-catalyzed addition of methylmagnesium bromide to the unsaturated
thioester. This reaction gives the product of conjugate addition rather than the product of
addition to the carbonyl group.48 It is interesting to note that the reaction of simple Gilman
reagents with saturated thioesters is economical—both alkyl groups bound to copper are
actually transferred to the electrophile, in contrast to the general observation with these
reagents.
O O
SEt MeMgBr, CuBr•SMe2 SEt

(12.37)
MeO (S,R)-Josiphos MeO
(93%)
TBDPSO TBDPSO
44. (a) Jallabert, C.; Luong-Thi, N.T.; Rivière, H. Bull. Soc. Chim. Fr. 1970, 797. (b) Posner, G.H.; Whitten,
C.E. Tetrahedron Lett. 1970, 4647. (c) Luong-Thi, N.T.; Rivière, H.; Bégué, J.-P.; Forestier, C. Tetrahedron Lett.
1971, 2113. (d) Posner, G.H.; Whitten, C.E.; McFarland, P.E. J. Amer. Chem. Soc. 1972 94, 5106.
45. Anderson, R.J.; Henrick, C.A.; Rosenblum, L.D. J. Am. Chem. Soc. 1974, 96, 36543.
46. Dieter, R.K.; Dieter, J.W. Chem. Commun. 1983, 1378.
47. El-Batta, A.; Bergdahl, M. Tetrahedron Lett. 2007, 48, 1761.
48. Vintonyak, V.V.; Maier, M.E. Org. Lett. 2008, 10, 1239.

Organozinc Reagents with Catalytic Copper

Diethylzinc does not react with cyclohexenone in hydrocarbon solvents. However, Noyori
and his coworkers discovered that (1) the combination of diethylzinc and a copper salt did
accelerate the reaction, and that (2) the addition of N-benzylbenzenesulfonamide (using
only 0.01 mol % Cu and 0.03 mol % sulfonamide; Example 12.38) dramatically accelerated
the conjugate addition. They also found that this provided a useful entry into zinc enolates
that could be trapped further by electrophiles such as π-allylpalladium species and
carbonyl compounds.49 Recently, it has been shown that the zinc enolates formed by
copper-catalyzed conjugate addition of dialkylzinc reagents to enones can be allylated to
give the trans dialkylated product by means of a diiron nonacarbonyltriphenylphosphine
catalyst, as shown in Example 12.39.50
O
O EtZnO n
Et2Zn, CuX (12.38)

PhCH2NHSO2Ph O HO
n n
R
O 1) Me2Zn (1.2 eq), CuTC (0.01 eq) O

chiral ligand (0.01 eq)
MTBE, 0°C, 3h (12.39)
2) H2C-CHCH2OAc (1.5 eq)
Fe2(CO)9 (0.1 eq), Ph3P (0.1 eq)
r.t. 4h
(80%)
As with alkylation reactions, Lipshutz cuprates perform much better in conjugate ad-
ditions to enones that do not react with simple cuprate reagents.51 There is both experi-
mental52 and computational53 evidence that the rate determining step of the conjugate
addition is the last step of the reaction: C—C bond formation by reductive elimination
from a copper (III) intermediate.
The effect of zinc on the regiochemistry of additions to enones is dramatic: while
methyllithium adds exclusively (or nearly so) to enones to give products of 1,2-addition,
lithium trimethylzincate gives almost exclusively 1,4-addition products. More impor-
tantly, perhaps, when a mixed zincate reagent is used, it is found that methyl transfer
occurs more slowly than transfer of primary or secondary alkyl groups; the transfer of
phenyl occurs much more slowly to give a mixture of products, including 1,2-addition
products. This makes mixed zincates, formed by the reaction between zinc chloride
TMEDA complex, methyllithium, and an alkylmagnesium halide (e.g., Example 12.40),
especially useful reagents for effecting conjugate additions to enones.54
49. Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron 1996, 5141.
50. Jarugumilli, G.K.; Cook, S.P. Org. Lett. 2011, 13, 1904.
51. (a) Yamamoto, Y.; Maruyama, K. J. Am. Chem. Soc. 1978, 100, 3240. (b) Brown, J.D.; Foley, M.A.; Comins,
D.L. J. Am. Chem. Soc. 1988, 110, 7445.
52. Frantz, D.E.; Singleton, D.A.; Snyder, J.P. J. Am. Chem. Soc. 1997, 119, 3383.
53. (a) Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc. 1997, 119, 4900. (b) Mori, S.; Nakamura, E. Chem.
Eur. J. 1999, 5, 1534. (c) Nakamura, E.; Yamanaka, M. J. Am. Chem. Soc. 1999, 121, 8941. (d) Krauss, S. R.; Smith, S. G.
J. Am. Chem. Soc. 1981, 103, 141. (e) Nakamura, E.; Yamanaka, M.; Mori, S. J. Am. Chem. Soc. 2000, 122, 1826.
54. Kjonaas, R.A.; Hoffer, R.K. J. Org. Chem. 1988, 53, 4133.

ZnCl2•TMEDA (1.0 eq.) O

O MeLi (0.67 eq.)
(12.40)
i-PrMgBr (1.0 eq), THF
(85%)
Worked Problem
Me2CuLi LiCH2OMOM, CuI

(a) O (b) O
O TMEDA, Me3SiCl
MeO2C
§Answers below.
Drill Problems
the reagents in list B? Note that not all combinations will give a useful reaction.
List A:
O CHO
CON(Me)OMe O
(i) (2) (3) (4) (5)
I
List B:
(i) (1) MeC ≡ CNa, THF, 0°C; (2) H2O
(ii) (1) Bu2CuLi, THF, 0°C; (2) NH4Cl, H2O
(iii) (1) EtMgBr, Et2O, 0°C; (2) NH4Cl, H2O
(continued)
Me2CuLi
(a) 1:1 mixture of
O O diastereoisomers
O O
MeO2C MeO2C
It is interesting to observe that in this reaction, the two oxygen atoms, which might be expected to coordi-
nate the lithium, and thus direct the copper reagent to one face of the alkene selectively, do not bias the stereo-
chemistry of the addition.
LiCH2OMOM, CuI
(b) O OTMS
TMEDA, Me3SiCl
OMOM
In this reaction, the enolate formed by addition is trapped with trimethylsilyl chloride to give the silyl enol
ether. This is a widely used technique to prevent this enolate from entering into competing reactions.
References: (a) J. Org. Chem. 1978, 43, 1750. (b) Org. Lett. 2003, 5, 1321.

(Drill Problems continued)
(iv) (1) Me2Zn, CH2Cl2; (2) NH4Cl, H2O

(v) (1) PhMgBr, CuCN, Et2O, 0°C; (2) NH4Cl, H2O
(vi) (1) BrZnCH2CO2Et, Et2O; (2) NH4Cl, H2O
Problems
12-2 What is the expected major organic product of each of the following reactions?
1) t-BuLi,Et2O-pentane, –78°C
2) CuCN, –78°C to -30°C
(a)
I O, Me3SiBr, –78°C
3)
PMB
CHO
O N
O ZnCl
(b) H
O THF, –78°C
H
O O
Me2C=CHCH2MgCl
(c) N OMe (62%)
Me
1) LDA, THF
(d) H CO2Et
CHO
2)
I
OEt 1) s-BuLi, KOBut, THF, –95°C

(e)
OEt 2) PhCHO, THF, –95°C to 25°C
3) H2O
(2 eq. base used)
References: (a) J. Am. Chem. Soc. 2006, 128, 13095. (b) Org. Lett. 2007, 9, 2143. (c) Org. Lett. 2009, 11,
2217. (d) Org. Lett. 2006, 8, 345. (e) Tetrahedron 1994, 50, 12463.
12-3 The two reactions below would appear to contradict two generalizations made
above about (1) the regiochemistry of deprotonations with “LICKOR,” and
(2) nucleophilic displacements of alkyl halides with alkyllithiums. If so, how
can the generalizations be modified to make them useful again? What caveats does
this raise about using this reagent in synthesis? [J. Am. Chem. Soc. 1987, 109, 7553].
1) LICKOR (3 eq)
THF, –78°C
O O SnBu3
2) Bu3SnCl
MOMO MOMO
OTBDMS
Br OTBDMS
OTBDPS
O Li O OTBDPS
THF-HMPA, 0°C
MOMO MOMO

12-4 What are the major organic products of each of the following reaction sequences?
TBDPSO
Me 1) n-BuLi, THF-HMPA
O
(a) SO2 OTf
H
2) O Ph
O
TESO O Ph
Me
1) t-BuLi, THF-HMPA, –78°C

(b) O O
Me
TBDMSO H
2)
S CHO
H
OMEM
O
1) s-BuLi, TMEDA, Et2O, –115°C
(c) Me3Si
EtO O
2)
CHO
References: (a) J. Am. Chem. Soc. 1997, 119, 4557. (b) J. Am. Chem. Soc. 1991, 113, 4037. (c) J. Org.
Chem. 1997, 62, 636.
Metal Alkyl Complexes of Other Transition Metals

As pointed out at the beginning of this section, this area of organic synthesis is now so
important that it merits its own chapter. As noted earlier in this chapter, we will discuss
the uses of transition metal catalysts in synthesis in Chapter 17.
Reaction Synopses
1,2-Addition of Metal Alkyls to Aldehydes, Ketones, and Imines
R R'M R'
X R' XH
R R
X = O, NR
Reagents:
X = O: R'MgX, Et2O; R'Li, Et2O; R 3ZnLi, Et2O; etc.
X = NR: RNa, THF, –75°C; R 3ZnLi, THF; etc.
1,2-Addition of Metal Alkyls to Acid Derivatives
X R'M R' R'
O R' OH or O
R R R
X = Cl, OR, NR 2
Reagents:
X = Cl: R'Li, THF; R'MgX, Et2O

12.3 Metal Enolates: Versatile Carbon Nucleophiles
Of all the carbon nucleophiles available to the synthetic organic chemist, few rival the
enolate anion for versatility. Enolate anions are obtained in two major ways: (1) deproton-
ation of a carbonyl compound or nitrile by a strong base and (2) reduction of a conjugated
carbonyl system with an active metal under conditions of the Birch reduction. Of the two
methods, deprotonation of the carbonyl precursor with a hindered amide base has become
the routine method for generating these valuable nucleophiles.
Enolate Regiochemistry
In general, enolate regiochemistry is fairly easy to control.55 The deprotonation reaction
has a stereoelectronic requirement that favors the removal of the proton that best overlaps
the π* orbital of the carbonyl group; this proton is usually close to perpendicular to the
plane of the carbonyl group. In open-chain compounds, which are conformationally flex-
ible, this requirement has no effect on the regiochemistry of deprotonation because this
conformation can, in principle, be attained by all α-hydrogens. The ensuing result is that
deprotonation under kinetic conditions leads to the less substituted enolate—deprotonation
at the less substituted α-carbon. Under thermodynamic (equilibrating) conditions, how-
ever, the more substituted enolate is formed as the major product (Example 12.41).
OM OM
R O R (12.41)
R
kinetic thermodynamic
In cyclic compounds such as cyclohexanones, kinetic deprotonation occurs by attack at
the axial, rather than at the equatorial α-hydrogen. In monosubstituted cyclohexanones,
both α-carbons carry an axial hydrogen, so the “normal” regiochemical outcome under ki-
netic conditions is observed, and the deprotonation occurs at the unsubstituted α-carbon.
On occasion, however, the stereoelectronic requirement will override the normal regiochem-
ical outcome, and kinetic deprotonation occurs at the more substituted site. This is illus-
trated by Examples 12.42 and 12.43. In the kinetic deprotonation (12.42), the bridgehead
hydrogen overlaps best with the carbonyl π* orbital, so despite forming a bridgehead alkene,
this proton is the one removed during deprotonation by slow addition of ketone to excess
base at –78°C. Under thermodynamic conditions (12.43), the less stable bridgehead enolate
is able to equilibrate with the more stable non-bridgehead enolate, despite it being less
substituted.56
1) add ketone to LDA (1.2 eq)
THF, DMPU, –78°C (12.42)
2) MeI/-30°C
H O Me O
1) add KHDMS(0.98 eq)

to ketone
PhMe, THF, 0°C (12.43)
Me
2) MeI/0°C
H O H O
55. Review: D’Angelo, J. Tetrahedron 1976, 32, 2979.

56. Shea, K.J.; Sakata, S.K. Tetrahedron Lett. 1992, 33, 4261.

Enolates from Conjugated Ketones: Dienolate Anions

The conjugation of the carbonyl group of a ketone introduces a new regiochemical factor
into the deprotonation reaction. In cyclohexenone, for example, the deprotonation may
occur at either the α' position or the γ position (Example 12.44). Deprotonation at the α'
carbon gives a cross-conjugated dienolate and is the favored process under conditions of
kinetic control (low temperatures, excess lithium amide bases). Deprotonation at the γ
carbon, on the other hand, gives a dienolate anion that is conjugated in a linear manner.
This dienolate is lower in energy than the cross-conjugated isomer and is therefore the
dienolate favored under thermodynamic or equilibrating conditions (sodium or potas-
sium alkoxide bases, higher temperatures, no excess base).
OLi O OLi
(12.44)
H Hγ Hα' H
thermodynamic kinetic
Cross-conjugated dienolate anions react like simple enolates, and there is no regiochem-
ical ambiguity in their reactions: all reactions where the enolate acts as a carbon nucleophile
occur through the α' carbon. Dienolates that are linearly conjugated, however, may react as
carbon nucleophiles through either the α carbon or the γ carbon. Which position is attacked
by the electrophile is influenced by both the exact nature of the substituents on the dienolate
anion and by the associated metal. For example, although lithium dienolates tend to react
with allyl halides at the α carbon by an SN2 mechanism to give the β,γ-unsaturated carbonyl
product, the more covalent (softer) copper (I) enolate tends to react through the γ carbon by
the SN2' mechanism to give the conjugated carbonyl product. This was especially the case
when the dianions of carboxylic acids were used as the nucleophiles.57
Enolate Stereochemistry
The stereochemical outcome of many important reactions of enolates is determined by the
stereochemistry of the enolate. For this reason, controlling enolate stereochemistry is
often a key task in designing a synthesis. There are a number of factors that influence eno-
late stereochemistry, as revealed by the study of symmetrical open-chain ketones (which
eliminate complications due to enolate regiochemistry).
Effect of Base and Carbonyl Substituent

The deprotonation of ethyl ketones and propionyl derivatives by strong bases such as lithium
diisopropylamide (LDA) is fairly well accounted for by the model proposed by Ireland.58 In
this model, hydrogen transfer occurs through a chairlike transition state, as shown in Figure
12.2. The enolate geometry is then determined by the balance of the two possible sources of
torsional strain: (1) a pseudo-1,3-diaxial interaction between the methyl group and R1 or R 2
R3 R3 Figure 12.2 Transition state

models for the deprotonation
O O of ethyl ketones
Me H H Me
R2 R2
Li Li
R2 R2
H H
N N
R1 R1
R1 R2 R1 R2
R2 R2
(12.45) (12.46)
57. Katzenellenbogen, J.A.; Crumrine, A.L. J. Am. Chem. Soc. 1976, 98, 4925.
58. Ireland, R.E.; Muller, R.H.; Willard, A.K. J. Am. Chem. Soc. 1976, 98, 2868.

Table 12.4 Effects of Base and Substrate Structure on Enolate in the activated complex leading to the Z enolate and (2) the
Geometry buildup of allylic strain between the methyl group and R3
R1 R2 R3 Z/E ratio Ref. as the reaction leading to the E enolate proceeds. The net
result of these strain effects is that when the group R3
H Me OMe 5 : 95 59 is small (e.g., alkoxy), the allylic strain is less than the
H Me OCMe3 5 : 95 59 1,3-diaxial interaction, and E enolate predominates (12.45).
When R3 is large (e.g., tert-butyl), the opposite is true, and
H Me SCMe3 10 : 90 60
the Z enolate predominates (12.46). Note how the planarity
–(CH2)3– Me Et 14 : 86 61 of the amide group leads to high levels of allylic strain and
H Me Et 23 : 77 (30 : 70) 59, 62 therefore to high proportions of the Z enolate. The results
of a number of studies are summarized in Table 12.4.
H Me CHMe2 60 : 40 59 As the base becomes more hindered, the proportion
–(CH2)3– Me CHMe2 32 : 68 59 of the Z enolate in the product mixture increases, as
shown in Figure 12.3 for a range of strong lithium amide
H Me CMe3 >98 : 2 59
bases. This result is not compatible with the chairlike
H Me Ph >98 : 2 59 model of deprotonation but is compatible with a boatlike
conformation instead (Figure 12.4). Thus, it appears that
H Me NEt 2 ≥97 : 3 63 as the base becomes more hindered, the chair conforma-
H Me –(CH2)4– ≥97 : 3 63 tion (which would require a large group in an axial posi-
tion) becomes disfavored relative to the boat. 5960616263
Figure 12.3 Effects of base

O OLi OLi
size on enolate geometry base
H + Me
Me H
LTMP LDA LICA LHMDS LiN(SiMe2Ph)2
%Z 14 23 35 66 100
Figure 12.4 The boat R3 R3

transition state for
deprotonation is favored
O O
when the base is very Me H H Me
hindered. R2 R2
Li R2 Li R2
H N H N
R1 R1
R2 R1 R2 R1
R2 R2
(12.47) (12.48)
59. Heathcock, C.H.; Buse, C.T.; Kleschick, W.A.; Pirrung, M.A.; Sohn, J.E.; Lampe, J. J. Org. Chem. 1980, 45,
1066.
60. Evans, D.A.; McGee, L.R. Tetrahedron Lett. 1980, 3975.
61. (a) Fataftah, A.A.; Kopka, I.E.; Rathke, M.W. J. Am. Chem. Soc. 1980, 102, 3959. (b) Nakamura, E.;
Hashimoto, K.; Kuwajima, I. Tetrahedron Lett. 1978, 2079.
62. Ireland, R.E.; Muller, R.H.; Willard, A.K. J. Am. Chem. Soc. 1976, 98, 2868.
63. Takacs, J.M. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 1981; cited in Evans, D.A. In
Morrison, J.D., Ed. Asymmetric Synthesis. Stereodeifferentiating Addition Reactions, Part B. (Academic Press:
New York, 1984), vol. 3, ch. 1, p. 1.

O Figure 12.5 Effects of solvent

70 composition on
stereochemistry of enolate
from 4-heptanone
percent Z enolate
LDA/solvent
60
Li
O
50
H, Et
40
0 50 100
percent hexane in THF
Solvent
In 1976, Ireland and his coworkers discovered a remarkable effect of solvent on enolate
geometry in the deprotonation of esters.62 In tetrahydrofuran (THF) as the solvent (or,
more correctly, THF-hexane, because the butyllithium used to deprotonate the diisopro-
pylamine was in hexane), the deprotonation of methyl propionate gave the E(O) enolate as
the major component of a 95:5 mixture. When the solvent was changed to 23% hexameth-
ylphosphoramide (HMPA)-THF (or the same solvent containing the hexane from the bu-
tyllithium), the stereochemistry was reversed, and the Z(O) enolate now became the major
component of an 84:16 mixture. Four years later, the same effect was observed in the
deprotonation of 3-pentanone, by Rathke and his coworkers,64 who also noted that the
presence of a small excess of 3-pentanone in the mixture was able to effect the same rever-
sal of stereochemistry. The effect of the hexane on the geometry of the enolate obtained by
LDA deprotonation of 4-heptanone was reported by Heathcock and Munchhoff.65 They
observed that, as the proportion of hexane in the solvent system increased, the proportion
of the Z enolate increased (Figure 12.5), leading to a reversal of stereochemistry of the
major enolate; from 50 to 100% hexane, the increase in the amount of the Z enolate was
approximately linear with the concentration of hexane in the solvent, and below approxi-
mately 33% hexane, a leveling effect is observed.
The effects of solvent have long been proposed to be the result of changes in aggregation
of the lithium amide base,66 but a series of studies of the solution structure of lithium amide
bases reveals that the addition of HMPA to a THF solution of LDA, for example, does not
change the aggregation state of the base.67 Instead, the structure of the activated complex
appears to be very dependent on the nature of the substrate and the solvent together, and
there is evidence that the most active form of the base may, in fact, be a dimer. The results
of two decades of work in this area have been summarized by Collum in a useful review
that provides guidelines for optimizing reactions of LDA with a range of substrates.68
Alkylation of Enolates
The highest energy occupied molecular orbital (HOMO) of the enolate anion is ψ2 of the
conjugated system, which makes the enlate anion an ambident nucleophile, exhibiting
both hard (oxygen-centered) and soft (carbon-centered) reactivity. Enolate anions react
64. Fataftah, A.A.; Kopka, I.E., Rathke, M.W. J. Am. Chem. Soc. 1980, 102, 3959.
65. Munchhoff, M.J.; Heathcock, C.H. Tetrahedron Lett. 1982, 33, 8005.
66. (a) Wardell J.L. In Wilkinson, G.; Stone, F.G.A.; Abel, E.W., Eds. Comprehensive Organometallic Chem-
istry, Vol. 1 (Pergamon: New York, 1982), chap. 2 (b) Szwarc, M., Ed. Ions and Ion Pairs in Organic Reactions,
(Wiley: New York, 1972), Vols. 1–2.
67. Collum, D.B. Acc. Chem. Res. 1993, 26, 227.
68. Collum, D.B.; McNeil, A.J.; Ramirez, A. Angew. Chem. Int. Ed. 2007, 46, 3002.

with hard electrophiles such as silyl halides and phosphoryl halides to give derivatives of
the enol as the product. With softer nucleophiles, such as alkyl halides and carbonyl com-
pounds, the major product of the reaction is the substituted carbonyl compound.
Enolate anions are powerful nucleophiles and generally react well with alkyl halides
and epoxides. The reactions are typical SN2 reactions, with inversion of configuration at the
electrophilic carbon. The alkylation of an enolate anion is a strongly exothermic reaction,
which means that the transition state for alkylation occurs early along the reaction coordi-
nate, with the result that the activated complex strongly resembles the starting enolate.69
This is manifest in the alkylation reactions of 4-tert-butylcyclohexanone (Example 12.49).
Unlike the reduction of cyclohexanones, which occur predominantly from the axial direc-
tion, the alkylation of the enolate of this ketone does not exhibit high levels of diastereose-
lectivity that one might expect by analogy with the reduction reaction.
NaOCMe2Et O
O PhMe
R2 (12.49)
R2I
R1 (14-46% d.e.) R1
Conjugation of the Enolate: Dienolate Anions

Linear conjugation of the enolate anion with a further double bond gives rise to an additional
regiochemical complication to the alkylation action, because the C-alkylation may now occur
at either the α carbon or the γ carbon. Attack at both positions has been observed. However,
the largest lobes in the HOMO of the dienolate are at the center of the system, which favors
attack of the electrophilic reagent at the center of the conjugated system.
Which position is attacked by the alkyl halide is influenced by both the exact nature
of the substituents on the dienolate anion and by the associated metal. Alkali metal
dienolates—whether kinetic (Example 12.50) or thermodynamic (Examples 12.51 and
12.52)—tend to react with alkyl halides at the α carbon by an SN2 mechanism to give the
β,γ-unsaturated carbonyl product. By contrast, more covalent (softer) enolates (e.g.,
copper (I) enolates) tend to react through the γ carbon by the SN2' mechanism to give the
conjugated carbonyl product. This is especially the case when the dianions of carboxylic
acids were used as the nucleophiles.70
O
1) LDA, THF, –78°C O
2) MeI
Cl (12.50)71
3) LDA, THF, –78°C
OEt 4) BrCH2CH2CH2Cl OEt
(93% overall)
O O
1) NaNH2, NH3
(12.51)72
2) MeCH(CH2CH2I)2
I
OMe OMe
KOBut
(12.52)73
MeI (2 eq.)
O O
69. House, H.O.; Tefertiller, B.A.; lmstead, H.D. J. Org. Chem. 1968, 33, 935.
70. Katzenellenbogen, J.A.; Crumrine, A.L. J. Am. Chem. Soc. 1976, 98, 4925.
71. Schultz, A.G.; Dittani, J.P. J. Org. Chem. 1983, 48, 2318.
72. Fukamiya, N.; Kato, M.; Yoshikoshi, A. Chem. Commun. 1971, 1120.
73. Stork, G.; Meisels, A.; Davies, J.E. J. Am. Chem. Soc. 1963, 85, 3419.

O-Alkylation and Acylation of Enolates

As the electrophiles become harder, enolates react through oxygen rather than carbon.
Thus, the reaction between an enolate and an acid chloride (which, although formally soft,
is a relatively hard electrophile) generally gives the enol ester, rather than the α-acyl prod-
uct, as shown by Example 12.53, which gives a mixed enol carbonate ester.74
ButO ButO
O 1) LDA, THF, –78°C O

2) TMEDA (12.53)
O
Cl O
3)
OCOCl
(73%) Cl
By far the most commonly used reagents to obtain enol derivatives are silyl halides,
and a wide range of trialkylsilyl chlorides have been used to convert an enolate anion to
the corresponding enol trialkylsilyl ether. The same reagents are widely used in the selec-
tive protection of alcohols.75 We will discuss these reactions in much more detail when we
discuss the use of protecting groups in organic synthesis.
The other class of acid chlorides that convert an enolate anion to the corresponding
enol ester is the phosphoric acid chlorides, often diethyl phosphorochloridate.76 This re-
agent was used in one key step of the synthesis of zoapatanol (Example 12.54).77 The enol
phosphates derived in this manner are most frequently then subjected to Birch reduction
to give the corresponding alkene.
EtO OEt
O
P O
O
1) LDA, TMEDA, HMPA O
–78°C (12.54)
O 2) (EtO)2P(O)Cl O
Ph
(85%) Ph
THPO
THPO
Drill Problems
the reagents in list B?
List A:
O
H
(i) (2) NC (3) O (4) O
List B:
(i) (1) LDA, THF, –78°C; (2) CD3I, –78° to r.t.
(ii) KOBut, THF, MeI (excess)
(iii) (1) LDA, THF, –78°C; (2) PhCHO, –78°C, 2 min; (3) NH4Cl, H2O
(iv) (1) LICA, THF, –78°C; (2) ICH2C(=CH2)CH2CH3
74. White, D.E.; Stewart, I.C.; Grubbs, R.H.; Stoltz, B.M. J. Am. Chem. Soc. 2008, 130, 810.
75. (a) Nelson, T.D.; Crouch, R.D. Synthesis 1996, 1031. (b) Crouch, R.D. Tetrahedron 2004, 60, 5833.
(c) Greene, T.W.; Wuts, P.G.M. Protecting Groups in Organic Synthesis, 3rd. ed. (Wiley: New York, 1991).
(d) Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shirahama, H.; Nakata, M. Synlett 2000, 1306.
76. Ireland, R.E.; Pfister, G. Tetrahedron Lett. 1969, 2145.
77. Kane, V.V.; Doyle, D.L. Tetrahedron Lett. 1981, 22, 3027.

p_12-4_c
Problems
O
Ph 1) LDA, THF, LiCl
N
(a) Me
OH Cl
O O 2) TBSO
O 1) LDA,THF, –78°C
(b) O
O O CHO
2) N
Cbz
O
Me
N 1) LDA, THF, –78°C 1) –78°C
(c) N
O Boc 2) HOAc
OMe N
Boc N
CHO
OMe
1) LDA, THF, –78°C (2 eq.)

(d)
2) Br
CO2H
O O
1) LDA, THF, –78°C (2 eq.)
(e) N O
2) I OTBDPS
Ph
MPMO O LDA, THF-HMPA, –10°C

OTBS
(f) I OTBS
H
O 1) LDA, THF
(g) O
2) MeI
H
References: (a) J. Am. Chem. Soc. 2009, 131, 16905. (b) Org. Lett. 2005, 7, 4419. (c) J. Am. Chem. Soc.
2011, 133, 6549. (d) J. Am. Chem. Soc. 2009, 131, 452. (e) Org. Lett. 2008, 10, 1247. (f) Org. Lett. 2011, 13,
2160. (g) Org. Lett. 2005, 7, 3371.
12-6 What is the major organic product expected from each of the following reactions?
O O
H 1) LICA (1.5 eq), THF, –78°C
(a)
S 2) HMPA (1 eq)
3) MeI (1 eq)
S

1) LHDMS (1.5 eq), THF, DMPU, –50°C

(b) MeO2C
N Ts 2) H2C=CHCH2I, –50°C
This reaction gives a single regioisomer of the product. Why?

OMe
CN
TBSO
H 1) LDA (2 eq), THF, –78°C
(c)
OMe
2) MeI, –78°C
References: (a) J. Org. Chem. 1988, 53, 1441. (b) J. Am. Chem. Soc. 2011, 133, 8877. (c) Org. Lett. 2007,
9, 1461.
Reaction Synopses
Enolate Generation
R R R
base
R R R R and/or R R
O OM OM
thermodynamic kinetic
Kinetic enolate usually less substituted; favored by amide base

Thermodynamic enolate more substituted; favored by alkoxide base
Effect of base on regiochemistry:
Thermodynamic enolate: NaH, PhH; NaNH2, THF; KOBut, t-BuOH; etc.
Kinetic enolate: LDA, THF, –78°C; t-BuLi, THF, –100°C; etc.
Sterically hindered bases favor Z(O) enolate.
Small groups (e.g., Me, OR) bonded to carbonyl carbon favor E(O) enolate; large
groups (e.g., t-Bu, NR 2) favor Z(O) enolate.
Trapping of Enolates
R R R E
E X E X
R R R R R R
O OM O
E
E = C=O, P=O, SiR3, etc. E = R, RS, RSe, etc.
Reagents: Me3SiCl, t-BuMe2SiCl, t-BuPh2SiCl, i-Pr3SiCl, etc.;
or RCOCl, (RO)2P(O)Cl, etc. (O-acylation);
or RI, RBr, ROTs, TOTf, etc. (C-alkylation);
or RSeSeR, RSeBr, RSBr, etc.
Hard electrophiles tend to favor reaction at oxygen; soft electrophiles favor reac-
tion at carbon.

12.4 The Aldol Addition Reaction78
Few reactions have had the impact on the direction of organic synthesis that the aldol
addition reaction had during the last quarter of the 20th century. The aldol addition is an
old reaction, having first been published by the Irish chemist Robert Kane,79 explored by
Russian composer-chemist Aleksandr Borodin in 1864,80 and extended by Wurtz81 and
Kekulé.82 Although these early workers did isolate the β-hydroxyaldehydes from their re-
action mixtures (i.e., they carried out aldol addition reactions; Example 12.55) for more
than a century after the discovery of the aldol reaction, the reaction was used in the form
of the aldol condensation (Example 12.56), in which an α,β-unsaturated carbonyl com-
pound is the major product. The difficulties inherent in the quantitative conversion of
simple carbonyl compounds to their enolates with the strong bases typically available to
organic chemists before 1970 meant that little attention was paid to using the reaction for
the stereocontrolled formation of new chiral enters. That changed in the late 1970s.
HO
R' CHO R R'
(12.55)
O aldol addition O R
R R R R'
R' CHO
(12.56)
aldol condensation O R
The development of the modern aldol addition has been driven by efforts directed toward
the synthesis of polyketide natural products, especially macrolide antibiotics such as eryth-
romycin (Example 12.57). An examination of the backbone of macrocyclic ring reveals that
practically every second carbon atom (marked by asterisks) carries an oxygen atom. Early
on, this substitution pattern, and a similar substitution pattern in aromatic natural prod-
ucts, led J. N. Collie to propose that these natural products might be formed by a polymer-
ization leading to products with repeating (–CH2—CO–) (or [–CHR—CO–]) units.83 This is
exactly the pattern that one obtains when one adds an enolate anion to a carbonyl com-
pound, which has made the aldol addition an important synthetic method.
O
OH
* *
* OH *
OH
O
O * * O
* O
O
HO NMe2
O
MeO
HO (12.57)
78. Reviews and monographs: (a) Mukaiyama, T. Org. React. 1982, 28, 203. (b) Heathcock, C.H. In Morrison,
J.D., Ed. Asymmetric Synthesis (Academic Press: Orlando, FL, 1984); Vol. 3., Ch. 2, p. 111. (c) Franklin, A.S.;
Paterson, I. Contemp. Org. Synth. 1994, 1, 317. (d) Cowden, C.J.; Paterson, I. Org. React. 1997, 51, 1. (e) Machajew-
ski, T.D.; Wong, C.-H. Angew. Chem. Int. Ed . 2000, 39, 1352. (f) Carriera, E.M. In Otera, J., Ed. Modern Carbonyl
Chemistry (Wiley-VCH: Weinheim, 2000); Chapter 8, p. 227. (g) Paterson, I.; Cowden, C.J.; Wallace, D.J. In
Otera, J., Ed. Modern Carbonyl Chemistry (Wiley-VCH: Weinheim, 2000); Chapter 9, p. 249. (h) Mahrwald, R.
Ed. Modern Aldol Reactions (Wiley-VCH: Weinheim, 2004). (i) Vicarion, J.L.; Badia, D.; Carillo, L.; Reyes, E.;
Etxebarria, J. Curr. Org. Chem. 2005, 9, 219. (j) Mahrwald, R. Aldol Reactions (Springer: Dordrecht, 2009).
79. (a) Kane, R. Ann. Phys. Chem. [2] 1838, 44, 475; J. Prakt. Chem. 1838, 15, 129.
80. Borodin, A. J. Prakt. Chem. 1864, 93, 413; Z. Chem. Pharm. 1864, 7, 353; Ber. dtsch. Chem. Ges. 1873, 6, 973.
81. (a) Wurtz, A. Bull. Soc. chim. Paris 1872, 17, 436–442; J. Prakt. Chem. 1872, 5, 457; Compt. Rend. Acad. Sci.
1872, 74, 1361.
82. (a) Kekulé, A. Ber. dtsch. Chem. Ges. 1869, 2, 365–368; 1870, 3, 135–137.
83. (a) Collie, J.N. J. Chem. Soc. 1893, 63, 329. (b) Collie, J.N. Proc. Chem. Soc. 1907, 23, 230. (c) Collie, J.N. J.
Chem. Soc. 1907, 91, 1806. (d) Collie, J.N.; Wilsmore, N.T.M. J. Chem. Soc 1896, 69, 293. (e) Collie, N.; Myers,
W.S. J. Chem. Soc. 1893, 63, 122.

R1 ‡ Figure 12.6 The use of the

R1 R1
Zimmerman-Traxler
O O O transition state model to
R3 R2 R3 R2 predict the stereochemistry
R3 R2 M of the major product formed
M M in an aldol addition
R4
R4 O O R4 O
R5 R5 R5
Much of the modern fascination with this old reaction stems from the fact that one can
incorporate two new chiral centers into a molecule with defined stereochemistry. The pos-
sibility of predicting the stereochemistry of the addition reaction was improved by the
discovery of Zimmerman and Traxler, who noted a stereochemical bias in the Ivanov ad-
dition of the dianion of phenylacetic acid to aldehydes and rationalized it on the basis of a
six-membered cyclic transition state.84 Today, the Zimmerman-Traxler transition state
model is a cornerstone of the discussions of stereochemistry in the additions of metal
enolates to aldehydes (and, to a lesser extent, ketones) under conditions of kinetic control.
This model (Figure 12.6) predicts that the stereochemistry of the enolate and the confor-
mation of the chairlike transition state both affect the final stereochemistry. The confor-
mation in the transition state is generally accepted to be that in which the larger group in
each of the pairs (1) R 2 and R 3 and (2) R4 and R 5 preferentially occupies an equatorial posi-
tion in the transition state. Provided that the reaction is carried out under conditions of
kinetic control (short reaction time, low temperature), this model generally does an ade-
quate job of predicting the stereochemistry of the major product. However, one should
always heed the caveat that:
When dealing with the aldol addition reaction, generalizations frequently fail.
Stereochemistry in the Aldol Addition

The modern aldol addition is very much concerned with the control of both relative and
absolute stereochemistry in the final product. When two new chiral centers are formed
in the reaction, four stereoisomers are possible (Figure 12.7), existing as two diastereo-
meric pairs of enantiomers (12.58 to 12.61). Thus, one may control the absolute stereo-
chemistry of the product (enantioselection), the relative stereochemistry of the product
(diastereoselection), or both. The clear target of the research since 1980 has been the con-
trol of both.
Diastereoselection: Factors Affecting the Diastereoisomer Ratio

Kinetic versus Thermodynamic Control
Much of the discussion that follows will focus on aldol addition reactions that are carried
out under conditions of kinetic control, an area that was pioneered by American chemist
Clayton Heathcock.85 This occurs because under these conditions, diastereoselectivity is
maximized. The aldol addition is, however, reversible, which allows the syn and anti iso-
mers of the aldol to equilibrate, and this process is generally facile. A good example of just
how facile this reaction can be is provided by the reaction in Example 12.62, where the
84. Zimmerman, H.; Traxler, M. J. Am. Chem. Soc. 1957, 79, 1920.
85. Clayton H. Heathcock (1936–) received his BSc from Abilene Christian College, Texas in 1958 and then
joined the Champion Paper and Fiber Company in Pasadena, Texas. In 1960 he entered the University of Colo-
rado (PhD, 1963). After a year of postdoctoral work with Gilbert Stork at Columbia, he joined the University of
California, Berkeley, where he spent his entire career. He was elected to the National Academy of Sciences in
1995, and received the Centenary Medal of the Royal Society of Chemistry in 1996. For more details, see: http://
chemistry.berkeley.edu/faculty/chem/emeriti/heathcock.

Figure 12.7 Stereochemical OH O OH O
terminology in the aldol syn enantioselection syn
addition. Diastereoselection (12.58) R1 G R1 G (12.59)
distinguishes isomers R R'CHO R'CHO R
vertically, and
OM
enantioselection
R C diastereoselection
distinguishes isomers H G
horizontally.
OH O R'CHO R'CHO OH O
anti anti
(12.60) R1 G R1 G (12.61)
R R
equilibration is rapid even at –60°C (the half-life of the reaction is approximately 1 minute
under these conditions,86 which corresponds to an activation energy for the equilibration
of just over 1 kcal mol–1). The factors affecting the syn-anti equilibrium are as one would
expect: the size of the groups attached to the carbonyl carbon of the enolate precursor and
the aldehyde, the identity if the counterion, and the enolate geometry.
O OH
Ph Ph
Keq=1.1
O OH
Ph Ph
(12.62)
Effects of Enolate Geometry

In keeping with the predictions of the Zimmerman-Traxler model, it is found that Z(O)
enolates often give higher levels of diastereoselectivity than E(O) enolates. If we examine
the model, shown in Newman projection form in Figure 12.8, we can see one possible
reason for this. In the reaction of the E(O) enolate, the group R is equatorial and gauche to
R" in both transition states, leading to the diastereoisomeric aldol products, which means
that the difference in conformational energy between the syn and anti aldol transition
states is relatively low and that diastereoselectivity, also, should be low. On the other hand,
in the addition involving the Z(O) enolate, the group R is forced to adopt an axial position.
G G G
H H R"
H R R
M M M
O R" O R" O H
R H H
(12.63) (12.64) (12.65)
Figure 12.8 Newman projections for Zimmerman-Traxler transition states

leading from Z(O) enolate to syn aldol product (12.63), E(O) enolate to anti aldol
product (12.64), and from E(O) enolate to syn aldol product (12.65). Note the
pseudo-1,3-diaxial interaction in (12.65).
86. Heathcock, C.H. In Nozaki, H, Ed. Current Trends in Organic Synthesis. IUPAC Symp. Ser. (Pergamon:
Oxford, 1983), p. 27.

This means that if the Z(O) enolate is to give the anti aldol, Table 12.5 Stereochemical Outcome of Kinetic Aldol Additions of
the alkyl group of the aldehyde must also be in a pseudo- Lithium Enolates*
axial position. It is gratifying to find that the Z(O) enolate LiO O OH O OH
PhCHO
is much more diastereoselective than the E(O) enolate and CHMe
THF, –78°C R Ph
+
R Ph
that it gives predominantly the syn aldol adduct.87 R
Table 12.5 summarizes the stereochemical outcome 2,3-syn 2,3-anti
of aldol addition reactions of the E(O) and Z(O) enolates Enolate

of ethyl ketones with benzaldehyde at –78°C. The same R Geometry 2,3-syn 2,3-anti
data are summarized graphically below the table. With H Z(O) 50 50
the exception of the Z(O) enolate of propionaldehyde, the
data fit a reasonable straight line, with an intercept at H E(O) 60 40
45% syn and a slope of just over 0.5, suggesting a fairly Et Z(O) 90 10
strong intrinsic preference for the syn aldol and that anti
Et E(O) 40 60
aldols might be difficult to prepare with high levels of
stereoselectivity. i-Pr Z(O) 90 10
i-Pr E(O) 50 50
The Counterion
t-Bu Z(O) 99 1
There is good evidence that the reversibility of the aldol ad-
dition may be modulated to some degree by the ability of *Data taken from Ref. 87
the cation to chelate the two oxygens of the aldol adduct.
Thus, no aldol adduct was isolated from the reaction of
benzaldyde with the thermodynamic enolate of phenylace-
tone when the non-chelating tris-(diethylamino)sulfonium
cation was the counterion. This presumably occurred be-
cause the equilibrium for formation of the aldol adduct was
unfavorable. However, Noyori did observe that trimethyl-
silyl fluoride, present as an impurity in the base, trapped
the minor component of the equilibrium mixture to give
the silyloxyketone (Example 12.66).88 With lithium ion,
which is a modest Lewis acid capable of chelating the two
oxygen atoms, the equilibrium shifts to the product side.
The reversibility of the reaction is now manifested in the
stereochemical consequences of the reaction, rather than
in the inability to isolate the product of the reaction.
S(NEt2)3 Me Me
O Ph Me3SiF Ph
+ PhCHO O O (12.66)
Ph
Me
Ph O Ph OSiMe3
Another important effect of the counterion is due to the bond lengths between the metal
and oxygen. Although the alkali metals are small, their metal-oxygen bonds are quite long
(Li, 1.92–2.00Å; Na, 2.24–2.33Å; K, 2.57–2.67Å),89 which makes the transition state fairly
loose, and reduces the effects of enolate stereochemistry. Good Lewis acids that also have
long bond distances to oxygen are zinc (1.975–1.982Å)90 and magnesium (1.908–1.921Å).91
These bond distances loosely correlate with a greater propensity to undergo equilibration at
low temperatures. The aluminum aldolates (Al—O bond lengths 1.85–2.06)92 appear to form
87. Heathcock, C.H. In Trost, B.M.; Fleming, I., Eds. Comprehensive Organic Synthesis (Pergamon: Oxford,
1991), vol. 2, p. 181.
88. Noyori, R.; Nishida, I.; Sakata, J.; Nishizawa, M. J. Am. Chem. Soc. 1980, 102, 1223.
89. Williard, G.P.; Carpenter, G.B. J. Am. Chem. Soc. 1986, 108, 462
90. Hlavinka, M.L.; Hagadorn, J.R. Organometallics 2006, 25, 3501.
91. Dove, A.P.; Gibson, V.C.; Marshall, E.L.; White, A.J.P.; Williams, D.J. Chem. Commun. 2002, 1208.
92. van der Steen, F.H.; van Mier, G.P.M.; Spek, A.L.; Kroon, J.; van Koten, G. J. Am. Chem. Soc. 1991, 113, 5742.

strong chelates, which prevents the isomerization of the aldolate. In such cases, the stereo-
chemistry of the aldol additions can be reliably predicted on the basis of the Zimmerman-
Traxler model. The stereochemical predictions in this case are shown in Examples 12.67 to
12.70.93 In contrast to most metal enolates, the boron-oxygen bond in boron enolates is short,
and boron aldolates can also form a stable chelate ring. Thus, the aldols formed from these
nucleophiles do not equilibrate. The stereochemistry of the aldol addition of a variety of
metal enolates with benzaldehyde are gathered in Table 12.6.
OH O
(12.69)
OAlMe2 MeCHO d.r. 100:0
O Me3Al (12.67)
Ni(acac)2
OH O (12.70)
MeCHO d.r. 93:7
OAlMe2
(12.68)
The information in Table 12.6 can also be obtained in

visual form. Some data for aldol addition reactions of var-
Table 12.6 Effect of Counterion on the Stereochemistry of Aldol ious metal enolates are gathered in the form of stereo-
Additions of Metal Enolates of Acid Derivatives chemistry plots in Figure 12.9. In these plots, the vertical
MO O OH O OH axis records the diastereoisomeric excess (d.e.) relative to
R'CHO
CHMe
THF, –78°C R R'
+
X R'
the syn isomer. Thus, in this diagram, anti-selective reac-
X tions project in the negative direction, whereas syn-
2,3-syn 2,3-anti selective reactions project in the positive direction.
M X R' E(O):Z(O) syn:anti In Figure 12.9A, the nonparticipating groups, X, are
arranged with ketones at the left, alkyl esters and thio-
Li SBut Ph 90:10 63:37
esters next, and amides last. In the diagram on the right,
Li N(CH2)4 Ph < 5:95 60:40 the ketones are located on the left, and the carboxylic acid
S derivatives on the right. In the diagram on the left, the first
thing that is obvious is that almost none of the reactions
Mg S N — 5:95 have a negative d.e. with respect to the syn stereoisomer—
Bn anti-selective reactions of metal enolates are quite rare. In
addition, only six of the reactions have d.e.'s of 80% or
AlEt 2 Ph Ph —* < 1:99 greater, which is the benchmark that reactions stereoselec-
AlEt 2 Ph Ph —† 62:38 tive enough to be used routinely in synthesis now need to
attain. In fact, most metal enolates do not participate in
BBu2 SBut Ph 95:5 10:90
highly selective aldol addition reactions, and when they
O do, they tend to be syn-selective. Lithium enolates, espe-
BBu 2 Ph < 3:97 98:2 cially, are not highly diastereoselective, with the excep-
O N
tion of reactions where the group X is large (tert-butyl or
Zn c-C5H7O ‡ Ph E 1.2:1 2,6-dialkylphenoxy); such a group may direct the proton-
ation of an enolate intermediate as shown in Example
TiCl3 SBu t
Ph — 86:14 12.71. Figure 12.9 also reveals that enolates of stronger
Cp2TiCl N(CH2)4 Ph — 2:98 Lewis acids (such as Zr) tend to give higher levels of syn
selectivity with acid derivatives, but seem to make little
Cp2ZrCl SBu t
Ph 90:10 93:7
difference with ketone enolates.
Cp2ZrCl N(CH2)4 Ph < 5:95 95:5
H
SnII NMe2§ Ph Z 92:8
R
O
*
0°C, thermodynamic control. O Li O
†
–78°C, kinetic control.
R
‡Cyclopentanone enolate.
R
§
Thioamide rather than amide. (12.71)
93. Jeffery, E.A.; Meisters, A.; Mole, T. J. Organomet. Chem. 1974, 74, 365, 373.

Figure 12.9 Stereochemistry of the aldol addition reactions of enolates of propionyl derivatives (A)
and geometric isomers of boron enolates (B). On the left, ODMP represents a 2,6-dimethylphenyl
ester, and OBHT represents a 2,6-di-tert-butyl-4-methylphenyl ester. On the right, Nox represents
an N-oxazolidinyl group.
Boron Enolates
The case with the boron enolates (Figure 12.9B) presents a stark contrast to the metal eno-
lates. The stereochemistry of the boron enolate exercises an absolute control over the aldol
stereochemistry: Z(O) boron enolates give syn aldols, and E(O) boron enolates give anti
aldols. Both geometric isomers of the enolate react with synthetically useful (d.r. ≥ 47)
diastereoselectivity. More importantly, it appears that other factors (e.g., the size of the
non-reacting group bonded to the carbonyl group) have only a small effect on the syn/anti
ratio—in contrast to the metal enolates.
Boron enolates are formed by treating a carbonyl compound with a suitable boron
species and a non-nucleophilic base. For example, the reaction between dicyclopentylbo-
ron triflate or 9-borabicyclo[3.3.1]non-9-yl triflate and a ketone in the presence diisoprop
ylethylamine (Hünig’s base, a hindered amine) gives the boron enolate of the ketone.94
The stereochemistry of the boron enolate formed in this reaction is determined in
large part, by the size of the alkyl group bonded to the carbonyl carbon and by the steric
requirements of the boron triflate used in the reaction. The formation of the boron enolate
is believed to follow the same course (Figure 12.10), where there is a rapid preequilibrium
Figure 12.10 Models for

NR3
L L predicting the stereochemistry
TfO B L
B of the boron enolate by a
H O H concerted pathway
O L
R H R Me
Me
syn Complex E(O) enolate
NR3
TfO L
H B O Me
B O L
L R H
L R Me
H
anti Complex Z(O) enolate
94. (a) Evans, D.A.; Nelson, J.V.; Vogel, E.; Taber, T.R. J. Am. Chem. Soc. 1981, 103, 3099. (b) Hirama, M.;
Masamune, S. Tetrahedron Lett. 1979, 20, 2225, 3937.

Lewis acid–Lewis base reaction between the borane and the carbonyl oxygen, followed by
rate-limiting deprotonation. The loss of the leaving group from boron may be concerted
with deprotonation, or it may occur prior to deprotonation. The preferred conformation
of the Lewis acid–Lewis base complex depends, in part, on the size of the borane group.
Sterically small groups (BL2=BBu 2 or 9-BBN, for example) tend to prefer the anti confor-
mation in the complex, but as the group becomes more sterically demanding (e.g.,
BL2=(c-C5H9)2B), eclipsing of the BL2 group and the R group on the carbonyl carbon in-
creases the energy to the point that the complex preferentially adopts the syn conforma-
tion. Deprotonation of the anti complex leads to the Z(O) enolate, and deprotonation of
the syn complex leads to the E(O) enolate. An alternative explanation for the observed
enolate stereochemistry posits that the Z(O) enolate formed by a hindered borane isom-
erizes fairly readily. Whatever the reason, by appropriately choosing the borane reagent,
one can fix the enolate geometry, and hence the aldol stereochemistry, as shown by Ex-
amples 12.72 and 12.73; both reactions give yields in excess of 80% with a range of
aldehydes.95
O
B OTf
RCHO
B (12.72)
i-Pr2NEt
O OH
O R
d.r.: 85-88% anti
O
BOTf R
2 RCHO
B O (12.73)
i-Pr2NEt
R OH
R
d.r.: >97% syn
Addition of Enolates to Chiral Aldehydes

The strong tendency of the Z(O) enolates of ketones with large nonparticipating groups to
undergo stereoselective addition to give the syn aldol adduct led to the development of a
number of surrogates for propanal or propionate esters (where the group bonded to the
carbonyl carbon is small). The common feature of these surrogates is their ability to be
degraded to an aldehyde or carboxylic acid under mild oxidative or reductive conditions.
Most of these surrogates are α,α-dialkyl-α-hydroxyketones or α,α-dialkyl-α-vinyl-
ketones. If the aldehyde component of the aldol addition has a chiral center at the α posi-
tion, the aldol addition conforms to Cram’s rule, as illustrated by the reactions leading to
aldols in Examples 12.74 to 12.77.
OH O
O Ph (12.74)
1) LDA, THF, –78°C 92
Ph 8 OH O
2) CHO Ph
Me (12.75)96
95. Van Horn, D.E.; Masamune, S. Tetrahedron Lett. 1979, 2229.

96. Mori, I.; Ishihara, K.; Heathcock, C.H. J. Org. Chem. 1990, 55, 1114.

O OH
Ph
O Me3SiO O (12.76)
1) LDA, THF, –78°C 78
Ph
Me3SiO Ph 22
2) CHO O OH
O
Ph Ph
97
Me3SiO O (12.77)
Ph
Asymmetric Aldol Additions

In the early 1980s, Evans98 extended the utility of boron enolates by developing a set of
chiral of boron enolates capable of inducing high levels of enantioselection and diastereo-
selection.99 This work revolutionized the application of the aldol addition reaction in or-
ganic synthesis. For such powerful chiral auxiliaries, the Evans chiral oxazolidinones are
remarkably simple compounds, formed from an appropriate β-aminoalcohol (S-valinol,
Example 12.78, or 1S,2R-norephedrine, Example 12.79) by treatment with a carbonate or
chloroformate ester.
HO NH2
HO NH2
S-valinol 1S,2R-norephedrine
(EtO)2CO or
EtOCOCl
O
O
O NH
O NH
(12.78) (12.79)
The treatment of the chiral oxazolidinone with butyllithium and propionyl chloride
gives the N-acyloxazolidinone, which reacts with dibutylboron triflate and triethylamine
to give the Z(O) enolate with a d.r. greater than 100:1. The aldol addition of the boron eno-
late of the chiral N-propanolyoxazolidinone gives a mixture of the four possible diastereo-
isomeric aldol adducts, of which all but one are formed in negligible amounts. The Z(O)
enolate of the N-propanoyl-oxazolodinone based on S-valinol gives the 2S,3R (syn) aldol,
97. Heathcock, C.H.; Montgomery, S.H. Tetrahedron Lett. 1983, 24, 4637.
98. David A. Evans (1941–) was educated at Oberlin College (AB, 1963) and the California Institute of
Technology (Caltech; (PhD, 1967). He was immediately appointed to the faculty of UCLA and subsequently
to Caltech (1974) and Harvard (1983). Evans has been a pioneer in developing a practical asymmetric aldol
addition reaction. He was elected to the National Academy of Sciences in 1985 and won the Tetrahedron
Prize in 1998. For an autobiographical sketch with some fascinating details, see: Evans, D.A. Tetrahedron
1999, 55, 8589.
99. Evans, D.A.; Bartroli, J.; Shih, T.L. J. Am. Chem. Soc. 1981, 103, 2127.

as in Example 12.80. The Z(O) enolate of the N-propanoyloxazolidinone based on

2S,3R-norephedrine gives the enantiomeric aldol, as in E
xample 12.81.100
O O O
1) BuLi, THF
O NH 2) EtCOCl, –78°C O N
(S)
1) Bu2BOTf, Et3N
2) Me2CHCHO
(12.80)
O O
OH
O N (S)
(R)
(S)
syn isomers: d.r. 497:1

<1% anti diastereoisomers
O O O
1) BuLi, THF
O NH 2) EtCOCl, –78°C O N
(R)
(S)
Ph Ph
1) Bu2BOTf, Et3N
2) Me2CHCHO
(12.81) O O
OH
O N (R)
(S)
(R)
(S)
Ph
syn isomers: d.r. >500:1
<1% anti diastereoisomers
Studies101 have shown that the conformation of the exocyclic C—N bond is the key
stereochemistry-controlling feature in the enolate and that by controlling the conforma-
tion of this bond, one can control the enantioselectivity of the reaction. The system from
the carbonyl oxygen to the end of the enolate is planar to maximize conjugation, so there
are two extreme conformations possible for these metal enolates: a non-chelated confor-
mation, where the carbonyl group and the enolate π bond are cisoid to each other (Exam-
ple 12.82), and a chelated conformation, where the same two π bonds are transoid to each
other (Example 12.83). In these two different conformations, the shielding group (shown
as the large black circle) inhibits the approach to opposite faces of the enolate, thus leading
to the opposite stereochemistry in the aldol product.
100. Evans, D.A.; Bartroli, J.; Shih, T.L. J. Am.Chem. Soc. 1981, 103, 2127.
101. Evans, D.A.; Takacs, J.M.; McGee, L.R.; Ennis, M.D.; Mathre, D.J.; Bartroli, J. Pure Appl. Chem. 1981, 53,
1109. For more recent computational work on this problem, see: (a) Li, Y.; Paddon-Row, M.N.; Houk, K.N. J. Org.
Chem. 1990, 55, 481. (b) Bernardi, A.; Capelli, A.M.; Comotti, A.; Gennari, C.; Gardner, M.; Goodman, J.M.;
Paterson, I. Tetrahedron 1991, 47, 3471.

R' M R'
O O
R M R
O N O N
O O
(12.82) (12.83)
non-chelated chelated
Being a second-row element, boron cannot expand its octet, so boron may only be
bonded to two oxygens at once in the aldol reaction of enol borinates. Because one of these
oxygens must be the enolate oxygen and the other must be the carbonyl oxygen of the al-
dehyde partner, the boron enolate must react through a non-chelated transition state. This
allows the stereochemistry of the reaction of the boron enolate to be predicted on the basis
of the model shown in Figure 12.11 for the Z(O) enolate. In the non-chelated conformation,
the isopropyl group of the S-valinol auxiliary is placed so that it interferes with the axial
alkyl group on boron in one of the two transition states but not in the other; the favored
conformation is enclosed in the frame. Thus, this reaction strongly favors one aldol prod-
uct over the other. In the chelated enolate, the opposite stereochemical finding is true; in
this case, the favored conformation of the enolate has the si face of the enolate more acces-
sible to the aldehyde. Thus, it has been found that the enantioselectivity of the titanium
enolates of N-acyloxazolidinones is reversed compared to the boron enolates, although
both Z(O) enolates are highly selective for the syn aldol.102
Chiral species have an intrinsic diastereoselectivity in reactions where new chiral
centers are formed. This intrinsic diastereoselectivity is illustrated by Cram’s rule selec-
tivity in addition reactions, for example. When both reacting species are of this type,
their intrinsic diastereoselectivities may be matched (e.g., Example 12.84), in which
case the reaction usually proceeds with very high levels of diastereoselectivity. Alterna-
tively, they may be mismatched (e.g., Example 12.85), in which case the reaction pro-
ceeds with lower (often quite low) levels of diastereoselectivity. The enolates derived
non-chelated Figure 12.11 Predicting the

re (enolate)–si (aldehyde) stereochemistry of the aldol
reaction of chiral Z(O)
Me R R Me enolates for non-chelated
O O
(boron) enolates and chelated
O L L O
O B B O metal (e.g., Ti) enolates,
N Me N using the same chiral
L L
O H O oxazolidinone
Me Me H
Me
chelated
si (enolate)–re (aldehyde)
Me R R Me
O L L O
O O
M L L M H
N L O N
H O L
O O
102. Nerz-Stormes, M.; Thornton, E.R. J. Org. Chem. 1991, 56, 2489.

from the Evans chiral oxazolidinones exhibit extremely high levels of intrinsic diastere-
oselectivity. In the reactions of their Z(O) zirconium enolates with a chiral α-substi-
tuted aldehyde, the intrinsic diastereoselectivity of the oxazolidinones almost completely
overrode Cram’s rule s electivity—the configuration of the new chiral centers was deter-
mined solely by the chirality of the oxazolidinone, and not by the chirality of the alde-
hyde.103 Note how even in the mismatched pair of chiral reactants, the diastereoisomer
ratio was close to 20:1.
O O 1) LDA, THF, 0°C O O OH
2) Cp2ZrCl2 (1.1 eq) Ph
O N O N O
OHC (12.84)
3) O Ph
(matched) 98.7% this isomer
O O 1) LDA, THF, 0°C O O OH

2) Cp2ZrCl2 (1.1 eq) Ph
O N O N O (12.85)
OHC
3) O Ph
(mismatched) 94.5% this isomer

As pointed out in the previous section (revisit Figure 12.9 to recall this), obtaining anti
aldols is a rather more difficult task than obtaining the syn aldols. Although this task can
be accomplished using boron enolates, it is frequently experimentally simpler to make
metal enolates, so considerable effort has gone into finding ways to obtain the anti aldol
from a metal enolate. This remains true for the asymmetric reaction as well. There has
been some success, however. An early report appeared in which the addition of a chiral
titanium enolate to the titanium tetrachloride complex of an aldehyde gives the anti aldol
with high levels of both enantio- and diastereoselectivity (Example 12.86).104
Ts Cl Cl
Ts Ti
NH O TiCl4 (1 eq) N O
O i-Pr2NEt (4 eq)
O
CH2Cl2, r.t.
CHO•TiCl4 (12.86)
Ts HO
HO NH O
LiOH, THF
O
r.t., 2 h O
HO
d.r >99:1
103. Evans, D.A.; McGee, L.R. J. Am. Chem. Soc. 1981, 103, 2876.
104. Ghosh, A.; Onishi, M. J. Am. Chem. Soc. 1996, 118, 2527.

Organocatalysis in Enolate Additions

The Wieland-Meischer ketone105 has become an important starting material in a wide
range of syntheses, including steroids and terpenoids. The synthesis of the racemic com-
pound is carried out in two stages. The first stage involves an acid- or base-catalyzed
Michael addition of 2-methyl-1,3-cyclohexanedione to methyl vinyl ketone. In the synthe-
sis of the racemic ketone, the intramolecular aldol condensation of the diketone is cata-
lyzed by pyrrolidine in refluxing benzene. In 1977, the synthesis of optically active ketone
was reported, using l-proline in dry dimethyl sulfoxide (Example 12.87) as an organocat-
alyst in the second step.106 This reaction was an early example of what has now become a
flood (the original Gutzwiller paper had been cited more than 100 times at the writing of
this chapter, for example). The most successful catalysts share a common pair of structural
features that are characteristic of proline: a five-membered cyclic secondary amine and a
group at the α-carbon of the five-membered ring capable of functioning as a base (Example
12.88). The group labeled Nu is frequently anionic in these organocatalysts, and large
groups R tend to enhance the stereoselectivity in reactions where they are used. The group
X may be another heteroatom (usually sulfur or oxygen).107
O N CO2H O
H
(12.87)
O Me2SO, 120 h, 25°C
O (57% S; 20% ±) O
R
R
X
(12.88)
N
H Nu
Stereochemistry of Organocatalytic Nucleophilic Additions

Unlike the additions of metal enolates to aldehydes, where the formation of the anti aldol is
the greater challenge, in organocatalytic reactions, the reverse is often true. The dimeriza-
tion of propionaldehyde catalyzed by l-proline in dimethylformamide, for instance
(Example 12.89), leads to a 3:1 mixture of anti and syn aldols. Each diastereoisomer is ob-
tained in high enantiomeric excess.108 Changing the solvent to a less polar solvent tends to
raise the anti:syn ratio at the expense of making the reaction slower. Extending the reaction
time leads to the formation of a trimeric product where, again, the major product (Example
12.90) is that of anti addition at each stage, and the minor product (Example 12.91) is that
formed by anti addition to the syn aldol. However, one should be careful in making gener-
alizations: in this reaction; for example, it has been reported that the product ratios show
epimerization of the initial aldol during the second aldol addition.109 Interestingly, the
105. (a) Wieland, P.; Miescher, K. Helv. Chim. Acta 1950, 33, 2215. (b) Ramachandran, S.; Newman, M.S. Org.
Synth., Coll. Vol. V 1973, 486.
106. (a) Gutzwiller, J.; Buchschacher, P.; Fürst, A. Synthesis 1977, 167. (b) Buchsacher, P.; Fürst, P.A.;
Gutzwiller, J. Org. Synth., Coll. Vol. 7, 1990, 368.
107. For examples of successful organocatalysts for additions of enolates and enolate surrogates, see: (a)
Notz, W.; Tanaka, F.; Barbas, C.F., III Acc. Chem. Res. 2004, 37, 580. (b) List, B. In Mahrwald, R., Ed. Modern
Aldol Reactions. Vol. 1: Enolates, Organocatalysis, Biocatalysis and Natural Product Synthesis; (Wiley-VCH:
Weinheim, 2004); Ch. 4, p. 161.
108. Northrup, A.B.; MacMillan, D.W.C. J. Am. Chem. Soc. 2002, 124, 6798.
109. Chowdari, N.S.; Ramachary, D.B.; Córdova, A.; Barbas, C.F., III Tetrahedron Lett. 2002, 43, 9591.

product of the first aldol addition is less reactive than propionaldehyde itself, which makes
isolation of the dimer or trimer possible simply by changing the reaction conditions.
N CO2H
O O OH
H
H 1M, DMF, 4°C, 11 h H
anti:syn 3:1; 99% ee

CHO, DMF, 3 d
(53%; 43% ee) (12.89)
HO O HO O
OH OH
8 1
(12.90) (12.91)
Reaction Synopses
Aldol Addition
O 1) base O OH O OH
R' and/or
R 2) R"CHO R R" R R"
R' R'
syn anti
Base:
Metal enolate, thermodynamic: NaH, PhH; NaNH2, THF;
KOBut, t-BuOH; etc.
Lithium enolate, kinetic: LDA, THF, –78°C; LICA, THF, 8°C;
t-BuLi, THF, –100°C; etc.
Metal enolate: (1) LDA, THD, –78°C; (2) MCln
Z(O) Boron enolate: Bu2BOTf, i-Pr2NEt; 9-BBN-OTf,
i-Pr2NEt; Bu2BOTf, Et3N; etc.
E(O) Boron enolate: (c-C5H9)2BOTf, i-Pr2NEt; etc.
Stereochemistry: may be predicted using Zimmerman-Traxler transition state
model, but addition is reversible, limiting reliability of stereo-
chemical predictions; addition of metal enolates to chiral
a ldehydes follows Cram’s rule.
Addition of boron enolates can be predicted with confidence using the Zimmerman-
Traxler model: Z(O) gives syn aldol, E(O) enolate gives anti aldol.
Evans Asymmetric Aldol Addition
O OBL2 O O OH O OBL2 O O OH
R' R"CHO R"CHO
N N R" N N R"
R' R' R'
G G G G
L = n-Bu or 9-BBN L = c-C5H9 or c-C6H11
Stereochemistry fixed by stereochemistry of boron enolate

Stereochemistry predicted with confidence by Zimmerman-Traxler model
Chirality of enolate fixes stereochemistry of product; Cram’s rule is overridden in
this reaction.
Chirality (but not syn/anti diastereoselectivity) of product aldol is reversed using
coordinating metal enolate (e.g., Ti, Zr) instead of boron enolate.

Organocatalysis of Aldol Addition

R R R
cat.
R CHO R CHO cat: X
DMF Nu
OH NH
Catalyst, R = H, alkyl, aryl; X = CH2, O, S, etc.; Nu = OR, NR 2, O–, etc.

Stereochemistry: strong tendency to anti stereochemistry
Worked Problem
12-4 What is the major product expected in the following reaction sequence? The
product is obtained as a mixture of diastereoisomers—which stereoisomer should
predominate, and why?
MeO
1) LDA, THF, –78°C
t
MeO CO2Bu 2) MeO
O
OMe MeO
H H
3) (CO2H)2, H2O-THF
§Answer below.
Drill Problems
What is the major organic product of each of the following reaction sequences?
Where appropriate, specify the absolute configuration of the major product.
O O O O
1) Bu2BOTf, EtNiPr2 1) Bu2BOTf, EtNiPr2
O N O N
(a) (b)
2) CHO 2) CHO
O O O O
1) 9-BBN-OTf, Et3N 1) 9-BBN-OTf, Et3N
O N O N
(c) (d)
2) CHO 2) CHO
(continued)

The two stereoisomeric major products of this reaction are related to each other as syn and anti aldol ad-
ducts, but the difference (and, in fact, the designation of each) is complicated by the fact that the electrophilic
component is a ketone instead of an aldehyde. However, one can say with some degree of certainty that the
lithium enolate will add to the carbonyl group from the exo face of the bicyclic system, giving the endo alcohol
as shown.
MeO CO2But
1) LDA, THF, –78°C MeO
MeO CO2But HO
2) MeO
O MeO H O
OMe MeO
H H OMe H
3) (CO2H)2, H2O-THF
[J. Am. Chem. Soc. 1981, 103, 5813]

(Drill Problems continued)
O O O O
O N O N
(e) (f)
2) CHO 2) CHO
Ph
O O O O
O N O N
(g) (h)
2) CHO 2) CHO
Ph
O O O O
O N O N
(i) (j)
2) CHO 2) CHO
Ph Ph
O O O O 1) LDA, THF, –78°C

1) Bu2BOTf, EtNiPr2 2) Cp2ZrCl2
O N O N
(k) (l)
2) CHO 3) CHO
Ph
Problems
12-7 What reaction conditions or reagents should be used to complete the following
transformations?
CO2H
(a) CO2H
OH
H H
O O
(b) O O O O
O H O H
OH
HO
SMe
(c) SMe
O O
O O
OH
H H
(d) O O
H H
H H
OPMB OPMB OH O
(e) CHO OMe
N
Me

Ph Ph
OPMB
(f) O O
N N
O O O O OH
References: (a) J. Org. Chem. 1974, 39, 1322. (b) Tetrahedron Lett. 1975, 743. (c) Tetrahedron Lett. 1980,
21, 3139. (d) J. Am. Chem. Soc. 1980, 102, 5085. (e) Synthesis 2005, 1183. (f) Org. Lett. 2004, 6, 1445.
12-8 What is the major organic product of each of the following reactions, which are
steps from some classic syntheses?
OH
H O 1 M NaOH
(a) C20H26O4
THF, r.t.
OHC
O
C20H26O4
O
O
O EtCO2But, LDA
(b) O THF, HMPA
O H –78 to –30°C
O
OTES
1) i-Pr2NMgBr, THF
(c) TBSO
2) CHO
H O
OAc
O
DMAP
(d) TIPSO CHO
CH2Cl2
HO O O Ph
O
O
Ph
O
CHO
Ph O
NaOMe, MeOH, r.t.
(e)
TBSO O
OPMB Ph
References: (a) Can. J. Chem. 1979, 57, 3348. (b) J. Am. Chem. Soc. 1988, 110, 649. (c) J. Am. Chem. Soc.
1994, 116, 1597. (d) J. Am. Chem. Soc. 1997, 119, 2757. (e) Chem. Eur. J. 1999, 5, 121.
12.5 Conjugate Addition of Enolates and Similar Compounds
Michael Addition of Enolate Anions

Conjugated carbonyl compounds react with nucleophiles to give either 1,2- or 1,4-adducts
(Example 12.92). Generally, the 1,4-adduct is favored thermodynamically, so where the
addition to the carbonyl group is reversible, the 1,4-adduct reaction dominates the product

mixture. This situation applies to the addition of most nucleophiles, with the exception of
metal hydrides, alkali metal alkyls, and Grignard reagents.
Nu O O Nu
O (12.92)
R R R R R R
Enolate anions add to the β carbon of an α,β-unsaturated carbonyl compound or ni-
trile as soft carbon nucleophiles, rather than the harder oxyanion nucleophile, to give a
new C—C bond; this reaction is known as the Michael addition.110 The product of the
Michael addition is the enolate anion of a 1,5-dicarbonyl compound, so it is important to
take precautions to reduce the reactivity of the product enolate anion to avoid polymeriza-
tion of the conjugated carbonyl compound. For this reason, the reaction has often been
carried out using the conjugate base of a β-dicarbonyl compound, an α-cyanocarbonyl
compound, or a nitroalkane as the nucleophile because the rapid intramolecular proton
transfer to the enolate anion prevents this side reaction. The usefulness of this form of the
reaction is attested by the number of Organic Syntheses preparations using it.111
The same effect may also be accomplished by incorporating a third-row atom (usually
silicon or sulfur) into the conjugated system at the α position to stabilize the enolate anion
formed. A good example is provided by the reaction in Example 12.93, from the total syn-
thesis of vincamine,112 where the intermediate lithium enolate is stabilized by the adjacent
sulfur, making it a less reactive nucleophile than the initial amide (lactam) enolate anion.
O
O N
N
1) LDA (2.1 eq.), THF, –78°C
SMe N
N 2) H
H MeS
CO2Me CO2Me
O
N
(12.93)
N
Li
MeS
CO2Me
As with the aldol addition, the availability of preformed enolates by deprotonation of

a suitable precursor expanded the potential scope of the Michael addition. As noted in the
beginning of this section, the addition of a nucleophile to an enone can occur by the 1,2- or
1,4- manifold, so that there are three possible products in each reaction: the 1,2-adduct, the
syn-1,4-aduct, and the anti-1,4-adduct (Examples 12.94 and 12.95). The results of the
Heathcock group’s extensive study of Michael addition reactions of enones under both
110. (a) Michael, A. J. Prakt. Chem. 1887, 35, 349; 1894, 49, 20. (b) Bergman, E.D.; Ginsburg, D.; Pappo, R. Org.
React. 1959, 10, 179.
Arthur Michael (1853–1942), an American chemist, never received a university degree but studied under
Hofmann (1871 and 1873–1876), Bunsen (1872–1873), and Wurtz (1876–1877); during this year, he visited Men-
deleev in St. Petersburg. He was twice Professor of Chemistry at Tufts College (1880–1891 and 1894–1907) and
at Harvard (1912–1936). Independently wealthy, he built and worked in his own research laboratory in Britain.
He was elected to the National Academy of Sciences in 1889. For more biographical information, see: Fieser, L.F.
Biogr. Mem. Natl. Acad. Sci. 1975, 331.
111. (a) Clarke, H.T.; Murray, T.F. Org. Synth., Coll. Vol. 1 1941, 272. (b) Shriner, R.L.; Todd, H.R. Org. Synth., Coll. Vol. 2
1943, 200. (c) Cason, J. Org. Synth., Coll. Vol. 4 1963, 630. (d) Moffett, R.B. Org. Synth., Coll. Vol. 4 1963, 652. (e) Horning,
E.C.; Finelli, A.F. Org. Synth., Coll. Vol. 4 1963, 776. (f) McMurry, J.E.; Melton, J. Org. Synth., Coll. Vol. 6 1988, 648.
112. Herrmann, J.L.; Cregge, R.J.; Richman, J.E.; Semmelhack, C.L.; Schlessinger, R.H. J. Am. Chem. Soc.
1974, 96, 3702.

kinetic and thermodynamic conditions,113 using amide enolates 12.96 (Z(O) enolate) and
12.97 (E(O) enolate) are summarized in Figures 12.12 and 12.13.
X X X
LiO X
O O O O O O
Me H OH (12.94)
Rγ Rα' [Z(O)] Rγ Rα' Rγ Rα' Rγ Rα'
1,2- syn-1,4- anti-1,4
X X X
LiO X
O O O O O O
H Me OH
(12.95)
Rγ Rα' [E(O)] Rγ Rα' Rγ Rα' Rγ Rα'
Me
OLi
N N OLi
(12.96) (12.97)
In the reactions in 12.98 and 12.99, contained in Figure 12.12, the enone moiety of the
electrophile is kept constant and the α' group is varied through the series: Et, i-Pr, t-Bu,
Chx, and Ph). The right-hand diagram shows that in most cases with these reactions, the
reaction favors the formation of the 1,4-adduct, more especially (but not always) under
thermodynamic control. The picture with respect to stereochemistry is much more straight-
forward. The Z(O) enolate is generally only modestly stereoselective, except for reactions
involving aromatic ketones, where it is strongly syn-selective, and the E(O) enolate is uni-
formly strongly anti selective under both kinetic and thermodynamic conditions.
In the reactions in 12.100 and 12.101, contained in Figure 12.13, the α' group is kept con-
stant at tert-butyl, and the γ group of the Michael acceptor is varied through the series:
Et, i-Pr, t-Bu, and Ph). The right diagram shows that in most cases with these reactions, the
reaction favors the formation of the 1,4-adduct, more especially under thermodynamic con-
trol. The picture with respect to stereochemistry is much less straightforward than in the
reactions in 12.98 and 12.99. The Z(O) enolate is still usually only modestly stereoselective,
except for reactions involving aromatic ketones, but now the E(O) enolate also exhibits low-
ered stereoselectivity (only four of the cases studied gave d.e.'s in excess of 90%).
Figure 12.12 Effects of

enone structure on the
stereochemistry of the
Michael addition of
the amide lithium enolate
to enones of the structure
Rγ -CH = CH-CO-R α' under
kinetic and thermodynamic
conditions. The reactions
with the Z(O) enolate (12.96)
are labeled Z(k) [kinetic] and
Z(t) [thermodynamic],
corresponding to reaction
with the corresponding
reactions of the E(O) enolate
(12.97) being labeled E(k)
and E(t).
113. Heathcock, C.H.; Henderson, M.A.; Oare, D.A.; Sanner, M.A. J. Org. Chem. 1985, 50, 3019.

Figure 12.13 Effects of enone

structure on the
stereochemistry of the
Michael addition of the
amide lithium enolate to
enones of the structure
Rγ -CH = CH-CO-R α' under
kinetic and thermodynamic
conditions. The reactions
with the Z(O) enolate (12.96)
are labeled Z(k) [kinetic] and
Z(t) [thermodynamic],
corresponding to reaction
with the corresponding
reactions of the E(O) enolate
(12.97) being labeled E(k)
and E(t).
Asymmetric Michael Additions

As with most important C—C bond-forming reactions, the Michael addition has also
been the subject of intense activity aimed at controlling the absolute stereochemistry of
the reaction. Numerous methods have been developed for a wide range of substrates and
nucleophiles.114 The reaction between enones and malonate esters, which is of both histor-
ical and economic importance, has also been the subject of intense activity.115 Ironically,
we have already discussed asymmetric Michael additions—during our discussion of
asymmetric Friedel-Crafts alkylations! Here, in fact, we see the dichotomy of the language
much of modern organic synthesis. Let us ask the simple question: is the reaction in
Example 12.102 electrophilic aromatic substitution of the pyrrole by an iminium ion
electrophile—or nucleophilic addition of the electron-rich π electron cloud of the pyrrole
to an iminium ion as a Michael acceptor, followed by subsequent deprotonation? The best
answer that this author can come up with is—BOTH!
O Me•HX
N Me
Ph
X N Me X
H CHO (12.102)
CHO
N Z
R R Z
Conjugate Addition of Cyanide

Cyanide anion is often referred to as a pseudohalide because in many ways its chemistry
mimics that of fluoride anion. It is, for example, the only simple carbanion nucleophile
that adds reversibly to carbonyl groups, and, as such, it adds preferentially to conjugated
carbonyl compounds to give γ-ketonitriles. However, simple cyanide salts often give poor
yields with conjugated ketones because the equilibrium constant for addition is not always
114. Reviews: (a) Tsogoeva, S.B. Eur. J. Org. Chem. 2007, 1701. (b) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri,
A.; Petrini, M. Chem. Rev. 2005, 105, 933. (c) Berner, O.M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
(d) Jha, S.C.; Joshi, N.N. Arkivoc 2002, vii, 167. (e) Sibi, M.P.; Manyem, S. Tetrahedron 2000, 56, 8033.
115. (a) Miyazaki, T.; Maekawa, H.; Yonemura, K.; Yamamoto, Y.; Yamanaka, Y.; Nishiguchi, I. Tetrahedron
2011, 67, 1598. (b) Somaiah, S.; Sashikanth, S.; Raju, V.; Reddy, K.V. Tetrahedron: Asymmetry 2011, 22, 1. (c) Fang,
H.; Wu, X.; Nie, L.; Dai, X.; Chen, J.; Cao, W.; Zhao, G. Org. Lett. 2010, 12, 5366. (d) Sun, Y.; Fan, R. Chem.
Commun. 2010, 46, 6834. (e) Figueiredo, R.M.; Christmann, M. Eur. J. Org. Chem. 2007, 2575.

favorable. This can be remedied quite simply by changing the nucleophile to a dialkylalu-
minum cyanide (e.g., Example 12.103).
1) Et2AlCN (1.2 eq), PhH CN
2) [Bu4N][F2SiPh3] (1.2 eq)
(12.103)116
3) Tf2O
O (81%) OTf
Problem
12-9 What is the major organic product of each of the following reactions, which are
steps from some classic syntheses?
O
O
NC CO2Et
(a)
Et3N, EtOH
MeO
OMe
CO2Me CO2Me
(b) CO2Me PhCH2NMe3+ OH–
MeOH
OMe
O CH2(CO2Me)2
(c) NaOMe, MeOH
O
O CO2Et
(d)
NaOMe, MeOH
References: (a) J. Am. Chem. Soc. 1950, 72 228. (b) J. Am. Chem. Soc. 1962, 84, 3222. (c) J. Org. Chem.
1971, 36, 2021. (d) J. Am. Chem. Soc. 1985, 107, 4341.
Reaction Synopses
Michael Addition
G R' R' G
R R'
E E
R O R R
E: COR, CO2R, CONR 2, CN, NO2, SO2R, etc.

G: H, R, SR, SeR, SiR 3, etc.
Reagents: (1) RCOCH2R, LDA, THF, (2) R'2C = C(R)-COR'; etc.
or (1) R"2N-C(R')=CR'2, (2) HOAc, H2O, THF; etc.
(continued)
116. Peese, K.M.; Gin, D.Y. J. Am. Chem. Soc. 2006, 128, 8734.

Polymerization suppressed in enolate additions if G is SR, SeR, SiR 3, or other

third-row or higher group
Stereochemistry influenced by enolate geometry: E(O) enolates tend strongly to
anti products; Z(O) enolates tend to be less stereoselective
Conjugate Addition of Cyanide
R R
R NC
E E
R R R
E: COR, CO2R, CONR 2, CN, NO2, SO2R, etc.

Reagents: KCN, EtOH, ∆; Et2AlCN, PhH; etc.
Aluminum reagent tends to give higher yields
12.6 Azaenol Derivatives: Imines, Hydrazones, and Enamines
Metalated Imines and Hydrazones

Enolate anions from carbonyl compounds are always subject to undesired self-condensation
by the aldol or Claisen mechanism, and alkylation of ketone enolates is frequently difficult
to control so that the monoalkylated product is obtained. Depending on the rate of proton
transfer from the alkylated ketone to the unalkylated enolate, it may be impossible to pre-
vent polyalkylation. For these reasons, a need was seen for a surrogate for the carbonyl
group in these types of reactions. The obvious surrogates were compounds in which the
carbonyl oxygen is replaced by nitrogen: imines and hydrazones.
It was quickly found, however, that although there is a structural homology between
the C = O and C = N groups, homology does not extend to their reactivities. Enolization
of cyclohexanone, for example, is too fast to monitor, even at –78°C, and the deprotonation
of the corresponding imines by LDA occurs slowly at temperatures below 0°C. In addi-
tion, the much lower electrophilicity of the C = N group compared to the C = O group
means that self-condensation is virtually nonexistent in reactions of imine anions.
Work by Collum117 has shown that the deprotonation of imines is not always amenable to
a simple explanation, particularly given the relatively easy syn-anti isomerization in these
and similar compounds. Nevertheless, these systems are amenable to enantioselective al-
kylation reactions with high levels of asymmetric induction. A preference for deprotonation
of ketimines at the less substituted α-carbon was observed by Meyers in his asymmetric al-
kylation work, but the observation is not universal. As shown in Example 12.104,118 Meyers
found that it was necessary to heat the initial product under reflux to induce syn/anti isom-
erization of the imine and obtain good levels of deprotonation (only ≈ 33% of the imine
deprotonates without heating).
Me
1) LDA, THF, –78°C
2) MeI, –78°C
N O (12.104)
3) LDA, THF, ∆
4) MeI, –78°C
H Ph 5) HOAc, NaOAc, H2O Me
OMe
(77%, 85% e.e.)
117. Liao, S.; Collum, D.B. J. Am. Chem. Soc. 2003, 125, 15114 and references therein.
118. Meyers, A.I.; Williams, D.R.; Erickson, G.W.; White, S.; Druelinger, M. J. Am. Chem. Soc. 1981, 103, 3081.

One class of imines that can be alkylated with a strong preference for axial alkylation are
the N,N-dialkylhydrazones.119 Although the alkylation of the N,N-dimethylhydrazone of
2-methylcyclohexanone (Example 12.105) was reported to give the trans product as the
major component of a 10:1 mixture,120 later workers found that the cis isomer dominates the
product mixture under kinetic conditions of short reaction times and low temperatures.121
Me NMe2 Me
N 1) LDA, THF, –78°C O
(12.105)
2) MeI, –78°C
3) CuCl2, THF, H2O Me
The metalated hydrazone method has been transformed into one of the most effective
and general enantioselective alkylation procedures: the SAMP/RAMP hydrazone proce-
dure of Enders.122 These hydrazones can be deprotonated by LDA to give an anion that will
react with a wide range of electrophiles with relatively high enantioselectivity levels (above
95% e.e. for alkylation reactions). The carbonyl compound can be recovered by exhaustive
N-alkylation and hydrolysis; oxidative cleavage by ozonolysis (as shown in Example
12.106) or neutral hydrogen peroxide; or by acid-catalyzed hydrolysis, depending on the
functionality in the product.
MeO
O N
SAMP N
∆
1) LDA, Et2O, 0°C

(56-58% overall) 2) n-PrI, –110°C
(12.106)
MeO
N
O O3, CH2Cl2 N
–78°C
(97-98% e.e.)
The stereochemistry of the alkylation of a SAMP hydrazone may be rationalized in
terms of the transition state model in Figure 12.14. In this model, the lithiated hydrazone
adopts a conformation in which the pyrrolidine ring and the lithium chelate ring approx-
imate a trans-hydrindane with the six-membered ring in a boatlike conformation, and the
side chain in a pseudoequatorial position. In this conformation, alkylation of the si face of
the alkene π bond (as designated in Figure 12.14) requires the alkyl halide to approach
along a trajectory eclipsed by the adjacent methylene group of the pyrrolidine ring; alkyla-
tion of the re face requires the much less hindered approach eclipsed by the lone pair on
nitrogen. Thus, one predicts that the product of this alkylation will be the ketone where
the alkyl group is bonded to the re face of the enolate.
A more recent development is the use of sulfinylimines, sulfur-based chiral compounds
that have been found to be good substitutes for aldehydes and ketones in both alkylation
and aldol addition reactions. They also react with simple organometallic nucleophiles to
give amine derivatives. In this case, the chirality transferred to the product is from a chiral
119. Review: Hickmott, P.W. Tetrahedron 1982, 38, 1975.

120. Corey, E.J.; Enders, D. Chem.Ber. 1978, 111, 1337.
121. Collum, D.B.; Kahne, D.; Gut, S.A.; DePue, J.S.; Mohamadi, F.; Wanat, R.A.; Clardy, J.; Van Duyne, G.
J. Am. Chem. Soc. 1984, 106, 4865.
122. Enders, D.; Kipphart, H.; Fey, P. Org. Synth., Coll. Vol. 8 1993, 403.

Figure 12.14 Transition state RX (si)

model for SAMP hydrazone H
alkylation.
N R2
N
Li RX (re)
R1
O
Me
sulfur, rather than chiral carbon. The chiral sulfinylimines derived from tert-butylsulfi-
nylamine (Example 12.108)123 possess a chiral sulfur atom, making them some of the
most (if not the most) widely used chiral auxiliaries today. They permit the formation of
β-hydroxycarbonyl compounds from the methyl ketones or acetaldehyde with high
levels of diastereoselectivity—something the Evans oxazolidinones cannot do. Impor-
tantly, the sulfur in this compound and its derivatives is quite configurationally stable, so
it can be used as a chiral auxiliary in a wide range of applications. One of these is the
asymmetric addition of the corresponding metal azaenolates to aldehydes to give chiral
β-hydroxyaldimines that can be elaborated to a wide range of other products.
H2N S (12.108)
O
The aldimine or ketimine required (12.109) is formed from the chiral tert-butylsulfi-
nylamine and the carbonyl compound under Lewis acid catalysis by anhydrous copper
sulfate (aldehydes) or titanium tetraethoxide (ketones).124 Note how both Lewis acid cata-
lysts also serve as water scavengers. Deprotonation of the imine by LDA occurs on the less
substituted side and is usually followed by exchange with magnesium bromide to give a
magnesium azaenolate that then adds to the carbonyl group through a chairtype transi-
tion state (12.110) to give the β-hydroxyimine (12.111). Yields in this reaction are typically
above 50% (usually above 75%), and d.r.'s range from 73:27 to 98:2 depending on the exact
substitution pattern of the ketone and aldehyde partners. The β-hydroxyimine products
can be converted to a wide range of products by relatively simple chemistry, as shown in
Example 12.112, where the β-hydroxycarbonyl product is shown.
‡
R1 R1
1 1) LDA N S N S
R
N S M O O
2) MgBr2 H
Me O O OH
3) R2CHO
R2 R2
(12.109) (12.110) (12.111)
AcOH
MeOH-H2O
S O 40°C O OH
N OH (12.112)
1 2
R R
R1 R2
123. Reviews: (a) Ellman, J.A.; Owens, T.D.; Tang, T.P. Acc. Chem. Res. 2002, 35, 984. (b) Ellman, J.A. Pure
Appl. Chem. 2003, 75, 39. (c) Ferreira, F.; Botuha, C.; Chemla, F.; Pérez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162.
(d) Roback, M.T.; Herbage, M.A.; Ellman, J.A. Chem. Rev. 2010, 110, 3600.
124. (a) Liu, G.; Cogan, D.A.; Ellman. J.A. J. Am. Chem. Soc. 1997, 119, 9913. (b) Cogan, D.A.; Ellman, J.A. J.
Am. Chem. Soc. 1999, 121, 268.

One of the most important applications of chiral sulfinylimines is in the synthesis of

chiral amines by addition of organometallic nucleophiles. Unlike most imines, sulfinylim-
ines react with simple organometallic reagents to give sulfinylamine products that can be
hydrolyzed to amines. The high levels of diastereoselectivity in the addition reactions
come from the pronounced conformational preference of the sulfinylimine group itself.
Computations125 reveal that there is a strong conformational preference for the S = O
bond and the N = C bond to be syn-coplanar (Example 12.113). In this conformation,
there is the possibility of significant π delocalization of the lone pair on nitrogen into the
S–O σ* orbital. A second low-energy conformation (Example 12.114) places the two lone
pairs in an antiperiplanar arrangement; this is consistently some 6 kcal mol–1 higher in
energy than the conformation in 12.113.
S—O σ*
O
HS R1 O S R1
N N
R2 R2
(12.113) (12.114)
The addition of the Grignard reagent occurs through a cyclic activated complex simi-
lar to that shown in Example 12.115. The formation of this type of chelated activated com-
plex suggests that the enantioselectivity of this reaction in solvents capable of coordinating
the magnesium atom should be lower than in hydrocarbon or chlorocarbon solvents. It is
reassuring to find that this is the case.126 Interestingly, the stereochemistry of the addition
is reversed when alkyllithium reagents are used as the nucleophiles in the presence of
Lewis acid additives and in coordinating solvents. It is proposed that in this case, the re-
action proceeds through an open transition state, making the addition intermolecular
rather than intramolecular. The complexation of the sulfinyl oxygen by the Lewis acid
should further stabilize the conformation shown in Example 12.117, with the result that
the metal alkyl now attacks from the face opposite the tert-butyl group, giving the stereo-
chemistry shown in Example 12.118. One example from drug synthesis is shown in Exam-
ple 12.119.127 The free amine is liberated from the sulfinylamine as the hydrochloride salt
by treatment with methanolic hydrogen chloride.
‡
R1 R1
S S
N R2 N R2
Mg 3 H
O R O R3
(12.115) (12.116)
LA LA
O O
S R1 S R1
N N R3
R2 H R2
(12.117) (12.118)
125. (a) Bharatam, P.V.; Uppal, P.; Kaur, A.; Kaur, D. J. Chem. Soc., Perkin Trans. 2, 2000, 43. (b) Bharatam,
P.V.; Kaur, A.; Kaur, D. J. Phys. Org. Chem. 2002, 15, 197.
126. Cogan, D.A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55, 8883.
127. Pflum, D.A.; Krishnamurthy, D.; Han, Z.; Wald, S.A.; Senanayake, C.H. Tetrahedron Lett. 2002, 43, 923.

S PhMgBr, Et2O S
N O HN O
H (12.119)
PhMe
H
(78%; d.r. = 91:9)
Cl Cl
It is worthwhile noting that conjugated sulfinylimines do undergo 1,4-addition of alkyl
groups in the presence of copper (I) cyanide and a Lewis acid catalyst, as shown in Exam-
ple 12.120.128
BuLi, CuCN
S O
S BF3•OEt2 N
N O
(12.120)
THF, –78°C
(78%; 49:1 d.r.)
Enamines
Another alternative to the enolate anion is the enamine, formed by condensing a carbonyl
compound with a secondary amine. The resultant compound, which has the nitrogen di-
rectly bonded to one of the sp2-hybridized carbons of the alkene, is known as an
enamine.
The synthetic utility of enamines was recognized by Belgian-born American chem-
ist Gilbert Stork,129 whose work helped to develop enamines into powerful intermediates
for organic synthesis. The enamine double bond is very electron-rich, so that it reacts as
a nucleophile—effectively as a much less basic, neutral equivalent of an enolate anion.
This reactivity has been rationalized on the basis of resonance (Example 12.121). The
nitrogen atom of the enamine is sp2 hybridized, and its lone pair of electrons is delocal-
ized into the carbon-carbon π bond. The minor contributor to the resonance hybrid has
carbanionic character, and we therefore expect that the enamine will be a carbon
nucleophile.
N N (12.121)
major minor
The alkylation of an enamine occurs predominantly at carbon to give an intermediate
iminium ion that can be hydrolyzed under mild acidic conditions (e.g., dilute aqueous
acetic acid) to give the carbonyl compound. An early example of the formation and use of
enamines is provided by the steps from the synthesis of atrylacton, in Example 12.122.130
The enamine alkylation has two major advantages over enolate alkylation: (1) there is no
propensity for self-condensation of the enamine as occurs with cyclopentanone enolates,
128. McMahon, J.P.; Ellman, J.A. Org. Lett. 2005, 7, 5393.

129. Gilbert Stork (1921–) was born in Brussels, and received his early education in Paris. His family moved
to the United States early in World War 2. Stork graduated from The University of Florida (BS, 1942) and the
University of Wisconsin (PhD, 1945). In 1953, after spending time in industry in Milwaukee and then at Har-
vard, Stork joined the faculty at Columbia University in New York. He spent his entire career there, and was
instrumental in developing that department into one of the best in the world. For more biographical details,
see: Hoffman, F. Aldrichimica Acta 1982, 15, 3.
130. Minato, H.; Nagasaki, T. Chem. Comm. 1965, 377.

for example,131 and (2) it avoids polyalkylation in especially enolizable ketones such as
2-tetralones.132 However, because the enamine is also a less nucleophilic species, it often
requires a more electrophilic partner to give reasonable reaction rates.
H
O N N
PhH, TsOH, ∆
H H
CO2Et
Me Br
(12.122)
O
CO2Et
H
Reaction Synopses
Enamine Formation
O NR'2
R R
R R
Reagents: R'2NH, TsOH, PhH, ∆; etc.

SAMP/RAMP Hydrazones
MeO MeO R3
O N N R3
R2 O
N N R2
R1 R2 R2
R1
R1 R1
Reagents: (1) SAMP or RAMP, ∆, (2) LDA, THF, –78°C, (3) RX

or other electrophile, (4) O3, CH2Cl2;
or (1)–(3) the same, then (4) H2O2, MeOH;
or (1)–(3) the same, then (4) HCl, H2O, THF;
or (1)–(3) the same, then (4) MeI (excess), (5) HCl, H2O
Electrophiles: RX, RCHO, R 2C = CR–E, etc.
Sulfinylimine Anion Reactions
O
O a b S HCl
S N O R OH
N O
R Me R OH
R'
R Me
R'
Reagents: (a) ButSONH2, CuSO4; etc.

(b) (1) LDA, THF; then (2) MgBr2; then (3) R'CHO
Most useful as a method for generating a functional chiral enolate of a methyl ketone
(continued)
131. There is a significant self-condensation of cyclopentanone under conditions of the Michael addition:
(a) Prelog, V.; Metzler, O. Helv. Chim. Acta 1947, 30, 878. (b) Burkhalter, J.H.; Kurath, P. J. Org. Chem. 1959, 24, 990.
132. Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkowicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85, 207.

Additions to Sulfinylimines
NH2
O a b S HCl
S HN O R
N O H H
R H R
R H H R'
Reagents: (a) Bu SONH2, CuSO4; etc.

t
(b) R'MgX, Et2O
Chapter Summary
This chapter has been focused on displacement and addition reactions of carbon nucleop-
hiles. In nucleophilic substitution reactions of alkyl halides, the metal alkyls of the higher
alkali metals, or “ate” complexes of other metals (especially Lipshutz cuprates) work best.
Nucleophilic ring openings of epoxides, and nucleophilic addition to carbonyl compounds
are facilitated by the presence of a cation capable of acting as a Lewis acid (e.g., Li, Mg, Zn).
Used catalytically or stoichiometrically, copper (I) facilitates 1,4- addition to conjugated
carbonyl compounds. The Reformatskii reagents, prepared from α-haloesters or α-haloke-
tones and zinc metal, are excellent reagents for the preparation of β-hydroxycarbonyl
compounds, especially in hindered systems.
Enolate anions are prepared by deprotonation of the α carbon of carbonyl compounds
and similar species (nitro compounds, nitriles). Enolate anions can be formed under kinetic
conditions using strong amide bases such as LDA, lithium isopropylcyclohexylamide
(LICA), and lithium hexamethyldisilazide (LHMDS); kinetic deprotonation gives the less
substituted enolate. Thermodynamic deprotonation is carried out with oxyanion bases (e.g.,
KOBut) at higher temperatures and in the presence of a catalytically small amount of excess
ketone. Thermodynamic enolates have the more substituted double bond. Enolate anions are
ambident nucleophiles that react with (1) harder electrophiles (acid halides, phosphoryl
halides, silicon halides) through oxygen and (2) softer nucleophiles (alkyl halides, carbonyl
compounds) through carbon.
Enolates are capable of exhibiting E/Z isomerism; the stereochemistry is best described
using the E(O)/Z(O) system. The stereochemistry of the enolate can be affected by the size of
the groups attached to the carbonyl group and by the size of the deprotonating base. Large
bases and large groups attached to the carbonyl group favor the Z(O) enolate. The aldol
addition reaction under kinetic conditions may be viewed in terms of the Zimmerman-
Traxler model for the transition state, which predicts that Z(O) enolates will give higher
levels of diastereoselectivity than the corresponding E(O) enolates. The highest levels of
diastereoselectivity in aldol additions are obtained by using boron enolates, and Evans
chiral boron enolates also override the Cram’s rule selectivity of chiral aldehydes to allow
the prediction of the absolute configuration of the product. 1,4-Regiochemistry in addi-
tions to conjugated carbonyl compounds is favored by softer nucleophiles and occurs best
under thermodynamic conditions rather than kinetic conditions when the nucleophile is
an enolate anion (when the reaction is known as a Michael addition). Michael additions
under thermodynamic conditions tend to give anti products. E(O) amide enolates are
more stereoselective than their Z(O) counterparts.
The oxygen in an enolate may be replaced by nitrogen to give an aza-enolate. Aza-enolate
anion can be formed from imines or hydrazones, or from sulfinylimines; enamines are neu-
tral aza-enolate nucleophiles. The use of aza-enolates in asymmetric synthesis is facilitated
by means of Enders SAMP/RAMP hydrazones and chiral tert-butylsulfinylimines.

Key Terms
aldol addition Michael addition sulfinylimines

enamine Reformatskii reaction Zimmerman-Traxler
Evans asymmetric aldol SAMP/RAMP hydrazones model
addition sulfinylamines
Additional Problems
OTBS
Me
MgBr [Tetrahedron Lett.
(a)
CuBr/Me3SiCl 2011, 52, 2037]
O TMEDA/THF
O Br 1) LiHMDS, THF, –78°C
2) ZnBr2, Et2O, 0°C

OTES 3) MeCHO
OMe
[J. Am. Chem. Soc.

(b)
2003, 125, 1498]
1) LDA, LiBr, THF
MeCO2But
Br
O
2) OTES
OMe
Is there anything surprising about the first of these two
reactions?
OEt 1) s-BuLi, KOBut, THF, –95°C
OEt 2) t-BuCOMe, THF, –95°C to 25°C [Tetrahedron 1994,
(c) 3) H2O 50, 12463]
(2 eq. base used)
OEt
EtO 1) n-BuLi, KOBut, THF
[Org. Lett. 2009, 11,
(d) 2)
S N Ts 3914]
(2 eq. base used)
O
1) LDA, THF [J. Am. Chem. Soc.
(e) 2) MeI 2004, 126, 14358]
3) KOH, H2O-MeOH,
O O
H2C=O
O O
1) Bu2B-OTf, Et3N, 0°C [J. Org. Chem. 1997,
(f) O N
2) H2C=C(Me)CHO 62, 454]
Ph 3) H2O2 (work-up)
TBSO Me
MeONHMe•HCl [Tetrahedron Lett.
(g)
Me3Al, THF 2011, 52, 2037]
MeO2C OSiMe3

Ph
MOMO
O NaOMe [J. Org. Chem. 1991,
(h) MeO
56, 2115]
MOMO O O
Ph
MeO CHO
Me O [J. Am. Chem. Soc.

1) LDA, THF (1.1 eq), –78°C
S
(i) Ph N 2) MgBr2, –78°C 2002, 124, 6518;
3) Me2CHCHO, –78°C 2003, 125, 11276]
CO2H
1) n-BuLi (4 eq.), KOBut (4 eq.)
[Tetrahedron Lett.
(j) THF, –78°C
2000, 41, 3157]
2) Ph2CO
MeO OMe
O
1) Bu2B-OTf, i-Pr2NEt, CH2Cl2, –78*C
[Org. Lett. 2009, 11,
(k)
2) N 1179]
O CHO
H
MgBr
O O [Org. Lett. 2011, 13,
(l) OTBDPS
6018]
Et2O, –20°C, 16 h
O
t-BuLi, CuCN, Me3SiCl [J. Am. Chem. Soc.
(m) OMe
Et2O, Et3N, –78°C to —10°C 1988, 110, 649]
MeO
O
PhCO2 [J. Org. Chem. 2009,
(n) OPMB
74, 7220]
OHC NEt3, (c-C6H11)2BCl
1) Bu2BOTf, EtN(i-Pr)2
CO2Et [J. Org. Chem. 2006,
(o) OAc
2) 72, 1235]
CHO
1) LDA, THF, –78°C

O OO
CHO [Org. Lett. 2005, 7,
(p) O
2) 4419]
N Cbz
I 1) LDA, THF, –78°C

OTBS
H [Org. Lett. 2011, 13,
(q) CN
2) CHO 6268]
OTMS
12-11 What reagent, or sequence of reagents, should be used to complete the following
transformations?
OTBS OTBS
ButO2C O ButO2C HO
Ph Ph
O O [J. Am. Chem. Soc.
(a) O t
O t
O CO2 Bu Ph O CO2Bu Ph 1994, 116, 12111]
O O
[J. Org. Chem.
(b) Ph O Ph OTMS 1995, 60, 7837]

Ts
Ts
N
N H O
H O HO
O
OHC O N
N O
O
[J. Am. Chem. Soc.

(c)
2007, 129, 11987]
TsHN
TBDPSO CO2Et CO2Me
TBDPSO
O N CO2Et
O N
Ph
Ph
CONMe2 CONMe2
H H OH
CHO
[Tetrahedron Lett.
(d)
1990, 31, 2517]
HO2C
TBDPSO O
PhCH2O2C [Angew. Chem.
PMP
(e) N Int. Ed. 2011, 50,
CHO OH 3497]
TBDPSO
ButCO2 CONMe2 ButCO2 CONMe2

H H
O O
[J. Am. Chem. Soc.
(f)
O O O O 2003, 125, 11510]
O O
O O
[J. Am. Chem. Soc.

(g) CO2H 2002, 124, 9974]
O
S N N S S O [Org. Lett. 2004, 6,

(h) O O S NH N
3621]
O
12-12 Answer the following questions about the reaction shown.
(a) What reagent is required to couple the two reactants?

(b) In what order should the reactants be added to the reaction flask?
(c) Provide a reasonable explanation for the regiochemistry of the reaction.
OH
O
OH H
O O O O OH
H
O +
OH
OMe HO O
O
OHC
OMe

12-13 Write a reasonable mechanism for the transformation shown. [Reference: J. Am.
Chem. Soc. 1997, 119, 2755.]
OR OR
MeLi, CuI, Et2O
O –78°C to r.t., 18 h
OH CO2Et
CO2Et

Chapter thirteen
Reactive Intermediates III

Free Radicals, Carbenes, Arynes, and Nitrenes
13.1 Free Radicals1
Free radicals are species where at least one atom carries an unpaired electron; simple free
radicals contain an odd total number of electrons. The chemistry of free radicals in solu-
tion has been studied since 1900, when Russian-born American chemist Moses Gomberg2
attempted to prepare hexaphenylethane. What he obtained was a white solid that dis-
solved in solvents such as benzene to give a pale yellow solution that reacted with species
such as oxygen to give products that could not be explained on the basis of its assumed
identity as hexaphenylethane. Gomberg deduced that these products were consistent with
a free trivalent carbon species and suggested that the colorless hexaphenylethane dissoci-
ated as it dissolved to give a yellow solution of free triphenylmethyl.3 The structure of the
dimeric compound became a source of much perplexity, dubbed “the hexaphenylethane
riddle,” over the almost seven decades before its structure was unambiguously deduced to
be the dimeric compound shown,4,5 first proposed by Paul Jacobson in 1905.6 Gomberg’s
free radical hypothesis was confirmed experimentally when conclusive evidence for the
existence of free radicals was provided by Paneth and Hofeditz in 1929 in studies of the
pyrolytic decomposition of tetramethyllead (Figure 13.1).7
2 (13.1)
1. Monographs: (a) Pryor, W.A. Free Radicals (McGraw-Hill: New York, 1966). (b) Kochi, J.K. Free Radicals, 2
vols. (Wiley-Interscience: New York, 1973). (c) Nonhebel, D.C.; Walton, J.C. Free-Radical Chemistry (Cambridge
University Press: Cambridge, 1974). (d) Nonhebel, D.C.; Tedder, J.M.; Walton, J.C. Radicals (Cambridge Univer-
sity Press: Cambridge, 1979).
Reviews: (e) Griller, D.; Ingold, K.U. Acc. Chem. Res. 1976, 9, 13. (f) Kaplan, L. React. Intermed. (Wiley) 1978,
1, 163; 1981, 2, 251; 1985, 3, 227.
2. Moses Gomberg (1866–1947) was born in Russia, which he left around 1884. He was educated at the Uni-
versity of Michigan (Michigan; PhD, 1894) and began a 43-year tenure on the faculty there in 1893, eventually
becoming Professor and Chair. He spent 1896–1897 in Heidelberg and Munich. At Michigan, he rose to
Professor and became Chairman of the Department of Chemistry. Gomberg’s observations of triphenylmethyl
initiated the field of free radical chemistry. For more biographical details, see: (a) Schoepple, C.S.; Bachmann,
W.E. J. Am.Chem. Soc. 1947, 69, 2921; (b) Bailar, J.C., Jr. Biogr. Mem. Nat. Acad. Sci. 1970, 141.
3. (a) Gomberg, M. J. Am. Chem. Soc. 1900, 22, 757. (b) Gomberg, M. Ber. dtsch. chem. Ges. 1900, 33, 3150.
4. (a) Lankamp, H.; Nauta, W.T.; MacLean, C. Tetrahedron Lett. 1968, 249. (b) Smith, W.B. J. Chem. Educ.
1970, 47, 535.
5. For a history of the hexaphenylethane riddle, see: McBride, J.M. Tetrahedron, 1974, 30, 2009.
6. Jacobson, P. Ber. dtsch. chem. Ges. 1905, 38, 196.
7. Paneth, F.; Hofeditz, W. Ber. dtsch. chem. Ges. 1929, 62, 1335.
497

498 Advanced Organic Chemistry | Chapter thirteen
cold hot cold cold cold

PbMe4 PbMe4
Pb metal Pb metal
deposits here is
here removed
Figure 13.1 The Paneth and Hofeditz experiment to demonstrate the existence of free radicals. The
tetramethyllead is decomposed thermally and deposits lead metal in the front part of the
apparatus. Lead metal in the cold region of the tube downstream is gradually removed by the
radicals in the effluent gas.
OCH3
O O
C
OCH3
3 O
(13.2) (13.3)
Subsequently, much work was focused on the dimerization of triarylmethyl free radicals,
and it has become apparent that the major causes of the stability of such radicals are steric
rather than electronic. The tris-(2,6-dimethoxyphenyl)methyl radical (13.2) is completely
unassociated even in the solid state, but the sesquixanthydryl radical (13.3) dimerizes to
such an extent that there is no evidence of anything but dimer, even in solution.8
Worked Problem
13-1 The sesquixanthydryl radical dimerizes, and it has been suggested that it can do
so because steric factors do not prevent the dimerization. How could the struc-
ture of this radical be altered to provide evidence for this assertion?
§Answer below.
8. Sabacky, M.J.; Johnson, C.S.; Smith, R.G.; Gutowsky, H.S.; Martin, J.C. J. Am. Chem. Soc. 1967, 89, 2054.

Oxygen is a very small atom, so gradually replacing the oxygen bridges by more sterically demanding groups
(e.g., CMe2 groups) might prevent dimerization or gradually change the molecule from one that dimerizes to
one that does not. One example of such a series of molecules might be the three molecules below:
O O

Reactive Intermediates III 499
Structure and Bonding in Free Radicals

Organic free radicals are trivalent carbon species with an unpaired non-bonding electron
on the carbon atom. Because the carbon atom carries one electron, the radical represents
a species that is intermediate between the carbocation, where the central carbon carries a
formal positive charge and is devoid of non-bonding electrons, and the carbanion, where
the central carbon atom carries a formal negative charge and has a pair of non-bonding
electrons. The electronic structure of free radicals represents a stage intermediate between
the carbocation and the carbanion; therefore, free radicals might reasonably be expected
to exhibit properties intermediate between the extremes defined by the cation and the
anion. This appears to be the case.
The most direct method for obtaining data about the structure and bonding in free
radicals is by electron paramagnetic resonance (EPR) spectroscopy. This technique is
analogous to nuclear magnetic resonance spectroscopy, with one exception. It is the orien-
tation of the unpaired electron spin in an external magnetic field that is monitored rather
than the orientation of nuclear spins. Based on EPR spectra, the evidence suggests that the
preferred geometry of the radical center in simple hydrocarbon free radicals is planar with
the unpaired electron occupying a 2p orbital.
O
∆
R CMe3 R + CMe3 CO2
O O
(13.5)
Me
Me Me
1.0 0.4 0.05 0.004
However, there is also abundant experimental evidence that free radicals are not
forced to be planar. Many bridgehead radicals are known where the geometry of the
carbon skeleton cannot accommodate an sp2 hybridized carbon, and an excellent exam-
ple of just how much a free radical may deviate from planarity is provided by the cubyl
radical (13.4), a key intermediate in the first total synthesis of the highly strained hydro- (13.4)
carbon cubane.9 However, the preference for planar geometry is shown by the relative
rates of formation of the series of radicals shown (13.5) by pyrolysis of the tert-butyl
peresters of the corresponding carboxylic acids.10 Of the set, only the tert-butyl radical
can easily attain planarity.
The relative stability of free radicals may be obtained by comparing bond dissociation
energies of the corresponding hydrocarbons: the greater the bond dissociation energy, the
less stable the radical. Typical values of the bond dissociation energies for a few represen-
tative hydrocarbons are presented in Table 13.1.
It is evident from the values in Table 13.1 that alkyl free radicals are easier to form (i.e.,
R
less reactive) than vinyl or aryl free radicals, and the stability of radicals increases as the H
R
number of substituents at the radical center increases. This order of stability is the same as
that observed in carbocations. In the saturated carbocations, the order of stability was
rationalized in terms of hyperconjugation, so it may be reasonable to suggest that free
radicals are similarly stabilized by hyperconjugation, as shown in Example 13.6. Conju-
H H
gated free radicals (e.g., the allyl and benzyl radicals) are more stable than non-conjugated
radicals, and the stability increases as the extent of conjugation increases. (13.6)
9. Eaton, P.E.; Cole, T.W., Jr. J. Am. Chem. Soc. 1964, 86, 3157.
10. (a) Lorand, J.P.; Chodroff, S.D.; Wallace, R.W. J. Am. Chem. Soc. 1968, 90, 5266. (b) Fort, R.C.; Franklin,
R.E. J. Am. Chem. Soc. 1968, 90, 5267.

Table 13.1 Dissociation Energies* of C—H Bonds in Hydrocarbons When compared with carbon-centered free radicals,
heteroatom-centered free radicals where the heteroatom
Bond (kcal mol –1) (kJ mol –1)
is a second-row nonmetal are extremely energetic. At the
C6H5—H 110† 461† same time, the presence of a heteroatom in a molecule
≥ 108† ≥ 452† tends to stabilize a carbon-centered free radical if the he-
H2C=CH—H
teroatom is located on the α carbon of the radical (e.g.,
H3C—H 104 435 13.7). It is generally accepted that this stabilization occurs
(CH2)2CH—H 101 421 by a hyperconjugative mechanism similar to the stabiliza-
tion of carbocations by an adjacent heteroatom (e.g., 13.8;
RCH2—H 98 410 Figure 13.2).
R 2CH—H ‡
95 398 The effects of a heteroatom are illustrated by the data
in Table 13.2, where bond dissociation energies of repre-
R 3C—H 92 385
sentative C—H and O—H bonds of hydroxy compounds
H2C=CH–CH2—H 89 372 and ethers are gathered. The data in Table 13.2 show that
incorporation of an sp3-hybridized oxygen atom adja-
H2C=CH–CH(R)—H 83 347
cent to the radical center reduces the dissociation energy
C6H5CH2—H 85 356 of the C—H bond compared to the hydrocarbon,
whereas the homolysis of the O—H bond consistently
*
Experimental error in values is ± 1 kcal mol –1 (± 4 kJ mol –1). requires more energy than homolysis of the C—H bond
†
± 2 kcal mol –1 (± 8 kJ mol –1).
‡
Includes cyclopentyl and cyclohexyl groups. in the hydrocarbon. In addition, it is clear that as the
stabilization of the radical by hyperconjugation or con-
jugation increases, the amount of additional stabilization conferred by the heteroatom
diminishes. There is one exception to the general rule that oxygen-centered radicals are
extremely high energy—phenol, where the energy required for the homolysis of the
O—H bond compares favorably with that required for the homolysis of the benzyl C—H
bond of toluene. In the case of phenol, the homolysis of the O—H bond leads to a
resonance-stabilized phenoxy radical, thus making it much more stable than the satu-
rated oxygen-centered radicals.
The much higher energy of non-conjugated oxygen-centered free radicals is mani-
fested in much higher reactivity. For example, hydroxy or alkoxy radicals will abstract a
hydrogen atom from most hydrocarbons to give an alkyl free radical. This is one of the
reasons that organic peroxides, which decompose to alkoxy radicals, are used to initiate
many free radical reactions.
Reactivity of Free Radicals

As the only reactive intermediates with an unpaired electron, free radicals might be ex-
pected to exhibit some unique types of reactivity. This is most obvious in the mechanisms
of free radical reactions: unlike ionic reactions, where it is possible for a reaction to pro-
ceed by a concerted mechanism, this is not possible in most free radical reactions.
Figure 13.2 Comparison
R R
between the stabilization of a
free radical by an adjacent O O
oxygen atom (left) and the
stabilization of a carbocation
by an adjacent oxygen atom
(right). Both involve H H H H
delocalization of electron
density from oxygen to H2C OR H2C OR H2C OR H2C OR
carbon.
(13.7) (13.8)

Table 13.2 Bond Dissociation Energies in Hydrocarbon Derivatives
Bond (kcal mol –1) (kJ mol –1) Bond (kcal mol –1) (kJ mol –1)
CH3–H 104 435 HO–H 119 498
HOO–H 90 377
RCH2–H 98 410 RCH2O–H 104 437
HOCH2–H 94 393
MeOCH2–H 93 389
R 3C–H 92 385 HOCMe2–H 91 381
C6H5–H 110 461
C6H5CH2–H 85 356 C6H5O–H 88 368
H2C=CH-CHR–H 83 347 H2C=CH–CH(OH)–H 82 341
O=CR–H 87 364 RCOO–H 103–110 431–469
Free radical reactions differ from ionic reactions in one very important way: they
tend to occur as chain reactions.11 In a free radical chain reaction there are three dis-
tinct phases.
1. Initiation, the reaction or reactions where an initial source of free radicals to begin the
reaction is generated
2. Propagation, the steps where the products of the reaction are formed
3. Termination, the reaction or reactions where the free radicals that carry the chain re-
action are removed from the reaction mixture
Neither the initiation nor the termination steps contribute appreciably to the overall
product of the radical reaction, and virtually all the products are generated during the
propagation steps. In fact, the balanced equation for the net chemical reaction corresponds
to the sum of the balanced equations for the propagation steps only. However, a free radical
reaction will not occur until at least one free radical has been generated in an initiation
step—until an initiating radical is available, no formation of products can take place.
Propagation
The differences between ionic and radical reactions are probably best illustrated by making
a side-by-side comparison of a reaction that proceeds by an ionic mechanism (e.g., the
addition of bromine to cyclohexene) and a reaction that proceeds by a free radical mecha-
nism (the allylic bromination of cyclohexene).
Br
Br (13.9)
Br
In the ionic reaction, bromine adds to the alkene to give the 1,2-dihalide. The reaction,
which requires no discrete initiation step (beyond providing sufficient energy to overcome
the activation energy), proceeds by two steps (Example 13.9). In the first step, the alkene
11. Huyser, E.S. Free Radical Chain Reactions (Wiley-Interscience: New York, 1970).

Figure 13.3 Cycle diagram initiation termination

for the free radical
bromination of cyclohexene. Br
Br•
Chain carrier:
Radical 1
from chain
carrier 2
Chain carrier:
Br Br Radical 2 H Br
from chain
carrier 1
initiation termination
displaces bromide ion from the bromine molecule to give a cyclic bromonium ion that
then reacts with a bromide ion to give the observed product. In the second step, the bro-
mide ion may come from the same bromine molecule or a different one, so it is possible for
both bromine atoms in the product to come from the same bromine molecule. More im-
portantly, this means that the two bromine atoms in the product do not have to come from
different bromine molecules.
In a free radical reaction, product formation requires at least two steps, and it is the
hallmark of a free radical reaction that one of the chain carrying radicals is consumed and
another chain-carrying radical is formed in each propagation step. In the bromination of
cyclohexene, the first step involves the abstraction of the allylic hydrogen from cyclohex-
ene by a bromine atom to give hydrogen bromide (one of the observed products of the re-
action) and the 2-cyclohexenyl radical. The second step of the reaction involves the
reaction between the 2-cyclohexenyl radical and molecular bromine to give 3-bromo-1-
cyclohexene and a bromine atom. Note that the two bromine atoms in the product must
come from different bromine molecules.
Free radical chain reactions can be represented as cycle (“carousel”) diagrams, and
this representation does a good job of showing the dynamics of free radical reactions, as
illustrated by the free radical bromination of cyclohexene (Figure 13.3). In this diagram,
the free radical chain carriers (the reactive intermediates) are located within the cycle,
whereas the stable compounds (reactants, products, or initiators) are located outside
the cycle. It is important for the success of a free radical reaction that the relative rates of
the steps permit highly selective reactions. For this reason, much effort has been expended
in measuring the rates of radical reactions.12
Initiation
The initiation of free radical chain reactions requires the production of an initiating
free radical from an easily homolyzed precursor, known as an initiator. Most initiators
function by homolysis of a relatively weak bond or by the formation of an exceptionally
stable molecule during the homolysis. The most widely used initiators are organic azo
compounds (that homolyze to give N2, an extremely stable molecule) and organic per-
oxides (where it is the weak O—O bond that homolyzes). Two of the most popular
radical initiators are azo-bis-isobutyronitrile (AIBN 13.10) and benzoyl peroxide
(13.11), both of which undergo homolysis under thermal or photochemical reaction
conditions.
12. For a leading review, see: Newcomb, M. Tetrahedron 1993, 49, 1151.

NC N ∆ or hν NC N (13.10)
N CN N CN
AIBN
O O
Ph O ∆ or hν Ph O
O Ph O Ph (13.11)
O O
benzoyl peroxide
Oxygen-centered free radicals often undergo fragmentation to give simple alkyl free
radicals and a carbonyl compound. The bond energy of a carbonyl group is typically be-
tween 170 and 180 kcal mol –1, and the average bond dissociation of the C—O σ bond is
approximately 86 kcal mol –1. This means that the dissociation energy carbonyl π bond is
quite high (≥ 85 kcal mol –1), which makes the formation of the carbonyl compound and an
alkyl free radical (e.g., 13.12) thermodynamically favorable. In similar fashion, carboxy
radicals lose carbon dioxide to give alkyl free radicals (13.13).
R
CO2
R R O O
R O R• (13.12) R R• (13.13)
R O
The initiation step in a free radical reaction is very important if the reaction is to be
used in synthesis, so the site-selective formation of free radicals will be examined in much
more detail in Chapter 14.
Termination
At some point during a free radical chain reaction, two radicals will be generated in close
enough proximity to each other for as radical-radical reaction to occur. Such reactions,
which remove a free radical from a chain reaction without replacing it, will terminate the
chain reaction. The most common termination reactions are radical recombination reac-
tions (13.14), where a new σ bond is formed, or atom-transfer reactions (13.15, 13.16) be-
tween radicals, which lead to the formation of a new π bond and a new σ bond. Most
importantly, both reactions generate only non-radical products.
Atom transfer
H X
+ H X (13.15)
Radical recombination
H
R• + R• R R
(13.16)
R• + X• R X H
X• + X• X X H
H
(13.14)
Radicals in Synthesis
To reiterate: a pointed out just above, free radicals have become quite useful intermediates
in organic synthesis, and we will discuss their use in synthesis in much more detail in
Chapter 14.

Reaction Synopses
Methods for Generating Free Radicals
hν RH N R hν
RO OR RO• R• R N R•
or ∆ or ∆
Peroxide initiators: (PhCO2)2; Me3CO—OH; H2O2/Fe2+; etc.

Azoalkane initiators: AIBN, etc.
Radical Fragmentation
R O
R O R• R R•
R O
Fragmentation of alkoxy radicals produces an aldehyde or ketone.

Fragmentation of acyloxy radicals produces carbon dioxide.
Worked Problem
13-2 The initiation of free radical reactions by hydroxy or alkoxy radicals usually
occurs by hydrogen atom abstraction and by the 2-cyanopropyl radical usually
occurs by addition to a carbon-carbon π bond. What is the reason for these
differences?
H O C N
hydroxy radical 2-cyanopropyl radical
§Answer below.
Problems
13-1 When he treated the dimer of triphenylmethyl radical with HCl, Russian
chemist Aleksei Chichibabin obtained a new hydrocarbon with the formula
C 38H 30. What is the most likely structure of this hydrocarbon and how is it
formed?

The bond energy of the O—H bond is more than 100 kcal mol –1, so abstraction of a hydrogen atom from
sp3-hybridized carbon (bond energy ≈ 85–95 kcal mol –1) by the oxygen-centered hydroxy or alkoxy radicals is
usually exothermic. This makes the hydrogen atom abstraction reaction a favorable and rapid reaction for
these radicals. In contrast to this, the 2-cyanopropyl radical is carbon-centered. It will not usually participate
in hydrogen atom abstraction reactions because they are not strongly exothermic. This leaves the predomi-
nant reaction of these radicals to be addition to a carbon-carbon π bond; because the C—C σ bond formed is
stronger than the C—C π bond broken, this addition is almost always exothermic, making the addition
favorable.
The addition of the hydroxy or alkoxy radical to the alkene is a possible reaction pathway, but with these
highly reactive radicals, hydrogen atom abstraction, which leads to the formation of a new C—O σ bond, is
considerably less exothermic and therefore less favorable.
R' R'
R O H R' R OH R'
R' R' C N C N

13-2 The radical (Me3C)3C• is unusually unreactive for a non-conjugated free radical.
For example, it exists in the solid state as the free radical, rather than the dimer,
and it does not react with oxygen. Why should it be so unreactive?
13-3 The following free radical, which has only two aromatic rings in a position to
conjugate with the free radical center, is a stable solid that does not react, even
with oxygen. Why is this radical so stable?
Cl Cl Cl Cl Cl
Cl Cl
Cl Cl Cl Cl
13-4 The final step in the Eaton synthesis of cubane [J. Am. Chem. Soc. 1964, 86, 3157]
involved heating a tert-butyl perester in diisopropylbenzene, as illustrated below.
Suggest a mechanism for this transformation.
O Me2CHC6H4CHMe2
O
O
150°C
30%
13-5 The Barton reaction is a reaction of a nitrite ester that led to the formation of an
oxime of an aldehyde in Barton’s synthesis of the corticosteroid, aldosterone. The
oxime formed is the enol tautomer of a nitrosoalkane. Suggest a mechanism for
the transformation.
O
OH
N
O O OH N O
OH hν OH
O O
An isomeric product with a three-membered ring is formed in the same reaction.

Based on your proposed mechanism, what is this product?
13-6 Oxygen reacts with ethers in the presence of light to generate explosive ether perox-
ides. What is the most probable structure of these ether peroxides, and by what mech-
anism are they formed? Draw a carousel diagram of your proposed mechanism.
13.2 Carbenes13,14
In 1950, Hine surprised the organic chemistry community with the first solid evidence
that a neutral divalent species, a carbene, was involved in the reaction of aqueous hydrox-
ide ion with chloroform.15 A carbene is a neutral carbon electrophile with a formally diva-
lent carbon bearing only six valence electrons, :CR 2. It can, therefore, act as an electron-pair
13. Monographs: (a) Hine, J. Divalent Carbon (Ronald Press: New York, 1964). (b) Jones, M., Jr.; Moss, R.A. Carbenes,
2 vols. (Wiley-Interscience, New York, 1973–1975). (c) Kirmse, W. Carbene Chemistry, 2nd ed. (Academic Press: New
York, 1971). (d) Rees, C.W.; Gilchrist, T.L. Carbenes, Nitrenes, and Arynes (Nelson: London, 1969).
Reviews: (e) Moss, R.A.; Jones, M., Jr. React. Intermed. (Wiley) 1978, 1, 69; 1981, 2, 59; 1985, 3, 45. (f) Bethell, D. Adv.
Phys.Org. Chem. 1969, 7, 153. (g) Closs, G.L. Top. Stereochem. 1968, 3, 193. (h) Herold, B.J.; Gaspar, P.P. Fortschr.
Chem. Forsch. 1966, 5, 89. (i) Kirmse, W. Angew. Chem. Int. Ed. Engl. 1965, 1, 4. (j) Schreck, J.O. J. Chem. Educ. 1965,
42, 260. (k) Köbrich, G. Angew. Chem. Int. Ed. Engl. 1967, 5, 41. (l) Buehle, C.A. J. Chem. Educ. 1972, 49, 239.
14. The term, “carbene” was, to quote footnote 9 of Doering, W.v.E.; Knoz, L.H. J. Am. Chem. Soc. 1956, 78,
4947, “collaborately conceived by W. von E. Doering, S. Winstein, and R.B. Woodward in a nocturnal Chicago
taxi, and later delivered diurnally in Boston.”
15. Hine, J. J. Am. Chem. Soc. 1950, 72, 2438.

acceptor, and it is a Lewis acid. Carbenes exist in two forms: singlet carbenes, in which all
R R the electrons are paired, and triplet carbenes, in which there are two unpaired electrons.
C C
R R Singlet carbenes have two possible structures, with the center carbon being sp2 hybrid-
ized and the lone pair of electrons in an sp2 hybrid orbital (13.17a), or the center carbon is
(13.17a) (13.17b) approximately sp3 hybridized with each electron occupying a hybrid orbital (13.17b). Both
singlet carbene models predict a bent structure. Herzberg16 first isolated singlet methylene, and his subse-
quent work resulted in general acceptance of the sp2 hybridized model for this species.
R R This model, which allows the carbene to be represented formally as a zwitterion (13.18)
allows a rationalization of the effect of heteroatoms on carbene reactivity: the delocaliza-
X X
(13.18)
tion of the lone pair from the heteroatom to the electron-deficient carbon reduces the
electrophilicity of the carbene.
R R Likewise, there are two models for triplet carbenes. In one model (13.19b), the carbene
C
R
C is linear, with the center carbon being sp hybridized and the two unpaired electrons in the
R
two unhybridized p orbitals. The other model (13.19a) resembles the sp3 model of the sin-
glet carbene with one spin reversed. The structure is predicted to be linear by one model
(13.19a) (13.19b)
and bent by the other. Both experimental17 and theoretical18 work suggests that triplet
triplet carbene methylene is bent, with an H—C—H angle of 136°.
As their electronic structure implies, triplet carbenes are diradicals that react by a free
radical mechanism; this means that reactions involving triplet carbenes cannot proceed
by a concerted mechanism. Singlet carbenes, on the other hand, have an empty p orbital,
like a carbocation, and an sp2 orbital carrying a lone pair, like a carbanion. Thus, a singlet
carbene behaves in much of its chemistry as a zwitterion: a hybrid of an electrophilic car-
bocation and a nucleophilic carbanion. In most of its reactions, it behaves predominantly
as an electrophile.
Carbenes or their equivalents are most commonly generated from their precursors by
the process of α-elimination (Table 13.3). During the reaction, a carbanion carrying a leav-
ing group on the α carbon is formally generated, and the loss of the leaving group formally
results in production of the carbene. The carbenes may be free, as
Table 13.3 Generation of Carbenes by α-Elimination occurs when they are generated from α-haloalkylmercury halides,19 or
R R R they may be transferred directly from the organometallic precursor,
R Y R X R
without the intervention of the free carbene, as happens with the anal-
X
ogous α-haloalkylzinc halides.20 Photolysis of a wide range of com-
Reaction pounds, including diazoalkanes and diazirines, remains a standard
X Y Conditions method for the production of carbenes.
H X (Cl, Br, I) Base An alternative method for the generation of carbenes involves the
removal of (1) a carbonyl oxygen atom from an ester or amide (X=O)
X (Cl, Br, I) X (Cl, Br, I) RLi or (2) a thiocarbonyl sulfur atom from a thionoester or thioamide
RHg X (Cl, Br, I) ∆ (X=S) by heating the appropriate substrate with a trivalent phospho-
rus compound (usually a trialkyl phosphite). This reaction is critical
=N2 (diazo compound) None ∆ or hν in the Corey-Winter olefin synthesis (13.20) by syn elimination of the
None cyclic carbonate or thiocarbonate of a 1,2-diol.21 Evidence that a car-
=N2 (diazirine) ∆ or hν
bene is involved as an intermediate in this reaction was provided by
16. (a) Herzberg, G.; Shoosmith, J. Nature 1959, 183, 1801. (b) Herzberg, G. Proc. Roy. Soc. 1961, A 262, 291.
17. (a) Wasserman, E.; Yager, W.A.; Kuck, V.J. Chem. Phys. Lett. 1970, 7, 409. (b) Bunker, P.R.; Sears, T.J.;
McKellar, A.R.W.; Evenson, K.M.; Lovas, F.J. J. Chem.Phys. 1983, 79, 1211. (c) McKellar, A.R.W.; Yamada, C.;
Hirota, E. J. Chem. Phys. 1983, 79, 1220. (d) Bunker, P.R.; Jensen, P. J. Chem. Phys. 1983, 79, 1224.
18. (a) Bender, C.F.; Schaefer, H.F., III J. Am. Chem. Soc. 1970, 92, 4984. (b) Schaefer, H.F., III Science, 1986,
231, 1100; 1986, 232, 1319. (c) Wasserman, E.; Schaefer, H.F., III Science 1986, 233, 829.
19. (a) Seyferth, D.; Mui, Y.-P.; Burlitch, J.M. J. Am. Chem. Soc. 1967, 89, 4953. (b) Seyferth, D. Acc. Chem. Res.
1972, 5, 65.
20. Charette, A.B.; Marcoux, J.-F. J. Am. Chem. Soc. 1996, 118, 4539.
21. (a) Corey, E.J.; Winter, R.A.E. J. Am. Chem. Soc. 1963, 85, 2677. (b) Corey, E.J.; Hopkiss, P.B. Tetrahedron
Lett. 1982, 23, 1797.

the work of Horton and Tyndall.22 The driving force for the reaction almost certainly
comes from the highly exothermic formation of the P=O or P=S groups in the
phosphorus-containing product.
X
P(OR)3 X P(OR)3 R1 R2
O O
O O O O
R1 R2 R3 R4
R3 R4 R1 R2 R1 R2
R3 R4 R3 R4
(13.20)
Carbenoids
Often, a carbene formally appears to be involved in a reaction, but there is evidence
that no free carbene is actually produced in the reaction. The reagent in such reactions
is called a carbenoid. Almost always it is an organometallic halide capable of eliminat-
ing a metal halide during the reaction, or it may be a species where there is a metal-
carbene complex with a formal metal-carbon double bond. These species are most often
formed by the reaction of a diazoalkane with rhodium (e.g., 13.21) or copper
(e.g., 13.22).23 The reactive intermediate in the Simmons-Smith cyclopropanation reac-
tion is iodomethylzinc iodide, I—Zn—CHI 2.24 Copper- and rhodium-catalyzed decom-
position of sulfonium and iodonium ylides also appears to involve the formation of
metal carbenoid intermediates.25
O
O
N2
H O
O O 26
TBSO O TBSO (13.21)
hν (254 nm) O
H O
CO2Me H
N2 CO2Me 27
CuI, (MeO)3P
O (13.22)
O
Br
H Me
C H Me
Br Br
Me H Br
Br KOBut Me H 28
H C Br
Br (13.23)
Br Me H
Me H Br
C
Br Br
Me H
Me H
22. Horton, D.; Tyndall, C.G., Jr. J. Org. Chem. 1970, 35, 3558.
23. (a) Moser, W.R. J. Am. Chem. Soc. 1969, 91, 1135. (b) Doyle, M.P. Chem. Rev. 1986, 86, 919. (c) Brookhart,
M. Chem. Rev. 1987, 87, 411.
24. Charette, A.B.; Marcoux, J.-F. J. Am. Chem. Soc. 1996, 118, 4539.
25. Müller, P.; Fernandez, D.; Nury, P.; Rossier, J.C. J. Phys. Org. Chem. 1998, 11, 321.
26. Livinghouse, T.; Stevens, R.V. Chem. Commun. 1978, 754.
27. Nakayama, M.; Ohira, S.; Okamura, Y.; Soga, S. Chem. Lett. 1981, 731.
28. Skell, P.S.; Garner, A.Y. J. Am. Chem. Soc. 1956, 78, 3409

Carbene Addition
In their reactions, carbenes almost always form two bonds to the carbene carbon to com-
plete its octet. Probably the most characteristic reactions of carbenes involve addition to a
π bond to give a three-membered ring and insertion into a σ bond to give a pair of new σ
bonds. The addition reactions of carbenes to π bonds can be distinguished by carbene
type. Singlet carbenes add stereospecifically in a one-step, concerted reaction with syn
stereochemistry, so the stereochemistry of the starting alkene is retained in the cyclopro-
pane product (e.g., 13.23).29
The reactivity of singlet carbenes toward alkenes reveals their electrophilic nature,
paralleling the reactivity of known electrophilic reagents such as bromine30 and peracids31
toward alkenes. The results of a series of competitive cyclopropanations of alkenes and
isobutylene by halogenated carbenes32 are presented in Table 13.4.
The addition of triplet carbenes to alkenes requires addition to the π bond in a two-
step reaction, which leads to loss of stereochemistry of the original alkene; this is shown
schematically for addition of triplet CH2: to a cis alkene in Figure 13.4. Thus, the closure of
the three-membered ring after the initial addition of the carbene to the π bond requires
spin inversion, which allows the rapid rotation about the carbon-carbon σ bond of the
original alkene to occur. This results in the stereochemistry of the cyclopropane product
becoming unrelated the stereochemistry of the starting alkene.
The other reaction characteristic of carbenes is the insertion into σ bonds (e.g., 13.24).33
The reactions of singlet methylene with saturated hydrocarbons is essentially random,
while the reaction of the triplet shows selectivity for more substituted C—H bond insertion,
as would be expected for a two-step reaction involving initial C—H homolysis. Thus, the
reaction between propane and triplet carbene, generated by photolysis of ketene, gives a
Table 13.4 Relative Rates of Additions of Halocarbenes to Alkenes
Alkene CFCl CCl2 CBr2 Alkene CFCl CCl2 CBr2
Me Me Me
31 6.5 3.5 0.097 0.15 —
Me Me Me
Me
6.5 2.8 3.2 0.0087 0.011 —
Me Me
Me
1 1 1 — 0.023 0.07
Me
Me Me 0.14 0.23 — — 0.12 0.4
29. (a) Doering, W.v.E.; LaFlamme, P. J. Am. Chem. Soc. 1956, 78, 5447. (b) Skell, P.S.; Woodworth, R.C. J.
Am. Chem. Soc. 1956, 78, 4496.
30. (a) Ingold, C.K.; Ingold, E.H. J. Chem. Soc. 1931, 2354. (b) Anatakrishnan, S.V.; Ingold, C.K. J. Chem. Soc.
1935, 984, 1396.
31. Swern, D. J. Am. Chem. Soc. 1947, 69, 1692.
32. (a) Moss, R.A.; Gerstl, R. J. Org. Chem. 1967, 32, 2268. (b) Moss, R.A.; Gerstl, R. Tetrahedron, 1967, 23,
2549. (c) Skell, P.S.; Garner, A.Y. J. Am.Chem. Soc. 1956, 78, 5430. (d) Doering, W.v.E.; Henderson, W.A., Jr. J.
Am. Chem. Soc. 1958, 80, 5274.
33. (a) Kirmse, W. Carbene Chemistry (Academic Press: New York, 1964), ch. 2. (b) Hine, J. Divalent Carbon
(Ronald Press: New York, 1964), ch. 2. (c) Ring, D.F.; Rabonovitch, B.S. Can. J. Chem. 1968, 46, 2435. (d) Seyferth, D.;
Mai, V.A.; Gordon, M.E. J. Org. Chem. 1970, 35, 1993. (e) Seyferth, D.; Burlitch, J.M.; Yamamoto, K.; W ashburn, S.S.;
Attridge, C.J. J. Org. Chem. 1970, 35, 1989.

R R R R Figure 13.4 Addition of

H R fast H H a triplet carbene to an
H R alkene π bond results in
H H H2C H2C
stereochemical equilibration.
1) spin inversion (slow)

2) radical combination
H H (fast)
R R R H
H H H R
mixture of butane and isobutane in the ratio 63:37.34 On the other hand, the reaction be-
tween pentane and singlet carbene, generated by photolysis of diazomethane, gives a mix-
ture of hexane, 2-methylpentane, and 3-methylpentane in the ratio 49:34:17, which is close
to the statistical ratio of 6:4:2,35 and insertion into heptane is close to statistical.36 The reac-
tion between singlet methylene (:CH2) and cyclohexene gives 40% addition to the π bond
and 60% insertion products divided among 1-methylcyclohexene (10%), 3-methylcyclohexene
(25%), and 4-methylcyclohexene (25%). This shows that for this very reactive carbene, there
is an approximate 8:1 preference for addition over intermolecular insertion and that inser-
tion into sp3 C—H bonds is favored by a factor of approximately 1.25 over insertion into sp2
C—H bonds. The insertion of singlet dichlorocarbene into (S)-(+)-2-phenylbutane (13.25)
gives products with at least 97% retention of configuration at carbon.37 Similar observa-
tions have been made with respect to carbene insertion into Si—H bonds.38
R R R R R
R R
H R H H
H R3 R3 3 R3
R1 2 R1 2 R1 2 R R1 2
R R R R
singlet triplet
(13.24)
PhHgCCl2Br
(13.25)
80°C, 3 h
CHCl2
(87% based on
(S) recovered starting
(97% S)
material)
Carbenes and Carbenoids in Synthesis

The advent of the olefin metathesis reaction, which is catalyzed by a transition metal-
carbene complex, has revolutionized the way that carbenes are used in organic synthesis.
Copper and zinc carbenoids react predictably by addition to alkenes to give cyclopropanes
or by insertion into bonds to give products of homologation.
34. Frey, H.M.; Kistiakowski, G.B. J. Am. Chem. Soc. 1957, 79, 6373.
35. (a) Doering, W.v.E.; Laughlin, R.G.; Buttery, R.G.; Chaudhuri, N. J. Am. Chem. Soc. 1956, 78, 3224.
(b) Frey, H.M. J. Am. Chem. Soc. 1958, 80, 50005.
36. Richardson, D.B.; Simmons, M.C.; Dvoretzky, I. J. Am. Chem. Soc. 1961, 83, 1934.
37. (a) Seyferth, D.; Cheng, Y.M. J. Am. Chem. Soc. 1971, 93, 4072. (b) Seyferth, D.; Cheng, Y.M. J. Am. Chem.
Soc. 1973, 95, 6763. These results contradict an earlier report that the insertion of carbenes into 2-phenylbutane
occurs with racemization (Franzen, V.; Edens, R. Justus Liebigs Ann. Chem. 1969, 729, 33) by noting that the
product formed has a very small specific rotation.
38. Sommer, L.H.; Ulland, L.A.; Parker, G.A. J. Am. Chem. Soc. 1972, 94, 3469.

MLn
MeO
MeO (13.26)
R1 R2 1 2
R R
M = Cr, Mo, W
More recently, carbenes in the form of their transition metal complexes have become
important synthetic reagents. Early on, the Fischer carbene complexes (13.26;
MLn=Cr(CO)5) found use in the synthesis of a wide range of phenolic compounds from
alkynes by addition of the carbene and carbon monoxide (itself, formally a carbene) to an
alkyne.39,40 The reaction proceeds by a multistep mechanism that involves a metallocycle
intermediate—a common finding in many reactions involving organometallic complexes
of the Group VIB (Group 6) metals. The currently accepted mechanism for the formation
of phenolic products from the reaction of a Fischer carbene complex with an alkyne is
The carbene complexes of molybdenum, developed especially by the research group of
Richard Schrock,41 and ruthenium, developed especially by the research group of Robert
Grubbs,42 react with alkenes to give metallacyclobutanes (13.32). These then fragment to
give a new carbene complex and the metathesized alkene (13.33).43
Figure 13.5 Formation of a proceeds via alkyne

RL π complex
phenol by addition of a
Fischer carbene complex to RL RS RL
an alkyne. Cr(CO)5 RS Cr(CO)4 Cr(CO)4
MeO MeO RS MeO Cr(CO)4
OMe
R1 R2 R1 R2 R1 R2
R1 R2
(13.26) (13.27) (13.28)
CO insertion
RS RL RS RL RS RL
tautomerization electrocyclization
MeO OH MeO O MeO C
aromatization
(OC)3Cr O
R1 R2 R1 H R2 R1 R2
(13.31) (13.30) (13.29)
39. Ernst Otto Fischer (1918–2007) was educated at the Technische Universität München (PhD, 1952) after
“work service” under the Nazis and military service during World War II. He spent his career at the University
of Munich (1957–1964), the Technical University (1964–1984). He shared the 1973 Nobel prize in Chemistry. For
more details, see the Nobel Foundation website.
40. Reviews and monographs on carbenes in synthesis: (a) Wulff, W. D. In Abel, E.W.; Stone, R.G.A.; Wilkinson,
G., Eds. Comprehensive Organometallic Chemistry II (Pergamon Press: New York, 1995); Vol. 12, p 469.
(b) Bernasconi, C.F. Chem. Soc. Rev. 1997, 26, 299. (c) Hegedus, L.S. Tetrahedron 1997, 53, 4105. (d) Wulff, W.D.
Organometallics 1998, 17, 3116. (e) Dötz, K.H.; Tomuschatt, P. Chem. Soc. Rev. 1999, 28, 187. (f) Herndon, J.W. Coord.
Chem. Rev. 1999, 181, 177. (g) Dörwald, F.Z. Metal Carbenes in Organic Synthesis (Wiley-VCH: New York, 1999).
41. (a) Schrock, R.R. Acc. Chem. Res. 1990, 23, 158. (b) Schrock, R.R.; Hoveyda, A.H. Angew. Chem. Int. Ed.
2003, 42, 4592. (c) Schrock, R.; Rocklage, S.; Wengrovius, J.; Rupprecht, G.; Felmann, J. J. Mol. Catal. 1980, 8, 73.
Richard Royce Schrock (1945–) obtained his PhD from Harvard (1971), and after postdoctoral study at
Cambridge (1971–1972) and working at Du Pont (1972–1975), he joined the Massachusetts Institute of Technol-
ogy, where he remains today. For his contributions to the development of olefin metathesis, Schrock shared the
Nobel Prize in Chemistry for 2005. For more biographical details, see the Nobel Foundation web site.
42. (a) Grubbs, R.H. Comp. Organometal. Chem. 1982, 8, 499. (b) Grubbs, R.H.; Chang, S. Tetrahedron 1998,
54, 4413. (c) Chatterjee, A.K.; Morgan, J.P.; Scholl, M.; Grubbs, R.H. J. Am. Chem. Soc. 2000, 122, 3782. (d) Lee,
C.W.; Grubbs, R.H. Org. Lett. 2000, 2, 2145. (e) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3102. (f) Trnka,
T.M.; Grubbs, R.H. Acc. Chem. Res. 2001, 34, 18.
Robert Howard Grubbs (1942–) obtained his PhD from Columbia in 1968. After a year of postdoctoral
study, he began his independent career at Michigan State University (1969–1978) before moving to the California
Institute of Technology (1978–). Grubbs shared the Nobel Prize for Chemistry in 2005 for his work developing
catalysts for olefin metathesis. For more biographical detail, see the Nobel Foundation web site.
43. Hérisson, J.-L.; Chauvin, Y. Macromol. Chem. 1971, 141, 161.

R1 R2 R1 R2
R1 R2
LnM LnM LnM

R2 R2
R2
(13.26) (13.32) (13.33)
Rearrangements in Carbenes
Like carbocations, with which they share the structural feature of an empty p orbital on
the carbene carbon, singlet alkylcarbenes often undergo 1,2-rearrangement of hydrogen to
give alkenes. In most alkylcarbenes, the rearrangement is much faster than competing
intramolecular insertion reactions to give cyclic products, as shown in the example below,
where the carbene (13.36) is generated by thermolysis of the conjugate base of a sulfonyl-
hydrazone (13.35).44 Note how the hydrogen on the more substituted adjacent carbon re-
arranges preferentially to give the alkene 13.37 as the major product of the reaction,
although not to the extent observed in carbocations.
Me Me Me
NaOMe
H
N Ar N Ar N Ar
N S 180°C (13.35) N S
N S
O O O O O O
(13.34)
H
Me Me
(13.36)
rearrangement insertion
38% 16% trace
Me Me
(13.37) (13.38) (13.39)
Although the rearrangement of hydrogen is usually preferred, where there is no hy-

drogen atom available, rearrangement of alkyl has been observed. In the rearrangement of
the neophyl carbene (in Example 13.40), for example, where either phenyl or methyl may
migrate, the major product is formed by migration of phenyl although there is now sub-
stantial insertion into the adjacent methyl C—H bond to give cyclopropane products.45
This relative order of migration correlates with the rearrangement of the corresponding
cation.46 Similar rearrangements of carbenes have been used, for example, in the synthesis
of highly strained bridgehead alkenes.47
Me Me Me Me
Me CH2 CHMe
Me (13.40)
50 : 9 : 41
In contrast to saturated alkylcarbenes, allylcarbenes (e.g., 13.41) usually give cyclopro-

penes (e.g., 13.4248). This reaction may be viewed as either a carbene rearrangement, or as
an intramolecular carbene addition to the π bond.
44. Wilt, J.W.; Wagner, W.J. J. Org. Chem. 1964, 29, 2788.
45. Philip, H.; Keating, J. Tetrahedron Lett. 1961, 523.
46. See, for example, Ando, T.; Kim, S.-G.; Matsuda, K.; Yamataka, H.; Yukawa, Y.; Fry, A.; Lewis, D.E.; Sims,
L.B.; Wilson, J.C. J. Am. Chem. Soc. 1981, 103, 3505.
47. Gudipati, M.S.; Radziszewski, J.G.; Kaszynski, P.; Michl, J. J. Org. Chem. 1993, 58, 3668.
48. York, E.J.; Dittmar, W.; Stevenson, J.R.; Bergman, R.G. J. Am. Chem. Soc. 1973, 95, 5680.

Ar
O
S
O
HN
N
(13.41) (13.42)
Stable Carbenes49
During the last decades of the 20th century, much effort was expended in an effort to
obtain a carbene stable enough to be isolated. This work was crowned with success in 1991,
when the synthesis of two stable singlet carbenes, 13.43 and 13.34, was reported.50 Of the
two groups of carbenes reported, the N-heterocyclic carbenes (NHCs; e.g., 13.43) prepared
by Arduengo’s group have assumed a dominant position in the field.
N
P SiMe3
N N
N
(13.43) (13.44)
The idea that heterocyclic carbenes might function as nucleophilic catalysts had been
suggested early on by Breslow. In 1958, he hypothesized that the conjugate base of a thi-
azolium ion (13.45, which is formally a heterocyclic carbene—see Figure 13.6) functioned
as a nucleophile in promoting the benzoin condensation of aromatic aldehydes.51 He pro-
posed that the reaction occurs by initial addition of the carbene to the carbonyl group to
give the adduct (13.46) that then isomerizes to the enamine 13.47. This nucleophile then
adds to a second molecule of the aldehyde to give a new adduct (13.48) that eventually
eliminates the acyloin (13.50) to regenerate the starting carbene. Extending Breslow’s ob-
servations that NHCs are nucleophilic in nature, the deduction that these compounds
could be useful ligands for transition metal cations was a logical one to test. This has
proved to be correct, and stable NHCs have become widely used ligands for transition
metals in a wide variety of catalytic organic reactions.52
Figure 13.6 Reactivity of a O
thiazolium ion as a O H
H Ar
heterocyclic carbene. Ar R O R OH
R R S S
S S
H (13.47)
R N Ar R N Ar
R N R N
R R
R R
(13.45)
(13.46)
HO O
O R S Ar R S Ar
Ar Ar (13.48)
Ar
(13.50) OH R N O N
R OH
Ar R R
(13.49)
49. Reviews: (a) Arduengo, A. Acc. Chem. Res. 1999, 32, 913. (b) Bourissou, D.; Gueret, O.; Gabbaï, F.P.;
Bertrand, G. Chem. Rev. 2000, 100, 39.
50. (a) Arduengo, A.J., III; Harlow, R.L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361. (b) Regitz, M. Angew.
Chem. Int. Ed. Engl. 1991, 30, 674.
51. Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
52. (a) Herrmann, W.A. Angew. Chem. Int. Ed. Engl. 2002, 41, 1290. (b) Herrmann, W.A.; Köcher, C. Angew.
Chem. Int. Ed. Engl. 1997, 36, 2162. (c) Weskamp, T.; Schattenmann, W.C.; Spiegler, M.; Herrmann, W.A.
Angew. Chem. Int. Ed. Engl. 1998, 37, 2490. (d) Nolan, R.A.; Kelly, R.A., III; Navarrro, O. J. Am. Chem. Soc.
2003, 125, 16194. (e) Herrmann, W.A.; Elison, M.; Fischer, J.; Köcher, C.; Artus, G.R.J. Angew. Chem. Int. Ed.
Engl. 1995, 34, 2371. (f) Scholl, M.; Trnka, T.M.; Morgan, J.P.; Grubbs, R.H. Tetrahedron Lett. 1999, 40, 2247.
(g) Choi, T.-L.; Grubbs, R.H. J. Chem. Soc., Chem. Commun. 2001, 2648. (h) Fürstner, A.; Ackkermann, L.; Gabor,
B.; Goddard, R.; Lehmann, C.W.; Mynott, F.; Stelzer, F.; Thiel, O.R. Chem. Eur. J. 2001, 7, 3236.

Worked Problem
13-3 The Corey-Winter reaction shown below is one step of a synthesis of a methy-
lenecepham derivative by intramolecular cyclization [Bioorg. Med. Chem. 2003,
11, 1957].
(a) What carbene is formed in this reaction?
(b) What alternative carbenes could have been formed in this reaction?
(c) Provide a rationalization for why this particular carbene is the one that gives
the observed product.
OR
H
OR S
H
S N H
P(OMe)3
O
N O C6H4Me2 O
O ∆ O
O O
§Answers below.

(a) The location of the cyclopropane specifies the location of the carbene carbon in the deoxygenation
product:
OR OR
H H
S S
N N H
O O
RO2C RO2C
(b) There are three carbonyl groups in the starting compound, and each is part of a carboxylic acid deriva-
tive. Consequently, three carbenes could form:
OR OR OR
H H H
S S S
N N O N O
O O
O OR OR O OR
(c) All three of these carbenes can be stabilized by the lone pair on an adjacent heteroatom. When we exam-
ine the three carbenes and take into account resonance stabilization of the carbenoid center, we observe the
following:
OR OR
OR OR
H H
H H S S
S S
N O N O
N N O O
O O
OR OR
O OR O OR
OR OR
H H
S S
N O N O
O OR O OR
Of the three possible carbenes, we see that the first (top left above) gives rise to the zwitterionic contributing
structure with the maximum conjugation and the minimum strain, so we expect that this carbene should be
the one preferentially formed.

Reaction Synopses
Carbene Preparation
Carbenes from α-Elimination
H R HN SO2Ar base R X RM
R base R R R
N or M
R R R R
X R R Y
X = Cl, Br, I; Y=F, Cl, Br, I M=Li, Zn base=RO–, NR 2–

Reagents: BuLi, THF; Et2Zn, THF; Zn(Cu), Et2O; etc.
KOBut, pentane; NaNH2, THF; LDA, THF; etc.
Carbenes by Deoxygenation
X X
PZ3
O
Y ∆ Y
X, Y = OR, NR 2, etc. Z=alkyl, alkoxy

Carbenes by Photolysis or Thermolysis
R R R R R R
hν Cu or N hν
N2 N2
Rh2(OAc)4 N
R R R R R R
Carbene is often triplet when generated photochemically and singlet when gener-
ated via the metal carbenoid.
Carbene Addition
R R
:CR2
Reagents: CHCl3, KOBut; CH2I2, Et2Zn; etc.

Stereochemistry: addition is syn (suprafacial); stereochemistry of alkene is re-
tained in cyclopropane product.
Carbene Insertion
:CR2 R
H H
R
Stereochemistry: insertion occurs with retention of stereochemistry.

Regiochemistry: insertion into C—H bonds is usually preferred over insertion
into C—C bonds; insertion into sp3-C—H bonds is preferred
over insertion into sp2-C—H bonds.
Carbene Rearrangements
R1 R2 R1
R2
R3 R4 R3 R4
Rearrangement of hydrogen is usually preferred.

Problems
13-7 Carbenes can be formed by each of the three methods below. Suggest mecha-
nisms for these reactions.
R Cl Cl
H R
N Ar NaOMe base
R N S Cl C CO2H C
180°C R Cl ∆ Cl
O O
S
O O P(OR)3 O O
R1 R2 R1 R2
R3 R4 R3 R4
13-8 In the two reactions that follow, diphenylsulfonium methylide reacts with
2-octene in the presence of a copper (II) acetylacetonate catalyst to give cyclopro-
pane products. The two stereoisomers of 2-octene give different products. Provide
a mechanism that rationalizes these observations.
H H H H
H
Ph2S CH2 Ph2S CH2 H
H Cu(acac)2/THF H Cu(acac)2/THF
13-9 The Wolff rearrangement is a reaction of α-diazoketones that leads to the forma-
tion of a ketene.
O hν
N2 C
O
Write a mechanism for this reaction. Does your mechanism change if the reac-
tion of the diazoketone labeled in the carbonyl carbon leads to a product where
the label is distributed through two positions, as indicated below? If so, how?
O hν *C
N2 *O
*
13-10 The reaction between 1,1-dibromoalkenes and butyllithium gives an alkyne as
shown below. Write a mechanism that accounts for this transformation.
R Br BuLi R Li
R R
R Br R Br
13-11 Diazirines are frequently used as substrate analogs for photochemical tagging of
proteins. For example, the compound below was used as a means for probing the
biochemistry of anesthesia. When this photolabel was activated, three amino acid
residues were labeled: one glutamate residue, and two serine residues [J. Biol.
Chem. 2004. 179, 17640]. Suggest probable structures for the photolabeled amino
acids if the diazirine gives the triplet carbene on photolysis.
O N N
N
O
N

13.3 Nitrenes
The monovalent nitrogen species with an open sextet on nitrogen, structurally analogous
to carbenes, are known as nitrenes.53 It is not surprising that, because they carry only one
group attached to the nitrogen and are therefore not amenable to the exploitation of steric
hindrance, no stable nitrenes have yet been isolated. In fact, nitrenes are, in general, more
reactive than the corresponding carbenes. In addition, nitrenes are less well known. Like
carbenes, nitrenes can exist as both singlet (13.51) and triplet (13.52) species. Reactivity
attributable to both forms has been observed, although the singlet nitrene is the more
usual reacting species.
R N (13.51) R N (13.52)
N ∆ or hν (13.53)
R N
R N
N
O O O O O O O
S base (13.54)
S
Ar N OR Ar N OR N OR
H
Nitrenes are formed by only two truly general methods. One is the decomposition of
azides (13.53) by either photolysis or thermolysis, which is the more general method. The
other is the base-promoted α-elimination from N-(p-nitrobenzenesulfonyl)urethanes
(13.54), which provides a method for the preparation of alkoxycarbonylnitrenes.
H
O C6H6 O
+ O N
N
MeO N (13.55)
MeO OMe
Nitrenes undergo both addition reactions to give aziridines and insertion reactions to
give amines, and the two frequently compete. For example, methoxycarbonylnitrene reacts
with benzene to give a mixture of N-carboxymethylazepine and methyl N-phenylurethane,
as in Example 13.55. Cyclohexene reacts with the same nitrene to give a mixture of the
aziridine by addition and the isomeric urethanes formed by insertion.54 The insertion of a
nitrene into a C—H bond is a stereospecific process and occurs with retention of configu-
ration, as illustrated by Examples 13.56 and 13.57 for intermolecular55 and intramolecular56
insertion reactions, respectively. The facility with which nitrenes insert into C—H bonds
53. Monographs: (a) Scriven, E.F.V. Azides and Nitrenes (Academic Press: New York, 1984). (b) Lwowski, W.
Nitrenes (Wiley: New York, 1970).
Reviews: (c) Scriven, E.F.V. React. Intermed. (Plenum: New York, 1982), vol. 2,p. 1. (d) Lwowski, W. React.
Intermed. (Wiley: New York, 1978), vol. 1,p. 197. (e) Lwowski, W. React. Intermed. (Wiley: New York, 81), vol. 2,p.
315. (f) Lwowski, W. React. Intermed. (Wiley: New York, 1985), vol. 3,p. 305. (g) Lwowski, W. Angew. Chem. Int.
Ed. Engl. 1967, 6, 897. (h) Abramovitch, R.A. In McManus, S.P. Reactive Intermediates (Academic Press:
New York, 1973), p. 127. (i) Hünig, S. Helv. Chim. Acta 1971, 54, 1721. (j) Belloli, R. J. Chem. Educ. 1971, 48, 422.
(k) Meth-Cohn, O. Acc. Chem. Res. 1987, 20, 18. (l) Horner, L.; Christmann, A. Angew. Chem. Int. Ed. Engl.
1963, 2, 599. (m) Abramovitch, R.A.; Davis, B.A. Chem. Rev. 1964, 64, 149.
54. (a) Berry, R.S.; Cornell, D.; Lwowski, W. J. Am. Chem. Soc. 1963, 85, 1199. (b) Cornell, D.W.; Berry, R.S.;
Lwowski, W. J. Am. Chem. Soc. 1965, 87, 3626.
55. Simson, J.M.; Lwowski, W. J. Am. Chem. Soc. 1969, 91, 5107.
56. Smolinsky, G.; Feuer, B.I. J. Am. Chem. Soc. 1964, 86, 3085.

has made azides popular reagents for the photochemical labeling of proteins. Addition re-
actions to alkenes are stereospecific suprafacial reactions, consistent with the singlet ni-
trene as the reacting species.
EtOCON3
hν (13.56)
NHCO2Et
O ∆ O (13.57)
H NH
O N3 O
Like carbenes, whose formation and use can be catalyzed by transition metals through
the medium of metallocarbenes, nitrenes can also be prepared catalytically using appro-
priate precursors and transition metal catalysts (e.g., 13.58). In 1991, for example, Evans57
reported the copper-catalyzed aziridination of alkenes using (N-(p-toluenesulfony1)
imino)phenyliodinane (PhINTs) as the source of the nitrene and a copper catalyst; both
Cu (I) and Cu (II) were effective catalyzing the reaction. The reaction has spurred consid-
erable research into the use of this reagent and metal catalysts.58 Iron and manganese
compounds can also serve as catalysts, but Evans found that the copper catalysts were the
most efficient. A recent review shows how oxidation of a sulfonamide by phenyliodine
diacetate in the presence of rhodium (II) carboxylates to give products from nitrenes.59
Ph
Ph H PhI NTs
N Ts (13.58)
Cu(MeCN)4ClO4
Ph H
or Cu(acac)2 Ph
The utility of nitrene insertion into C—H σ bonds received a significant boost when
Che60 and Du Bois61 found that sulfamate esters would react in the presence of a rhodium
(II) catalyst and a terminal oxidant. The reaction produced the necessary iodinane in situ
to give products of insertion with complete retention of configuration at carbon (e.g.,
13.59). This reaction has been elegantly applied by Du Bois in the synthesis of complex
natural products such as tetrodotoxin62 and saxitoxin.63
O
H 2N O O
S O S
[Rh(OAc)2]2, PhI(OAc)2 HN O
H O
(13.59)
MgO, CH2Cl2 CO2Et
CO2Et (85%)
OTBDPS OTBDPS
57. Evans, D.A.; Faul, M.M.; Bilodeau, M.T. J. Org. Chem. 1991, 56, 6744.
58. Review: Halfen, J.A. Curr. Org. Chem. 2005, 9, 657.
59. Dauben, P.; Dodd, R.H. Synlett. 2003, 1571.
60. (a) Liang, J.-L.; Yuan, S.-X.; Chan, P.W.H.; Che, C.-M. Org. Lett. 2002, 4, 4507. (b) Yu, X.-Q.; Huang, J.-S.;
Zhou, X.-g.; Che, C.-M. Org. Lett. 2000, 2, 2233. (c) Au, S.-M.; Zhang, S.-B.; Fung, W.-H.; Yu, X.-Q.; Che, C.-M.;
Cheung, K.-K. Chem. Commun. 1998, 2677. (d) Au, S.-M.; Huang, J.-S.; Che, C.-M.; Yu, W.-Y. J. Org. Chem.
2000, 65, 7858.
61. (a) Espino, C.G.; Wehn, P.M.; Chow, J.; Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935. (b) Espino, C.G.; Du
Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598. (c) Fiori, K.W.; Fleming, J.J.; Du Bois, J. Angew. Chem., Int. Ed.
2004, 43, 4349. (d) Espino, C.G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598. (e) Kim, M.; Mulcahy, J.V.;
Espino, C.G.; Du Bois, J. Org Lett. 2006, 8, 1073. (f) Espino, C.G.; Fiori, K.W.; Kim, M.; Du Bois, J. J. Am. Chem.
Soc. 2004, 126, 15378. (f) Wehn, P.M.; Lee, J.; Du Bois, J. Org. Lett. 2003, 5, 4823.
62. Hinmann, A.; Du Bois, J.H. J. Am. Chem. Soc. 2003, 125, 11510.
63. Fleming, J.J.; Du Bois, J.H. J. Am. Chem. Soc. 2006, 128, 3926.

Reaction Synopses
Methods for Generating Nitrenes
From Nitrogen Anion Precursors
R N X R N
X = OSO2Ar, Cl, Br, N2+, etc.

Reagents: RN3, hν; RNHOTs, KOBut, ∆; etc.
From Iodinanes
Ts Cu (I) or Cu (II)
I N N Ts
Ph
Reagents: PhINTs, Cu(MeCN)4ClO4; Cu(acac)2; Mn(TPP)Cl; Fe(TPP)Cl;

Rh2(OAc)4; Co(acac)2; etc.
or PhI(OAc)2, RSO2NH2, Rh2(OCOR)4
Nitrene Addition
R
R1 R3 R N R1 N R3
R2 R4 R2 R4
Stereochemistry: addition is syn; stereochemistry of alkene is retained.

Nitrene Insertion
R' R N R' H
R' H R' N
R' R' R
Stereochemistry: reaction occurs with retention of configuration.
13.4 Arynes64
In 1953, John D. Roberts65 obtained unequivocal proof of the existence of a symmetrical

intermediate formed by the elimination of HCl from chlorobenzene-1-14C with sodium
amide in liquid ammonia (13.60).66 The possibility that this same symmetrical neutral
intermediate might be formed in the reaction between fluorobenzene and phenyllithium
(13.61) had been considered by Wittig in 1942,67 but his report that o-fluoroanisole and
64. Reviews: (a) Bunnett, J.F. J. Chem. Educ. 1961, 38, 278. (b) Wittig, G. Angew. Chem. Int. Ed. Engl. 1965, 4,
731. (c) Kauffmann, T. Angew. Chem. Int. Ed. Engl. 1965, 4, 543.
A large part of a special issue of the Australian Journal of Chemistry has been dedicated to reviews and papers
on benzyne chemistry: (d) Wentrup, K. Aust. J. Chem. 2010, 63, 979. (e) Kitamura, T. Aust. J. Chem. 2010, 63, 987.
(f) Brown, R.F.C. Aust. J. Chem. 2010, 63, 1007. (g) Winkler, M.; Sander, W. Aust. J. Chem. 2010, 63, 1013.
Monographs: (i) Hoffmann, R.W. Dehydrobenzene and Cycloalkynes (Academic Press: New York, 1967).
65. John Dombrowski Roberts (1918–) was educated at the University of California, Los Angeles (BA, 1941;
PhD, 1944) and began his independent career at Harvard (1945–1947) and the Massachusetts Institute of Tech-
nology (1947–1950) before moving to the California Institute of Technology (1950–1988). Roberts made major
contributions in physical organic chemistry and organic spectroscopy. His autobiography contains more detail:
Roberts, J.D. The Right Place at the Right Time (American Chemical Society: Washington, D.C., 1990).
66. Roberts, J.D.; Simmons, H.E.; Carlsmith, L.A.; Vaughan, C.W. J. Am. Chem. Soc. 1953, 75, 3290.
67. Wittig, G. Naturwiss. 1942, 30, 696.

m-fluoroanisole gave different products appeared to eliminate the possibility. It was not
until the work of Huisgen,68 12 years later, that this error was corrected. Huisgen found
that not only do these two halides give the same product mixture, but that this is not a
unique situation.
Cl NH2 NH2
* NaNH2 *
+ * (13.60)
*= 14C
X = Cl 43% 53%
X = I 46% 52%
OMe OMe OMe
F
PhLi PhLi (13.61)
Ph F
Benzyne is prepared by a wide variety of methods, several of which are summarized
in Figure 13.7. The original method is the treatment of a halobenzene with strong base
such as amide anion, but this suffers from the limitation that it cannot be used in the
presence of base-sensitive functionality. The formation of an o-halophenyl anion
during this reaction leads to the obvious extension of this method to the formation of
benzyne by dehalogenation of o-dihalobenzenes. This is, indeed, observed when one
attempts to prepare the Grignard reagent from o-bromofluorobenzene.69 A similar
method for the preparation of benzyne is the reaction between fluoride anion and
o-trimethylsilylphenyl triflate.70
Benzyne may be generated from suitable precursors by either photolysis or thermol-
ysis. Photolysis of o-diiodobenzene71 and thermolysis of phthalic anhydrides72 or benzo-
thiadiazole dioxides73 also provide methods for the formation of benzyne. The
thermolysis or photolysis of zwitterionic precursors also provides an entry into benzyne
chemistry. The internal salt of o-phenyliodoniumbenzoic acid74 gives benzyne on ther-
molysis or photolysis, as does the zwitterion formed by diazotization of anthranilic acid
with isoamyl nitrite.75 Because the strongly electron-withdrawing diazonium group
renders the ortho hydrogens especially acidic, the zwitterionic intermediate formed by
decarboxylation of the diazonium carboxylate can also be generated by the reaction
between an aryldiazonium ion and a weak base (e.g., potassium acetate).76 Nitrene pre-
cursors to benzyne, which may also be viewed, formally, as having zwitterionic contrib-
utors to the resonance hybrid, may be formed (1) by oxidation of 1-aminobenzotriazole
with lead tetraacetate77 or (2) by reduction of 1-nitroso-benzotriazole with ethyl
diphenylphosphonite.78
68. Huisgen, R.; Rist, H. Naturwiss. 1954, 41, 358.

69. Wittig, G.; Pohmer, L. Chem. Ber. 1956, 89, 1334.
70. (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211. (b) Liu, Z.; Larock, R.C. Org. Lett.
2003, 5, 4673.
71. Kampmeier, J.A.; Hoffmeister, E. J. Am. Chem. Soc. 1962, 84, 3787.
72. Fields, E.K.; Meyerson, S. Chem. Commun. 1965, 474.
73. Wittig, G.; Hoffmann, R.W. Chem. Ber. 1962, 95, 2718.
74. Le Goff, E. J. Am. Chem. Soc. 1962, 84, 3786.
75. (a) Stiles, M.M.; Miller, R.G. J. Am. Chem. Soc. 1960, 82, 3802. (b) Friedman, L.; Longullo, F.M. J. Am.
Chem. Soc. 1963, 85, 1549.
76. Rückhardt, C.; Tan, C.C. Angew. Chem. Int. Ed. Engl. 1970, 9, 522.
77. (a) Campbell, C.D.; Rees, C.W. Proc. Chem. Soc. 1964, 296. (b) Campbell, C.D.; Rees, C.W. J. Chem. Soc.
C 1969, 742.
78. Cadogan, J.I.G.; Thomson, J.B. Chem. Commun. 1969, 770.

Figure 13.7 Methods for O X

the production of benzyne.
Reagents: (a) room temp. O b
(b) NaNH2, PhLi, etc. (c) Mg, H
Et 2O. (d) CsF, MeCN. X
O O X
(e) RONO. (f) Pb(OAc)4. O c
(g) (PhO)2P(O)H. (h) hν S
j
or ∆. (i) ∆. (j) ∆ or hν. N a Y
N i
d
OTf
SiMe3
h
CO2
CO2 CO2H
Ph e
I N
N N2 NH2
N2
N N f N
g
N N N
N N N
NO N NH2
Structure and Bonding in Benzyne
Singlet Singlet Triplet

alkyne diradical diradical
Benzyne is characterized by an unusual bond formed by π-type overlap of sp2 hybrid
orbitals on adjacent carbons. There are two possible Kekulé structures for this species:
one carrying a triple bond and the other carrying a cumulated triene moiety. The avail-
able spectra of benzyne seem to indicate (1) that the resonance contributor with the
triple bond is more representative of the actual structure and (2) that benzyne is best
viewed as a benzene molecule with an aromatic sextet, with distorted geometry due to
shortening of one C—C bond.79 The geometry of benzyne has been obtained from mi-
crowave measurements80 and computationally.81 The geometry shows that there is clearly
a significant bonding interaction between the two benzyne carbons (the bond distances
calculated at quite high levels of theory all have the distance between these two carbons
79. (a) Laing, J.W.; Berry, R.S. J. Am. Chem. Soc. 1976, 98, 6660. (b) Münzel, N.; Schweig, A. Chem. Phys. Lett.
1988, 147, 192.
80. Kukolich, S.G.; Tanjaroon, C.; McCarthy, M.C.; Thaddeus, P. J. Chem. Phys. 2003, 119, 4353.
81. de Visser, S.P.; Filatov, M.; Shaik, S. Phys. Chem. Chem. Phys. 2000, 2, 5046, and references therein.

close to 1.27Å, which lies between the triple bond length of 1.21 Å and the double bond
length of 1.34 Å), but the geometry of the molecule also suggests that benzyne might also
be described as a diradical rather than as a strained alkyne. This question has been
resolved by measuring the singlet-triplet gap in benzyne; the value obtained is 37.5 kcal
mol –1.82 This ensures that the ground state of benzyne—whether a strained alkyne or a
diradical—is a singlet.
Reactivity of Benzyne
The reactive benzyne π bond is orthogonal to the aromatic π system, so there is no inter-
action between the two. Instead, the reactive π bond is best described as being part of the
σ bonding system of the ring, so the σ bonding framework of the ring is the major deter-
minant of regiochemistry in benzyne reactions. This reasoning leads to the conclusion
that the most important factor determining the regiochemistry of benzyne reactions is the
electronegativity of the substituent on the aromatic ring, whose effect is transmitted by
induction through the σ framework.
Benzyne is an electrophile that reacts with a variety of nucleophiles to generate the
phenyl anion. The outcomes of the reactions between a series of aromatic halides and
amide anion,83 each of which involves a benzyne intermediate, are summarized in
Table 13.5. The choice of substituents in this study was predicated on the premise that the
regiochemistry of the reaction could be affected at two stages: (1) the deprotonation step,
controlled by the relative acidities of the hydrogens, and (2) the addition step, controlled
by the relative energies of the isomeric aryl anions. Four substituents were used in the
study: (1) a trifluoromethyl group, which is strongly electron-withdrawing by induction
and weakly electron-withdrawing by resonance; (2) a methoxy group, which is electron-
withdrawing by induction and strongly electron-releasing by resonance; (3) a fluoro group,
which is electron-withdrawing by resonance, and relatively weakly electron-releasing
by resonance; and (4) a methyl group, which is electron-releasing by both induction and
resonance.
What is immediately apparent from Table 13.5 is that (1) o-bromoanisole and m-
bromoanisole both give m-anisidine as the sole product of the reaction and that (2) (o-
chlorophenyl)trifluoromethane and its m- isomer also both give m-trifluoromethylaniline
as the sole product. This is consistent with the o- and m- halides both giving the same
benzyne. Because there is only one proton situated ortho to the halogen, the ortho iso-
mers can give only one benzyne but the m- isomer can give two possible benzynes. This
means that the deprotonation of the m- isomer must be regiospecific at the position
between the substituent and the halogen—the hydrogen that is rendered most acidic by
the electron-w ithdrawing inductive effects of the substituent and the halogen. Because
these benzynes each give only one product, they must undergo regiospecific addition of
the nucleophile to give only one of the two possible aryl anions. Again, the regiochem-
istry is such that the nucleophile becomes bonded to the carbon further from the sub-
stituent, placing the negative charge on the carbon closer to the electron-withdrawing
substituent.
In contrast to the halides carrying electronegative substituents, the o-halotoluenes do
not give a single product but mixtures of both possible products, with the m- isomer of the
product slightly predominating. Recalling that carbanions are not stabilized by adjacent
alkyl groups, this regiochemical outcome could have been predicted. The m-halotoluenes
give both possible benzynes and a mixture of all three possible products, which is consis-
tent with the deductions made from the results with the simpler o-halotoluenes.
82. Wenthold, P.G.; Squires, R.R.; Lineberger, W.C. J. Am. Chem. Soc. 1998, 120, 5279.
83. Roberts, J.D.; Vaughan, C.W.; Carlsmith, L.A.; Semenow, D.A. J. Am. Chem. Soc. 1956, 78, 611.

Table 13.5 Regiochemistry of Formation and Addition Reactions of Benzyne
R R R R
X NH2
NH2 NH2
+
NH3 NH3
NH2
R = CF3; X = Cl 0 100
R = CH3; X = Cl 45 ± 4 55 ± 4
R = CH3; X = Br 48.5 ± 2 51.5 ± 2
R = OCH3; X = Br 0 100
R R R R
NH2 NH2
+
NH3 NH3
NH2
X NH2
R = CF3; X = Cl 50 ± 5 50 ± 5
R = CH3; X = Cl 62 ± 4 38 ± 4
R = OCH3; X = Br 49 ± 1 51 ± 1
R = F; X = Br 20 ± 1 80 ± 1
R R R R R R
NH2
NH2 NH2
+ + +
NH3 NH3
X NH2
NH2
R = CF3; X = Cl 0 100 0
R = CH3; X = Cl 40 ± 4 52 ± 4 8±4
R = CH3; X = Br 22 ± 4 56 ± 4 22 ± 4
R = OCH3; X = Br 0 100 0
Like the ortho isomers, the p-substituted halobenzenes can give only one regioisomeric
benzyne. In this case, however, the substituent is located at least one bond further from the
benzyne group, so its inductive effect is attenuated. Thus, Roberts and his coworkers found
that only the most strongly electron-withdrawing substituent by induction (F; electronega-
tivity = 4.0) gave predominantly the p-substituted aniline, whereas for p-choroanisole
(O; electronegativity = 3.5), an essentially equal mixture of the two p ossible products is
formed. This trend continues, with the alkyl group (C; electronegativity = 2.5) actually
giving more of the m-toluidine.
As a highly strained alkyne, benzyne is a highly active dienophile in the Diels-
Alder reaction. Thus, generation of benzyne in the presence of dienes such as furan
(13.62)84 and anthracene (13.63)85 leads to the formation of Diels-Alder adducts. In the
absence of nucleophiles or other reactive species, benzyne dimerizes to o-biphenylene
(13.64).86
84. Wittig, G.; Polmer, L. Angew. Chem. 1955, 67, 348.

85. Friedman, L.; Longullo, F.M. J. Org. Chem. 1969, 34, 3089.
86. Longullo, F.M.; Seitz, A.H.; Friedman, L. Org. Syn. 1968, 48, 17.

O + O (13.62)
+ (13.63)
+ (13.64)
p-Benzyne and m-Benzyne

In addition to the benzyne intermediate just discussed, which is sometimes referred to as
o-benzyne, there are two other dehydrobenzenes that have been implicated as intermediates
in certain organic reactions. These are 1,4-didehydrobenzene, also known as p-benzyne, and
1,3-didehydrobenzene, also known as m-benzyne. The three didehydrobenzene isomers are
shown in Figure 13.8, along with their highest energy occupied molecular orbitals (HOMOs)
and lowest energy unoccupied molecular orbitals (LUMOs).87 The HOMO of the first two
isomers is the symmetric orbital, ϕS, relative to the σv plane of symmetry relating the dehydro
carbon atoms, with the LUMO being the antisymmetric orbital, ϕA; in p-benzyne, this situ-
ation is reversed. This means that p-benzyne is best described as a singlet diradical in the
ground state, rather than having an unusual transannular bond.
p-Benzyne has been much more widely studied than m-benzyne because of its relative
ease of formation by the electrocyclic ring closure of cis-3-ene-1,5-diynes, called the
Bergman cyclization,88 and its importance in the biological activity of antineoplastic
agents such as the calicheamycins89 and esperamicins.90
Figure 13.8 Frontier orbitals

of isomeric benzynes. The
molecular orbital is the
upper orbital of each pair,
and the highest energy
occupied molecular orbital is
the lower orbital of each pair.
87. Wierschke, S.G.; Nash, J.J.; Squires, R.R. J. Am. Chem. Soc. 1993, 115, 11958.
88. (a) Jones, R.R.; Bergman, R.G. J. Am. Chem. Soc. 1972, 94, 660. (b) Bergman, R.G. Acc. Chem. Res. 1973,
6, 25. (c) Lockhart, T.P.; Comita, P.B.; Bergman, R.G. J. Am. Chem. Soc. 1981, 103, 4082. (d) Johnson, G.C.;
Stofko, J.J.; Lockhart, T.P.; Brown, D.W.; Bergman, R.G. J. Org. Chem. 1979, 44, 4215.
89. (a) Lee, M.D.; Dunne, T.S.; Siegel, M.M.; Chang, C.C.; Morton, G.O.; Borders, D.B. J. Am. Chem. Soc.
1987, 109, 3464. (b) Lee, M.D.; Dunne, T.S.; Chang, C.C.; Ellestad, G.A.; Siegel, M.M.; Morton, G.O.; McGahren,
W.J.; Borders, D.B. J. Am. Chem. Soc. 1987, 109, 3466. (c) Zein, N.; Sinha, A.M.; McGahren, W.; Ellestad, G.A.
Science (Washington, D.C.) 1988, 240, 1198.
90. (a) Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishnan, B.; Okhuma,
H.; Saitoh, K.; Doyle, T.W. J. Am. Chem. Soc. 1987, 109, 3462. (b) Nicolaou, K.C.; Ogawa, Y.; Zuccarello, G.;
Kataoka, H. J. Am. Chem. Soc. 1988, 110, 7247. (c) Nicolaou, K.C.; Smith, A.L. Acc. Chem. Res. 1992, 25, 497.

Me
CO2Me SMe
O O
HO HN Me
MeO H
Me H O MeO OMe Me O OH
H O MeO2C
HO O O S NH
N H O HN O
O H NH O H OH H
O O
H OHO O OH
H MeO
O OH Me I O OMe H H
S O O HO O O
H O
S MeO H
OH H
MeS HO Me S NHEt
MeO NHEt S OMe
calicheamicin γ1 esperamicin A1 MeS
In contrast to o-benzyne, there is ample evidence that p-benzyne is a singlet diradical

rather than a bridged ion. Pyrolysis of cis-hex-3-ene-1,5-diyne under a variety of condi-
tions gives only products of free radical atom abstraction, and no evidence of ionic
intermediates.91
The mechanism of action of the calicheamicin and esperamicin antibiotics in-
volves hydrogen atom abstraction from the backbone of the DNA, followed by chain
scission of both chains. The essential features of the mechanism of DNA damage are
shown in Figure 13.9. The key to this mechanism is the cleavage of the trisulfide by a
nucleophile to give a sulfide anion that undergoes an intramolecular conjugate addi-
tion to the enone. This changes the hybridization of the β carbon of the enone from
sp2 to sp3. This rehybridization removes a bridgehead π bond and, at the same time,
brings the two ends of the enediyne system close enough together to allow the Berg-
man cyclization to proceed.
Figure 13.9 Involvement of

the Bergman cyclization of O O CH2O2Me O CO2Me
CO2Me
enediynes in the action of R R R
NH NH NH
esperamicin-type
antineoplastic agents. HO HO HO
H H S H S
O O O
sugar sugar sugar
S
MeS S (13.66) (13.67)
Nu
(13.65) Rb H H Ra
calicheamicin: R=H DNA damage Rb Ra

esperamicin: R=O—sugar
O CO2Me
R
NH
HO
H S
O
sugar
(13.68)
91. Jones, R.R.; Bergman, R.G. J. Am. Chem. Soc. 1972, 94, 660.

R Figure 13.10 Involvement of

S the Myers-Saito cyclization
O O O O of eneyne-allenes in the
action of neocarzistatin
RO H O RO H O chromophore antineoplastic
H2O
(13.70) agents.
O OH
R'O R'O
(13.69)
DNA damage
O O O O
H O H O
R• RH
OH OH
RO RO
R'O R'O
(13.72) (13.71)
A cycloaromatization reaction similar to the Bergman cyclization is the Myers-Saito

cyclization of enyne-allenes92 to give 3,α-didehydrotoluenes. The barrier to cyclization is low
enough that cyclic enyne-allenes are virtually unknown (unlike cyclic enediynes), and they
appear to cyclize to the diradical on formation.93 Enyne-allenes are represented in nature by
the neocarzistatin chromophore (13.69; this is the small prosthetic group bound to the apo-
protein to give neocarzistatin itself) and its analogs.94 The mechanism by which neocarz-
inostatin chromophore cleaves DNA involves the formation of the diradical from the
enyne-cumulene formed by attack of a thiol on the double bond in the five-membered ring
of 13.69 in an SN2'-type ring opening of the epoxide to give the allenic alcohol 13.70. Cycliza-
tion of this enyne-allene leads to the diradical 13.71, which then abstracts hydrogen atoms
from DNA, causing strand cleavage. This mechanism is summarized in Figure 13.10.
OH
O O O
O H O
OMe O
O
H
MeHN
O
(13.69)
HO
OH
neocarzinostatin chromophore
92. (a) Myers, A.G.; Kuo, E.Y.; Finney, N.S. J. Am. Chem. Soc. 1989, 111, 8057. (b) Nagata, R.; Yamanaka, H.;
Okazaki, E.; Saito, I. Tetrahedron Lett. 1989, 30, 4995. (c) Myers, A.G.; Dragovich, P.S.; Kuo, E.Y. J. Am. Chem.
Soc. 1992, 114, 9369.
93. (a) Toshima, K.; Ohta, K.; Kano, T.; Nakamura, T.; Nakata, M.; Kinoshita, M.; Matsumura, S. Bioorg.
Med. Chem. 1996, 4, 105. (b) Bekele, T.; Brunette, S.R.; Lipton, M.A. J. Org. Chem. 2003, 68, 8471.
94. (a) Ishida, N.; Miyazaki, K.; Kumagi, K.; Rikimaru, M. J. Antibiot. 1965, 18, 68. (b) Napier, M.A.;
Holmquist, B.; Strydom, D.J.; Goldberg, I.H. Biochem. Biophys. Res. Commun. 1979, 89, 635. (c) Kappen, L.S.;
Napier, M.A,; Goldberg, I.H. Proc. Natl. Acad. Sei. U.S.A. 1980, 77, 1970. (d) Povirk, L.F.; Goldberg, I.H. Bio-
chemistry 1980, 19, 4773. (e) Napier, M.A.; Holmquiet, B.; Strydom, D.J.; Goldberg, I.H. Biochemistry 1981, 20,
5602. (f) Ohtauki, K.; Ishida, N. J. Antibiot. 1980, 33, 744. (f) Suzuki, H.; Mura, K.; Kumada, T.; Takeuchi, T.;
Tanaka, N. Biochem. Biophys. Res. Commun. 1980, 94, 255.

Worked Problem
13-4 It has been suggested [J. Org. Chem. 1987, 52, 5685] that the reaction below involves
a benzyne intermediate. Write a mechanism for the reaction consistent with this.
OMe CN MeO O
LDA (3 eq.)
+ O
THF/–40°C
Cl
O O
§Answers below.
Reaction Synopses
Methods for Generating Arynes
From Substituted Phenyl Anions
Y Y
X
X=H, SiR 3 halogen; Y=halogen, OSO2R, N2+, etc.
Reagents: X=H: NaNH2, NH3; LDA, THF; PhLi; etc.
X=SiR 3: CsF, MeCN
X=halogen: Mg, Et2O; BuLi, THF; etc.
By Thermolysis or Photolysis
Y
∆ or
hν
X
X, Y = CO-O-CO; N=N-SO2; CO2– and PhI+; CO2– and N2+

The LDA deprotonates both reactants—the m-chloroanisole between the substituents, to give 3-methoxy-
benzyne, and the nitrile at the α position to give an enolate anion that adds to the benzyne. The resulting phenyl
anion now adds to the carbonyl group of the ester. The reaction is completed by elimination of cyanide anion.
R2N H
N C O O
N C O O N
C
CN
O
O
O
Cl Cl
OMe MeO O
H
OMe OMe OMe
NR2
O
MeO O

From Benzotriazole Derivatives

N [H] or
N
N [O]
N X
X=H2, O
Reagents: X=O: (MeO)3P;
X=H2: Pb(OAc)4
Bergman Cyclization of Enediynes
R
R
∆
R
R
Reaction: proceeds spontaneously if the termini of the ene-diyne are close

enough together
Myers-Saito Cyclization of Enyne-Allenes
R R
R R
Problems
13-12 The substitution of aromatic halides by strongly basic nucleophiles changes in the
order Br > I > Cl >> F. The strengths of the carbon-halogen bonds increases in
the order C—I < C—Br < C—Cl < C—F, whereas the electronegativity of the hal-
ogen increases in the order I < Br < Cl < F.
Using these data, rationalize the relative order of reactivity of halobenzenes
in nucleophilic substitution by the benzyne mechanism. You might want to
consider whether the rate-determining step of the reaction remains constant
or changes.
13-13 The naphthalene derivative below reacts with lead tetraacetate and diethyl acety-
lenedicarboxylate to give the product shown. What is the most reasonable inter-
mediate in this reaction and how is it formed?
N NH2 EtO2C CO2Et

N N
Pb(OAc)4
EtO2C CO2Et
13-14 The reaction below is significantly affected by the nature of the substituent on the
ten-membered ring. Provide a reasonable explanation for the effect of the substit-
uent [Org. Lett. 2000, 2, 3761].

OH
Me2CHOH OMe OH
OMe [enediyne] = 0.020 M (10 h, 82.5°C); 93%
∆
N [enediyne] = 0.001 M (36 h, 40°C); trace
N [enediyne] = 0.001 M (hν; 24 h; 40°C); 82%
hν [enediyne] = 0.005 M (hν; 2 h; 40°C); 83%
MeO N Me2CHOH MeO N
O
OMe Me2CHOH OMe O
∆
N N [enediyne] = 0.020 M (10 h, 80°C); 92%
hν [enediyne] = 0.005 M (hν; 2 h; 40°C); 10%
MeO N Me2CHOH MeO N
13-15 Suggest a reason why the Myers-Saito cyclization should be so much more facile
than the Bergman cyclization.
Chapter Summary
In this chapter, we have discussed the chemistry of the remaining reactive intermediates
of organic chemistry: free radicals, which possess at least one unpaired electron; carbenes,
which are divalent carbon electrophiles with six valence electrons around carbon; ni-
trenes, which are monovalent nitrogen species with six valence electrons around nitrogen;
and arynes, which are reactive intermediates possessing an aromatic ring lacking two of
the C—H σ bonds. Free radicals are preferentially planar but are not restricted to planar-
ity, which makes free radical reactions at bridgehead positions possible. Carbenes exist as
both singlet and triplet forms; singlet carbenes possess characteristics of both a nucleop-
hile and an electrophile, whereas triplet carbenes react as a typical diradical. Complexes
of carbenes with metals, or organometallic precursors to carbenes, are termed carbenoids
and react as singlet carbenes, including adding to alkenes to give cyclopropanes and react-
ing with alkenes via metallocyclobutanes in olefin metathesis. Like carbocations, carbenes
do rearrange. The synthesis of stable carbenes (especially NHCs) has provided a wide va-
riety of useful ligands for transition metal catalysis. Nitrenes are too reactive to have yet
been made as an isolable species. Nitrenes and carbenes insert into C—H bonds with re-
tention of configuration. Only o-benzyne (or simple “benzyne”) and p-benzyne have been
widely studied. Benzyne reacts as a singlet diradical and is an electrophilic species. p-Ben-
zynes are formed in the Bergman cyclization of ene-diynes and are reactive diradicals
capable of removing a hydrogen atom from, for example, DNA.
Key Terms
aryne carbenoid Myers-Saito cyclization

benzyne free radical nitrene
Bergman cyclization N-heterocyclic carbene
carbene (NHC)
Additional Problems
13-16 Suggest a mechanism for the reaction below. The silicon reagent acts as a source
of fluoride anion.
H
OTf O Bu4N Ph3SiF2 (2 eq.) N
R2
R1 + R2 R1
N R3 PhMe, 50°C, 16 h O
SiMe3 H
R3

13-17 Photochemical reduction of benzophenone in isopropyl alcohol gives one mole-

cule of benzpinacol for each photon absorbed. Suggest a mechanism consistent
with this observation, given that the absorption of a photon excites the benzophe-
none molecule to a triplet diradical. What is the function of the isopropyl alcohol
in this reaction? Suggest a reason why it is so effective in this role.
Ph hν, Me2CHOH Ph Ph
O HO OH
Ph Ph Ph
13-18 The reaction below was involved in Problem 11-17. What is the function of the
rhodium (II) acetate in this reaction? [Org. Lett. 2006, 8, 2511.]
N2
N N EtO2C CO2Et N N
S O S S O S
Rh2(OAc)4
xylenes, ∆ EtO2C CO2Et
EtO2C CO2Et
13-19 The reaction below was used as a key step in the synthesis of cytosporone B
[Chem. Lett. 2010, 39, 508]. Suggest a mechanism for the reaction that accounts
for the regiochemistry observed.
OMe OMe O
SiMe3 KF, 18-crown-6, THF
C7H15
C7H15
CO2Et CO2Et
MeO OTf MeO
O
13-20 The reaction below is an example of a group transfer reaction. It occurs by a free
radical mechanism. What are the propagation s.epsof the reaction? [J. Am. Chem.
Soc. 1994, 116, 4279.]
Me
NC
Ph SePh
NC
Ph SePh
CN
AIBN or hν
CN
Me
13-21 The reaction below is an interesting photochemical transformation of

1,4-benzoquinone derivatives carrying a side chain with a benzylic hydroxyl
group. Suggest a mechanism that accounts for the formation of the products
shown. [J. Chem. Soc. (C) 1971, 2244.]
O OH O O OH O
R hν R R
+
O O OH
13-22 When 2-bromo-6-ethoxypyridine is treated with potassium amide in liquid am-

monia, the two products shown below are obtained. What intermediate is impli-
cated in their formation? [Tetrahedron Lett. 1969, 1943.]
NH2
KNH2, NH3
+
Br N OEt H2N N OEt N OEt

13-23 When the zwitterion below is heated in slightly moist tetrahydrofuran, the two
products shown are formed. Provide a rationalization for this observation. [Tetra-
hedron Lett. 1970, 407.]
O Ph
Ph
O
O
+
∆
O2C N2 O
OH
Ph
13-24 The dimerization of the stable carbene below to give the alkene shown only
occurs in the presence of acid. The dimerization in the absence of acid is slow,
and first order in the carbene. What conclusions about the mechanism of this
reaction do these facts permit? [Chem. Commun. 1997, 1513.]
N H N N
cat.
N N N
13-25 The treatment of 1,2-bis-trimethylsilylbenzene with PhI(OAc)2 and trifluorometh-

anesulfonic acid gives the iodonium salt shown below [J. Am. Chem. Soc. 1999,
121, 11674]. When this salt is treated with tetrabutylammonium fluoride in the
presence of 2-methylfuran, the product shown is obtained. Provide a mechanism
for both reactions in the sequence.
Me O
Me
SiMe3 PhI(OAc)2, TfOH SiMe3 Bu4N F
O
CH2Cl2, 0°C to r.t. THF
SiMe3 IPh OTf
(100%)
13-26 In a 1989 paper, Wiberg and Chaves [J. Am. Chem. Soc. 1989, 111, 8052] reported
that the intramolecular addition of the cyclopropylidene (carbene) generated
by the reaction between the dibromide below and methyllithium gave approxi-
mately 50% of the allene and two tricyclic products in the approximate ratios
shown.
D H D H D H
H H H H
C
:CBr2 Br MeLi D D H
Br H D
D H D H H H D H
D H
(E,E) (E,E) (E,Z) (E,E)
40% 10% 50%
(a) How is the allene formed?

(b) Discuss the formation of the two tricyclic products with particular reference
to the stereochemistry of the addition.
(c) The tricyclic products are likely to be quite strained, but they still constitute
half of the total product. What conclusions do you draw from this?
13-27 Unlike carbocations, which readily undergo Wagner-Meerwein rearrangements,
free radicals do not usually rearrange. The two reactions shown demonstrate that

when free radicals do rearrange, the rearrangement may be reversible, and it

may also involve migration over more than one carbon. Suggest a common
mechanism for these two rearrangements that accounts for the formation of the
products in both reactions.
13-28 The insertion of dichlorocarbene into the Si—H bond of a series of aryldimethyl-
silanes has been studied, and fitting the observed relative rate constants to the
Hammett equation gives a Hammett ρ value of –0.632 for the reaction. What in-
ferences can you draw from this about the structure of the activated complex in
this reaction? [J. Am. Chem. Soc. 1968, 90, 2944.]
X Me :CCl2 X Me
Si H Si CHCl2
Me Me
13-29 Provide a reasonable rationalization of the effect of solvent on the reactions

shown. In each reaction, the major product is given, but both products are
formed in both reactions. If the proportions of the two products in the top reac-
tion change with the concentration of the base, what does this tell you about the
mechanism of the reaction?
NaOMe
(MeOCH2CH2)2O
∆
N—NHTs
NaOMe
HOCH2CH2OH
∆
13-30 The Garratt-Braverman reaction, presented here, is analogous to the Bergman

and Myers-Saito cyclizations, with bis-allenes as the reactants. The diradical
formed can cyclize further, as shown in the example below. Suggest a mechanism
for this reaction.
X
X
R R
R R
O
O O S
O O S O
S
13-31 The reaction shown, which would be expected to give the carboxylic anhydride
when the acid was treated with dicyclohexylcarbodiimide (a dehydrating agent)
is common for a series of substituted 3-arylpropynoic acids, which give the sub-
stituted 1-phenylnaphthalene-2,3-dicarboxylic anhydrides [Aust. J. Chem. 1973,
26, 557]. Suggest a mechanism for this reaction.

O
R C R
N N
H H O
X
X
CO2H O
N O
R C R
N
X
13-32 Nitroxyls are stable oxygen-centered free radicals that have found widespread use
in biochemistry. One of the most widely used nitroxyls is 2,2,6,6-tetrameth-
ylpiperidyloxy (TEMPO), whose structure is shown. Why is this radical stable
when alkoxy radicals are so reactive?
N
O
13-33 Suggest a reaction pathway whereby the reaction shown can take place. [Tetrahe-
dron Lett. 1991, 32, 6735.]
OR MeO OR OMe
I
BuLi, THF
+ O
OTf –78°C, 10 min
OH
13-34 The reaction between an aryne and a urea gives the product of formal insertion
into a C—N bond. Provide a mechanism that rationalizes the regiochemistry of
this reaction. [Angew. Chem. Int. Ed. 2002, 41, 3247.]
O
O
Me N N Me Me
N
R R
20°C
N
Me
13-35 The oxidation reaction shown was used in a recent total synthesis of (–)-muramycin
D2 and its epimer [J. Org. Chem. 2010, 75, 1366]. Suggest a m
echanism by which the
observed transformation may take place. Account for the stereochemistry of the
reaction. [See also J. Am. Chem. Soc. 2007, 129, 14106.]
CbzHN CbzHN
O O
PhI(OAc)2, CH2Cl2 H
S O S O
H2N N
O H O
NHBoc CO2 NHBoc
Rh 2:1 mixture of
CO2 this isomer and
2 its epimer

Chapter fourteen
Organic Reactions IV
Applications of Free Radical Chemistry in Synthesis
14.1 Methods for Site-Specific Generation

of Free Radicals1
In Chapter 13, we discussed the structure and reactions of free radicals. As implied in that
chapter, much of the usefulness of free radical chemistry in synthesis is predicated on the
ability to accomplish site-specific generation of radicals, so that we know where the free
radical center is. There are several methods for doing this. Among these are fragmenta-
tion, atom abstraction, radical addition, and electron transfer, as well as the homolysis of
nonradical precursors.
There are two major tasks in synthetic organic chemistry for which free radicals are
well suited: the formation of carbon-carbon σ bonds and the activation of unactivated
alkane hydrocarbons (the replacement of a carbon-hydrogen σ bond by a carbon-
heteroatom σ bond, which requires the abstraction of a hydrogen atom from that position
and its replacement by a heteroatom). The key to forming the specific radical necessary in
each of these processes is often the initiator used in the reaction.
Initiators can be divided into two broad classes: those that abstract a hydrogen atom
and those that abstract a heteroatom or add to a π bond. We can illustrate all these options
with the bromination of cyclohexene, shown as the cycle diagram in Figure 14.1. The ho-
molysis of azobisisobutyronitrile (AIBN) (14.1) leads to a free radical (14.2) that is not re-
active enough to abstract a hydrogen atom from cyclohexene. However, this radical is
reactive enough to generate a bromine atom, Br•, by abstracting a bromine atom from the
bromine molecule itself. It can also add to cyclohexene to generate a new radical (14.3) that
abstracts a bromine atom from the bromine molecule, thus generating the bromine atom
indirectly. Thus, both these pathways lead to the generation of a bromine atom that then
enters the chain reaction as a chain carrier. In contrast to the homolysis of AIBN, the ho-
molysis of a peroxide leads to a radical (14.4) that is extremely reactive—certainly reactive
enough to abstract a hydrogen atom from the alkene to give the allylic free radical, which
then enters the cycle.
Simple Homolysis of Nonradical Precursors

The generation of free radicals by homolysis of weak bonds is one of the most general
methods for forming radicals. The bonds most susceptible to homolysis are σ bonds be-
tween heteroatoms, especially X‑X, N-N, N‑O, O-O, O‑X, and N+-X bonds. Free radical
halogenations, for example, are initiated by the homolysis of the halogen-halogen bond to
1. Reviews: (a) Schiesser, C.H.; Wild, L.M. Tetrahedron 1996, 52, 13265. (b) Beckwith, A.L.J. Tetrahedron 1981,
37, 3073. (c) Ramaiah, M. Tetrahedron 1987, 43, 3541. (d) Beckwith, A.L.J. Chem. Soc. Rev. 1993, 143. (e) Schiesser,
C.H. Chem. Comm. 2006, 4055. (f) Curran, D.P. Synthesis 1988, 417. (g) Curran, D.P. Synthesis 1988, 489.
(h) Walton, J.C. Acc. Chem. Res. 1998, 31, 99. (i) Porter, N.A.; Giese, B.; Curran, D.P. Acc. Chem. Res. 1991, 24, 296.
533

534 Advanced Organic Chemistry | Chapter fourteen
Figure 14.1 Processes for

initiating free radical chain N2
reactions. Note how NC N NC
initiation with N CN
azobisisobutyronitrile leads
(14.1) (14.2)
to the formation of bromine
atoms, whereas initiation CN (14.3)
with peroxides generates an Br Br
alkyl radical.
NC Br Br Br
CN
Br•
Br
Br
Br Br H Br
(PhCO2)2 PhCO2• + PhCO2H

(14.4) H
give halogen atoms. A number of typical radical precursors of this type are collected in
Table 14.1. Many of these reactions are used to initiate other free radical reactions because
they give highly reactive oxygen- or nitrogen-centered free radicals capable of abstracting
hydrogen from carbon atoms to give synthetically useful alkyl radicals.
Let us now examine each of these major types of homolysis reactions in turn.
R R
R R
O R R R• + O
R O
R R O R
R (14.7)
(14.8) (14.9)
O
O
O R + O R
R O
R R O R
R R
(14.10) (14.6) (14.9)
O—O Homolysis
The homolysis of a peroxide link, which can be accomplished under thermal or photo-
chemical conditions, is a common method for the formation of highly reactive alkoxy or
acyloxy radicals. The homolysis of the peroxide link occurs by more than one mecha-
nism, depending on the solvent and the peroxide. Dialkyl peroxides (Example 14.8) de-
compose by simple homolysis of the O—O bond.2 The situation with diacyl peroxides
(Example 14.5), peroxy esters (Example 14.10), and alkyl hydroperoxides is less straight-
forward, however. In solvents that do not react with free radicals, the cleavage is a simple
O—O homolysis and obeys first-order kinetics.3 However, in solvents capable of
2. (a) Raley, J.H.; Rust, F.F.; Vaughan, W.E. J. Am.Chem. Soc. 1948, 70, 88, 1336.
3. Hammond, G.S.; Soffer, L.M. J. Am. Chem. Soc. 1950, 72, 4711.

Organic Reactions IV 535
reacting with a free radical, the reaction occurs by an in- Table 14.1 Nonradical Precursors of Free Radicals
duced decomposition mechanism, where the solvent or other Bond General Type
reagent participates in the homolysis mechanism by reacting
with the acyloxy radicals formed in the simple homolysis.4 X—X Cl2, Br2
Thus, the substrate for the free radical reaction initiated by a O—O RCO2—O2CR, RO—OR, RCO2—OR
diacyl peroxide or a perester often accelerates the reaction by
itself catalyzing the decomposition of the initiator to the re- O—N R—O—N=O, R 2N—OCOR
active free radicals. A third source of free radicals by the O—X RO—Cl, RCO—O—I
cleavage of peroxides is the one-electron reduction of the
peroxy linkage of an alkyl hydroperoxide by metal (usually N—X R 2NH+—Cl, R 2NH+—I
Fe2+) ions. In this reaction, the alkoxy radical is produced, M—H R—Hg—H, Bu3Sn—H
with the hydroxy group appearing in the product as a hy-
droxide anion.5
O homolysis fragmentation
O O
O R R• + C
R O
R O O
O
(14.5)
The formation of acyloxy radicals is especially useful as a means of initiating free radical
reactions, not only because of this induced homolysis of the initiator, but also because these
radicals undergo a facile loss of carbon dioxide (e.g., Example 14.6) to give the alkyl radical
(Example 14.7),6 with rate constants approaching 106 s–1 at –80°C.7 This fragmentation of
carboxy radicals to carbon dioxide and an alkyl radical is a manifestation of the high energy
of oxygen-centered radicals and their propensity to fragment to carbon-centered radicals
and carbonyl compounds in the absence of a source of hydrogen atoms.8 In a manner similar
to carboxy radicals, tertiary alkoxy radicals (Example 14.9) decompose to ketones and
alkyl radicals.
O—N Homolysis
R
R hν R
N R + • NO
R O O
R O
(14.11) (14.6)
The homolysis of an N—O bond as a source of free radicals is represented by the homolysis
of nitrite esters (e.g., Example 14.11)9 and the homolysis of the N—O bond of esters of
N-hydroxy-2-pyridinethione (Example 14.12).10 These are known as Barton esters. Nitrite
4. Bartlett, P.D.; Nozaki, K. J. Am. Chem. Soc. 1947, 69, 2299.

5. Richardson, W.H. J. Am. Chem. Soc. 1965, 87, 247.
6. (a) Martin, J.C.; Taylor, J.W.; Drew, E.H. J. Am. Chem. Soc. 1967, 89, 129. (b) Greene, F.D.; Stein, H.P.;
Chu, C.-C.; Vane, F.M. J. Am. Chem. Soc. 1964, 86, 2080. (c) Bartlett, P.D.; Hiatt, R.R. J. Am. Chem. Soc.
1958, 80, 1398.
7. Chateauneuf, J.; Lusztyk, J.; Ingold, K.U. J. Am. Chem. Soc. 1987, 109, 897.
8. (a) Gray, P.; Williams, A. Chem. Rev. 1959, 59, 239. (b) Greene, F.D.; Savitz, M.L.; Osterholtz, F.D.; Lau,
H.H.; Smith, W.N.; Zanet, P.M. J. Org. Chem. 1963, 28, 55. (c) Walling, C.; Padwa, A. J. Am. Chem. Soc. 1963, 85,
1593. (d) Walling, C.; Padwa, A. J. Am. Chem. Soc. 1963, 85, 1597.
9. The best known application of this homolysis is the Barton reaction, used in the synthesis of aldosterone
acetate: (a) Barton, D.H.R.; Beaton, J.M.; Geller, L.E.; Pechet, M.M. J. Am. Chem. Soc. 1960, 82, 2640. (b) Barton,
D.H.R.; Beaton, J.M. J. Am. Chem. Soc. 1960, 82, 2641; 1961, 83, 4083. (c) Barton, D.H.R.; Basu, K.K.; Day, M.J.;
Hesse, R.H.; Pechet, M.M.; Starratt, A.N. J. Chem. Soc., Perkin Trans. 1 1975, 2243. (d) Hesse, R.H. Adv. Free
Radical Chem. 1969, 3, 83. (e) Akhtar, M. Adv. Photochem. 1964, 2, 263.
10. (a) Barton, D.H.R.; Crich, D.; Motherwell, W.B. J. Chem. Soc., Chem. Commun. 1983, 939; Tetrahedron
1985, 41, 3901. (b) Barton, D.H.R.; Lacher, B.; Zard, S.Z. Tetrahedron Lett. 1985, 26, 5939. For a review, see:
(c) Barton, D.H.R. Aldrichimica Acta 1990, 23, 3.

esters undergo photochemical homolysis into an alkoxy radical (Example 14.6) and the
stable free radical, nitric oxide. In fact, much of the driving force for the reaction comes
from the fact that one of the radicals formed, nitric oxide, is a stable free radical. The ho-
molysis of Barton esters, which also results in a very stable free radical (the 2-pyridylmer-
capto radical; Example 14.13), has become one of the most useful methods for the formation
of carboxy radicals (e.g., Example 14.14) and, therefore, of alkyl free radicals (e.g., Example
14.15). The ready availability of these esters from acid chlorides has made this one of the
methods of choice for the generation of alkyl radicals.
O
O
O N O
O N O
O
Ph O O
N Ph O
O
O
S (14.14)
(14.12) N
S
(14.13) CO2
O
O N O
Ph O
(14.15)
O—Halogen and N—Halogen Homolysis
I I
Pb(OAc)4 I
R XH R X Pb(OAc)3 R X R X
(14.16) (14.18) (14.19)
(14.17)
X = O, NR, CO2
The homolysis of alkyl and acyl hypohalites is another important method for the produc-
tion of alkoxy and acyloxy free radicals, and the homolysis of N-haloammonium ions is an
important method for the formation of the analogous highly reactive, nitrogen-
centered aminium cation-radicals. The reactants for these homolyses are obtained a
number of ways, almost always involving the oxidation of alcohol or amine precursors in
the presence of the halogen. For example, the oxidation of an alcohol by lead tetraacetate
in the presence of iodine (e.g., Example 14.16; X=O) gives the corresponding hypoiodite
(Example 14.19),11 which can then undergo further reaction. The function of the iodine in
the reaction appears to be to intercept the initially formed radical (Example 14.18) and
thus suppress further oxidation of the radical by lead (III) or lead (IV).
Homolysis of Organometallic Compounds
R Hg H R Hg R + Hg°
(14.20) (14.21) (14.7)
11. (a) Heusler, K.; Kavolda, J. Angew. Chem. Int. Ed. Engl. 1964, 3, 525. (b) Akhtar, M.; Barton, D.H.R. J. Am.
Chem. Soc. 1964, 86, 1528. (c) Kavolda, J. Chem. Commun. 1970, 1002. (d) Heusler, K.; Wieland, P.; Meystre, C.
Org. Syn. 1965, 45, 57. (e) Menkert, E.; Mylari, B.L. J. Am. Chem. Soc. 1967, 89, 174. (f) Shalon, Y.; Yanuka, Y.;
Sarel, S. Tetrahedron Lett. 1969, 957, 961.

Carbon-metal and metal-hydrogen bonds in organomercury12 hydrides (e.g., Example

14.20) and organocobalt compounds are susceptible to relatively facile homolysis, which
makes these compounds useful precursors to free radicals. Organomercury hydrides, es-
pecially, are readily available by the sodium borohydride reduction of the corresponding
halides and carboxylates, as occurs in the second step of the oxymercuration-demercura-
tion sequence. In fact, the formation of radicals by this reduction is responsible for the loss
of stereospecificity in the second step of that reaction.
Fragmentation of Radicals and Nonradical Precursors

CN
R
R N R R CN
N R + N +
R N
CN CN R R
(14.22) (14.23) (14.23)
Another popular method for the generation of free radicals is the fragmentation of a non-
radical precursor to give an especially stable product. We have already touched on the ho-
molysis of heteroatom-heteroatom bonds. There are circumstances, however, when carbon-
heteroatom bond cleavage can lead to the formation of free radicals. The most widely used
of these reactions is the cleavage of azoalkanes (e.g., Example 14.22) to give two alkyl free
radicals (Example 14.23) and a molecule of nitrogen; the driving force for the reaction
comes from the formation of the especially stable N2 molecule. There is evidence that the
overall fragmentation occurs by a concerted pathway when the alkyl radicals formed are
strongly stabilized and by a stepwise pathway when the free radicals formed are not.13
Among the most important radical initiators that operate by this mechanism are the α,α'-
azo-bis-alkanenitriles (e.g., Example 14.22, which was used as an initiating reaction
in Figure 14.1), which homolyze rapidly to strongly stabilized α-cyanoalkyl radicals.14
A similar type of radical formation driven by the formation of an extremely stable by-
product is the formation of alkyl radicals by the homolysis of diacyl peroxides. In this case,
the formation of carbon dioxide provides the driving force.
Reduction Reactions to Generate Free Radicals

The transfer of an unpaired electron from an active metal to the σ* orbital of a carbon-
heteroatom bond or to a π* orbital is known as single electron transfer, or s.e.t.. The prod-
uct of s.e.t. is a free radical. However, the initial product of s.e.t. to a neutral molecule is a
radical anion, and this species may or may not undergo further unimolecular reactions
before reacting with itself or other species in the reaction mixture. When the receiving
orbital is a carbon-heteroatom σ* orbital, the radical anion is usually unstable, and the
s.e.t. is followed rapidly by loss of the heteroatom as an anion to yield the simple free rad-
ical. When the receiving orbital is a π* orbital, the radical anion is usually long-lived
enough to react with itself or other reagents in the reaction mixture. Radical anions gen-
erated by s.e.t. are intermediates in a number of important reactions, including the Birch
12. (a) Giese, B.; Hueck, K. Chem. Ber. 1979, 112, 3759; Tetrahedron Lett. 1980, 21, 1829; Chem. Ber. 1981, 114,
1572. (b) Giese, B.; Horler, H.; Zwick, W. Tetrahedron Lett. 1982, 23, 931. (c) Giese, B. Angew Chem. Int. Ed. Engl.
1985, 24, 553. (d) Review: Baraluenga, J.; Yus, M. Chem. Rev. 1988, 88, 487.
13. (a) Keonig, T. In Kochi, J.K., Ed. Free Radicals (Wiley: New York, 1973), vol. 1, p.143. (b) Crawford, R.J.; Takagi, K.
J. Am. Chem. Soc. 1972, 94, 7406. (c) Seltzer, S.; Dunne, F.T. J. Am. Chem. Soc. 1965, 87, 2628. (d) Prior, W.A.; Smith, K.J.
J. Am. Chem. Soc. 1970, 92, 5403. (e) Engel, P.S.; Bishop, D.J. J. Am. Chem. Soc. 1975, 97, 6754. (f) Green, J.G.; Dubay, G.R.;
Porter, N.A. J. Am. Chem. Soc. 1977, 99, 1264. (g) Porter, N.A.; Marnett, L.J.; Lochmüller, C.H.; Closs, G.L.; Shobataki, M.
J. Am. Chem. Soc. 1972, 94, 3664. Neumann, R.C., Jr.; Lockyer, G.D., Jr. J. Am. Chem. Soc. 1983, 105, 3982.
14. (a) Overberger, C.G.; O’Shaughnessy, M.T.; Shalit, H. J. Am. Chem. Soc. 1949, 71, 2661. (b) Overberger,
C.G.; Berenbaum, M.B. J. Am. Chem. Soc. 1951, 73, 2618. (c) Overberger, C.G.; Biltech, H.; Finestone, A.B.;
Lilker, J.; Herbert, J. J. Am. Chem. Soc. 1953, 75, 2078. (d) Overberger, C.G.; Lebovitz, A. J. Am. Chem. Soc. 1954,
76, 2722. (e) Overberger, C.G.; Hale, W.F.; Berenbaum, M,.B.; Finestone, A.B. J. Am. Chem. Soc. 1954, 76, 6185.

reduction (via Example 14.24),15 the pinacol16 and acyloin17 reactions (via Example 14.26),
and the Wurtz coupling18 of alkyl halides (via E
xample 14.27).
e NH3 H
NH3 H
(14.24) (14.25)
R Mg(Hg) R
O O (14.26)
R R
R R R
Na°
X X + X
R R R
(14.27)
RCO2 N2
N O
N
Ph N N O2C R Ph N R Ph •
Ph N
O
e
(14.28) (14.29) (14.30) (14.31)
The reduction of arenediazonium ions is an important method for the production of aryl
free radicals. When an arenediazonium ion is treated with base or a carboxylate salt, a deriv-
ative of the diazoic acid (Example 14.29) is formed in a reversible reaction. When the base is
hydroxide anion, the reaction is known as the Gomberg-Bachmann reaction.19 Under the
typical reaction conditions, the diazonium ion is reduced by s.e.t. (where the single electron
comes from is often nebulous!) to start the radical chain reaction by forming the diazenyl
radical (Example 14.30), which then loses nitrogen to give the aryl radical (Example 14.31).
A related reaction occurs when N-nitrosoamides (Example 14.32) are heated in a hydrocar-
bon solvent. In this reaction, the initial step involves the isomerization of the nitrosoamide
to the ester by a formal 1,3-sigmatropic rearrangement; the ester then undergoes reversible
ionization to the diazonium ion. The same reduction of the diazonium ion by s.e.t. gives the
diazenyl radical, which loses nitrogen to give the aryl radical.20 Because carbon dioxide is
not isolated in this reaction, it is unlikely that the homolysis of the N—O bond occurs.
N O
Ph N (14.29) Ph N N (14.30) (14.31)
R
O
(14.32)
15. (a) Birch, A.J. J. Chem. Soc. 1944, 430; 1945, 809; 1946, 593; 1947, 1642. (b) Watt, G.W. Chem. Rev.
1950, 46, 317.
16. (a) Rausch, M.D.; McEwen, W.E.; Kleinberg, J. Chem. Rev. 1957, 57, 417. (b) Adams, R.; Adams, E.W. Org.
Syn., Coll. Vol. 1 1944, 459. (c) Vigevani, A.; Pasqualucci, R.; Gallo, G. Tetrahedron 1969, 25, 573. (d) Corey, E.J.;
Danheiser, R.L.; Chandrasekaran, S.; Siret, P.; Keck, G.E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031.
(e) Corey, E.J.; Danheiser, R.L.; Chandrasekaran, S.; Keck, G.E.; Gopsalom, B.; Larsen, S.D.; Siret, P.; Gras, J.-L. J.
Am. Chem. Soc. 1978, 100, 8034.
17. (a) Bouveault, L.; Loquin, R. Compt. rend. 1905, 140, 1593. (b) McElvain, S.M. Org. React. 1948, 4, 256. (c) Finley,
K.T. Chem. Rev. 1964, 64, 573. (d) Snell, J.M.; McElvain, S.M. Org. Syn. 1943, Coll. Vol. 2, 114. (e) Ames, D.E.; Hall, G.;
Warren, B.T. J. Chem. Soc. C 1968, 2617. (f) Prelog, V. J. Chem. Soc. 1960, 420. (g) Schaefer, J.P.; Bloomfield, J.J. Org.
React. 1967, 15, 1.
18. (a) Wurtz, A. Ann. Chim. Phys. [3] 1855, 44, 275; Ann. Chem. Pharm. 1855, 96, 364. (b) Kosolapoff, G.M.
Org. React. 1951, 6, 326.
19. (a) Gomberg, M.; Bachmann, W.E. J. Am. Chem. Soc. 1924, 46, 2339. (b) Hey, D.H.; Waters, W.A. Chem.
Rev. 1937, 21, 169. (c) Elks, J.; Haworth, J.W.; Hey, D.H. J. Chem. Soc. 1940, 1284. (d) Dermer, O.C.; Edmison,
M.T. Chem. Rev. 1957, 57, 77. (e) Augood, D.R.; Williams, G.H. Chem. Rev. 1957, 57, 123. (f) Bachmann, W.E.;
Hoffman, R.A. Org. React. 1944, 2, 224.
20. Cadogan, J.I.G. Acc. Chem. Res. 1971, 4, 186.

Oxidation Reactions to Generate Free Radicals

Conceptually, at least, one of the simplest methods for site-selective formation of alkyl free
radicals by oxidation is the electrolytic oxidation of carboxylate anions (Example 14.33),
which forms the basis for the Kolbe electrolysis.21 Another major method for preparing
free radicals in a site-selective manner is the reaction between an alcohol or amine and
lead tetraacetate and iodine to generate an alkyl hypoiodite, whose homolysis was dis-
cussed earlier in this chapter.
R CO2 –e R CO2 R• (14.33)
Manganese (III) Acetate Oxidation

Manganese (III) compounds are excellent one-electron oxidants for carbonyl compounds
(especially β-dicarbonyl compounds). The mechanism of these reactions may be viewed as
shown in Figure 14.2. In this mechanism, the initial complexation of the carbonyl oxygen
(14.34) by manganese is followed by proton loss to give the Mn(III) enolate complex
(14.35). The transfer of a single electron from the ligand to the metal results in loss of the
metal and formation of the enolate radical (14.36). These radicals will react with manga-
nese (III) acetate to give the corresponding acetates (14.37), as illustrated by Example
14.38, or they will add to alkenes to give addition products.
O O
OAc
Mn(OAc)4 (2 eq.) 22
(14.38)
PhH, ∆, 10 h
(64%)
The exact product depends to a degree on the reaction conditions (especially the reac-
tion solvent). As the oxidation of 14.39 below shows, when a copper (II) co-oxidant is used,
the initial radical (14.40) cyclizes to 14.41 and is then oxidized further to the carbocation.
This cation is trapped by copper in the form of a copper (III) complex (Example 14.43) that
then either generates the alkene (1 Example 4.45) by deprotonation (favored by more basic
solvents such as dimethyl sulfoxide) or a lactone (Example 14.44) by intramolecular trap-
ping of an ester carbonyl oxygen.
Figure 14.2 Mechanism of

O MnIII MnIII α-oxidation of ketones to
O O radicals by Mn(III) acetate
R MnIII
R R R
R (14.34) R R
H H
H R
(14.35)
MnII
O O O
R R R
R R R
OAc
R R (14.36) R
(14.37)
Mn(OAc)2 Mn(OAc)3
21. (a) Kolbe, H. Ann. Chem. Pharm. 1849, 69, 257. (b) Crum Brown, A.; Walker, J. Ann. Chem. Pharm. 1891, 261,
107. (c) Glasstone, S.; Hickling, A. Chem. Rev. 1939, 25, 333. (d) Weedon, B.C.L. Quart. Rev. (London) 1952, 6, 380.
22. Tanyeli, C.; Iyigün, C. Tetrahedron 2003, 59, 7135.

CO2Me CO2Me MeO2C CO2Me MeO2C CO2Me

Mn(OAc)3
MeO2C MeO2C Me
H
(14.41) (14.42)
(14.39) (14.40) R
OH
R O
O
MeO2C CO2Me MeO2C CO2Me CO2Me MeO2C CO2Me
CuX2 or
X2CuIII H
(14.41) + Cu(OTf)2, HOAc [+ Cu(OTf)2, Me2SO]

(14.43) or
+ Cu(OTf)2, MeCN, ∆
(14.45)23
(14.44)
Autoxidation of Trialkylboranes
Trialkylboranes (Example 14.46) react with molecular oxygen to give peroxide-containing
borane products (e.g., Example 14.47), with the concomitant formation of free radicals.24
In fact, the reaction between trialkylboranes and oxygen serves as an excellent method
for initiating free radical reactions (especially radical additions to alkenes or radical
cyclizations).
O
O
R R O
B R B O + R•
R R
(14.46) (14.47)
Photochemical Generation of Radicals: Ketone Photolysis

R R
hν
O O
R R
(14.48)
The irradiation of ketones leads to promotion of an electron from an occupied orbital

to the unoccupied π* orbital of the carbonyl group (Example 14.48). This process,
which gives a diradical, a species with two unpaired electrons, can occur in two ways:
promotion of the electron from a lone pair on oxygen to the π* orbital (n-π*) and pro-
motion of the electron from the C=O π orbital to the π* orbital (π-π*). The two pro-
cesses are not equally facile. The π-π* transition is symmetry-allowed and occurs
rapidly and easily. At the same time, the reverse process also occurs rapidly, so the di-
radical formed only survives for a short time (usually too short for any subsequent
chemical reaction).
In contrast to the π-π* process, the n-π* transition is symmetry-forbidden, so the
probability of the transition occurring is low, and the reaction is slow. At the same time,
the reverse reaction, also, is symmetry-forbidden, so the diradical formed by this process
is long-lived enough to participate in subsequent reactions.
The formation of useful diradicals in the π-π* process can be facilitated by the use of
photosensitizers, which are compounds in which the singlet diradical initially formed
(Example 14.48) rapidly undergoes intersystem crossing (ISC; a symmetry-forbidden pro-
cess that inverts of the spin of one of the electrons) to give the much longer-lived triplet
diradical (Example 14.49). Diradicals formed in this process necessarily have one of the
unpaired electrons on oxygen. Because oxygen-centered radicals are very high energy,
23. Powell, L.H.; Docherty, P.H.; Hulcoop, D.G.; Kemmitt, P.D.; Burton, J.W. Chem. Commun. 2008, 2559.
24. Review: Brown, H.C.; Midland, M.M. Angew. Chem.Int. Ed. 1972, 11, 692.

these diradicals are highly reactive. Typically, they tend to abstract hydrogen atoms from
carbon (especially in intramolecular processes).
R π−π* R ISC R
O O O
(fast) (slow)
R R R
(14.48s) (14.48t)
Reaction Synopses
Homolysis
Peroxides
RO OR ∆ or hν 2 RO•
Reagents: (Me3CO)2, (PhCO2)2, etc.

Aliphatic Azo Compounds
RN NR ∆ or hν 2 R• + N2
R= Me2C(CN), AIBN; c-C6H10(CN), ACCN

Most widely used radical initiators
Nitrite Esters
RO N O ∆ or hν RO• + •NO
Barton Esters
S S
O ∆ or hν
+ R• + CO2
N N
O R
Organomercury Hydrides
NaBH4
R Hg X R•
NaOH
X = Cl, Br, OCOR, etc.

Reagents: NaBH4 , NaOH, H2O; etc.
Oxidation of Trialkylboranes
R O2
B R R•
R
Oxidation with Mn(III)

O O
R R products
R R
H
R R
Reagents: Mn(OAc)3, PhH, ∆; Mn(acac)3, PhH, ∆; etc.

Atom Abstraction
Hydrogen
R H R•
Reagents: ROOR, ∆ or hν; etc.
(continues)

Relatively nonspecific unless the C—H bond is activated or the reaction is intra-
molecular. Intramolecular reaction occurs through a six-membered cyclic transi-
tion state.
By Stannyl Radicals
R X R•
X = Cl, Br, I, SR, OC(=S)–SR SeR, etc.

Reagents: Bu3SnH, AIBN, ∆ or hν; etc.
Single Electron Transfer
R X R X •R + X-
Reagents: Li (Na, K, Ca, etc.), NH3; Li (Na, K, Mg, Ca, etc.), PhH; etc.
Photochemical Excitation of Carbonyl Compounds
R hν R
O O
R R
Diradical formed may be singlet or triplet. Symmetry-forbidden processes (n-π*,

ISC) give the longest-lived, most synthetically useful diradicals.
14.2 Reactions of Free Radicals
With the ability to generate free radicals in a site-selective manner comes the ability to use
the reactions of these useful intermediates in synthesis. The majority of free radicals react
by fragmentation, addition, or rearrangement.
OCMe3
O O Me
Me H
O O
Ar
(14.52)
(14.49) (14.50) (14.51) (14.53)
Fragmentation
We have already touched on the generation of alkyl free radicals by the decarboxylation of
carboxy radicals or by the fragmentation of tert-alkoxy radicals to give a ketone and the
alkyl radical. Most carboxy free radicals are formed by initial homolysis of a relatively
weak bond. Peresters, acyl peroxides, acyl hypohalites and Barton esters can all serve as
precursors to acyl radicals, as can electrolysis of carboxylate anions (the Kolbe electroly-
sis). The homolysis of a tert-butyl perester (Example 14.49) was a key step in Eaton’s syn-
thesis of cubane (Example 14.53).25
CO2Me Br2, CCl4, ∆ CO2Me
(14.54)26
CO2Ag (65-68%) Br
25. (a) Eaton, P.E.; Cole, T.W., Jr. J. Am. Chem. Soc. 1964, 86, 962, 3157.
26. Allen, C.F.H.; Wilson, C.V. Org. Syn., Coll. Vol. 3, 1955, 578.

O O
Br
O OAg
R R
R (14.6)
Br2
Br
CO2
O O
R•
AgBr
R (14.7)
(14.55)
CO2H Br
HgO, Br2 27
(14.56)
CCl4, ∆
(37%)
The Borodin-Hunsdiecker reaction28 is a reaction that leads to the conversion of a
silver29 or mercury30 salt of a carboxylic acid by elemental bromine into the alkyl bro-
mide of the next-lower homolog (Example 14.54). It is initiated by homolysis of the
oxygen-halogen bond of the acyl hypobromite (Example 14.55) to give the carboxy rad-
ical (Example 14.6). In the first propagation step, the carboxy radical decarboxylates to
the alkyl radical (Example 14.7), which abstracts the halogen atom from a molecule of
the acyl hypohalite in the second propagation step to give the alkyl halide and another
carboxy radical. During the 1960s, the reaction was modified to replace the silver in the
reaction by the less expensive (but more toxic) mercury. This modification (Examples
14.56 and 14.57) involves adding bromine to the carboxylic acid and mercuric oxide
heated in a halogenated solvent (although it is occasionally necessary to irradiate the
reaction mixture).
HgO, Br2
CO2H Br (14.57)31
Cl2CHCHCl2, ∆
(41-46%)
Atom Abstraction (Atom Transfer)

An alternative method to thermolysis or photolysis of weak bonds for the generation of
free radicals is atom abstraction—transfer of an atom from a molecule to a free radical. If
the σ bond forming between the radical and the transferring atom is stronger than the
original σ bond to the transferring atom, the atom transfer occurs rapidly.
27. Cristol, S.J.; Firth, W.C. J. Org. Chem. 1961, 26, 280.
28. Wilson, C.V. Org. React. 1957, 9, 332.
29. (a) Borodine, A. Z, Chem. 1861, 4, 5; 1869, 12, 342; Ann. Pharm. Chem. 1869, 121, 119. (b) Hunsdiecker, C.;
Hunsdiecker, H. Vogt, E. U.S. Pat. No. 2,176,181 (1939). (c) Hunsdiecker, H.; Hunsdiecker, C. Ber. Deut. chem.
Ges. 1942, 75, 291. (d) Wilson, C.V. Org. React. 1975, 9, 341.
Heinz Hunsdiecker (1904–1981) took his PhD in 1929 at Göttingen and worked in the laboratories of Dr.
Vogt and Company, a chemical plant in Köln, where he was a chemist and partner. Hunsdiecker passed his
career in industry, and he received several patents. With his wife, Cläre Hunsdiecker, née Dieckmann (1903–
1995), he patented the reaction that now bears their joint names. This patent may hold the record for the time
between public disclosure of a method and award of a patent for that method.
Aleksandr Porfir’evich Borodin (Borodine) (1833–1887) earned his MD from St. Petersburg University,
and he then became Professor at the Medical-Surgical Academy in St. Petersburg after study in Germany and
Italy. Borodin was a fine composer, although he always considered himself a chemist first. Much of his music
was incomplete when he died, suddenly, of an aneurysm; it was completed by his friends. Borodin is the only
chemist to have won a Tony award for best musical score in a Broadway show (Kismet, 1953). For more detail,
see: Friedman, H.B. J. Chem. Educ. 1941, 18, 521.
30. (a) Ref. 27. (b) Davis, J.A.; Herynk, J.; Carroll, S.; Bunds, J.; Johnson, D. J. Org. Chem. 1965, 30, 415.
(c) Jennings, P.W.; Ziebarth, T.D. J. Org. Chem. 1969, 34, 3216. (d) Meek, J.S.; Osuga, D.T. Org. Syn. 1963, 43, 9.
31. Meek, J.S.; Osuga, D.T. Org. Syn., Coll. Vol. 5, 1973, 126.

Table 14.2 Bond Dissociation Energies of σ Bonds to Hydrogen
Bond (kcal mol–1) (kJ mol–1) Bond (kcal mol–1) (kJ mol–1)
CH3–H 104 435 HO–H 119 498

RCH2–H 98 410 HOO–H 90 377
R 3C–H 92 385 RCH2O–H 104 437
C6H5CH2–H 85 356 RCOO–H 103–110 431–469
H2CCHCHR–H 83 347 C6H5O–H 88 368
HOCH2–H 94 393
MeOCH2–H 93 389 H2N–H 102 427
HOCMe2–H 91 381
H2C=CHCH(OH)–H 82 341 HS–H 95 397
CH3S–H 74 310
C6H5–H 110 461
O=CR–H 87 364
One can predict the probable outcome of atom-transfer reactions by determining the
exothermicity of the reaction from bond dissociation energies. In the transfer of a bro-
mine atom from molecular bromine to an alkyl radical, for instance, the bromine-bromine
bond (46.3 kcal mol–1, 194 kJ mol–1) is broken and a carbon-bromine bond (70 kcal mol–1,
293 kJ mol–1) is formed as the reaction is written. Thus, as written, the reaction is exother-
mic by 23.7 kcal mol–1 (99 kJ mol–1), and it is expected to be favorable.
The abstraction of a hydrogen atom is widely used for initiating free radical reactions.
The abstraction of hydrogen from sp3 carbon by an oxygen-centered radical or atom is
usually an exothermic process, as can be calculated from the values in Table 14.2. How-
ever, unless one particular C—H bond is especially activated toward homolysis, hydrogen
atom abstraction is a relatively nonselective method for generating of free radicals. Conse-
quently, the use of hydrogen atom transfer reactions in laboratory synthesis is generally
restricted to the generation of allylic free radicals. Abstraction from sp2 or sp carbon is
usually endothermic and seldom synthetically useful.
There is one exception to the generalization that the abstraction of a hydrogen atom
from a nonallylic sp3 carbon is nonselective; that is the intramolecular abstraction of hy-
drogen from carbon by oxygen- or nitrogen-centered radicals.32 In these cases (e.g.,
Example 14.58), the hydrogen that is abstracted can be predicted with a high degree of
certainty because intramolecular hydrogen atom transfer reactions occur preferentially
through a six-membered cyclic transition state unless there are unusual circumstances that
prevent this or make other transition states more favorable.33
X X ‡ X
H H H
(14.58)
X = O, NH, NH2 , NCOR, etc.

Intermolecular hydrogen atom abstraction is usually nonspecific. However, the ab-
straction of halogen atoms or sulfur- or selenium-based groups by tin-centered radicals, a
32. For a brief review of early work in this area, see: Acott, B.; Beckwith, A.L.J. Aust. J. Chem. 1964, 17, 1342.
33. (a) Hesse, R.H. Adv. Free Radical Chem. 1969, 3, 83. (b) Barton, D.H.R. Pure Appl. Chem. 1968, 16, 1.

hν Figure 14.3
AIBN CN Stannane reduction
or ∆ Bu3SnH
H CN
Bu3Sn • R X
R H
Bu3SnH Bu3SnX
R•
X = Cl, Br, I, SR, SeR, etc.
highly selective reaction, has the added advantage of giving a radical where the location of
the free radical center is known. The trialkyltin radicals do not abstract hydrogen from
organic compounds. The free radical reaction between an alkyl halide and tri-n-butyltin
hydride (tri-n-butylstannane) is often the preferred method for the replacement of a halo-
gen atom by hydrogen in organic compounds.34 The reduction of an alkyl halide, sulfide,
or selenide by tri-n-butylstannane may be represented by the cycle diagram in Figure 14.3;
examples are shown below (Examples 14.59 and 14.60).
Cl
Bu3SnH 35
(14.59)
AIBN, PhMe
∆
(97%) trans:cis = 6:1
Br Bu3SnH H
36
(14.60)
Cl AIBN, PhMe Cl
∆
(97%)
Stannanes not only cleave C—X σ bonds, they also readily add to C=S π bonds. This
reaction forms the basis for the reduction of xanthate esters or other thionoesters with
tri-n-butylstannane, which has become an important method for the deoxygenation of
alcohols37 known as the Barton-McCombie reaction. This use of stannanes to reduce al-
cohols is illustrated by Examples 14.61 and 14.62.
O O
O 1) NaH, THF O
2) CS2
(14.61)
O OH 3) MeI O
O 4) Bu3SnH, PhMe, ∆ O
(94% overall)
34. (a) Kuivila, H.G. Acc. Chem. Res. 1963, 1, 1968; Synthesis 1970, 499.
35. Greene, F.D.; Lowry, N.N. J. Org. Chem. 1967, 32, 882.
36. Seyferth, D.; Yamazaki, H.; Alleston, D.L. J. Org. Chem. 1963, 28, 703.
37. (a) Barton, D.H.R.; McCombie, S.W. J. Chem. Soc. Perkin Trans. 1 1975, 1574. (b) Hartwig, W. Tetrahedron
1981, 39, 2609. (c) Robins, M.J.; Wilson, J.S. J. Am.Chem. Soc. 1981, 103, 933. (d) Robins, M.J.; Wilson, J.S.;
Hansske, F. J. Am.Chem. Soc. 1983, 105, 4059. (e) RajanBabu, T.V. J. Am.Chem. Soc. 1987, 109, 609; J. Org. Chem.
1988, 53, 4522. (f) Prisbe, L.J.; Martin, J.C. Synth. Commun. 1985, 15, 401. (g) Barton, D.H.R.; Jaszberenyi, J.C.
Tetrahedron Lett. 1989, 30, 2619.

1) NaH, THF
2) CS2
3) MeI
4) Bu3SnH, PhMe, ∆ (14.62)
(72% overall)
HO
The reaction has been modified (Example 14.63) for the deoxygenation of tertiary al-
cohols by means of a mixed oxalate ester with a Barton ester at one end of the molecule.38
In this case, the tin reagent is not necessary for reduction, but a thiol is used instead.
OH
1) (COCl)2 (14.63)
2) , t-BuSH
AcO N S AcO
ONa
Addition
In general, free radical additions to alkenes are favorable because the bond formed, which
LUMO is a σ bond, is lower energy than the bond broken, which is a π bond. The addition of free
SOMO radicals to alkenes is initiated by the overlap of the radical singly occupied molecular or-
bital (SOMO; 2p orbital) and the alkene lowest energy unoccupied molecular orbital
(LUMO; the π* orbital). Because of the location of the nodal plane in the π* orbital per-
pendicular to the center of the σ bond, this frontier orbital overlap has one very important
geometric consequence. The frontier overlap for the addition of a free radical to an alkene
occurs at one end of the π bond and not in the middle, as occurs when carbocations add to
alkenes, a reaction that involves the highest energy occupied molecular orbital (HOMO;
π) of the alkene and the LUMO (2p) of the cation (Figure 14.4). This has important re-
LUMO HOMO giochemical consequences, especially in reactions such as radical cyclization.
Figure 14.4 Frontier orbital A free radical addition, that was not recognized as such, puzzled organic chemists for
overlap in addition of decades until the solution was published by American chemist Morris Kharasch39 in
radicals (top) and cations 1933.40 The problem was a deceptively simple one: under certain circumstances, the addi-
(bottom) to alkenes. HOMO, tion of hydrogen bromide to alkenes proceeded according to Markovnikov’s rule, whereas
highest energy occupied
under other circumstances, it gave the anti-Markovnikov product. What was even more
molecular orbital; LUMO,
frustrating, workers often had difficulty reproducing their own results—even when using
molecular orbital; SOMO, chemicals from the same bottles! In 1937, however, Kharasch succeeded in identifying the
singly occupied culprit for the lack of reproducibility in this reaction: organic peroxides formed by the
molecular orbital. reaction between the alkene and oxygen. These peroxides served as free radical initiators
38. Barton, D.H.R.; Crich, D. J. Chem. Soc., Chem. Commun. 1984, 774.
39. Morris Selig Kharasch (1895–1957) was born in Ukraine, and migrated to the United States in 1908. He
was educated at the University of Chicago (BS, 1917; PhD, 1919), where he was appointed to the faculty after grad-
uation; he remained there for the rest of his life except for a hiatus at the University of Maryland from 1924–1928.
Just prior to his death in 1957, the university created an Institute of Organic Chemistry, with Kharasch as its first
director. For more biographical details, see: Westheimer, F.H. Biogr. Mem. Natl. Acad. Sci. 1960, 123.
40. (a) Kharasch, M.S.; Mayo, F.R. J. Am. Chem. Soc. 1933, 55, 2468. (b) Kharasch, M.S.; McNab, M.C.; Mayo,
F.R. J. Am. Chem. Soc. 1933, 55, 2531. (c) Kharasch, M.S.; Hinckley, J.A., Jr. J. Am.Chem. Soc. 1934, 56, 1642.
(d) Kharasch, M.S.; Engelmann, H.; Mayo, F.R. J. Org. Chem. 1938, 2, 288. (e) Hey, D.H.; Waters, W.A. Chem.
Rev. 1937, 21, 169.

in the reaction with hydrogen bromide, thus allowing the reaction to proceed by a radical
rather than an ionic pathway (Example 14.64).
Br
H
Me Me Me
(14.64)
Br Br
• Br
The addition of hydrogen halides to alkenes also illustrates the importance of enthalpy
in determining the course of radical reactions. Of the four, only hydrogen bromide reacts
by a free radical mechanism under any conditions. The radical addition of a hydrogen
halide must occur by a two-step process involving (1) sequential addition of the halogen
atom to the alkene π bond and (2) subsequent abstraction of the hydrogen atom from the
hydrogen halide. In order for this reaction to occur at a reasonable rate, both propagation
steps of the reaction must be exothermic. The values in Table 14.3 show that only for the
reaction between hydrogen bromide and an alkene are both steps exothermic.
The free radical copolymerization of maleic anhydride and styrene leads to the forma-
tion of an alternating copolymer (Example 14.65), where the styrene and maleic anhydride
units alternate along the backbone. This result illustrates the fact that free radicals can
exhibit either nucleophilic or electrophilic propensities. Simple alkyl radicals, for example,
are generally nucleophilic in nature and will add more rapidly to electron-poor double bonds.
In contrast, radicals carrying an electron-withdrawing
(e.g., carbonyl or nitro) group directly bonded to the radical Table 14.3 Reaction Enthalpies for Free Radical Addition of HX
center tend to be electrophilic and add preferentially to to Alkenes*
electron-rich double bonds. R R R R
H
R R R R
O X
O HX X
O HF –46 +36
HCl –17 +4
Ph Ph (14.65)
HBr –3 –11
O
O HI +12 –27
O n *Values adapted from Reference 41.
Problems
14-1 Draw a reaction cycle diagram (a “carousel” diagram) identifying the initiation
step and the propagation steps of each of the following reactions.
Me Me
Br2 Br Cl Bu3SnH
(a) hν
(b) AIBN, hν
CO2Ag Br2 Br HBr

(c) (d) ROOR, hν Br
S
O BrCCl3
N Br
(e)
O hν
(continues)
41. Isenberg, N.; Grdinic, M. J. Chem. Educ. 1969, 46, 601.

14-2 What will be the final alkyl (carbon-centered) free radical formed when each of
the following compounds is heated or photolyzed?
Ph ONO
O
O
(a) O (b) O (c)
Ph
Ph
Me O
(d) N
Me (e) O O
I Ph
Reaction Synopses
Fragmentation
Alkoxy Radicals
R R
O R O + •R
R R
Reagents: (t-BuO)2, etc.

Carboxy Radicals
R R
XO O •R + CO2
O O
X = Br, OCOR, OR, etc.

Reagents: RCO2OR'; RCO2Ag, Br2; (RCO2)2; etc.
Addition of Radicals to Alkenes
H R H R
R• + R
H R H R
Regiochemistry: Markovnikov
14.3 Reactions of Free Radicals Useful for Synthesis42
Regardless of how they are generated, free radicals always tend to react by the most exo-
thermic pathway available, so one can predict the probable outcome of a radical reaction
based on the bond dissociation energies of the bonds involved. Synthetically important
free radical addition reactions of alkenes to form new carbon-carbon bonds are relatively
uncommon as yet, although the fact that many functional groups do not react with free
radicals has provided an incentive for their development because there is often no need to
protect sensitive functional groups during radical reactions.
42. Monographs: (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds (Pergamon:
Oxford, 1987). (b) Renaud, P.; Sibi, M. (Eds.) Radicals in Organic Synthesis (VCH-Wiley: Weinheim, 2001).
(c) Zard, S.Z. Radical Reactions in Organic Synthesis (Oxford University Press: Oxford, 2003). (d) Togo, H. Ad-
vanced Free Radical Reactions for Organic Synthesis (Elsevier: Amsterdam, 2004).

Radical Decarboxylations: Substitution of a Carboxyl Group

The oxidative decarboxylation of carboxylic acids through carboxy radicals has become a
popular method for the generation of free radicals under a wide variety of conditions. As
we discussed in the previous section, there are three common precursors to carboxy radi-
cals: acyl peroxides and peresters, acyl hypohalites, and Barton esters. In their reactions,
all these precursors generate the carboxy free radical, which then rapidly decarboxylates
to give the alkyl free radical.
Barton Modification of the Borodin-Hunsdiecker Reaction

One of the more useful modifications of the Borodin-Hunsdiecker reaction to be developed
in recent years is the Barton modification, where the carboxy radical is obtained by homolysis
of a Barton ester (Example 14.66). This modification has far-reaching environmental implica-
tions. By removing the need for silver or mercury compounds, it obviates the necessity for
disposal of these heavy metals in an environmentally sound manner. The typical procedure
simply requires heating or photolyzing the Barton ester in the presence of a carbon tetraha-
lide (carbon tetrachloride to obtain chlorides, bromotrichloromethane to obtain bromides) or
iodoform (to obtain an iodide). The alkyl radical (Example 14.67) then abstracts the halogen
with the weakest C—X bond to give the product halide (Example 14.68).43
O O
N O Ph S BrCCl3, hν N O Ph
O O
O (73%)
N Br
O O O
(14.66) (14.68)
O
N O Ph
O
Br CCl3
O
(14.67)
Another modification of the Borodin-Hunsdiecker reaction, also developed by Barton,
yields alkyl iodides as the major product. This reaction involves irradiating a heated solu-
tion of the carboxylic acid, iodine and lead tetraacetate (Example 14.69). The active inter-
mediate in this reaction is the acyl hypoiodite. An alternative reagent, tert-butyl hypoiodite
(formed from potassium tert-butoxide and iodine; used in Example 14.70), was superior for
the Borodin-Hunsdiecker decarboxylation of hindered and bridgehead carboxylic acids.
(CH2)10CO2H I2, Pb(OAc)4 (CH2)10I
AcO AcO (14.69)44
(CH2)5CH3 CCl4, hν, ∆ (CH2)5CH3
(82%)
CO2H I
t-BuOI (14.70)
45
PhH, hν
(62%)
43. (a) Barton, D.H.R.; Crich, D.; Motherwell, W.B. Tetrahedron 1985, 41, 3901. (b) Barton, D.H.R.; Lacher, B.;
Zard, S.Z. Tetrahedron Lett. 1985, 26, 5939.
44. (a) Barton, D.H.R.; Faro, H.P.; Serebryakov, E.P.; Woolsey, N.F. J. Chem. Soc. 1965, 2438. (b) Kochi, J.K.
J. Am. Chem. Soc. 1965, 87, 2500; J. Org. Chem. 1965, 30, 3265. (c) Gunstone, F.D. Adv. Org. Chem. 1960, 1, 117.
45. Barton, D.H.R.; Faro, H.P.; Serebryakov, E.P.; Woolsey, N.F. J. Chem. Soc. 1964, 2438.

The same combination of reagents (lead tetraacetate and iodine) can also be used to
form other compounds with iodine-oxygen bonds, as well as compounds with iodine-
nitrogen bonds. Such compounds are useful precursors to other oxygen-centered and
nitrogen-centered free radicals.
Intramolecular Hydrogen Atom Transfer

Hydrogen atom transfer can serve as a method for the oxidation of alkanes, as we dis-
cussed in Chapter 11, and now let us discuss hydrogen atom transfer as a method for incor-
porating functional groups into unactivated (saturated hydrocarbon) locations in organic
molecules. This involves the generation of a highly reactive radical in a position that allows
the subsequent intramolecular transfer of a hydrogen atom to give a carbon-centered rad-
ical at the remote site. The typical reactive radicals in these reactions are electron-deficient
and centered on nitrogen or oxygen, and the hydrogen atom transfer is driven by the for-
mation of the stronger heteroatom-hydrogen bond. The atom transfer itself almost always
occurs through a six-membered, cyclic transition state.
Hofmann-Löffler-Freytag Reaction and Related Reactions
H
N 1) Cl2, NaOH, ligroin, 0°C
(14.71)46
2) 80% H2SO4, 90-100°C N
3) NaOH, H2O
(70-80%)
H H Cl
N N
1) NCS, Et2O 47
(14.72)
2) CF3CO2H, hν
CO2Me (77%) CO2Me
In the Hofmann-Löffler-Freytag reaction,48 the electron-deficient atom is the nitrogen
of the aminium cation radical, formed by homolysis of the conjugate acid of an N-haloamine
(e.g., Examples 14.71 and 14.72). Because these amines are generally weak bases, the reac-
tion requires strongly acidic conditions. A simple modification that allows the reaction to
occur under much milder conditions involves the homolysis of the N-haloamine by transi-
tion metals (e.g., FeII or CuI). A similar reaction can be carried out by means of an amide
radical, formed by homolysis of an N-haloamide, as illustrated in Figure 14.5. In this reac-
tion, the N-haloamide (14.73) undergoes homolysis to give the amide radical (14.75) that
then undergoes intramolecular hydrogen atom transfer to give the alkyl radical 14.76.
Trapping of this radical by transfer of the halogen atom from the starting haloamide com-
pletes the radical chain reaction, yielding the haloamide 14.74. The advantage of this reac-
tion is that it can be carried out under neutral conditions to give the alkyl halide. What is
interesting about the haloamides that are formed in this reaction is that they give lactones
(e.g., 14.78), rather than lactams, on treatment with base.49
46. Coleman, G.H.; Nichols, G.; Martens, T.F. Org. Syn., Coll. Vol. 3 1955, 159.
47. Uskokovic, M.R.; Henderson, T.; Reese, C.; Lee, H.L.; Grethe, G.; Gutzwiller, J. J. Am. Chem. Soc.
1978, 100, 571.
48. (a) Hofmann, A.W. Ber. Dtsch. Chem. Ges. 1883, 16, 558. (b) Löffler, K.; Freytag, C. Ber. Dtsch. Chem. Ges.
1909, 42, 3427. Reviews: (c) Wolff, M.E. Chem. Rev. 1963, 63, 55. (d) Neale, R.S. Synthesis 1971, 1. (e) Minisci, F. Syn-
thesis 1973, 1. (f) Mackiewicz, P.; Furstoss, R. Tetrahedron 1978, 34, 3241. (g) Majetich, G. Tetrahedron 1995, 51, 7095.
49. (a) Barton, D.H.R.; Beckwith, A.L.J.; Goosen, A. J. Chem. Soc., 1965, 181. (b) Petterson, R.C.; Wambsgans,
A. J. Am. Chem. Soc. 1964, 86, 1648. (c) Beckwith, A.L.J.; Goodrich, J.E. Aust. J. Chem. 1965, 18, 747. (d) Neale,
R.S. Synthesis 1971, 1.

Figure 14.5 Synthesis of

δ-haloamides and δ-lactones
from N-haloamides
MeN MeN H
OH O
(14.76) (14.75)
MeN I NMe
Me O O
N H
I O (14.77)
(14.74)
(14.73) HO
1) hν
O O
2) base, ∆
(14.78)
Radical Coupling
Free radicals can be generated by oxidation or reduction under conditions where the rad-
icals couple to form new products. We have already examined a number of such reactions:
oxidative coupling of phenols, the pinacol reaction, and the McMurry reaction are three
of the major reactions of this type.
Despite its longevity as a method for forming carbon-carbon bonds, the stereochemis-
try of the pinacol reaction was not subjected to systematic investigation until the 1980s,
when McMurry carried out a series of studies of the titanium-promoted pinacol coupling
of dialdehydes (Example 14.79).50 This work revealed that (1) the amount of trans (racemic)
diol (Example 14.83) increased with the size of the ring formed and (2) the formation of the
six-membered ring led only to the cis (meso) diol. As the ring size becomes large enough to
permit levels of flexibility similar to open-chain compounds, the ratio of the two stereoiso-
mers gradually stabilizes near 30% meso: 70% dl. The inclusion of double bonds in the ring
substantially increases the amount of the dl isomer. In intermolecular reactions, the stereo-
chemistry is not so well controlled, and is often dependent on the exact metal used.51
H H
O TiCl3 HO
H Zn-Cu H
O (89%, d.r. 7:3) OH
(14.80) (14.83)
2 Ti+3 (14.79)
2 Ti+4
H H
O O
H H
LnTi O LnTi O
(14.80) (14.83)
50. McMurry, J.E.; Rico, J.G. Tetrahedron Lett. 1989, 30, 1169.
51. (a) Mundy, B.P.; Srinivasa, R.; Kim, Y.; Dolph, T.; Warnet, R.J. J. Org. Chem. 1982, 47, 1657. (b) Mundy, B.P.;
Bruss, D.R.; Kim, Y.; Larsen, R.D.; Warnet, R.J. Tetrahedron Lett. 1985, 26, 3927.

Samarium (II) Iodide: A Versatile Reagent for Radical

Formation in Synthesis52
Samarium (II) iodide was introduced as a reagent for the one-electron reduction of car-
bonyl groups and halides by Kagan.53 The reagent has since found widespread use for the
formation of carbon-carbon bonds in reactions analogous to the Grignard and Refor-
matskii reactions as well as in pinacol-type reactions. The reagent is capable of adding a
single electron to C—X σ bonds in alkyl halides, sulfonates, and sulfones—and to C—O π
bonds. In its reactions with alkyl halides (Example 14.84), an intermediate alkylsamarium
diiodide is formed as an intermediate. This organometallic intermediate permits samar-
ium (II) iodide to mediate Reformatskii- and Barbier-type additions to carbonyl acceptors.
SmII SmIII
SmI2
R X R• R SmI2 (14.84)
X
It is currently accepted (Figure 14.6) that the samarium (II)-mediated pinacol reaction
takes place by an initial one-electron reduction of one of the carbonyl partners by samar-
ium (II) to give a samarium (III) complex of the ketyl (14.85). This samarium (III) complex
contains a fairly hard Lewis acid that can complex the carbonyl oxygen of the second re-
actant (14.86). Radical addition to the carbonyl π bond then gives a highly reactive oxygen-
centered radical (14.87) that abstracts a hydrogen atom from the solvent to give the samar-
ium (III) chelate; the cyclization and hydrogen abstraction steps may operate in concert
with each other. This intramolecular coupling reaction has a further consequence. When
the chelate is formed, it does so such that the two larger groups attached to the carbonyl
carbons are trans to each other in the five-membered ring, leading to preferential forma-
tion of the dl pinacol (14.88) in an intermolecular reaction, and preferential formation of
the cis diol in the intramolecular case.
Figure 14.6 Proposed R RS
mechanism of the SmI2- O O
R R R' RL
promoted pinacol reaction SmII
that accounts for the O O SmIII
observed stereochemistry R' R' SmIII RL
O
of the reaction RS
(14.85)
(14.86)
RS RS
RL OH H2O or ROH RL O
SmIII
RS OH RS O
RL RL
(14.88) H
solvent
(14.87)
52. For reviews of Sm(II) in modern synthesis, see: (a) Molander, G.A. Chem. Rev. 1992, 92, 29; Org. React.
1994, 436, 211. (b) Molander, G.A.; Harris, C.R. Chem. Rev. 1996, 96, 307. (d) Molander, G.A. Acc. Chem. Res.
1998, 31, 603. (c) Edmonds, D.J.; Johnston, D.; Procter, D.J. Chem. Rev. 2004, 104, 3371.
53. (a) Namy, J.L.; Girard,P.; Kagan, H.B. Nouv. J. Chim. 1977, 1, 5. (b) Girard, P.; Namy, J. L.; Kagan, H. B.
J. Am. Chem. Soc. 1980, 102, 2693.

Problem
14-3 The cyclization of γ-iodoamides with aqueous potassium hydroxide gives the
γ-lactone rather than the γ-lactam. Write a reasonable mechanism that ac-
counts for the formation of the product and give reasons why the lactam is
not formed.
O
KOH KOH
R N O NH2 R O
H O
R I
Phenol Coupling54
Phenols and phenoxide anions, especially, are susceptible to single electron oxidation by a
wide range of reagents to give phenoxy radicals (or the related radical cations) that often
undergo radical coupling. Aromatic amines undergo similar reactions to give cation rad-
icals that then undergo analogous radical coupling reactions. The prototypical example of
such reactions is the phenol coupling reaction.
The phenoxy radical is resonance-stabilized, so the unpaired electron density is spread
over several atoms of the radical, which allows the formation of a wide range of products,
depending on the regiochemistry of the coupling reaction, as shown in Figure 14.7. The
oxidation of a phenoxide anion gives a strongly stabilized free radical that adds to e lectron-
rich π bonds, such as those in phenoxide anions, to form new carbon-carbon bonds. This
reaction has been portrayed historically as the coupling of phenoxy radicals, but it actually
involves the intramolecular addition of a radical to a phenoxide anion, followed by rapid
oxidation of the adduct to give the observed product.55 Among the most popular oxidizing
agents are iron (III) compounds, lead (IV) compounds, vanadium (V) compounds, and
manganese (III) compounds.
The examples in Figure 14.7 illustrate the variety of compounds that can be prepared by
this reaction. It is no accident that several of the examples below are based on a 1-benzyl-1,
2,3,4-tetrahydroisoquinoline ring system. This occurs because there are several important
families of natural products (among them the morphine alkaloids) whose carbon skeletons
are based on the phenol coupling products that can be obtained from this ring system.
Indeed, there is good evidence that this reaction is the one that the opium poppy itself uses
to construct the polycyclic ring systems of these compounds.56
Another important example of this coupling reaction is the coupling of 2-naphthol to
give the dimer shown (Example 14.89), often known as BINOL. This molecule is an im-
portant C2-symmetric ligand for a wide range of asymmetric reactions and the starting
54. (a) Bacon, R.G.R.; Hill, H.A.O. Quart. Rev. 1965, 19, 95. (b) Scott, A.I. Quart. Rev. 1965, 19, 1. (c) Taimir,
L.; Popisil, J. Tetrahedron Lett. 1971, 2809. (d) Mahoney, L.R.; Weiner, S.A. J. Am. Chem. Soc. 1972, 94, 585.
(e) Mahoney, L.R.; Weiner, S.A. J. Am. Chem. Soc. 1972, 94, 1412. (f) Anderson, R.A.; Dagleish, D.T.; Non-
hebel, D.C.; Paulson, P.L. J. Chem. Res. (S) 1977, 12. (g) Iqbal, J.; Bhatia, B.; Nayyar, N.K. Chem. Rev.
1994, 94, 519.
Monographs: (h) Battersby, A.R.; Taylor, W.I, Eds. Oxidative Coupling of Phenols (Dekker: New York, 1967).
(i) Dhingra, O.P. In Trahanovsky, W.S., Ed. Oxidations in Organic Chemistry (Academic: New York, 1982),
Part D, Ch. 4.
55. McDonald, P.D.; Hamilton, G.A. J. Am. Chem. Soc. 1973, 95, 7752.
56. (a) Kupchan, S.M.; Kim, K.-C.; Lynn, J.T. J. Chem. Soc., Chem. Commun., 1976, 86. (b) Gervay, G.E.;
McCapra, F.; Money, T.; Sharma, G.M.; Scott, A.I. Chem. Commun., 1966, 142. (c) Barton, D.H.R.; James, R.;
Kirby, G.W.; Turner, D.W.; Widdowson, D.A. J. Chem. Soc. (C), 1968, 1529. (d) Review: Herbert, R.B. The Bio-
synthesis of Secondary Metabolites, 2nd ed.; (Chapman & Hall: London, 1989); p. 146.

Figure 14.7 Regioisomeric OH HO O
products that can be formed O
by free radical coupling NaOCl (1%)
of phenols NaOH
(66%)
ortho-O coupling57
OH OH K3Fe(CN)6 O
O
KOH
"low yield"
para-O coupling58
MeO MeO
NMe NMe
HO K3Fe(CN)6 HO
MeO KOH
MeO
(50%) O
MeO OH MeO
ortho-ortho coupling 59
MeO MeO
NMe NMe
HO HO
K3Fe(CN)6
MeO
KOH MeO
(49%)
HO
O OMe
OMe
ortho-para coupling60
Ac
N
VOCl3, Et2O, –78°C
O
N (50%)
HO Ac OH
HO
para-para coupling61
57. Shearing, E.A.; Smiles, S. J. Chem. Soc. 1937, 1931.

58. (a) Barton, D.H.R.; Chow, Y.L.; Cox, A.; Kirby, G.W. J. Chem. Soc. 1965, 3571. (b) Bacon, R.G.R.; Izatt,
A.R. J. Chem. Soc. (C) 1970, 2543. (c) Schulte-Frohlinde, D.; Erhardt, F. Annalen 1964, 671, 88.
59. (a) Jackson, A.H.; Martin, J.A. J. Chem. Soc., Chem. Commun. 1965, 420. (b) Shamma, M.; Slusarchyk,
W.A. J. Chem. Soc., Chem. Commun. 1965, 528. (c) Jackson, A.H.; Martin, J.A. J. Chem. Soc. C 1966, 2222.
60. Battersby, A.R.; Bradbury, R.B.; Herbert, R.B.; Monro, M.H.G.; Ramage, R. J. Chem. Soc., Perkin Trans. 1
1974, 1394.
61. (a) Schwartz, M.A.; Holton, R.A.; Scott, S.W. J. Am. Chem. Soc. 1969, 91, 2800. (b) Tobinaga, S.; Kotani, E.
J. Am. Chem. Soc. 1972, 94, 309. (c) Schwartz, M.A.; Rose, B.F.; Holton, R.A.; Scott, S.W.; Vishnuvajala, B. J. Am.
Chem. Soc. 1977, 99, 2571.

material for the preparation of many important C2-symmetric ligands for asymmetric cat-
alytic hydrogenation and other asymmetric synthetic reactions.62
OH OH
FeCl3 (14.89)
OH
This general method of forming carbon-carbon bonds by coupling of free radicals ob-
tained from easily oxidized anions has been extended to the oxidation of anions of phenols
carrying aliphatic nitro groups (Example 14.90)63 or strongly enolized β-dicarbonyl groups
(Example 14.91)64 at the end of a side chain. The range of oxidizing agents that have been ap-
plied to this reaction has gradually expanded, and it is now possible to oxidize arenes without
a phenolic hydroxyl group. This is accomplished by carrying out the oxidation in strongly
acidic media (often trifluoroacetic acid with co-solvents such as dichloromethane), using as the
oxidizing agent thallium (III) trifluoroacetate,65 iron (III) chloride and m-chloroperbenzoic
acid,66 vanadium (V) oxyhalides,67 or lead tetraacetate.68 A recent addition to this arsenal in-
volves activation of manganese dioxide by trifluoroacetic acid (Example 14.92).69
KOH, K3Fe(CN)6
(14.90)
HO
(83%)
NO2 O NO2
O O
KOH, K3Fe(CN)6
(14.91)
(88%) O
HO O
O
OMe OMe
MeO MeO
CO2Me MnO2, CF3CO2H CO2Me

(14.92)
(95%)
OMe MeO
OMe OMe
Problem
14-4 When p-cresol (4-methylphenol) is treated with potassium ferricyanide in aque-

ous base, a tricyclic ketone, Pummerer’s ketone (C14H14O2), is formed. This ketone
contains one alkene π bond and an ether group, as well as a carbonyl group and
an aromatic ring. What is its structure and how is it formed?
62. Review: Brunel, J.M. Chem. Rev. 2005, 105, 857.

63. Kende, A.S.; Koch, K. Tetrahedron Lett. 1986, 27, 6051.
64. Kende, A.S.; Koch, K.; Smith, C.A. J. Am. Chem. Soc. 1988, 110, 2210.
65. (a) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem. Int. Ed. Engl. 1990, 29, 977. (b) Taylor, E.C.;
Andrade, J.G.; Rall, G.J.H.; McKillop, A. J. Am. Chem. Soc. 1980, 102, 6513.
66. Wang, K.L.; Lü, M.Y.; Yu, A.; Zhu, X.Q.; Wang, Q.M.; Huang, R.Q. J. Org. Chem. 2009, 74, 935.
67. (a) Liepa, A.J.; Summons, R.E. J. Chem. Soc., Chem. Commun. 1977, 826. (b) Halton, B.; Maidment, A.I.; Offi-
cer, D.L.; Warner, J.M. Aust. J. Chem. 1984, 37, 2119. (c) Wang, K.; Wang, Q.; Huang, R. J. Org. Chem. 2007, 72, 8416.
68. Feldman, K.S.; Ensel, S.M. J. Am. Chem. Soc. 1994, 116, 3357.
69. Wang, K.; Hu, Y.; Li, Z.; Wu, M.; Liu, Z.; Su, B.; Yu, A.; Liu, Y.; Wang, Q. Synthesis 2010, 1083.

Reaction Synopses
Borodin-Hunsdiecker Reaction
R R
R CO2H R X
R R
Reagents: Ag2O, Br2, ∆; etc. or

(1) (COCl)2; (2) Na+ –ONC5H4S; (3) CCl3Br or CCl4, ∆; or
Pb(OAc)4, I2, hν; or
t-BuOI, hν
Hofmann-Löffler-Freytag and Related Reactions
R H R X R X
NR' NR' NHR'
G G G
G=H2, O; X=Cl, Br, I

Reagents:
G=H2: (1) Cl2, NaOH; 2) H2SO4, ∆; or
(1) Cl2, NaOH; 2) CF3CO2H, hν; or
(1) NCS, Et2O; 2) CF3CO2H, hν; etc.
G=O: (1) I2, Pb(OAc)4, CCl4, ∆ or hν; or
t-BuOI, PhH, hν
Pinacol and McMurry Reactions
Stereochemistry: meso isomer favored in cyclizations that give small (≤6 members)
rings; dl isomer is favored from open-chain compounds and in cyclizations that
give large rings.
R R R R R
O HO OH
R R R R R
Reagents: SmI2, THF

Mg(Hg), Et2O; etc.
TiCl3, Zn-Cu, THF; etc.
Phenol Coupling
OH OH OH OH
X
X X X and/or X O
Reagents:
Fe (III): K 3Fe(CN)6, KOH; FeCl3, m-CPBA; Fe(ClO4)3; etc.
V (V): VOCl3, Et2O; VOF3, CH2Cl2; etc.
Pb (IV): Pb(OAc)4, AcOH; etc.
Mn (IV): MnO2, CF3CO2H; MnO2, MsOH; etc.
other: NaOCl, NaOH; etc.

14.4 Additions and Cyclizations of Free Radicals
Many of the radical reactions that are widely exploited in organic synthesis are addition
reactions to carbon-carbon π bonds. For example, bromoform reacts with alkenes in the
presence of a free radical initiator to give a 1,1,1-tribromoalkane with one carbon more
than the original alkene, and carbon tetrachloride adds to alkenes under the same condi-
tions to give a similar 1,1,1,2-tetrachloroalkane (e.g., Example 14.95). Both reactions in-
volve a trihalomethyl radical, which adds to an alkene to give an intermediate alkyl radical
(Example 14.94). This radical then abstracts a halogen or a hydrogen atom from the halo-
genated reactant. An example of this reaction is the radical addition of carbon tetrachlo-
ride to the alkene 14.93; treatment of the product with two equivalents of base provides the
cyclopropanecarboxylic acid part (Example 14.96) of a synthetic pyrethroid insecticide.70
Cl3C
CO2Et
CO2Et CCl4
(14.94)
(14.93) Cl3C
CO2Et
Cl3C•
CCl4, AIBN, ∆ Cl (14.95)
(86%) NaOEt, EtOH, ∆
Cl3C Cl (94%)
CN
Cl
Cl CO2Et
(14.96)
CN CN
Br (14.97)
Bu3SnH, hν
(98%)
NC CN
CN
I (14.98)
Bu3SnH, hν CN
(72%)
With the advent of newer methods for forming free radicals, it has become possible to
form new carbon-carbon bonds by the addition of free radicals to a wide variety of alkenes.
The most popular alkenes for use in this reaction tend to be conjugated with an electron-
withdrawing group or an aromatic ring, because the free radicals used are almost always
alkyl radicals (and, therefore, nucleophilic). Examples of this method for forming carbon-
carbon bonds are provided by the reactions in Examples 14.97 to 14.99.71
O H O O CN O H O O
O O Bu3SnH, hν O O (14.99)
H H
O (75%)
S
MeS NC
70. (a) Matsui, K.; Negishi, A.; Takahatake, Y.; Sugimoto, K.; Fujimoto, T.; Takashima, T.; Kondo, K. Bull.
Chem. Soc. Japan 1986, 59, 221. (b) Kondo, K.; Matsui, K.; Negishi, A. In Elliott, M, Ed. Synthetic Pyrethroids,
ACS Symp. Ser. 1977, 42, 128. (c) Kondo, K.; Matsui, K. U.S. Patent No. 4,454,343 [June 12, 1984]. (d) Arlt, D.;
Jautelat, M.; Lantzsch, R. Angew. Chem. Int. Ed. Engl. 1981, 20, 703.
71. Taken from Giese, B.; González-Gómez, J.A.; Witzel, T. Angew. Chem. Int. Ed. Engl. 1984, 23, 69.

Figure 14.8 The cyclization of 109.5°

a free radical requires a
different set of orbitals, and
so leads to a different product
from carbocation cyclization.
90°
The intramolecular version of this reaction results in cyclization of unsaturated radi-

cals and provides an especially useful method for forming cyclopentane derivatives. The
outcome of this reaction is determined by the frontier orbital overlap. It is an example of a
reaction where the products formed are determined by a stereoelectronic effect—the ge-
ometry of the participating orbitals controls which final product is formed, rather than the
relative stabilities of the possible products.
In the addition of a carbocation to an alkene, the cation carbon approaches the
center of the π bond from the orthogonal direction, whereas the addition of a radi-
cal to an alkene π bond occurs at one end of the bond and from a direction close to
109.5°.72 This favors cyclopentane geometry by approximately 5 kcal mol–1 . Thus, in
contrast to the cyclization of the 5-hexenyl cation, which gives the more stable cy-
clohexyl cation, the cyclization of the 5-hexenyl radical (which is essentially irre-
versible under normal reaction conditions unless the open-chain radical is very
stable) gives the cyclopentylcarbinyl radical (Figure 14.8). When the radical reaction
is carried out under reversible conditions the predominant products contain
six-membered rings.73
Alkenes and alkynes can both serve as acceptor π bonds for the addition reaction, as
illustrated by Examples 14.100 and 14.101. The cyclization of free radicals with appropriate
functionality can also be used to prepare heterocycles,74 as also illustrated by 14.100.
O OAc O OAc
Bu3SnH 75
N N H (14.100)
SPh (71%)
SiMe3
SiMe3
Bu3SnH, AIBN 76
OH (14.101)
Br PhH, hν, ∆
(70%) OH CN
CN
The reaction has also served to form the basis of a tandem polycyclization reaction, as
illustrated by the key reaction (Example 14.102) from the synthesis of the natural product,
capnellene.77 An alternative method for the production of free radicals is shown by the
cyclization of the iodoalkyne in Example 14.103. In this reaction, the free radical reaction
72. Dewar, M.J.S.; Olivella, S. J. Am. Chem. Soc. 1978, 100, 5290.
73. Julia, M. Acc. Chem. Res. 1971, 4, 386; Pure Appl. Chem. 1974, 40, 553.
74. Review: Bowman, W.R.; Bridge, C.F.; Brookes, P. J. Chem. Soc., Perkin Trans. 1, 2000, 1.
75. Choi, J.K.; Hart, D.J. Tetrahedron 1985, 41, 3959.
76. Stork, G.; Mook, R. J. Am. Chem. Soc. 1983, 105, 3720.
77. Curran, D.P.; Chen, M.H. Tetrahedron Lett. 1985, 26, 4991.

is initiated by the reaction between triethylborane and oxygen, with trimethylsilane as the
hydrogen atom transfer agent.78
Br H H
Bu3SnH (14.102)
(61%)
H
CO2Me CO2Me
Et3B, O2
(14.103)
I Me3SiH
(72%)
The cyclizations above all involve hydrogen atom transfer to the radical as the final
step in the radical chain. However, the transfer of other atoms can also lead to the forma-
tion of useful products. For example, when a mixture of a halide and an alkene is heated
or irradiated with a stannane reagent under conditions where the stannane is present in
catalytic, rather than stoichiometric quantities, the product of the reaction is one in which
there has been an effective insertion of the π bond into the carbon-halogen σ bond or
addition of the carbon-halogen bond across the π bond. This is illustrated by Examples
14.104 and 14.105, where the stannane serves as the initiating radical but where the chain
is carried on by iodine atom transfer.
I
Bu3SnH 79
I (14.104)
(0.1 eq.)
I
O
O 80
Bu3SnSnBu3 H (14.105)
I O
O (10 mol %)
80°C H
(83%)
When geometric constraints are removed and the stereoelectronic requirements for
ring closure can be met by attack of the radical at either end of the alkene, the addition
occurs preferentially to give the more stable of the two possible radicals. This has extended
the value of radical cyclizations to the macrocyclization of ω-alkenyl radicals to large-ring
cycloalkanes. For example, Pattenden has been able to construct large rings and polycyclic
ring systems by radical cyclization pathways, as shown by Examples 14.106 to 14.108.
O O
H
Bu3SnH, PhH
81
AIBN, ∆ (14.106)
(25%)
H H
I
78. (a) Lowinger, T.B.; Weiler, L. I. Org. Chem. 1992, 57, 6099. (b) Evans, P.A.; Roseman, J.D. J. Org. Chem.
1996, 61, 2252.
79. Curran, D.P.; Chen, M.-H.; Kim, D. J. Am. Chem. Soc. 1986, 108, 2489; 1989, 111, 6256.
80. Curran, D.P.; Tamine, J. J. Org. Chem. 1991, 56, 2746.
81. Hitchcock, S.A.; Pattenden, G. Tetrahedron Lett. 1992, 33, 4843.

I
H
Bu3SnH, PhH 82
(14.107)
AIBN, ∆ O
O
O H
O
I
O Bu3SnH, PhH O
O O O O (14.108)
83
AIBN, ∆
O (n=1, 76%; n=2, 72%) O
n (n=3, 70%; n=4, 63%) n
(n=5, 50%)
Although tin hydrides have been the most widely used reagents to initiate radical cy-
clizations, samarium (II) iodide can also be used to promote free radical cyclization of
unsaturated carbonyl compounds. One of the most useful characteristics of the SmI2-
promoted ketyl-alkene cyclization is its ability to form cyclooctanols in the presence of
hexamethylphosphoramide (e.g., Example 14.109).84
SmI2 (2 eq)
(14.109)
O THF, t-BuOH, HMPA OH
(63%; d.r. >30:1)
A similar cyclization to the less thermodynamically stable radical is observed with
3‑butenyl (homoallyl) free radicals, which rapidly cyclize to the cyclopropylcarbinyl radi-
cal (Example 14.110). Unlike the cyclization of the 5-hexenyl radical to the cyclopentylcar-
binyl radical (Example 14.111), however, the cyclization of the 3‑butenyl radical to the
cyclopropylcarbinyl radical is reversible and almost always favors the open-chain product.
In fact, the ring opening of cyclopropylcarbinyl radicals is widely used as a test for the
intervention of free radicals in a reaction mechanism and as a “clock reaction” to measure
the rates of fast radical reactions.85
(14.110)
(14.111)
The ring opening of cyclopropylcarbinyl radicals allows the radical cyclization reac-
tion to be extended to the synthesis, under kinetic conditions, of compounds containing
six-membered rings. Two examples of this type of cyclization are shown as Examples
14.11286 and 14.113. The alkyl free radical required to initiate the intramolecular cycliza-
tion reaction can be generated by single electron transfer to a carbonyl group. Two excel-
lent examples of this are provided by the reactions 14.114 and 14.115, where s.e.t. to the
carbonyl group of the ketone gives a radical anion that adds to the alkyne triple bond,
82. Blake, A.J.; Hillingworth, G.J.; Pattenden, G. Synlett 1996, 643.

83. Pattenden, G.; Wiedenau, P. Tetrahedron Lett. 1997, 38, 3647.
84. Molander, G.A.; McKie, J.A. J. Org. Chem. 1994, 59, 3186
85. (a) Newcomb, M.; Glenn, A.G. J. Am. Chem. Soc. 1989, 111, 275. (b) Bowry, V.W.; Lusztyk, J.; Ingold, K.U.
J. Am. Chem. Soc. 1991, 113, 5687. (c) Newcomb, M. Tetrahedron 1993, 49, 1151. (d) Newcomb, M.; Toy, P.H. Acc.
Chem. Res. 2000, 33, 449.
86. Kilburn, J.D.; Santagostino, M. Tetrahedron Lett. 1995, 36, 1365.

closing the ring. Nitrogen-centered radicals will also add to alkene π bonds to give cyclic
amines, as illustrated by Examples 14.116 and 14.117, below.
Br
Bu3SnH, AIBN CO2Et
PhH, ∆
CO2Et
(61%)
(14.112)
CO2Et CO2Et CO2Et
N SiMe3 CHSiMe3
S N
Bu3SnH, AIBN
O (14.113)87
PhH, ∆
(79%)
O O O OH
Na, NH3 (14.114)88
O (70%) O
Na, THF
(88%) (14.115)89
O
OH
H H
CuBr (0.1 mol %)
(14.116)90
N CH2Cl2, 0°C N
Br
(85%) H Br
Ph
Ph
CN
Me N
OTBS N OTBS
NC
OCOPh Me O
Bu3SnH, PhMe, ∆ (14.117)91
N H H
(48%)
N O
O
O Me
The formation of the product in Example 14.117 is especially instructive and illustrates
just how well free radicals can enter into cascade reactions (Figure 14.9). Thus, the initial
attack of the radical from the initiator or the tributylstannyl radical (Bu3Sn•) is on the ben-
zoyl oxygen and leads to formation of the amide radical 14.119. This radical then cyclizes
onto the cyclopentenone to give a cyclopentyl-carbinyl radical (14.120) that is set up to carry
out a second cyclization to give the new cyclopentylcarbinyl radical 14.121. This radical fi-
nally reacts with the stannane by hydrogen atom transfer to give the final product (14.122).
87. Pradhan, S.K.; Kadam, S.R.; Kolhe, J.N.; Radhakrishnan, T.V.; Sohani, S.V.; Thakker, V.B. J. Org. Chem.
1981, 46, 2622.
88. Motherwell, W.B.; Harling, D.J. J. Chem. Soc., Chem. Commun. 1988, 1380.
89. Stork, G.; Boeckmann, R.K.; Taber, D.F.; Still, W.C.; Singh, J. J. Am. Chem. Soc. 1979, 101, 7107.
90. Corey, E.J.; Chen, C.-P.; Reichard, G.A. Tetrahedron Lett. 1989, 30, 5547.
91. Cassayre, J.; Gagosz, F.; Zard, S.Z. Angew. Chem. Int. Ed. 2002, 41, 1783.

Figure 14.9 Cascade R• CN OTBS

cyclization in Example 14.117 Me N
O OTBS N Me O
NC
O H
Ph Bu3SnH, PhMe, ∆
N H N O
(48%) Me
O (14.122)
O
(14.118)
PhCO2R OTBS
Me OTBS Me O
OTBS
Me O H
N H N O
H
N O
O (14.121)
O
(14.119) (14.120)
Notice how the formation of the two rings must occur more rapidly than the hydrogen atom
transfer reaction.
Worked Problem
14-1 (a) What is the structure of the major product of the following reaction? The
product has only one aromatic ring.
I SmI2 (5 eq.), HMPA (18 eq.)
C15H15NO2
i-PrOH (2 eq.), THF, –35°C
N OMe
O
Me
(b) Why does the final product in the reaction below still have a double bond?
[Org. Lett. 2008, 10, 4049]
O
O
Bu3SnH, AIBN
O SPh
PhMe, ∆ O
O Me O
§Answers below.

(a) The samarium (II) iodide will reduce the carbon-iodine bond to give an aryl radical that will then cyclize
to give the spirocyclic product [J. Org. Chem. 2008, 73, 7145]:
OH
H
I
OMe OMe
OMe O O
N N OMe
O O N N
Me Me Me
Me
The carbon-iodine bond is reduced because this bond has the most accessible LUMO. What other reaction
might occur if the bromide were used?
(b) The closure of the first ring gives a five-membered ether, and so is basically irreversible. The closure of the second
ring, however, gives a cyclopropylcarbinyl radical that is thermodynamically less favorable than the butenyl radical.
O O O O
O O O O O O
O O
O O O
Me SPh Me

Problems
14-5 What is the major product formed when each of the of each of the following com-
pounds is heated with tri-n-butylstannane and AIBN?
SPh
Br
(a) (b) (c) (d) (CH2)3SePh
Cl
14-6 Draw the structure of the major organic product of each of the following
reactions.
O
1) Mg(Hg), THF SiMe3 1) Ti, THF
(a) (b)
CHO 2) HCl, H2O 2) HCl, H2O
S
H O
CO2Ag Br2 hν
(c) (d) N
O
14-7 Write a reasonable mechanism for each of the following transformations:

Br CO2Et
Bu3SnH, AIBN CO2Et
(a)
PhH, ∆
PhI(OAc)2, I2 O [This reagent converts

(b)
hν an alcohol to an alkyl
OH
hypoiodite]
O
PhSe Bu3SnH, AIBN
O
(c) PhH, ∆
OMe
OMe
I
H
Bu3SnH, AIBN
(d) H H
PhH, ∆
CO2But CO2But
hν H
(e) O PhH O
OH
CHO
MeO2C (19%) MeO2C
References: (a) Tetrahedron Lett. 1995, 36, 1365. (b) Tetrahedron Lett. 1993, 34, 127; Tetrahedron Lett.
1991, 32, 1591; Aust. J. Chem. 1995, 48, 381. (c) Org. Biomol. Chem. 2005, 3, 340. (d) Tetrahedron Lett.
2004, 45, 4027. (e) Tetrahedron Lett. 2006, 47, 3937.
Addition to Carbene- and Nitrene-like Compounds
O C R N C
O C O C R N C R N C
(14.123) (14.124)

Carbon monoxide and its isoelectronic counterpart isocyanide (Example 14.124) are
molecules stabilized by resonance in which there is at least one carbenoid canonical form
that can be represented as either a singlet or a triplet. Free radicals react with carbenes (it
is easier to think of this reaction as a radical coupling reaction with a triplet carbene) to
give new free radicals. One such reagent that reacts with free radicals in an atom transfer
chain reaction is tert-butyl isocyanide, which reacts with radicals to give new free radicals
containing one carbon atom more than the starting radical, as shown in cycle diagram
14.125. Stork has used this addition as the basis for the formation of nitriles by free radical
cyclization of bromoacetals (Examples 14.126 and 14.127).92 It is important in this reac-
tion to use the distannane as the radical initiator, because hydrogen atom transfer from
tri-n-butylstyannane is more rapid than addition to the isocyanide.
R2
R2 N C N
R1
R3SnSnR3
1
R • (14.125)
R1 CN
R2 SnR3
R3SnX R3Sn•
R1 X
OEt OEt
O O
Ph3SnSnPh3
Br (14.126)
t-BuNC
(58%) CN
OEt EtO
HO
1) O
Br Br (14.127)
2) Ph3SnSnPh3, t-BuNC
CN
(61%)
Carbonylation of free radicals with carbon monoxide is a reversible reaction (due to

the high stability of carbon monoxide). However, when alkyl radicals are generated under
carbon monoxide at high pressure, they react to give acyl radicals that can be trapped by a
range of atom donors to give a variety of carbonyl compounds. For example, when the
radical is a vinyl radical (formed by adding the tributyltin radical to the alkyne), free rad-
ical carbonylation can be followed by trapping with an amine to provide a versatile route
to acrylamides (e.g., Example 14.128).93
Cl
O NH
Cl
Bu3SnH (0.3 eq.), AIBN (0.2 eq.)
(14.128)
PhH, CO (85 atm), 90°C, 4 h
(76%) O N
O
In similar fashion, radicals react with azides (e.g., Example 14.129) to give what are
formally products of a free radical reacting with a triplet nitrene. These nitrogen-centered
radicals readily add to alkenes, so this provides an excellent method for the formation of
92. Stork, G.; Sher, P.M. J. Am. Chem. Soc. 1983, 105, 6765.
93. Uenoyama, Y.; Fukuyama, T.; Nobuta, O.; Matsubara, H.; Ryu, I. Angew. Chem. Int. Ed. 2005, 44, 1075.

complex amines, with the intramolecular addition providing a convenient entry into ni-
trogen heterocycles.94
S OPh Ts
H
O 1) (Me3Si)3SiH, AIBN N
N3 (14.129)
2) TsCl
(60%) CO2Me
CO2Me
Problem
14-8 What are the expected products when the alcohols below are treated with the se-
quence of reagents given?
OH
(a) Me (b) OH
(1) BrCH2CH(OEt)Br, base; (2) Ph3SnSnPh3, Me3C-NC
Group Transfer Reactions and the Persistent Radical Effect

The persistent radical effect is a principle that explains the highly selective cross-coupling
between a persistent and a transient radical when both species are formed at equal rates.95
The Barton photolysis of nitrite esters (Example 14.130) is an example of this type of reac-
tion. In this reaction, two radicals are formed in the same step. One of these radicals, nitric
oxide (•NO), is a stable, or persistent, free radical. The other radical formed in the Barton
reaction, the alkoxy radical RO•, is a highly reactive, or transient, free radical.
O O
R NO + •NO (14.130)
R
It is a feature of persistent free radicals that they do not self-couple (or do so reversibly),
so they must form cross-coupled products in a free radical reaction. This also means that the
concentration of the persistent radical increases as the reaction progresses until a steady-
state concentration is obtained. Although self-coupling of the transient radical does occur,
the concentration of the transient radical is always low, so the dimerization (second order in
the transient radical) is kinetically slow compared to the cross-coupling reaction (first order
in the transient radical) except at the very beginning of the reaction. In the bimolecular
coupling reaction, the cross-coupled product quickly becomes kinetically preferred.
The persistent radical effect can be exploited in synthesis because it guarantees that the
cross-coupling product will dominate the product mixture. Typical persistent radicals
are stable radicals such as nitric oxide (formed in the photolysis of nitrite esters or
N-nitrosoamines) and 2,2,6,6-tetramethylpiperidyloxy (TEMPO) (shown in Example
14.133; formed by homolysis of N-alkoxy-2,2,6,6-tetramethylpiperidines). The homolysis
of these precursors provides reactive radicals that can be trapped by alkenes prior to re-
combination reactions to give the final product. This is illustrated by the thermolysis of
the hydroxylamine derivative 14.131. The initial homolysis gives the persistent radical
94. Kim, S.; Joe, G.H.; Do, J.Y. J. Am. Chem. Soc. 1994, 116, 5521,
95. Reviews: (a) Fischer, H. Chem. Rev. 2001, 101, 3581. (b) Studer, A. Chem,. Eur. J. 2001, 7, 1159; Chem. Soc.
Rev. 2004, 33, 267.

TEMPO and a transient radical (Example 14.132) that undergoes cyclization to the cyclo-
pentylmethyl radical 14.134 and the cyclohexyl radical 14.135 before being trapped by
TEMPO to give the final products.96 In this particular reaction, a mixture of all four pos-
sible regio- and stereoisomers is formed.
Ph Ph
N N (TEMPO)
O + O
(14.131) (14.132) (14.133)

Ph
Ph
TEMPO
H Ph Ph
O H
O
N N
TEMPO
(14.134) (14.135)
Reaction Synopses
Radical Additions
Intramolecular Radical Cyclization
H 2C (CH2)n
(CH2)n
H2C
n = 1, 2, 3, 4
Closure to 3- to 6-membered rings gives smaller of two possible rings.
Intermolecular Additions to Alkenes
R R Y
XY
X
R R
Reactants: CCl4, ROOR; BrCCl3, ROOR; HBr, ROOR; etc.

First step always gives more stable radical: Markovnikov addition for most re-
agents (anti-Markovnikov with HBr).
Additions to Carbene and Nitrene Equivalents
Y
X Y Y
A Z
R• X X
R R A
X=Y: :CO, R-NC:, R-N3; etc.

Reactants: Bu3SnH, CO, R 2NH; Bu3SnH, RN3; Bu3SnH, RNC:; etc.
Group Transfer Reactions and the Persistent Radical Effect
X R X• + •R R'• X R'
R = alkyl, alkoxy, etc.; X=TEMPO, NO, I, 2-pyridylthio, etc.
96. Studer, A. Angew. Chem. Int. Ed. 2000, 39, 1108.

14.5 Diradicals: Formation and Uses in Synthesis
In Section 14.1, we briefly discussed diradicals. In general, diradicals are not stable, but
they occur as reactive intermediates that are formed and consumed during reactions. One
important exception to this is molecular oxygen, which exists as a stable triplet diradical.
A diradical is designated as either a singlet or a triplet, depending on whether the two
unpaired electron spins are parallel (triplet) or antiparallel (singlet). The triplet state of
most diradicals is the low-energy state. Molecular oxygen exists as a stable triplet diradi-
cal, and linear carbenes also exist as triplets.
Diradicals react much like simple free radicals: they add to π bonds, oxygen-centered
diradicals abstract hydrogen atoms from carbon atoms, and they combine with other rad-
icals to give coupled products. If the diradical is a singlet, reactions that give nonradical
products may be concerted. Triplet diradical reactions, however, cannot be concerted.
Ketone Photolysis
When a ketone is irradiated, the excitation of an electron from the nonbonding orbital
of the oxygen to the π* orbital of the carbonyl group leads to a singlet diradical excited
state with one of the unpaired electrons on oxygen. The fate of the diradical depends
on the structure of the starting carbonyl compound, but generally two processes com-
pete. In the first, there is cleavage of the bond between the carbonyl group and the α
carbon to give an alkyl radical and an acyl radical that rapidly loses carbon monoxide
to give a second alkyl radical. This process is known as the Norrish type I cleavage,
after Nobel Prize-winning British chemist R. G. W. Norrish, who first described and
rationalized it.97
The alternative fragmentation of this diradical is known as the Norrish type II frag-
mentation. In this pathway, as in the Barton reaction, the alkoxy radical abstracts a
hydrogen atom from the δ carbon of the ketone to give a carbon-centered diradical.
Coupling of the two radical centers gives a cyclobutanol (e.g., Example 14.136),98 or their
fragmentation further gives an alkene and an enol. The Norrish type II reaction has been
used to make some extremely strained systems, as illustrated by the formation of the
bicyclo[1.1.1]pentane derivative in Example 14.137.99
hν
HO (14.136)
(70%)
O O HO
H
H H H
O HO
hν
C6H6 (14.137)
(11%)
97. Bamford, C.H.; Norrish, R.G.W. J. Chem. Soc. 1935, 1504.

Ronald George Wreyford Norrish (1897–1978) was educated at Cambridge (PhD, 1924), and remained
there for his entire career. He was a pioneer in photochemistry and shared the 1967 Nobel Prize in Chemistry.
For more detail, see: Dainton, F.; Thrush, B.A. Biogr. Mem Fellows Roy. Soc. 1981, 27, 379.
98. (a) Cookson, R.C.; Hudec, J.; Szabo, A.; Usher, G.E. Tetrahedron 1968, 24, 4353. (b) Cookson, R.C.;
Rogers, N.R. J. Chem. Soc., Chem. Commun. 1972, 809. (c) Cookson, R.C.; Rogers, N.R. J. Chem. Soc., Perkin
Trans 1 1974, 1037.
99. Padwa, A.; Eisenberg, W. J. Am. Chem. Soc. 1970, 92, 2590; 1972, 94, 5852, 5858.

Homolysis of Cyclic Azo Compounds

The homolysis of cyclic azo compounds provides the second major method for the forma-
tion of diradicals in organic chemistry. When these compounds are irradiated, they un-
dergo loss of nitrogen to give a diradical. Depending on the conditions of the irradiation,
the diradical may be a singlet or triplet. In the presence of a photosensitizer, irradiation
almost always results in the formation of a triplet diradical. A photosensitizer is a mole-
cule that absorbs light and transfers the energy absorbed to another molecule (usually the
molecule that is actually to undergo the photochemical reaction); the most common pho-
tosensitizers are aromatic ketones such as benzophenone.
The five-membered azo compounds, which are readily available by the [3 + 2] cycload-
dition of diazomethane to alkenes, decompose on irradiation to give cyclopropane deriv-
atives (e.g., Example 14.138) through intermediate diradicals.100
H
H N
N hν
(14.138)
(87%)
H
H
Six-membered azo compounds, likewise, decompose to diradicals that may cyclize to

a cyclobutane derivative. However, these diradicals may also fragment to two alkene mol-
ecules. In simple six-membered azo compounds, irradiation favors fragmentation rather
than cyclization to the cyclobutane (e.g., Example 14.139).101
N N hν
+ (14.139)
(60-77%) (19-39%)
Regardless of the possible reaction outcomes of simple azo compounds, when the pre-
cursor to the diradical contains a suitably disposed alkene π bond, and especially when
the diradical is stabilized by resonance to slow down competing fragmentation, the intra-
molecular trapping of the diradical can occur to give cyclized products. An excellent ex-
ample of this is provided by the reaction in Example 14.140, which was the key step in the
synthesis of the natural product hirsutene.102
CO2Me
CO2Me CO2Me H H
MeCN/∆
N (14.140)
N (86%)
H
Bergman Cycloaromatization
In 1972, Bergman and Jones reported the conversion of cis-hex-3-en-1,5-diyne into the
1,4-phenylenediyl radical, or 1,4-dehydrobenzene, by heating the parent compound to ap-
proximately 200°C.103 This reaction has since become known as the Bergman cycloaroma-
tization reaction. Because temperatures of 200°C or more were required for the cyclization,
it appeared that the reaction would remain simply an esoteric mechanistic study. How-
ever, this changed dramatically, when a series of potent anticancer natural products con-
taining the enediyne moiety were discovered.104 These compounds react with nucleophiles
100. Wiberg, K.B.; Lupton, E.C., Jr.; Wasserman, D.J.; de Meijere, A.; Kass, S.R. J. Am. Chem. Soc. 1984, 106, 1740.
101. Bartlett, P.D.; Porter, N.A. J. Am. Chem. Soc. 1968, 90, 5317.
102. Little, R.D.; Muller, G.W. J. Am. Chem. Soc. 1981, 103, 2744.
103. (a) Jones. R.R.; Bergman, R.G. J. Am. Chem. Soc. 1972, 94, 660. (b) Bergman, R.G. Acc. Chem. Res. 1973,
6, 25. (c) Lockhart, T.P.; Gomita, P.B.; Bergman, R.G. J. Am.Chem. Soc. 1981, 103, 4091.
104. Review: Nicolaou, K.C.; Dai, W.M. Angew. Chem. Int. Ed. Engl. 1991, 30, 1387.

to give the 1,4-phenylenediyl radical that then cleaves double-stranded DNA by abstract-
ing a hydrogen atom from the sugar moieties of the DNA backbone.105
In Bergman’s original study, temperatures of 200°C were required to drive the cycliza-
tion, but in the naturally occurring compounds, incorporation of the enediyne group into
in a medium-sized ring results in a much more facile cyclization. As we saw in Chapter 13,
and we again see in Example 14.141, in the cyclization of calicheamicin γ1, the nucleophilic
cleavage of the trisulfide generates a thiolate anion that undergoes intramolecular Michael
addition as the first step of the Bergman cyclization. The change in hybridization of the
β-carbon of the enone brings the ends of the enediyne into close enough proximity to
allow the ring closure to the diradical to occur at ambient temperatures.
H
O
O
NHCO2Me
NHCO2Me
HO
Nu HO
O—sugar S
MeSS S O—sugar
(14.141) O
NHCO2Me
HO
Reaction Synopses
Homolysis of Azo Compounds
R G R G
hν or ∆ R G R
R R R R
R R
N N R R
Bergman Cycloaromatization
R'
R R R'
∆
R R R'
R'
Chapter Summary
The site-specific generation of free radicals is an indispensable part of making these reac-
tive intermediates useful in synthesis. This can be accomplished by means of addition re-
actions, site-specific hydrogen or halogen abstraction (as in stannane reductions of
halides), or single-electron oxidation (e.g., oxidation of phenoxide anions to phenoxy rad-
icals) or reduction (e.g., reduction of carbonyl compounds with metals to give ketyl radical
105. (a) Nicolaou, K.C.; Smith, A.L. Acc. Chem. Res. 1992, 25, 497. (b) Nicolaou, K.C.; Winssinger, N. J. Chem.
Educ. 1998, 75, 1225.

anions). One especially useful method involves the homolysis and decarboxylation of
Barton esters. Synthetically important reactions involving free radical intermediates in-
clude the Borodin-Hunsdiecker reaction, via an acyl hypobromite; the Barton-McCombie
deoxygenation, via a xanthate ester that is reduced with a stannane reagent; and the
Gomberg-Bachmann reaction, via a diazonium ion that is reduced to a diazenyl radical.
Although radicals do not usually rearrange, they do cyclize. Radical cyclization under
kinetic control is subject to a stereoelectronic requirement due to the SOMO-LUMO over-
lap required. This leads to the formation of cyclopentylmethyl radicals instead of the more
stable cyclohexyl radical from the 5-hexenyl radical. Cyclopropylmethyl radicals undergo
rapid ring opening to homoallyl radicals. Radicals react with carbene or nitrene equiva-
lents to give acyl radicals or their equivalents that can be trapped to give synthetically
useful products. Suitable unsaturated radicals undergo macrocyclization to give large-
and medium-sized ring products. Diradicals may be generated by photolysis or thermoly-
sis of aliphatic azo compounds and can be useful intermediates in synthesis.
Key Terms
Barton ester Gomberg-Bachmann Norrish type I cleavage

Barton-McCombie reaction Norrish type II cleavage
deoxygenation Hofmann-Löffler- persistent radical effect
Barton reaction Freytag reaction pinacol reaction
Borodin- ketyl
Hunsdiecker reaction Kolbe electrolysis
Additional Problems
14-9 The intermediate diradical (shown) in the cyclization reaction to give the
triquinane in Example 14.140 can be represented by several canonical forms.
Draw them. What isomeric product might be formed in this cyclization and why
does the cyclization occur to give the product shown instead of the isomer?
CO2Me
14-10 Draw mechanisms to show the formation of the cyclization and fragmentation
products that will be obtained by irradiating the compound shown. Is the stereo-
chemistry of the starting compound expected to affect the product distri-
bution? How?
N N
14-11 The reaction shown gives the amine indicated as the major product after treatment
with base. Why is this product formed—and not the isomeric five-membered
amine? (Build models here—it will help.)
Cl H2SO4/65°C N Ph Ph
N
N but not
30 min
Ph
14-12 Usnic acid is a compound that accounts for up to 2% of the dry weight of certain
lichens. It was synthesized by dehydration of usnic acid hydrate, which was itself

prepared by a phenolic coupling reaction. What phenol was used? Write a mecha-
nism to show the conversion of this phenol to usnic acid hydrate.
O O
Me Me
OH
O O
K3Fe(CN)6 HO O H2SO4 HO O
?
Na2CO3
Me O Me O
Me Me
OH HO OH HO
Me Me
Usnic acid hydrate Usnic acid

14-13 Each of the reactions below has been used in the synthesis of a natural product
or in model studies used to test critical steps in a proposed synthesis of a natural
product. Draw the structure of the major organic product that will be formed in
each reaction.
CO2Me Bu3SnH
Br [J. Am. Chem. Soc. 1986,
(a) AIBN
MeO
108, 5893]
O
OTBS
O Bu3SnH, AIBN, ∆ [J. Am. Chem. Soc. 2002,
(b) Br
O 124, 2080]
O
SePh Me
Bu3SnH, AIBN
(c) O O
C6H6, ∆
[Tetrahedron 1990, 46, 545]
Ph
O
Bu3SnH
(d) N Cl AIBN
[J. Org. Chem. 1983, 48, 1841]
O
CO2Me
O Ph
O
O Bu3SnH, AIBN, ∆ [J. Am. Chem. Soc. 1997,
(e) OS N
Me 119, 6226]
Ph
CO2Et
O
OR Bu3SnH, AIBN [J. Am. Chem. Soc. 1983,
(f) C6H6, ∆
Br
105, 3720]
MeO
O Bu3SnH, AIBN, ∆
(g) [J. Org. Chem. 2006, 71, 449]
HO Br
N Me
Ts SPh
1) Hg(OAc)2, AcOH
2) NaBH(OMe)3
O
(h) O [J. Org. Chem. 1982, 47, 2231]

Ph
1) Hg(OAc)2, AcOH
2) NaBH(OMe)3
O Bu3SnH, AIBN [Tetrahedron Lett.

(i) MeO PhH, ∆
O Br 1988, 29, 4995]
14-14 When the β-pinene is irradiated in carbon tetrachloride in the presence of benzoyl
peroxide, the major organic product of the reaction is an addition compound that is
monocyclic. What is the structure of this compound? Write a mechanism that

accounts for its formation and explain why the expected addition compound is not
isolated. If the pinene used is optically active, will the product be optically active also?
CCl4, PhCO2—O2CPh
hν
14-15 Draw the structure of the intermediate(s) formed when each of the compounds below
is heated. What is the major product of each reaction (ignore stereochemistry)?
CO2Me
N N N
(a) (b) (c)
N N N
OH OTBDMS
14-16 Gomberg’s work, which culminated in the generation of triphenylmethyl, began as

a project to prepare highly hindered hydrocarbons. He prepared tetraphenylmeth-
ane by a reaction in which a diazo compound was heated to high temperature, and
it was to demonstrate that other similar hindered polyarylalkanes could exist that
he attempted to prepare hexaphenylethane. What is the most likely structure of the
azo compound that Gomberg prepared as the precursor to tetraphenylmethane and
by what mechanism is it converted to tetraphenylmethane on heating?
Note that the reaction between Bu3SnCl and NaBH3CN generates Bu3SnH.
H
O OSiR3 Bu3SnCl, NaBH3CN 1) Hg(OAc)2, AcOH
(a) EtO (b) O
C5H11 2) NaBH(OMe)3, CH2Cl2
I
Me3Si O
I
HO Bu3SnH, AIBN Bu3SnH, AIBN
(c) NO2 (d)
C6H6, 80°C C6H6, 80°C
Br
Bu3SnH, AIBN Bu3SnH, AIBN
(e) (f) Cl
C6H6, 80°C C6H6, 80°C
14-18 Suggest reasonable mechanisms for the following transformations.
Br SO2Ph
N N SO2Ph
SPh Bu3SnH, AIBN
(a) C6H6, 80°C
N N
PhCO (95%) PhCO
OCH2Ph OCH2Ph
I
Bu3SnH, AIBN
(b) PhH, ∆
[Synlett 2005 900]
SiMe2Ph (39%) PhMe2Si
OTBS
Me O
H
N O
Me
OTBS
X=H
OCOPh Bu3SnH, PhMe, ∆ [Angew. Chem. Int.
(c) N H or
CN
N OTBS
Ed. 2002, 41, 1783]
X O N
O NC Me O
H
N O
X=Cl

O
O
O O
O O Cl
Cl
(d) Br
Cl
Bu3SnH, AIBN
+
C6H6, 80°C
H (75%) H H

I
Bu3SnH, AIBN
(a) PhS
C6H6, ∆ [J. Am. Chem. Soc. 1998, 120, 5128]
O
1) NCS, CH2Cl2, 0°C

(b) N 2) CF3CO2H, hν
[Chem. Pharm. Bull. 1985, 33, 3187]
H
N
H
HO
(c) [Tetrahedron 1964, 20, 1719]
1) NCS, CH2Cl2, –5°C
2) CF3CO2H, hν
SO2Ph
SmI2 (2.5 eq.)
(d) O CHO
MeOH (2.5 eq.), THF [Tetrahedron Lett 2007, 48, 43]
O O
Ph O
H H
1) Cp2TiCl, THF
(e) H [Tetrahedron Lett. 2008, 49, 500]
2) H3O
O
O CHO
O H SmI2 (3 eq.), MeOH (4.4 eq)
CO2Et
(f) H
O
THF, -5°C, 15 min [Angew. Chem. Int. Ed. 2002, 41, 4751]
O
CHO Ph
H
Cl Bu3SnH, CO (80 atm)
(g) PhH, 80°C [Org. Lett. 2007, 9, 563]
Cl
H
What is the stereochemistry of the product?
OMOM S
HO 1) Cl OPh, py
(h) 2) Bu3SnH, AIBN, ∆
[Org. Lett. 2003, 5, 1321]
N
N O Bu3SnH, AIBN, ∆
(i) O [J. Org. Chem. 2002, 67, 5969]
S
CO2Me
SmI2 (2.5 eq.)

H MeOH (1.5 eq.)
(j) O
SO2Ph THF, 0°C [J. Org. Chem. 2008, 73, 3040]
CHO
O
Bu3SnH, ACCN
(k) N Br PhMe, ∆ [Org. Lett. 2008, 10, 197]
O
SmI2 (2.5 eq.)

H MeOH (1.5 eq.)
O
SO2Ph THF, 0°C
CHO
(l) [Tetrahedron Lett. 2007, 48, 43]
SO2Ph SmI2 (2.5 eq.)
H MeOH (1.5 eq.)
O
THF, 0°C
CHO
These two reactions give different
diastereoisomers

(m) SmI2, t-BuOH, PhSH [J. Org. Chem. 2007, 72, 1755]
THF, HMPA
SiMe3
EtO
P Sm° (3 eq.), SmI2, (3 eq.)
EtO
(n) O t-BuOH (1 eq), THF, 0°C-r.t.
[Org. Lett. 2007, 9, 469]
O
Product has two rings.
O
CO2Me
O O H Supply the missing reagent
(o)
[Tetrahedron Lett. 2007, 48, 8234]
O SmI2, THF, ∆
(p) [J. Am. Chem. Soc. 2005, 127, 13813]
CHO
O O Ph
O N Mn(OAc)3 (3 eq.)
(q) Me
O
HOAc, 60°C [Angew. Chem. Int. Ed. 2006, 45, 4345]
Ph N
Ph
EtO2C OTBS
H H Mn(OAc)3, Cu(OAc)2
(r) O
HOAc-CF3CH2OH (1:10)
[Org. Lett. 2008, 10, 45]
H H
O O
R
O Mn(OAc)3
N
(s) HOAc, ∆ [Org. Lett. 2008, 10, 1437]
O
O R'
OHC
SmI2 (2.5 eq.)
(t) O
t-BuOH-THF, 0°C [Tetrahedron Lett. 2009, 50, 3224]
OHC
O
S O O
O
(u) N CH2Cl2, hν
C27H33NO4S
[Tetrahedron 2011, 66, 8280]
O
N Bu3SnH, RNNR
(v) N O PhMe, ∆ [Tetrahedron Lett. 2009, 50, 6342]
SPh
Boc CO2Et (R = c-C6H11)
Br
Bu3SnH (1,5 eq.)
N Me
(w) MeO
AIBN (0.7 eq.) [Eur. J. Org. Chem. 2009, 793]
O PhMe, 80°C, 3 h
H (81%)
Me
O O N
O S
Bu3SnH, hν
(x) PhH
[Angew. Chem. Int. Ed. 2007, 46, 3942]
O
O AIBN, PhMe
C15H21NS
(y) O
N 100°C
[J. Am. Chem. Soc. 2004, 126, 12565]
S

14-20 Suggest mechanisms for the transformations below.

I
O O SmI2 (6 eq.), MeOH (3 eq) OH
(a) NiI2 (3 mol %), THF [Tetrahedron Lett. 2006, 47, 6225]
O
–78 to –20°C, 24 h
I
H
MeO MeO
Mn(OAc)3 H
(b) OH
Cu(OAc)2
O [Org. Lett. 2009, 11, 2285]
O Ph HOAc, 23°C O Ph
O O
CO2Me SmI2 (3eq.)

(c) THF, –78°C to r.t. [Tetrahedron Lett. 2008, 49, 6393]
CO2Me O O
(63%)
O
PhCO2 Cl O
N MeO2C
H
O Bu3SnH, PhCF3 O N
(d) O
CO2Me ACCN [Org. Lett. 2006, 8, 831]
O O
SmCl2 (4-6 eq.), THF, t-BuOH CO2But
(e) CO2But [J. Org. Chem. 2005, 70, 1497]
Me N N Me
O O
O
AcO OAc
CHO
SmI2 (2.5 eq) HO

(f) THF-t-BuOH (5:1) [Angew. Chem. Int. Ed. 2009, 48, 9315]
CHO 0°C CO2Me
CO2Me HO
14-21 The reactants in the two reactions below differ by only a single chlorine atom.
Write a mechanism for the reaction that accounts for the different outcomes
using the two reactants. [Angew. Chem. Int. Ed. 2006, 45, 4345].
Ph
O O
N O
O
O Ph X=H O O Ph X = Cl N Ph
O
N O H
Mn(OAc)3 (3 eq) N Mn(OAc)3 (2.5 eq.) Ph O
O O O Ph
N HOAc, 60°C N HOAc, 60°C O
H (63%) X (87%) O
Ph Ph Ph Ph N O
O
N
Ph
H Cl
Ph Cl
approximately equal
proportions

Chapter Fifteen
Organic Synthesis
Retrosynthetic Analysis, Protecting Groups,
and the Strategy of Organic Synthesis
15.1 What Is Organic Synthesis?
Organic synthesis may well be the heart of organic chemistry, because everything we
do as organic chemists ultimately requires the synthesis of organic compounds. Com-
pounds are synthesized for a variety of reasons: to confirm structures assigned on the
basis of spectroscopic studies or chemical degradation, to elucidate the stereochemis-
try of a compound whose stereochemistry cannot be established by other means, to
modify an existing natural compound to make it more active, and to develop methods
for the preparation of important medicinal compounds that may be in short supply
from natural sources. Exploring the limits of structure and bonding has resulted in
syntheses of compounds with multiple small rings, for example. The synthesis of cy-
clobutadiene (Example 15.1)1 was an important target for testing theories of aromatic-
ity and the synthesis of prismane (Example 15.2)2 showed that this fully saturated
isomer of benzene could, in fact, exist, which provided insights into the synthesis of
highly strained molecules. (15.1) (15.2)
Organic synthesis is defined as the process of constructing a complex molecule from
less complex precursors. In many ways, it resembles the process of building a fine piece
of furniture. Just as one must learn to use the tools before one can build a piece of fur-
niture, so one must learn to use the tools of organic synthesis—reactions—if one is to
design the synthesis of a complex molecule. This means that the first task facing the
synthetic chemist is to become thoroughly familiar with the tools of the discipline—the
reactions of organic chemistry. That has been the focus of the last several chapters.
The design of a complex synthesis requires being able to combine reactions in such
a way that the potential problems between the beginning of the synthesis and the for-
mation of the final product are addressed. These problems will depend, in large part, on
why the synthesis is being carried out (Figure 15.1). This can, in turn, be decided by
answering several questions. How much of the product is needed? Must the product be
a single compound, or will a mixture of isomers suffice? Does the product need to be a
single diastereoisomer, or is a mixture of diastereoisomers adequate for the needs?
Does the product need to be prepared as a single enantiomer, or can the racemate be
used? Must certain reagents be avoided? Is the synthesis designed to demonstrate the
wide synthetic potential of a new reaction? Every one of these questions will have a
bearing on how the synthesis is designed and carried out. It is the goal of this chapter
and, to some extent, the remainder of this book, to show how these questions are
answered.
The questions above describe different levels of sophistication in synthesis, and the
design of a synthesis depends very much on its ultimate goals. The least selective (and,
1. Review: Pettit, R. Pure Appl. Chem. 1968, 17, 253.

2. Katz T.J.; Acton N. J. Am. Chem. Soc. 1973, 95, 2738.
577

578 Advanced Organic Chemistry | Chapter Fifteen
Figure 15.1 The three critical

determinants of a synthesis
SCALE — PURITY —
how much product constitutional isomers
is needed? allowed?
only one constitutional
isomer allowed?
REAGENTS — only one
reagents that diastereoisomer
must be avoided allowed?
reagents that only one enantiomer
must be used allowed?
therefore, the least sophisticated) synthesis is one that can give a mixture of isomers
without being unacceptable, and such a synthesis will differ from a synthesis where
(15.3) (15.4) a single isomeric product is required. A synthesis designed to prepare a compound by
the ton will be very different from a synthesis where milligrams of the final product
will suffice.
The target compound for a synthesis almost always reveals the reasons for the synthe-
sis, and can be as varied as the answers to the questions above. For example, chemists have
long been fascinated by geometry, so the synthesis of the saturated hydrocarbon analogs
(15.5) of the Platonic solids (the tetrahedron, cube, octahedron, dodecahedron and icosahedron)
has been the subject of numerous synthetic efforts. Of the Platonic solids, valence consid-
erations limit the potential for a saturated hydrocarbon analog to tetrahedrane (Example
15.3),3 cubane (Example 15.4),4 and dodecahedrane (Example 15.5).5 Each of these com-
N N pounds, in its own way, tests the limits of bonding capability. Arduengo’s synthesis of the
first stable N-heterocyclic carbenes (Example 15.6)6 provides another window into the ex-
(15.6) tremes of bonding whose answers were supplied by synthesis.
Defining the ways that to make a particular target compound, and, more espe-
cially, identifying the best way to make a target compound, is the essence of organic
synthesis. This is no trivial task, and some idea of the work involved can be gauged by
noting that a 1994 textbook devoted to organic synthesis had more than 1500 pages,
and the series Comprehensive Organic Synthesis, published in 1991, covered nine vol-
umes averaging more than 1000 pages each. Obviously no single chapter, nor any
sequence of chapters totaling just over 200 pages, can go into that kind of detail. This
means that this chapter and those that follow it must serve just as an introduction to
3. Synthesis of tetra-tert-butyltetrahedrane: (a) Maier, G.; Pfriem, S.; Schaffer, U.; Matusch, R. Angew. Chem.
Int. Ed. Engl. 1978, 17, 520. (b) Maier, G.; Pfriem, S. Angew. Chem. Int. Ed. Engl. 1978, 17, 519.
4. Eaton. P.E.; Cole. T. W.; Jr. J. Am. Chem. Soc. 1964, 86, 962, 3157.
5. (a) Ternansky, R.J.; Balogh, D.W.; Paquette, L.A. J. Am. Chem. Soc. 1982, 104, 4503. (b) Paquette, L.A.;
Ternansky, R.J.; Balogh, D.W.; Kentgen, G. J. Am. Chem. Soc. 1983, 105, 5446. (c) Fessner, W.-D.; Murty,
B.A.R.C.; Worth, J.; Hunkler, D.; Fritz, H.; Prinzbach, H.; Roth, W.D.; Schleyer, P.v.R.; McEwen, A.B.; Maier,
W.F. Angew. Chem., Int. Ed. Engl. 1987, 26, 452.
6. (a) Arduengo, A.J., III; Harlow, R.L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361. (b) Regitz, M. Angew.
Chem. Int. Ed. Engl. 1991, 30, 674.

Organic Synthesis 579
organic synthesis and to the broad principles involved in designing a synthesis of an

organic compound, rather than as an exhaustive treatise.
Elegance or, “What Constitutes a Good Organic Synthesis?”

The philosophical question of what constitutes an ideal synthesis is one that is being con-
templated more frequently these days. The more reasonable—and pertinent—question
may, in fact, be, “What constitutes a good synthesis?” As with all other largely philosoph-
ical questions of this sort, the answer becomes highly subjective. Every chemist has his or
her own concept of just what constitutes a good synthesis (for this author, it was Wood-
ward’s synthesis of (±)-reserpine7 that first defined elegance in synthesis). It will be for you
to find your own.
Most synthetic chemists have a feel for what makes a good synthesis, although, like
aromaticity, the concept can be hard to frame in words. There are, however, several
common features of syntheses described as “elegant.” For one, they usually exhibit a com-
mand of both stereochemistry and regiochemistry that results in a very short synthesis
with very high levels of control. However, a quantitative measure of synthetic efficiency is
still lacking.
The first to attempt to address the question of quantitating efficiency in an organic
synthesis was Hendrickson who defined an “ideal synthesis” in 19758 as one that “. . . cre-
ates a complex molecule . . . in a sequence of only construction reactions involving no in-
termediary refunctionalizations, and leading directly to the target, not only its skeleton
but also its correctly placed functionality.” In 1975, this ideal was certainly far beyond
contemporary abilities. In fact, many complex molecules that have since been synthesized
were despaired of ever being prepared in the laboratory at that time. However, the ensuing
decades have changed the landscape appreciably.
The last two decades of the 20th century provided a number of measures that could be
used to quantitate synthetic efficiency. Among these was the concept of atom economy,
first proposed by Trost.9 In this measure of synthetic efficiency, the major goal is to mini-
mize the number of atoms in the reactants that do not end up in the final product. What
Trost pointed out in these articles was the change that transition metal-catalyzed reac-
tions had wrought in organic synthesis. Prior to the advent of these catalytic reactions, few
C—C bond-forming reactions were atom economical. The notable exceptions were pericy-
clic reactions such as the Diels-Alder reaction and the Claisen and Cope rearrangements.
Strictly speaking, atom economical reactions should be additions or rearrangements, with
any other species involved being catalytic. Other important C—C bond-forming reactions
were decidedly not atom economical. For example the Claisen and Dieckmann condensa-
tions involve the loss of a molecule of alcohol, and the Wittig and Horner-Wadsworth-Em-
mons reactions lead to the loss of a phosphoryl-containing by-product. The concept of
atom economy has achieved more prominence with the rise of “green” chemistry,10 which
7. (a) Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. J. Am. Chem. Soc. 1956, 78, 2023,
2657; Tetrahedron 1958, 2, 1.
8. Hendrickson, J.B. J. Am. Chem. Soc. 1975, 97, 5784.
9. (a) Trost, B.M. Science 1991, 254, 1471. (b) Trost, B.M. Angew. Chem. Int. Ed. Engl. 1995, 34, 259. (c) Trost,
B.M. Acc. Chem. Res., 2002, 35, pp 695.
10. Reviews: (a) DeVito, S.C.; Garrett, R.L. Green Chemistry for Pollution Prevention. ACS Symp. Ser. (American
Chemical Society, Washington, D.C.) 1996, 640. (b) Anastas, P.T.; Williamson, T.C. Green Chemistry. Designing
Chemistry for the Environment ACS Symp. Ser. (American Chemical Society, Washington, D.C.) 1996, 626.
(c) Anastas, P.T.; Kirchhoff, M.T. Acc. Chem. Res., 2002, 35, 686. (d) Jessop, P.G.; Trakhtenberg, S.; Warner, J. In
Flank, W.H.; Abraham, M.A.; Matthews, M.A., Eds. Innovations in Industrial and Engineering Chemistry, ACS
Symp. Ser. (American Chemical Society: Washington, D.C.), 2009, 1000, ch. 12, 401.

is a deliberate attempt to design syntheses with a minimum of waste.11 The search for atom
economical methods of synthesis has led to the development of many transition
metal-catalyzed C—C bond-forming reactions.
The concept of step economy was introduced by Wender in the last decade of the 20th
century.12 Step economy is an integral part of the development of organic synthesis as
target molecules become more and more complex. Every step in a synthesis costs time,
money, and effort, and every step of a synthesis has an economic and environmental
impact. Consequently, reducing the number of steps in a synthesis is critically important.
Too many steps, and a synthesis is no longer practical. Based on yield alone, if every step
of a synthesis gives a 97% yield, a 10-step synthesis gives only a 76% overall yield, and a
20-step synthesis gives only a 58% yield. And these yields are unrealistic for every step in
a synthesis. This is the one reason, of course, why convergent syntheses are so often viewed
as being much more elegant than linear syntheses.
The relationship between target complexity and the number of steps required for its
synthesis has changed over time. As we have developed new reactions capable of introduc-
ing greater complexity in a single step, the number of steps required or the synthesis has
decreased, and the complexity of realistic target molecules has increased. This is illus-
trated graphically in the diagram on the left in Figure 15.2, which is an adaptation of the
Wender diagram.12d
The diagram on the right in Figure 15.2 is a representation of how the length of total
syntheses of the same target compound has changed over time, and it shows that there has
been a general slow improvement in step economy until the discovery of important new
reactions leads to a rapid increase in the value a brief period of time. The step economy
then plateaus again until another synthetic breakthrough again rapidly improves the step
economy of the synthesis. Of course, at some point, the number of steps will reach the
absolute minimum number possible, at which point the synthesis will no longer be amena-
ble to improvement in terms of step economy.
Molecular Complexity
Any discussion of step economy must also address the issue of molecular complexity. This
has been the subject of a number of efforts over the years, beginning with Hendrickson’s
definition that we alluded to at the beginning of this section. In 1981, Bertz proposed one
of the first general indexes of molecular complexity,13 and he expanded on the definition
in his subsequent works. Since Bertz’ initial proposals, other measures of molecular com-
plexity have been proposed.14
In its simplest form, the complexity of a molecule can be based on its line/polygon
formula. In this procedure, one simply counts the number of valence angles possible in
the formula, treating the component bonds of a multiple bond as separate entities.
These are then summed to give the value of N, and the complexity index is calculated
as Cc = (2N ln N).
11. “Green” chemistry has become so important that there are now journals devoted to it, including Green
Chemistry, which is published by the Royal Society of Chemistry.
12. (a) Wender, P.A.; Bi, F.C.; Gamber, G.G.; Gosselin, F.; Hubbard, R.D.; Scanio, M.J.C.; Sun, R.; Williams,
T.J.; Zhang, L. Pure Appl. Chem. 2002, 74, 25. (b) Wender, P.A.; Handy, S.T.; Wright, D.L. Chem. Ind. (London)
1997, 765. (c) Wender, P.A.; Miller, B.L. In Hudlicky, T., Ed. Organic Synthesis: Theory and Applications (JAI:
Greenwich, 1993); Vol. 2, pp 27–66. (d) Wender, P.A.; Croatt, M.P.;Witulski, B. Tetrahedron 2006, 62, 7505.
(e) Wender, P.A.; Verma, V.A.; Paxton, T.J.; Pillow, T.H. Acc. Chem. Res. 2008, 41, 40. (cf Wender, P.A.; Miller,
B.L. Nature 2009, 460, 197.
13. (a) Bertz, S.H. J. Chem. Soc., Chem. Commun. 1981, 818. (b) Bertz, S.H. J. Am. Chem. Soc. 1981, 103, 3599.
(c) Bertz, S.H.; Sommer, T.J. Chem. Commun. 1997, 2409.
14. (a) Barone, R.; Chanon, M. Tetrahedron 2005, 61, 8916. (b) Chanon, M.; Barone, R.; Baralotto, C.; Julliard,
M.; Hendrickson, J.B. Synthesis 1998, 1559.

(impractical)
past present
critical new
NUMBER OF STEPS
reactions
(practical) developed
NUMBER OF STEPS
future
(ideal)
past limit of present limit future limit of

complexity of complexity complexity past present future
TARGET COMPLEXITY TIME PERIOD
Figure 15.2 The relationship between target complexity and step economy over time
Each atom within an unbranched chain contributes one unit to the overall complexity
2
index, a single branch point contributes three units, and a quaternary center contributes
six. A fully substituted sp2-hybridized carbon contributes five units, and a substituted 1 3
sp-hybridized carbon atom contributes three (Figure 15.3). 5
3 6
Molecular symmetry reduces the complexity of the molecule. If a molecule possesses
symmetry, the number of pairs of atoms related by symmetry (ns) is counted, and the
Figure 15.3 A simplified
complexity index is reduced by the symmetry factor [ns ln (ns)], to give Cc = (2N ln N – ns
version of Bertz’ index of
ln ns). Heteroatoms also add to the complexity of a molecule, and they contribute an addi- molecular complexity
tional term that is calculated the same way as the carbon skeleton. If nh is the total number
of heteroatoms, the heteroatom coefficient, H, is given by H = nh + 1; the coefficient for the
number of symmetry-related pairs of heteroatoms is equal to hs, defined analogously to ns.
Now, Ch = (2H ln H – hs ln hs) and Ctot = Cc + Ch.
We can illustrate this form of the Bertz index by examining some simple molecules
and reactions, shown in Figure 15.4. The first reaction is the Diels-Alder reaction be-
tween 1,4-naphthoquinone and cyclopentadiene. The complexity index calculated for
the 1,4-naphthoquinone is derived from the total number of valence angles (34) and
heteroatoms (2), but it is reduced by the number of pairs atoms (6) and heteroatoms
(1) related by symmetry. This gives a complexity index for naphthoquinone of 235.6.
The complexity indices for the cyclopentadiene and the cycloadduct may be calculated
similarly and gives values of 35.6 and 351.9, respectively. These values allow us to deter-
mine that this Diels-Alder reaction increases the overall molecular complexity of the
system by 80.7—a result very much in line with the qualitative view of the ability of this
reaction to increase molecular complexity. Likewise, we find that aldol condensation of
cyclohexanone results in an increase of (160.9 – 48.8 – 48.8) or 63.3 in molecular com-
plexity. By comparison, the hydration of an alkene to an alcohol is a reaction that we
do not usually view as adding significantly to molecular complexity of the system. In
fact, the hydration of 1-methylcyclohexene leads to a small decrease (–10.9) in the total
complexity index, and hydroboration of the same alkene leads to a slightly greater re-
duction in the complexity index (–14.5). The final example is an intramolecular photo-
cycloaddition taken from Wender’s synthesis of cedrene.15 This reaction gives one of
the largest increases in molecular complexity index (+54.3) for an intramolecular
reaction.
15. Wender, P.A.; Howbert, J.J. J. Am. Chem. Soc. 1981, 103, 688.

1
* 1 * O1 O1 1 1
O O
2 H 5
* * * 5 1 KOH, EtOH 1 5
1
* * * * 2 * * * * * * 5 1
1
2 5 3 * 1 1 1
2 2 5 2
5 5
2 1 1
2 N = 9; ns = 2 H 3 N = 11 ns = 2 N = 25; ns = 0
O1 O1
C = 35.6 H=2 H=2
N = 34; ns = 6 N = 47; ns = 8
C = 48.8 C = 160.9
H = 3; hs = 1 H = 3; hs = 2
C = 235.6 C = 351.9 1
2 1
MeO 5 2 MeO 2
2 3
5
OH 2 6
5 3 6 3
2 3
1 2 H2SO4 1 6 6
* 1 1
3
2 5
1 1 1 1 1
H2O *
1 1
N = 12; ns = 0 N = 11; ns = 2 n = 31; ns = 0 N = 37; ns = 0
C = 59.6 H=2 H=2 H=2
C = 48.7 C = 211.9 C = 266.2
Figure 15.4 Complexity indices for some common reactions
Problem
15-1 What is the increase or decrease in the modified Bertz complexity index resulting
from each of the following conversions?
O O Cl
Cl
(a) (b) O
O O
OH OH
O
(c) O (d) O O
O
OH
O ∆ CHO
(e) (f)
OH
A third measure of synthetic efficiency may be found in the concept of redox econo-
my.16 Baran has extended this concept to define a measure of ideality based on the number
and types of reactions in a synthesis17:
 ( # of construction rxns ) + ( # of strategic redox rxns ) 

% ideality 5 100  
 ( total # of steps) 
In this relationship, construction reactions are those that form C—C or C—hetero-
atom bonds in the skeleton of the target molecule, whereas strategic redox reactions are
those that establish the correct functionality directly from the precursor. All other reac-
tions are defined as concession steps—steps that are necessary as part of the synthesis but
do not directly lead to skeletal bonds or the correct final functionality in the final product.
Reactions of this type are non-strategic redox reactions (e.g., conjugated ester to allyl
16. (a) Richter, J.M.; Ishihara, Y.; Masuda, T.; Whitefield, B.W.; Llamas, T.; Pohjakallio, A.; Baran, P.S. J. Am.
Chem. Soc. 2008, 130, 17938. (b) Burns, N.Z.; Baran, P.S.; Hoffmann, R.W. Angew. Chem., Int. Ed. 2009, 48, 2854.
17. Gaich, T.; Baran, P.S. J. Org. Chem. 2010, 75, 4567.

alcohol to conjugated aldehyde), functional group interchanges (e.g., the conversion of

alcohols to sulfonates prior to further reaction), and protecting group manipulations. At-
taining ideality in a synthesis is not as simple as it might seem, and even the most elegant
syntheses are often no better than 50% ideal under this definition.
So Which Metric Do You Use?

Good question. Even given the discussion above, there is still no consensus about how one
evaluates two different syntheses of the same target compound. How they are ranked will
depend on the perspective of the evaluator, and a combination of all three types of econ-
omy or ideality will almost certainly be taken into account. As you develop your own
synthetic instincts, you will almost certainly also develop your own values for evaluating
syntheses. Good luck!§
15.2 Organic Reactions: Tools of the Synthetic Chemist
Let begin by examining the general form of an organic reaction once again. In introduc-
tory courses in organic chemistry, reactions are studied in terms of a starting compound
reacting with a reagent to give a product: “A reacts with B to give C,” as shown.
A+B→C
For the synthetic organic chemist, however, the critical question is seldom “What is
the product of the reaction between A and B?” but much more often “How can I convert
compound A into compound B?” When one must plan a synthesis, one does not normally
have the reactant and reagents, but one is usually given instead an end result—the target
molecule—and must determine the best way to obtain it. The synthetic chemist is more
often faced with the more general questions: “What reactions can be used to make C?” and
“What is the best way to make C?”
?+?→C
This is not so uncommon a situation as you might think at first. In fact, being con-
fronted by an end result and needing to piece together how it happened is so common in
modern living that we have a term for it—we call it “troubleshooting.” Designing a synthe-
sis involves the same kinds of thought processes. We “troubleshoot” problems by working
backward from the problem to its cause, and we design a synthesis by working backwards
from the target compound to available precursors. Consequently, the study of organic re-
actions from the viewpoint of the synthetic chemist is usually more concerned with prac-
tical details than we have been so far. Small differences in reactivity or stereochemistry are
relatively inconsequential when one is studying a single reaction; they can be critically
important when that reaction is part of a sequence.
The three participants in the reaction above are members of a closely linked set, so this
reaction can also be viewed in the light that “A and B always give C.” This has other impli-
cations: it also means that “To get C from A, you must use B,” and “It is A that reacts with
B to give C,” although we have not explicitly stated it this way yet. So any time one knows
two of the three participating species in a reaction (reactant, reagent and product), one can
§ There is an unspoken caveat in our discussion of organic synthesis—this chapter and those that follow will
contain the biases of the author, and I have chosen examples that I believe are both important and instructive.
Not everyone will agree with these choices, so, like medical advice, it is probably worth your while to get a
second opinion on some of these choices—talk to your instructors and colleagues, and read and appreciate
syntheses for yourself.

deduce the third. Thus, one can easily categorize reactions according to one of the three
protocols.
A + B → ? [Answer: C]
? + B → C [Answer: A]
A + ? → C [Answer: B]
We can illustrate the preceding discussion with a relatively simple reaction that exhib-
its some of the more important characteristics that are useful to the chemist in the process
of designing a synthesis—the reaction between 1-methylcyclohexene and aqueous bro-
mine to give the racemic trans, Markovnikov bromohydrin (Example 15.7).
Br2, H2O OH (15.7)
Br
Me Me
(±)
Br2, H2O
? (15.8)
Me
? OH (15.9)
Br
Me Me
(±)
Br2, H2O OH
? (15.10)
Br
Me
(±)
For this reaction, the three protocols above can now be represented as shown (Exam-
ples 15.8 to 15.10).
Most of the time, one of these three ways of writing a reaction will suffice to pick the
best way to make a molecule. Or, using the specific example above, we get the problem
shown as Example 15.11.
? ? OH (15.11)
Br
Me
(±)
Historical Development of Organic Synthesis18

Following Wöhler’s serendipitous synthesis of urea in 1828, chemists gradually turned to
the process of deliberately building organic molecules. The first such successful designed
synthesis was the total synthesis of acetic acid by Hermann Kolbe.19 This synthesis went a
long way toward ending the reign of vital force theory. From these humble beginnings, the
edifice that is modern organic synthesis arose. The rise of selectivity in organic synthesis
is shown in Figure 15.5.
18. For an entertaining review of the development of modern synthesis to the end of the twentieth century,
see: Nicolaou, K.C.; Vourloumis, D.; Winssinger, N.; Baran, P.S. Angew. Chem. Int. Ed. 2000, 39, 44.
19. Kolbe, H. Ann. Chem. Pharm. 1845, 54, 145.

MODERN SYNTHETIC REACTIONS Figure 15.5 The rise of

sophistication in organic
ENANTIOSELECTIVITY
synthesis
Reaction gives a single enantiomer, or a product
highly enriched in one enantiomer, from an achiral
precursor
1980s
DIASTEREOSELECTIVITY
Reaction gives the product as a single

diastereoisomer, or a mixture highly enriched in one
diastereoisomer. Product from an achiral precursor
will be racemic.
1900s
REGIOSELECTIVITY
Reaction gives the product as a single regioisomer,

or as a mixtures highly enriched in one regioisomer
1870s
CHEMOSELECTIVITY
Reagent reacts predominantly, but not always

exclusively, with one functional group in the molecule
EARLY SYNTHETIC REACTIONS
The first decades of organic synthesis were characterized by the development of a wide
range of new organic reactions. During these decades, the questions addressed were in the
area of chemoselectivity—designing reactions that were selective for one functional group
over another. This represents the lowest level of sophistication for selective transforma-
tions in organic compounds, and includes reactions such as the Tollens oxidation of
aldehydes.20
As the number of selective reactions available to the organic chemist increased, the
level of sophistication in their use also rose. In the 1870s, for example, the first investiga-
tions of reaction regiochemistry led to the formulation of Markovnikov’s rule21 for addi-
tion and the Zaitsev22 and Hofmann23 rules for elimination. With the formulation of these
rules, chemists could begin to plan syntheses with reasonable levels of regioselectivity.
By the turn of the 20th century, organic synthesis had become sufficiently sophisti-
cated to allow the synthesis of moderately complex molecules as single diastereoisomers
(e.g., the syntheses of camphor by Komppa 24 and glucose by Fischer25 belong to this class).
This period, when total syntheses of complex molecules were characterized by high levels
of diastereoselectivity, reached its zenith during the middle of the century, largely as a
result of the work of Robert B. Woodward, who reported total syntheses of complex
natural products such as strychnine26 and reserpine.27 In almost every case, however, the
20. Tollens, B. Ber. Deut. chem. Ges. 1882, 15, 1635.

21. (a) Markownikoff, W. Ann. Chem. Pharm. 1870, 133, 228. (b) Markovnikov, V. Comptes rend. 1875, 82,
668, 728, 776.
22. Saytzeff, A. Ann. Chem. Pharm. 1875, 179, 296.
23. Hofmann, A.W. Ann. Chem. Pharm. 1851, 78, 253; 1851, 79, 11.
24. Komppa, G. Chem. Ber. 1903, 36, 4332.
25. Fischer, E. Ber. Deut. chem. Ges. 1890, 23, 799.
26. (a) Woodward, R.B.; Cava, M.P.; Ollis, W.D.; Hunger, A.; Daeniker, H.U.; Schenker, K. J. Am. Chem. Soc.
1954, 76, 4749. (b) Woodward, R.B.; Cava, M.P.; Ollis, W.D.; Hunger, A.; Daeniker, H.U.; Schenker, K. Tetrahe-
dron 1963, 19, 247.
27. Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. J. Am. Chem. Soc. 1956, 78, 2023.
(b) Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. J. Am. Chem. Soc. 1956, 78, 2657.
(c) Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2, 1.

synthesis reported the preparation of the racemate, and not the enantiomerically pure
material.
The next advance in the sophistication of organic synthesis came in the last two de-
cades of the 20th century, which saw the discovery of the first reliable methods for the
synthesis from achiral or prochiral precursors of chiral molecules as single enantiomers28
(or nearly so). With these discoveries, a new era of enantioselectivity in organic synthesis
began.
OMe
O
N
O
OH O O O O OH
H
N H
O O O
MeO
(15.12) (15.13)
The turn of the 21st century has seen yet another advance in the toolkit available
to the modern organic chemist—the development of catalysts for a wide range of
carbon-carbon bond-forming reactions. It is worthwhile noting that the Nobel Prize in
chemistry has been awarded three times since the turn of the century for reactions using
catalysts. Just how powerful catalytic reactions can be in synthesis is illustrated by Wipf’s
synthesis of (–)-disorazole C1 (Example 15.12),29 whose deceptively simple C2-symmetric
macrocycle was closed by means of a palladium-catalyzed Sonagashira coupling and whose
conjugated (E,Z,E)-trienes must be introduced into the macrocycle very late in the synthe-
sis, after much of the sensitive functionality is already in place—a serious challenge because
one must find selective reactions that will not affect the sensitive groups in the molecule.
An even more impressive illustration of the power of modern catalytic methods for synthe-
sis is provided by Fürstner’s synthesis of the ecklonialactones (Example 15.13), a 13-step
synthesis in which five catalytic reactions are used as key steps and in which protecting
groups are not required.30 In addition, it has also seen the rise of combinatorial chemistry
or modular organic synthesis, now a significant part of modern drug discovery.
Since the middle of the 20th century, the sheer number of organic reactions available
to the modern synthetic organic chemist has been growing at an incredible rate, so some
means of classifying reactions becomes essential if one is to be able to design a reasonable
synthesis. There are many ways in which this can be accomplished, such as dividing re-
actions by the type of reagents involved or by the stereo- or regiochemical outcomes of
the reactions involved. In Chapter 5, we categorized reactions based on the frontier orbit-
als involved. Table 15.1, categorizes reactions according to the number and type of bonds
undergoing changes occurring during the reaction, and the types of changes occurring.
Although this is a very simplistic method of characterization, it is one that I have person-
ally found to be useful in organizing organic reactions. It is worthwhile noting that, as
with any system to organize organic reactions, these categories are somewhat arbitrary
and are not exclusive—a reaction may fall in more than one category, and many do. The
important thing is to find a way for categorizing reactions that works for you.
28. (a) Katsuki, T.; Sharpless, K.B. J. Am. Chem. Soc. 1980, 102, 5974. (b) Knowles, W.S.; Sabacky, M.J.; Vine-
yard, B.D.; Weinkauff, D.J. J. Am. Chem. Soc. 1975, 97, 2567. (c) Knowles, W.S. Acc. Chem. Res. 1983, 16, 106.
(d) Knowles, W.S. J. Chem. Educ. 1986, 63, 222.
29. Wipf, P.; Graham, T.H. J. Am. Chem. Soc. 2004, 126, 15346.
30. Hickmann, V.; Alcarazo, M.; Fürstner, A. J. Am. Chem. Soc. 2010, 132, 11042.

Table 15.1 Categorizing Organic Reactions
ONE-BOND (C—C) REACTIONS

R R
R M + O R OH Grignard addition
R R
R R R R
Wittig reaction (X=PR3); McMurry reaction (X=O)
X + O ozonolysis; Lemieux-Johnson cleavage, etc.
R R R R
X O Friedel-Crafts acylation
+ R Gattermann-Koch formylation
Y R Vilsmeier-Haack formylation
O O OH O
+ aldol addition; Bayliss-Hillman reaction; etc.
R H R R R retro-aldol fragmentation
R R
R O R O
+ aldol condensation
R O R R R
R R
X O O
+ alkylation of enolates
R R R R
R R
X
+ R R alkylation of alkynides
R
R
O R O
R + Michael addition
R R R R
R R
O O O O
Claisen condensation
+
R OR R R R retro-Claisen fragmentation
R R
R R R R
O + O HO OH pinacol reaction
glycol cleavage
R R R R
R R Heck coupling (X=halogen; Y=H)

+ X
Y Suzuki coupling (X=halogen; Y=B(OR2))
R H + X R Sonogashira coupling
(continued)

Table 15.1 Categorizing Organic Reactions (continued)
ONE-BOND (C—X) REACTIONS
O R O R
α-halogenation, sulfenylation, selenylation etc.
R R X α-hydrogenolysis
R R allylic/benzylic halogenation, etc.

allylic/benzylic hydrogenolysis, etc.
R R X
R R
X Y nucleophilic substitution (SN1, SN2, etc.)
R R
X aromatic nitration, halogenation, etc.
MULTI-BOND REACTIONS
R R
X
O acetal/thioacetal/ketal formation
X acetal/thioacetal/ketal hydrolysis
R R
R R R R
electrophililc addition of HX
H X base-promoted elimination (E1, E2, E1cb)
R R R R
R R R R
electrophililc addition of XY, hydroxylation, etc.
X Y reductive elimination
R R R R
R R
R R R R
R R
alkene metathesis
R R
R R R R
R R
R R R
O Wittig/McMurry reactions
R R R ozonolysis, Lemieux-Johnson oxidation, etc.
R R R R
cyclopropanation (Simmons-Smith, etc.)
R R R R
R R R R
epoxidation
R R R O R
R R R
O Darzens condensation; sulfur ylide addition, etc.
R R O R
R O
R R O
R [2+2] cycloaddition
C
R X
R R X
R
[4+2] cycloaddition (Diels-Alder reaction)
(continued)

Table 15.1 Categorizing Organic Reactions (continued)
OXIDATION AND REDUCTION REACTIONS
R R R R
H H hydrogenation
dehydrogenation
R R R R
R R R O R
epoxidation
R R R R
R R R R
addition of halogens; hydroxylation, etc.
X Y reductive elimination
R R R R
O HO reduction of carbonyl compounds
R R oxidation of alcohols
R R
O R O R
α-halogenation, sulfenylation, sulfonation, etc.
hydrogenolysis of α-halocarbonyl compounds, etc.
R R X
R R
allylic halogenation, oxidation, etc.
allylic hydrogenolysis
R R X
R R R
O acyloin condensation
RO O OH
R R R McMurry reaction
O ozonolysis; Lemieux-Johnson oxidation
R R R
R R R pinacol reduction
O HO OH periodate oxidation
R R R
R R
H
O Wolff-Kishner, Clemmensen or related reductions
H
R R
Birch reduction
X
nitration, halogenation, etc. of aromatic rings
REARRANGEMENT REACTIONS
R X Y R
R R Wagner-Meerwein rearrangement of cations
R R R R
R R X R
HX XH R pinacol rearrangement
R R R R
O R O R
X R Favorskii rearrangement
R R Y R
O R
R O C X Hofmann, Curtius, Lossen rearrangements
Y X
X O R Baeyer-Villiger rearrangement (X=O; Y=O)
R Y Beckmann rearrangement (X=NOH; Y=NH)
R R Schmidt reaction (X=O; Y=NH)
X X Cope (X=CR2) and Claisen (X=O) rearrangements

other sigmatropic rrearrangements
electrocyclization
n n

Worked Problem
15-1 Categorize each of the reactions in the list below according to the following
c riteria: (1) chemoselectivity (what functional groups may be involved?);
(2) regioselectivity (are regioisomers formed, and, if so, which is formed in
major amount?); (3) stereoselectivity (what is the stereochemistry of the reaction,
and which stereoisomer is formed in major amount?); and (4) interference (what
functional groups interfere with the reaction, and are side reactions possible?)
(a) dichlorocarbene addition to an alkene
(b) SN2 substitution
(c) addition of Br2, H2O to an alkene
§Answers below.
Problem
15-2 Categorize each of the reactions in the list below according to the following
c riteria: (1) chemoselectivity (what functional groups may be involved?);
(2) regioselectivity (are regioisomers formed, and, if so, which is formed in
major amount?); (3) stereoselectivity (what is the stereochemistry of the reaction,
and which stereoisomer is formed in major amount?); and (4) interference (what
functional groups interfere with the reaction; are side reactions possible?)
(a) Grignard addition to a carbonyl compound
(b) Diels-Alder cycloaddition
(c) E2 elimination from an alkane derivative
(d) Hydroboration-oxidation
(e) Alkylation of a ketone
(f) SN1 substitution
(g) Acid-catalyzed dehydration
(h) Friedel-Crafts acylation of anisole
(i) Michael addition to an enone
(j) Wadsworth-Emmons reaction of aldehydes

(a) Dichlorocarbene addition to an alkene: (1) the reaction involves the π bond of an alkene; (2) because the
reagent adds at both ends of the double bond simultaneously, there is no regiochemistry involved; (3) the reac-
tion is stereospecific, and proceeds by syn (suprafacial) addition only; (4) the carbene will react with any
strongly nucleophilic groups such as primary or secondary amines, and phenoxide anions.
(b) SN2 substitution: (1) the reaction involves a nucleophile and a compound with a good leaving group
bonded to a primary or secondary sp3-hybridized carbon atom; (2) since no rearrangement is involved, re-
giochemistry is not a factor in this reaction; (3) the reaction is stereospecific and gives the product with
inversion of configuration at carbon; (4) acidic groups often protonate the nucleophile and render it
unreactive.
(c) Addition of Br2, H2O to an alkene: (1) The reaction is typical of reactions involving an electrophile with a
lone pair on the electrophililc atom and an alkene π bond; (2) the reagent adds to the alkane with predomi-
nantly Markovnikov regiochemistry—the halogen ends up bonded to the atom less capable of bearing a formal
positive charge; (3) the reaction is stereospecific, and gives overall anti (antarafacial) addition; the reaction may
be diverted by other functional groups capable of reacting with the bromonium ion intermediate (e.g.,
electron-rich aromatics).

(k) Catalytic hydrogenation

(l) Simmons-Smith reaction
(m) Baeyer-Villiger oxidation
(n) Epoxide ring opening
(o) Allylic bromination with NBS
(p) Wittig reaction of aldehydes
(q) Aldol addition
(r) Olefin metathesis
(s) Suzuki coupling
Using Stereochemical Outcomes for Categorizing Organic Reactions

Another reaction characteristic that is extremely important, especially in modern synthe-
ses, is the stereochemistry of the reaction, and all modern syntheses strive for some level
of stereocontrol. In stereospecific reactions, stereocontrol is complete. Only one stereoiso-
mer of the product is formed, its stereochemistry is predictable based on the stereochem-
istry of the reactant, and its stereochemistry changes if we change the reactant
stereochemistry. This makes stereospecific reactions important tools for controlling ste-
reochemistry during a synthesis. In stereoselective reactions, the level of stereocontrol is
not quite so high. Now more than one stereoisomer of the product is formed, and the ste-
reochemistry of the product is not necessarily related to that of the reactant. Even so,
many stereoselective reactions exhibit high levels of stereoselectivity and are useful tools
for synthesis. Some of the more important stereocontrolled reactions available to the syn-
thetic chemist are presented in Table 15.2.
Let us now end this section of the discussion with another piece of advice—also prob-
ably unsolicited. You should remember that organic synthesis is probably the most indi-
vidualistic of the chemical sciences, so that you may find that an alternative method of
classification that works better for you. If that is the case, do it! As you begin the process
of designing your own syntheses, it is worthwhile expending some effort to develop your
own method of classification of reactions for use in answering synthetic problems.
15.3 Retrosynthetic Analysis: An Introduction to the Vocabulary

and Strategy of Organic Synthesis
Every organic structure contains within itself clues to how it might be assembled. The
critical problem facing the organic chemist planning a synthesis is to choose the pathway
that is most efficient. For the beginning student, this can be a daunting task—just choos-
ing where to start can be frightening! So where does one start?
One of the most logical starting points is the one we have already adopted: categoriz-
ing organic reactions according to their effect on the reactant structure. By doing so, we
become acquainted with the tools of organic synthesis and how to use them to control
compound structure and stereochemistry.
Retrosynthetic Analysis
The process of analyzing the structural and functional features of a target molecule to see
how it might be formed from simpler compounds is known as retrosynthetic analysis.
This process was first placed on a formal footing by Harvard chemist E. J. Corey, who

Table 15.2 Stereocontrolled Reactions
SUPRAFACIAL ADDITIONS
R1 R2 R1 R2
HO OH hydroxylation
R3 R4 R3 R4
R1 R2 R1 R2
H H hydrogenation
R3 R4 R3 R4
R1 R2
Lindlar hydrogenation
R1 R2
H H
1 2 1
R R R R2
epoxidation
R3 R4 R3 O R4
R1 R2 R1 R2
cyclopropanation
R3 R4 R3 R4
R1 R2 R1 R2
H BR2 hydroboration
R3 R4 R3 R4
R1 R2 R1 R2
R3 R4 Diels-Alder cycloaddition
R3 R4
R1 R2
H R1 R4 Diels-Alder cycloaddition
H
R3 R4 R2 R3
R1 R2 R1 R2
R3 R4 1,3-dipolar cycloaddition
R3 R4 X Z
Y
R1 R2
hydrometallation;
R1 R2 M=Al, Zr, etc.
H M
ANTARAFACIAL ADDITIONS
R1 R2 R1 R2
HO OH anti-hydroxylation
R3 R4 R3 R4
R1 R2 R1 R2
X Y halogen addition, etc.
R3 R4 R3 R4
R1 H
Birch Reduction
R1 R2
H R2
(continued)

Table 15.2 Stereocontrolled Reactions (continued)
ELIMINATIONS
R1 R2 R1 R2
H X E2 elimination
(anti)
R3 R4 R3 R4
R1 R2 R1 R2 reductive elimination
X Y syn or anti, depending on
R3 R4 R3 R4 leaving group)
R1 R2 Cope elimination (X=N)

R1 R2
R3 R4 (syn at low temperatures)
selenoxide elimination (X=Se)
H X R R3 R4 (syn)
O
R1 R2 R1 R2 ester pyrolysis (X=O, Y=alkyl)

R3 R4 xanthate pyrolysis (X=S, Y=SR)
H O R3 R4 (syn)
X
Y
R1 R2 R1 R2
R3 R4 Diels-Alder cycloreversion
(syn)
R3 R4
RETENTION OF CONFIGURATION
R1 R2 R1 R2
electrophilic substitution
of organometallics
R3 M R2 X
R1 R1 carbene (Y=CR2) or
X X
nitrene (Y=NR) insertion
H Y H
R2 R2
R1 R1
X R hydrogenolysis over Ni
R Nu
R2 R2
R6 R1
R2
R5 R6 Wagner-Meerwein
R1 R3
R4 rearrangement
R2
R3 R4 R5
O
R1 X R Baeyer-Villiger oxidation
R1 Beckmann rearrangement
R R2
R2 R3 O Schmidt rearrangement
R3
O
R1 X Hofmann rearrangement
R1 Y C Curtius rearrangement
X R2 O
R2 R3 Lossen rearrangement
R3
(continued)

Table 15.2 Stereocontrolled Reactions (continued)
INVERSION OF CONFIGURATION
R1 R1 SN2 substitution;
X H
X=halogen, sulfonate
H Nu Mitsunobu reaction (X=OH)
R2 R2
R1 O R2 R1 R2
Nu OH epoxide ring opening
R3 R4 R3 R4
R1 R1
X R hydrogenolysis over Pd
R H
R2 R2
developed much of the terminology of modern organic synthesis.31 It is now routinely ap-
plied by organic chemists in designing syntheses of organic compounds.32 In Corey’s ter-
minology, we define two directions: synthetic and antithetic (or retrosynthetic).
Processes that occur in the synthetic direction are called reactions; they occur in the real
world and describe the conversion of one real substance into another. One can actually
perform a reaction in a laboratory and isolate the product or products.
Processes that occur in the retrosynthetic direction are transforms; they describe possible
ways in which the target molecule might be disconnected to potential precursors, or synthons.
Transforms do not have an existence in the real world—they are conjectural intellectual con-
structs that simply describe possibilities. One cannot perform a transform in a laboratory.
Likewise, synthons are not necessarily stable molecules—they may be reactive inter-
mediates such as a carbene, a carbocation or a carbanion or simply be structures that show
reactivity patterns required. However, they do show the type of reagent that will be needed
to effect the particular conversion in the synthetic direction. We distinguish between re-
actions and transforms by the type of arrow that we use to draw the process. The differ-
ence between synthesis and the way we have learned about organic reactivity is illustrated
in Figure 15.6 by using a simple conjugate addition reaction as our example.
The verbal description of the reaction in Figure 15.6 would be “2-cyclohexenone reacts with
lithium diethylcuprate in tetrahydrofuran, or THF, to give 3-ethylcyclohexanone.” This pro-
cess has an existence in the physical world. One can actually carry out this reaction and con-
vert 2-cyclohexenone into 3-ethylcyclohexanone. The verbal description of the transform, on
the other hand, makes it clear that one is describing only one possibility from a range of possi-
bilities. “It is possible to disconnect the 3-ethylcyclohexanone molecule into an electrophilic
31. (a) Corey, E.J. Pure Appl. Chem. 1967, 14, 19. (b) Corey, E.J. Chem. Soc. Rev. 1988, 17, 111.
32. There are many textbooks and treatises dedicated to organic synthesis. Representative examples include:
(a) Warren, S. Organic Synthesis: The Disconnection Approach (Wiley-Interscience: New York, 1982). (b) Corey,
E.J.; Cheng, X.-M. The Logic of Chemical Synthesis (Wiley-Interscience: New York, 1989). (c) Ho, T.-L. Tactics of
Organic Synthesis (Wiley-Interscience: New York, 1994). (d) Norman, R.O.C.; Coxon, J.M. Principles of Organic
Synthesis, 3rd. ed. (Blackie Academic & Professional: Oxford, 1993). (e) Smith, M.B. Organic Synthesis, 2nd. ed
(McGraw-Hill: Boston, 2002). (f) Boger, D.L. Modern Organic Synthesis (TSTI Press: La Jolla, 1999). (g)
Fuhrhop, J.; Penzlin, G. Organic Synthesis: Concepts, Methods Starting Materials (Verlag Chemie: Weinheim,
1983). (h) Zweifel, G.S.; Nantz, M.H. Modern Organic Synthesis: An Introduction (W.H. Freeman & Co: New
York, 2007). (i) Hudlicky, T.; Reed, J.W. The Way of Synthesis (Wiley-VCH: New York, 2007).
There are several multivlume treatises on aspects of synthesis, also: (a) Barton, D.H.R.; Ollis, W.D., Eds.
Comprehensive Organic Chemistry (Pergamon Press: Oxford, 1979). (b) Trost, B.M.; Fleming, I., Eds. Compre-
hensive Organic Synthesis (Pergamon Press: Oxford, 1992). (c) Science of Synthesis (Thieme Chemistry: Stutt-
gart, 2000–2010). This multivolume treatise is an ongoing project with over 1700 contributing authors to date,
and regular updates since then.

Reality (Tangible) Possibility (Conjectural)
CH2CH3 CH2CH3
Et2CuLi/THF
CH3CH2
O O O O
Reaction Transform
Occurs in real world Hypothetical only
Forward (synthetic) direction Backward (retrosynthetic, antithetic) direction
Converts reactant to product Converts target to precursors or synthons
Figure 15.6 Comparing reactions and transforms
Et Et CH2 Figure 15.7 Alternative

synthons for
H2/Pd-C Me2CuLi/THF + RBr + CH3 3-ethylcyclohexanone
O O O
target molecule Figure 15.8

A retrosynthetic tree
precursor precursor precursor

A1 A2 A3
precursor precursor precursor precursor precursor

A1,1 A1,2 A2,2 A3,1 A3,2
etc etc etc etc etc
cyclohexanone synthon with the electrophilic center β to the carbonyl group and a nucleop-
hilic ethyl synthon.” This retrosynthetic analysis is then translated into terms that one can use
to select a reaction: the nucleophilic ethyl synthon could be an organometallic reagent such as
lithium diethyl cuprate, and 2-cyclohexenone could serve as the electrophilic ketone synthon.
Of course, there are other ways that one might envisage making this alkane. It might be pre-
pared by catalytic hydrogenation of an alkene or by a nucleophilic substitution reaction, as
shown in Figure 15.7, where the reactions corresponding to these transforms are also given.
Once you have become familiar with the principles of retrosynthetic analysis, the pro-
cess of designing a synthesis simply becomes one of applying these principles to the target
molecule and the successively generated precursors until one arrives at a point where the
synthon generated corresponds to an available compound or one that has been prepared
previously. This process quickly generates a retrosynthetic tree, which is simply a collec-
tion of potential pathways radiating backward from the target compound to available
starting materials (Figure 15.8).
In principle, one should be able to generate a retrosynthetic tree containing every pos-
sible synthetic pathway for the preparation of the target compound. Such an undertaking
would, however, be extremely time-consuming, and few bother to complete the task once
a viable route to the target compound is identified. In practice, many of the potential path-
ways are eliminated from consideration before they are completely described because the
early steps do not result in any simplification in the problem. For example, if we examine
the example on the right in Figure 15.7, we note that the disconnection used really does not
simplify the problem in this synthesis at all—the electrophilic synthon still carries most of
the structure and all of the functionality of the target compound. It is doubtful if it would

Figure 15.9 Comparing 90 81 73 66 59
linear and convergent Linear synthesis
syntheses
A B C D E F
90 81
A B C 73
Convergent synthesis F
90
D E
actually be used in a real synthesis unless there was some specific reason for using it (e.g.,
to incorporate a labeled carbon atom from methyl iodide).
Syntheses may be linear or convergent. In a linear synthesis, the target molecule is
assembled by a single sequence of reactions from a single starting compound. In a conver-
gent synthesis, the target molecule is assembled by two or more independent, parallel se-
quences of reactions to form major substructures of the target molecule that are assembled
in the late stages of the synthesis. In general, convergent syntheses give higher overall
yields of the target compound, and they require fewer steps. The comparisons of linear
and convergent syntheses are illustrated schematically in Figure 15.9, where the numbers
above the stages show the overall percent yield, assuming a 90% yield for each step.
Now let us study the process of retrosynthetic analysis in detail by examining Corey’s
original approach. Recall that this is the process of applying transforms to a target mole-
cule to generate synthons that can then be used to generate a retrosynthetic tree. Every
retrosynthetic transform corresponds to a reaction, and every reaction has its correspond-
ing transform. The reactions that one commonly uses were summarized in Tables 15.1 and
15.2; they can be conveniently divided into six major types:
1. Reactions that remove a functional group. These reactions often occur near the end of
a synthesis, when it is necessary to remove a functional group (e.g., a carbonyl group
or double bond) that has been used in the construction of the molecule. These reac-
tions, which are typified by catalytic hydrogenation or the Wolff-Kishner reduction,
are represented in retrosynthetic analysis by functional group addition (FGA)
transforms—transforms that add a functional group to the target molecule without
modifying its carbon skeleton.
2. Reactions that interchange functional groups. These reactions are among the most
common and the simplest to use. Reactions such as hydroboration-oxidation, oxida-
tion of alcohols to carbonyl compounds, and the formation and hydrolysis of acetals
and ketals belong to this class. In retrosynthetic analysis, these reactions correspond
to the functional group interchange (FGI) transforms—transforms that alter the
functional groups of the target structure without modifying its carbon skeleton.
3. Reactions that create a new functional group. These reactions often involve the re-
placement of benzylic or allylic hydrogens or electrophilic aromatic substitution by a
heteroatom electrophile. Nitrene insertion reactions, which form a new C—N bond,
also fall into this category. They are represented in retrosynthetic analysis by func-
tional group removal (FGR) transforms—transforms that remove a functional group
from the target structure without modifying its carbon skeleton.
4. Carbon-carbon bond-forming reactions. These reactions are those that form the c arbon-
carbon bonds in a molecule, and they correspond to some of the most powerful synthetic
methods available to the organic chemist. Reactions such as the Diels-Alder c ycloaddition,
Grignard and aldol additions, and Friedel-Crafts acylation are bond-forming reactions.
In retrosynthetic analysis, they correspond to bond d isconnection (DIS) transforms—
transforms that disconnect a bond in the target molecule. Bond disconnection almost
always results in simplification of the target molecule. In Table 15.3, ring disconnection
transforms are gathered in a separate group simply because the construction of rings is
often an important step in a total synthesis.

Table 15.3 Major Transforms Used in Retrosynthetic Analysis
Some Representative Examples
BOND DISCONNECTION (DIS)
retro-Grignard addition
HO R O R retro-alkynide anion addition
R R
R R R R
O X retro-Wittig transform
R R R R retro-McMurry transform
O
retro-acylation
O C R
retro-formylation
R
O OH O O
retro-aldol transform
R R R H R retro-Reformatskii transform
R R
O R O O
retro-aldol condensation transform
R R R R R
R R
O O X
retro-alkylation of enolate
R R R R
R R
X
R R retro-alkylation of alkynide anion
R
R
X
E E retro-alkylation of nitro compounds
R R (E=NO2), sulfoxides (E=SOR),
R R dithianes (E=(SR)2, etc.
O R O
retro-Michael addition transform
R R R R R
R R
O O O O
retro-Claisen condensation transform
R R R RO R
R R
R R R R
HO OH O O retro-pinacol transform
R R R R
R R R R
O O retro-acyloin condensation
O OH RO OR
Ar Ar Ar Ar
O O retro-benzoin transform
O OH H H
R X retro-Heck coupling
R retro-Suzuki coupling
Y
R X retro-Sonogashira coupling
H R
(continued)

Table 15.3 Major Transforms Used in Retrosynthetic Analysis (continued)
FUNCTIONAL GROUP INTERCHANGE (FGI)
R R
X O retro-hydride
R R reduction/reductive amination
retro-oxidation
R R R R
H X retro-elimination
R R R R retro-electrophilic addition
O
R R retro-alkyne hydration
R R
R R
X Y retro-SN1, SN2
R R
O X X
retro-ketal/thioketal hydrolysis
R R R R retro-ketal/thioketal formation
O retro-nitrile reduction
R C N retro-oxime dehydration
R H
OH O R
retro-Wharton reaction
R R R R
R O
R R
R R retro-Birch reduction
O R R
R R retro-epoxidation
R R R R
R R
R R retro-Lindlar hydrogenation
H H
R H
R R retro-Birch reduction
FUNCTIONAL GROUP REMOVAL (FGR)
R X R H
R R retro-allylic halogenation,
R R R R oxidation, etc.
R R
O X O H retro-α-halogenation,
R R sulfenylation,
R R R R selenylation, etc.
retro-nitration,
X halogenation, etc.
X H H X retro-Hofmann-Löffler-
Y Y Freytag reaction;
retro-Barton reaction, etc.
R R
NHR' H retro-nitrene insertion
R R R R
(continued)

FUNCTIONAL GROUP ADDITION (FGA)
R H R M retro-protonolysis
R R R R
H H retro-hydrogenation
R R R R
H H O
retro-deoxygenation
R R R R
H H RS SR
retro-desulfurization
R R R R
R H R X
R R retro-hydrogenolysis
R R R R
R R
O H O X
R R retro-α-reduction
R R R R
H X
R R retro-hydrogenolysis
R R
REARRANGEMENT (REARR)
R X Y R
Wagner-Meerwein
R R rearrangement of cations
R R R R
R R X R
HX XH R pinacol rearrangement
R R R R
O R O R
X R Favorskii rearrangement
R R Y R
O R
R O C X Hofmann, Curtius,
Lossen rearrangements
Y X
X O R Baeyer-Villiger rearrangement (X=O; Y=O)

R Y Beckmann rearrangement (X=NOH; Y=NH)
Schmidt reaction (X=O; Y=NH)
R R
R R
R R R R
R R olefin metathesis
R R
R R R R
R R
X Cope (X=CR2) and Claisen (X=O)

X
rearrangements
other sigmatropic rrearrangements
electrocyclization
n n
(continued)

FUNCTIONAL GROUP REMOVAL (FGR)
R X R H
R R retro-allylic halogenation,
R R R R oxidation, etc.
R R
O X O H retro-α-halogenation,
R R sulfenylation,
R R R R selenylation, etc.
retro-nitration,
X halogenation, etc.
X H H X retro-Hofmann-Löffler-
Y Y Freytag reaction;
retro-Barton reaction, etc.
R R
NHR' H retro-nitrene insertion
R R R R
RING DISCONNECTION (DIS)
+ retro-Diels-Alder cycloaddition
R R
R R R R R
R X X
retro-[3+2] dipolar cycloaddition
Y Y
+
R Z R R
R Z
X X
+ retro-[2+2] cycloaddition
C
O
O
R
+ :CHR2 retro-carbene addition
R
O R O
retro-Darzens condensation
R + :CR2
R R R retro-sulfonium ylide addition
R
(continued)

BOND RECONNECTION (REC)
R R R R
O O retro-ozonolysis transform
R R R R retro-Lemieux-Johnson transform
R R R R
O O HO OH retro-glycol cleavage transform
R R R R
O O O
aldol condensation transform
R H R R R
R R
O O OH O
aldol addition transform
R H R R R
R R
O O O O
Claisen transform
R OR R R R
R R
O O
CO2H retro-decarboxylation transform
R R
R R
R
O R O retro-Eschenmoser-
R R
Tanabe fragmentation
R R R
R O
5. Carbon-carbon bond-cleaving reactions. These reactions cleave carbon-carbon bonds.

Reactions such as ozonolysis or periodate cleavage of diols belong to this class of reac-
tions, as does the decarboxylation of β-ketoacids and the reverse of the aldol addition.
In retrosynthetic analysis, these reactions are represented by bond reconnection (REC)
transforms—transforms that reconnect a bond in the target molecule. Bond reconnec-
tion may result in a simplification or an increase in complexity of the target structure,
depending on which bond is reconnected.
6. Rearrangement reactions. These reactions alter the carbon skeleton of a molecule;
they include reactions such as the Wagner-Meerwein, Favorskii, Hofmann, and sig-
matropic rearrangements. They are represented in retrosynthetic analysis by rear-
rangement (REARR) transforms.
Most of the transforms in Table 15.3 correspond to reactions that are normally found in
introductory organic chemistry textbooks. If we take the first two-bond disconnection
(ring DIS) transforms as working examples, the first is the retro–Diels-Alder transform,
which disconnects a cyclohexene into a diene and a dienophile. If this transform occurs as
part of the retrosynthetic analysis, it indicates that a Diels-Alder reaction might be used to
form the cyclohexene ring in the target molecule. The second bond disconnection trans-
form in Table 15.3 disconnects the carbon-carbon bond to of an alcohol into a carbonyl
synthon and a nucleophilic alkyl synthon. If this transform occurs as part of the retrosyn-
thetic analysis, it indicates that one method for the formation of this bond of the target
molecule might be the addition of an organometallic compound to an aldehyde or ketone
(e.g., a Grignard reaction).

Table 15.4 Fuhrhop-Penzlin Designations of Synthons
Acceptor Synthons Donor Synthons
a0 d0
O R R R
Cl Ts Cl P S N R P R
O X R R R
X Tf Cl
O S O O R S R Se R
Tf Cl
aR dR
R X X = Cl, Br, I, OTs, OMs, OTf, etc. R Li R MgX
R
R R Y Y = R2S , R3N , R2O , etc. R2CuLi
R Z Z = AlCl4, TiCl5, SnCl5, ZnCl3, etc.
a1 d1
Y O
X = Cl, OCOR, SR', OR', C N C C R
Y = O, NR2
R X OPOCl2, etc.
FG R R FG SiR3 S NO2
NHR2 X R R R
X = OAlCl3, OTiCl4, etc. S
R OPOCl2 R Cl
a2 d2
O NO2
FG X = Cl, Br, OTs,
X OMs, etc FG O CN
R R
X R
X = O(H), N(H)R, S(H), etc.
X X = Cl, Br, OTs, OMs, etc.
a3 d3
O CO2R
FG CN SiR3
FG
CO2R
X
*Superscripts for synthons specify the relationship between the carbon atom that will react, and the carbon
atom with the other functional group in the synthon
Other Retrosynthetic Strategies

One can also use synthons revealed by applying transforms to a target molecule as a basis
for organizing reactions. This type of analysis forms the basis of the retrosynthetic termi-
nology developed by Fuhrhop and Penzlin33 (Table 15.4).
The real utility of this type of analysis comes when one realizes that the separation
between the functional groups in the product is the sum of the two superscripts. A M ichael
addition, for example, is the reaction between of a d2 synthon and an a3 synthon to give a
1,5-dicarbonyl compound, as illustrated in Example 15.14. The same type of transforma-
tion can also be accomplished by treating a γ-haloketone or ester (an a4 synthon) with the
conjugate base of nitromethane (a d1 synthon), as illustrated in Example 15.15.
33. Fuhrhop, J.; Penzlin, G. Organic Synthesis. Concepts, Methods, Starting Materials, 2nd ed. (VCH:
Weinheim, 1994).

a3
O
O
O
O
d2 (15.14)
a4
O O
X
NO2
NO2
1
d (15.15)
The two types of synthons are further subdivided into categories that denote the
number of carbon atoms between the atom where the bond is formed and the functional
group in the product, with that number shown as a superscript. Thus, an enolate anion in
an alkylation reaction (Example 15.16), for example, becomes a d2 synthon—in the car-
banion form of the ion, the anionic carbon is adjacent to (i.e., second to) the carbon atom
of the carbonyl group. An allyl halide (Example 15.17), on the other hand, is an a2 synthon.
Simple alkyl synthons that do not lead to a functional group in the final product of the
reaction are designated as aR or dR synthons.
O O
R R (15.16)
R' R'
2
d
R R (15.17)
2
a
The Evans-Lapworth Alternating Polarity Disconnection Method

The alternating polarity disconnection method34 is extrapolated from the alternating po-
larity theory originally developed by British chemist Arthur Lapworth35 in the 1920s for
rationalizing bonding and reactivity in organic compounds.36 It was transformed into a
useful method for retrosynthetic analysis in the 1970s by American chemist David Evans.
As an aside, Evans’ initial seminar presentation,37 which was rejected for publication when
it was submitted to the journals, may be the most widely disseminated and extensively
used unpublished paper of all time (the author of this book was given a copy of the manu-
script in Australia while he was still a student!).
In this method, each atom of the molecule is assigned an affinity label, either (+) or (–),
with affinity labels alternating around the skeleton of the molecule as much as possible. In
this chapter, we will use the labels (e) and (n), to avoid confusion that may arise by taking
the (+) and (–) labels of the Lapworth-Evans system for formal electronic charges. Atoms
given the affinity label (e) are part of an electrophilic synthon and they tend to be positions
34. (a) Evans, D.A. Acc. Chem. Res. 1974, 7, 147. (b) Ho, T.-L. Polarity Control of Synthesis (Wiley-Interscience:
New York, 1991).
35. Arthur Lapworth (1872–1941) was educated in Birmingham and spent most of his career at Manchester.
He became a pioneer of physical organic chemistry, especially in the elucidation of organic reaction mecha-
nisms. For more detail, see: Robinson, R. Obit. Notices Fell. Roy. Soc. 1947, 5, 554.
36. (a) Lapworth, A. Mem. Manchester Phil. Soc. 1920, 64 [iii], 1. (b) Lapworth, A. J. Chem. Soc. 1922, 121, 416.
(c) Lapworth, A.; Shoesmith, J.B. J. Chem. Soc. 1922, 121, 416. (d) Lapworth, A.; Robinson, R. Nature 1923, 112,
722. (e) Lapworth, A. Chem. Ind. 1924, 43, 1294; 1925, 44, 397. (f) Burkhardt, G.N.; Lapworth, A. J. Chem. Soc.
1925, 127, 1742. (g) Burkhardt, G.N.; Lapworth, A.; Walkden, J. J. Chem. Soc. 1925, 127, 2458.
37. Evans, D.A. “Consonant and Dissonant Relationships. An Organizational Model for Organic Synthesis”
UCLA Physical Organic Chemistry Seminar, May 6, 1971.

in the molecule that are susceptible to attack by nucleophiles. Those given the affinity label
(n) are part of a nucleophilic synthon and they tend to be positions in the molecule that are
susceptible to attack by electrophiles. The affinity labels of functional groups are assigned
first, and they are assigned so that they correspond to the polarity of the bonds of the func-
tional group (see Examples 15.18 and 15.19).
e e n n n e
n n e e
Br Li
e e n n
n e
(15.18) (15.19)
The real usefulness of the Lapworth-Evans affinity label method of retrosynthetic
analysis becomes apparent when one looks at compounds having more than one func-
tional group. In this situation, it allows one to deduce reasonable synthons that might be
used to assemble a target compound. In a molecule with several functional groups, the
relationship between pairs of functional groups can be particularly informative. It is in
analyzing the relationships between functional groups in polyfunctional compounds
that the real strength of the Evans method for analyzing the structures of complex or-
ganic compounds lies. This is done by defining two difunctional relationships: conso-
nant difunctional relationships, where the affinity labels alternate throughout the two
functional groups and the space between them, and dissonant difunctional relation-
ships, where there is at least one site where two like affinity labels must be placed on
adjacent atoms.
e n e n The two molecules shown in Figure 15.10 are instructive. In molecule 15.20, the affin-
n OMe ity labels all alternate, and it is not necessary to have any pairs of atoms with like affinity
e
n
e labels adjacent; the molecule is consonant. Consonant difunctional compounds tend to
nO e n
n be fairly easy to form because most of the common synthetic reactions in organic chem-
n e n e istry give consonant products (analyze the aldol addition, the Grignard addition and
(15.20) hydroboration-oxidation, for example).
In the molecule 15.21, however, regardless of how one assigns the affinity labels, it is
nO impossible to avoid at least one position in each ring where the same affinity label is on a
e n n pair of adjacent atoms; this molecule is dissonant. Inherently, there are fewer reactions
e
n e that give rise to dissonant products than to consonant products, and most of those are
redox reactions (e.g., epoxidation or hydroxylation, as well as the α-selenylation of a car-
e n e n
bonyl compound).
(15.21) It is often easiest to incorporate the dissonant element into the starting material.
Where this cannot be done, strategies have been devised to accomplish the task of gener-
Figure 15.10 Consonant
(upper) and dissonant ating the dissonant element. One strategy involves the process of affinity reversal, now
(lower) molecules universally referred to by its German name of umpolung.38 In an umpoled synthon, the
normal affinity labels are reversed. The simplest umpoled synthon is cyanide ion, where
the carbon carries the negative charge (and, therefore, the nucleophilic, or n affinity label),
despite being less electronegative than the nitrogen. It is worth noting that all umpoled
synthons have a built-in dissonant relationship.
38. Reviews: (a) Corey, E.J.; Seebach, D. Angew. Chem. Int. Ed. Engl. 1965, 4, 1075. (b) Gröbel, B.-T.; Seebach,
D. Synthesis 1977, 357. (c) Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239. (d) Hassner, A.; Lokanatha Rai,
K.M. In Trost, B.M.; Fleming, I., Eds Comprehensive Organic Synthesis (Pergamon Press: Oxford, 1991), Vol. 1,
p. 541. (e) Smith, A.B., III; Adams, C.M. Acc. Chem. Res. 2004, 37, 365.
Monograph: Hase, T.A. Umpoled Synthons: A Survey of Sources and Uses in Synthesis (John Wiley & Sons:
New York, 1987).

15.4 Applying Retrosynthetic Analysis to a Real Example
It is all well and good to talk about retrosynthetic analysis in the semiabstract terms that we
have used to this point, but let us now move the process forward by examining a real exam-
ple. The hydrocarbon twistane (15.22) is an interesting molecule in that it is a C2 hydrocarbon
composed solely of cyclohexane rings in the skew conformation, which also has the potential
to exist as enantiomers. In this case, the final product has no functional groups, so we have
considerable freedom in how we approach the synthesis. Regardless of how we choose to
proceed, it is clear that the first transform that we apply to the target molecule must be an
FGA transform. There are actually relatively few FGA transforms that will lead to viable pre-
cursors, as shown in Figure 15.11, because the symmetry of the target molecule makes a
number of positions equivalent. In the figure, three different additions of heteroatom-based
functional groups (G) are shown (15.23 to 15.25), as is the inclusion of one unsaturation
equivalent (15.26)—for a total of four potential synthons for this target molecule.
The inclusion of a functional group into the target now places more restrictions on
how we can proceed with the retrosynthetic analysis. Let us now take synthon 15.23 fur-
ther and see how this molecule, which possesses the complete twistane skeleton, can now
be further transformed into an earlier generation synthon. There are two major approaches
to this, depending on whether the group X is attached to the skeleton by a single bond (e.g.,
a cyano group, a sulfoxide, or a sulfide) or a double bond (e.g., a carbonyl group). In any
case, it is now time to apply a ring disconnection transform to the target. Every such dis-
connection will lead to cleavage of one of the six-membered rings of the target. There are
four simple possibilities for doing this, as illustrated in Figure 15.12. In disconnections a
and b, the bond to the carbon carrying the singly bonded functional group is discon-
nected to reveal two different bifunctional synthons, both based on the bicyclo[2.2.2]
octane ring system (15.27 and 15.28). Disconnection c results in a bicyclo[4.4.0]decane
synthon (15.29), whereas disconnection d results in the bicyclo[3.3.1]nonane synthon
(15.30). In all four of these new synthons, stereochemistry now plays an important role
because the new groups (X and Y) must be arranged in a way that will allow the synthetic
reaction to occur. The ring junction in synthon 15.29, for example, must be cis for the
twistane ring system to be formed successfully.
Some chemists can develop a rational retrosynthetic analysis to the starting compounds
without having to check for reasonableness. The author of this book is not one of them. I
G Figure 15.11 Functional
group addition transforms
applied to the twistane target
G molecule
(15.23) (15.25)
(15.22)
G
(15.24) (15.26)

Figure 15.12 Possible bond X X Y

disconnection transforms of Y
X Y
the first-generation Y
synthon 15.23 X
G b
a a b
(15.27) d (15.28)
X d c X X
(15.23)
H
Y
X Y H
Y
Y
(15.30) (15.29)
confess that I tend to become trapped by a certain level of tunnel vision when working in the
retrosynthetic direction, so I find it wise to stop after major transforms to see if what I am
proposing is synthetically reasonable. Let us do that here before we move forward in the ret-
rosynthetic analysis, because it may affect our plans moving forward (or backward) with the
retrosynthesis. At this point, one specifies the various groups in the synthon. For example, if
we assume that group X in synthon 15.29 is oxygen, and group Y is a leaving group of some
sort, we obtain an intermediate such as 15.31. Looking at this target molecule, we see that
there are now at least two problems that we will have to address at some point in the synthe-
sis itself: (1) as a cis-decalin, this molecule is conformationally flexible, so we will have to fix
it in one of the two conformers to get the correct leaving group stereochemistry; and (2) al-
though it is fairly obvious that the twistane ring system will be most easily formed by means
of a ketone alkylation, this means that we have to control which of the two possible enolate
anions are formed or we will have to arrange for the formation of one of the two products to
be strongly favored over the other. These problems do not generally reveal themselves during
the retrosynthetic analysis, so I recommend that you follow the practice of checking regu-
larly in the synthetic direction to see if there are any pitfalls or other problems that you may
have missed. This often leads to a much better retrosynthetic analysis in the end.
H
O OMs O
O OMs
H OMs
(15.31)
Let us now continue with the retrosynthetic analysis starting from synthon 15.29
(Figure 15.13). The one key feature of 15.29 is the cis fusion of the rings, and in the syn-
thetic direction, this strongly suggests that catalytic hydrogenation of an alkene should
be used. By applying an FGA transform to 15.29, we obtain the new synthon 15.32, and
an FGI transform now gives the highly symmetrical synthon 15.33. This type of dicar-
bonyl compound could, in principle, be obtained by reduction of the naphthalene 15.34.
In fact, this is exactly what Deslongchamps did in his synthesis of twistane,39 obtaining
Figure 15.13 Retrosynthesis H
X Y X Y X X X X
of synthon 15.29
H
(15.29) (15.32) (15.33) (15.34)
39. Gauthier, J.; Deslongchamps, P. Can. J. Chem. 1967, 45, 297.

the diketone 15.37 by catalytic hydrogenation of naphthalene-2,7-diol (15.35) and subse-

quent oxidation of the mixture or alcohols (15.36). These early stages of the synthesis
followed earlier work by Anderson and Barlow40 and gave the required diketone, albeit in
relatively low yield.
HO OH H2 (170-60 atm) H H
HO OH CrO3, H2SO4 O O
Ni, 150°C, 5 h H2O
(15.35) (63%) H (43%) H
(15.36) (15.37)
The problem now, of course was to prepare the required ketone, 15.31, which involves
differentiating the two carbonyl groups and reducing one to a particular diastereoisomer
of the alcohol. Deslongchamps’ approach to addressing this problem was to fix the decalin
in one of the two possible conformations. He accomplished this by converting the dike-
tone into the diethyl ketal, which exists as two conformers, 15.38 and 15.39. As is evident
from Figure 15.14, in one of the two conformers (15.38), there is an adverse steric inter-
action between one of the ethoxy groups and the axial α-hydrogen of the ketone. This
means that the other conformer, which lacks this high-energy non-bonded interaction, is
now strongly favored. What then remains is to reduce the carbonyl group to give the equa-
torial alcohol. Here again, however, we cannot use simple hydride reducing agents, be-
cause these will approach the carbonyl group from the less hindered exo face of the
molecule, giving the axial alcohol. A Birch reduction of the ketone, however, gave the
equatorial alcohol (15.40) as the sole product. The two-step conversion of the alcohol to
the mesylate, and mild hydrolysis of the ketal with aqueous oxalic acid in a two-phase
system gave the key ketone 15.31.
The next step of the synthesis is interesting from a practical perspective. The ketone
15.31 has two α-methylene groups, each of which has an acidic axial hydrogen. In order for
the twistane skeleton to be formed, the proton labeled “a” is the one that must be ab-
stracted by the base. Fortunately, this proton is in a less hindered environment that the
proton labeled “b,” and it was found that this proton was removed much faster. Thus,
heating the ketone 15.31 with sodium hydride in dioxane gave rise to a single product, the
twistanone 15.41. The remainder of the synthesis then consisted of the deoxygenation of
this ketone, which was accomplished by the two-step reductive desulfurization shown in
Figure 15.15.
OEt Figure 15.14 Synthesis of the

O O
H OEt key intermediate for
O HC(OEt)3, EtOH O OEt
cyclization to the twistane
–20 to 0°C, 60 min OEt ring system
(65%)
(15.37) (15.38) (15.39)
Li, NH3
(99%)
THF, EtOH
OEt
O
OEt
1) MsCl, py, CH2Cl2, –10°C
MsO HO
2) (CO2H)2, Et2O, H2O
(15.31) (59%) (15.40)
40. Anderson, A.G., Jr.; Barlow, D.O. J. Am. Chem. Soc. 1955, 77, 5165.

Figure 15.15 Completion of b

O
the synthesis of twistane a H
H NaH, dioxane
MsO ∆, 5 h
O
(15.31) (15.41)
(CH2SH)2, BF3•OEt2 (quant.)

HOAc
Ra-Ni, EtOH
∆ S
S
(15.22) (15.42)
Worked Problem
15-2 The retrosynthetic analysis below represents the Martin analysis of tirandamycic
acid, a degradation product of the antibiotic tirandamycin [J. Org. Chem. 1984,
49, 2512].
O
O
O O
O
O O
CO2R
CO2R CHO
FGI
REARR O O CHO
O CHO
OH OH OH
(a) To what class does each of the retrosynthetic transforms belong?

(b) Are all the intermediate compounds in the last bond disconnection specified
explicitly? If not, which are missing?
§Answers on the next page.
Problems
15-3 Place each of the following retrosynthetic transforms into one of the classes de-
fined in Table 15.3 and specify which member of the class the transform is. Give
reasons for your choice where appropriate.
O O
Br
NH
(a) (b)
Br
Br
(c) (d)
O O OH
O O
(e) (f)
O O
Me Br
(g) (h)

O O
Me
Me Me
(i) (j)
Me Br
O O
Me Me
(k) (l)
Ph
15-4 Place each of the transforms in the following retrosynthetic analysis into one of
the classes defined in Table 15.3. The reaction corresponding to transform (c)
occurs on heating with acid.
(a) Write a mechanism for the reaction corresponding to transform (c).
(b) Supply reagents that may be used to complete the synthesis of bicyclo[3.2.1]
octane from anisole through the intermediates shown.
a MeO2C c d e
b OMe OMe
O O MeO2C OMe
15-5 Design retrosynthetic analyses of the molecules below from the specified starting
materials and any other needed reagent(s).
HO
Br
(a) Br Br
H
(continues)

(a) FGI
O DIS
O
O O
O
O O
CO2R
CO2R CHO
FGI
REARR O O CHO
DIS O CHO
OH OH DIS OH
(b) Not all the intermediate compounds are shown. This is a retro-aldol addition transform that corresponds
to an asymmetric aldol addition reaction. This reaction uses the boron enolate of an N-acyloxazolidinone to
form the C—C σ bond, so the reaction product is also an N-acyloxazolidinone. To arrive at the aldehyde spec-
ified requires three more functional group interchange steps.
O
R2BO O
N
EtOLi/EtOH
N O
THF O CO2Et
O CHO O –78°C
O OH
OH O
TBDMS-Cl DIBAL-H
N O CO2Et –90°C O CHO
DMF CH2Cl2
OTBDMS OTBDMS
N
H
The silyl ether is required because the formation of the next bond will involve addition of an oranometallic
compound, which might be compromised by the presence of the alcohol hydroxyl group.

D D
(b) Me CO2 HCCH D2
CO2H
(c) CN
15-6 Assign the affinity labels to each structure in Problems 15-3 and 15-4. Which
of the reactions introduces a dissonant difunctional relationship into a conso-
nant molecule? What type of reaction does this? Can you draw any generaliza-
tions about interconverting consonant and dissonant elements in a synthetic
target?
15.5 Selectivity Revisited
Challenges in the synthesis of complex target compounds are associated with three types
of selectivity.
1. Chemoselectivity, which requires reactions that react preferentially with one of a set
of different functional groups
2. Regioselectivity, which requires reactions capable of selecting between two different
forms or locations of the same functional group or those that will preferentially gen-
erate one of a set of possible regioisomers
3. Stereoselectivity, which requires reactions that will react with the substrate to give
preferentially one of the set of possible stereoisomers. In modern synthesis, this is
often the need to control enantioselectivity.
Chemoselectivity
Chemoselectivity is usually the simplest of these problems to address; oxidation of alde-
hydes, for example, can be carried out in the presence of alcohols by means of reactions
such as the Kraus-Pinnick oxidation.41 Discriminating between identical functional
groups in different environments may also be fairly easy; as early as 1878, Menshutkin had
shown that substrate structure affects reaction rates.42 This can be illustrated by the acetyl-
ation of the three alcohols in Example 15.43. All three compounds carry the same func-
tional group.
OH
(15.43)
OH
H H OH
However, because primary alcohols are readily acetylated with acetic anhydride in
pyridine and tertiary alcohols are not, the selective formation of a primary acetate is usu-
ally quite straightforward in the presence of a tertiary alcohol. In addition, the rate differ-
ences in the esterification of primary and secondary alcohols usually renders selecting
41. (a) Kraus, G.A.; Taschner, M.J. J. Org. Chem. 1980, 45, 1175. (b) Kraus, G.A.; Roth, B. J. Org. Chem. 1980,
45, 4825. (c) Bal, B.S.; Childers, W.E., Jr.; Pinnick, H.W. Tetrahedron 1981, 37, 2091.
42. Menschutkin. N. Rec. Trav. Chim. Pays-Bas 1883, 2, 117. (b) Menschutkin. N. Ber. dtsch. chem. Ges. 1878
1, 1507. (c) Menschutkin, N. Ber. dtsch. chem. Ges. 1878, 11, 2117. (d) Menschutkin, N. Justus Liebigs Ann. Chem.
1879, 197, 193. (e) Menschutkin, N. J. Prakt. Chem. 1882, 26, 103. (f) Menschutkin, N. Justus Liebigs Ann. Chem.
1879, 195, 334.

between these two types possible. Generally speaking, achieving chemoselectivity pres-
ents the least of the problems faced by the synthetic chemist.
Regioselectivity
Protecting Groups43
In contrast to chemoselectivity, regioselectivity is not always so simple to control. The
easiest problems in regioselectivity occur when one is attempting to select between alter-
native positions within the same functional group, such as in the hydration of an alkene:
oxymercuration-demercuration gives the Markovnikov alcohol as the major product,
whereas hydration of the same alkene by hydroboration-oxidation gives the other regio-
isomer as the major product. Regioselectivity becomes much more problematic when one
is attempting to select between functional groups that are identical and in similar envi-
ronments. For example, ask yourself how the transformation in Example 15.44 could be
accomplished.
OH O
(15.44)
OH OH O
The problem here is that the three secondary hydroxyl groups end up as three different
functional groups or structural features in the final product: one is oxidized to a ketone,
one is replaced (with inversion of configuration) by an alkyl group, and one becomes part
of a lactone (with retention of configuration). There is more than one way to accomplish
these transformations selectively, but in order to do so, we need to use protecting groups.
A protecting group is chemically resistant derivative into which a functional group can be
transformed in order to prevent it from reacting. Every protecting group must possess
three fundamental characteristics to be useful.
1. It must be easily incorporated into the molecule without modifying other functional
groups
2. It must not react with reagents that would otherwise react with the functional group
that it modifies
3. It must be removable under conditions that will not affect the other functional groups
of the molecule
Although the goal of total synthesis without the need for protecting groups remains,
the simple fact is that organic synthesis has not yet matured to the point where protecting
groups are unnecessary—indeed, the complexity of modern synthetic targets almost man-
dates their use except in very uncommon cases. Thus, the definitive work on protecting
groups, Greene’s Protective Groups in Organic Synthesis, expanded from 473 pages in the
second edition (1991) to 1082 pages in the fourth (2007) as new protecting groups with
greater selectivity were developed. Like them or not, protecting groups remain an indis-
pensable part of (or necessary evil in) most modern syntheses.
One important concept underlying the use of protecting groups in modern organic
synthesis is the concept of orthogonality. The concept is illustrated in Figure 15.16.
43. Monographs: (a) Wuts, P.G.M.; Greene, T.W. Greene’ Protective Groups in Organic Synthesis; 4th. ed.
(John Wiley & Sons: New York, 2007). (b) Kocienski, P.J. Protecting Groups; 3rd. ed. (Georg Thieme Verlag: New
York, 2005). The initial appearance of this book in 1994 was followed by a series of annual reviews: Jarowicki,
K.; Kocienski, P. Contemp. Org. Synth. 1995, 2, 315; Contemp. Org. Syn. 1996, 3, 397; Contemp. Org. Syn. 1997, 4,
454; J. Chem. Soc., Perkin Trans. 1 1998, 4005; J. Chem. Soc., Perkin Trans. 1 1999, 1589; J. Chem. Soc., Perkin
Trans. 1 2000, 2495; J. Chem. Soc., Perkin Trans. 1 2001, 2109.

Figure 15.16 Orthogonality P3 e
G1 G2 G3 G1 G2 G3
in protection of functional
G4 G4
groups R a R
g
(15.49) (15.46)
P1 P2 P3
G1 G2 G3 P4
d G4
R
f b
(15.45)
P3 P1 P3
G1 G2 G3 P4 c G1 G2 G3 P4
G4 G4
R R
(15.48) (15.47)
A multifunctional molecule is said to have orthogonal protection of its functional groups

if each can be deprotected in turn, without the other functional groups in the molecule
also being deprotected. For example, compound 15.45 has four functional groups—
G1, G2, G3, and G4—that are protected by protecting groups—P1, P2, P3, and P4. In path-
way a, we see that every protecting group is lost in the deprotection step: this would be
an example of non-orthogonal protection of the functional groups. The corollary to this
is represented by the pathway b → c → d → e, where each of the protecting groups is
removed in its own unique deprotection step. Here all the functional groups are pro-
tected orthogonally. Pathways f and g represent situations where more than one of the
functional groups are protected using the same protecting group. In practical terms, it is
extremely difficult to have more than four orthogonally protected functional groups in
one molecule.
Directing Groups
Another strategy for the synthesis of complex target molecules involves the use of direct-
ing groups. Early on, it was recognized that substituents on an aromatic ring influence the
orientation and rate of electrophilic aromatic substitution. In fact, this gave rise to the
practice of deliberately incorporating groups such as amino or nitro groups in order to
influence the orientation and rate of the subsequent electrophilic substitutions.
In later years of the 20th century, this same practice was incorporated into aliphatic
chemistry as groups that could be used to influence the regiochemistry of reactions in
alkenes and similar aliphatic systems were discovered. As in electrophilic aromatic substi-
tution, the use of directing groups has been widespread in carbocation chemistry, where
the directing group can ensure the formation of one regioisomeric alkene from a given
carbocation.
In carbanion chemistry, the directing influences of substituent groups are often most
evident in stabilization of carbanions. However, these groups can often so alter the chem-
istry of the anionic species that the normal reactivity (electrophilic or nucleophilic) of a
particular location is reversed. This charge-type inversion is now known as umpolung.44 It
has become an important part of the toolbox of the synthetic organic chemist because it
allows one to use reagents that are surrogates for species such as carbonyl anions—in
effect, to direct the addition of an electrophile to the carbonyl carbon.
Stereoselectivity
Starting in the middle of the 20th century, increasing attention has been paid to the con-
trol of stereochemistry during a synthesis—to stereoselectivity. The first generation of ste-
reocontrolled syntheses were examples in which diastereoselectivity was the focus. These
44. Reviews: (a) Seebach, D. Angew. Chem. 1969, 81, 690. (b) Gröbel, B.-T.; Seebach, D. Synthesis 1977, 357.
(c) Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239.

e ‡
f d
x ‡
e
‡ f d
x ‡ x x
a c
b
a c c a c a
b b b
ENERGY
ENERGY
X X
a c c a
b b
X
X c
c
c a
a c a b b
a b b
Reaction Coordinate
Reaction Coordinate
Figure 15.17 The reaction of a prochiral substrate with an achiral reagent (left) proceeds through
enantiomeric transition states of equal energy and gives a racemic product. The same reaction in
a chiral environment (e.g., with a chiral reagent or in the presence of a chiral catalyst) proceeds
through diastereoisomeric transition states of different energy and thus gives a product enriched
in one enantiomer.
syntheses invariably led to the synthesis of racemates, but in the best examples of this
type, only one diastereoisomer of the product was obtained. The two necessary prerequi-
sites to being able to complete syntheses at this level were:
1. Developing of a toolkit of stereoselective reactions to use

2. Developing a knowledge of the relationship between conformation and stereochemis-
try, especially in acyclic systems. Woodward’s total synthesis of (±)-reserpine45 re-
mains one of the finest examples of this type of synthesis.
Beginning in the 1970s and gaining momentum after Sharpless’ report of the discov-
ery of the asymmetric epoxidation of allylic alcohols,46 the focus changed to developing
reactions that would control the absolute stereochemistry of the product—enantioselec-
tivity. To achieve good levels of asymmetric induction, it is necessary to arrange for the
two transition states leading to the two enantiomers of the product to be diastereoisomeric
and of substantially different energy (Figure 15.17).
There are three ways in which this can be accomplished, and all involve the interaction
of the prochiral substrate with a chiral entity. In the Sharpless asymmetric epoxidation,
the reaction is catalyzed by a chiral catalyst assembled from the dialkyl tartrate and the
titanium isopropoxide. An alternative approach involves the initial modification of the
prochiral substrate by a chiral auxiliary. This modified substrate, now being chiral, can
react with a non-chiral reagent to give diastereoisomeric products. One of the most suc-
cessful groups of chiral auxiliaries are the chiral oxazolidinones, first developed by Evans
for use in what is now known as the Evans asymmetric aldol addition.47 It is worthwhile
45. (a) Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstad, R.W. J. Am. Chem. Soc. 1956, 78, 2023,
2657; Tetrahedron 1958, 2, 1.
46. Katsuki, T.; Sharpless, K.B. J. Am. Chem. Soc. 1980, 102, 5974.
47. (a) Evans, D.A.; Takacs, J.M.; McGee, L.R.; Ennis, M.D.; Mathre, D.J.; Bartroli, J. Pure Appl. Chem. 1981,
53, 1109. (b) Evans, D.A.; Bartroli, J.; Shih, T.L. J. Am. Chem. Soc. 1981, 103, 2127.

Table 15.5 Protecting Groups for Alcohols noting that more than three decades after
Class Examples
their initial use, the Evans auxiliaries are
still in widespread use (even in reactions
Esters –OAc, –OCOPh, –OCOBut, –OCOCH2CCl3 (Troc), with chiral catalysts). The third motif for
–OCO2But (Boc), –OCO2CH2Ph (Cbz), generating one enantiomer of a chiral prod-
–OCO2CH2CH(o-C6H4)2 (Fmoc) uct from a prochiral precursor involves the
Ethers –OMe, –OCH2Ph, –OCH2C6H4OMe (PMB), –OCPh3 (Tr) use of a chiral reagent. One early example of
this approach was provided by Brown’s
Acetals and ketals –OCH2OMe (MOM), –OCH2OCH2CH2OMe (MEM),
–OCH(Me)OEt, –OCMe2OMe (MOP), –O(C5H9O) (THP), asymmetric hydroboration of cis alkenes
–OCH2OCH2CH2SiMe3 (SEM) with diisopinocampheylborane.48
In the following sections, we will focus
our attention of the role of protecting groups
Table 15.6 Conditions for Removing Protecting Groups from Alcohols
in organic synthesis. We will defer our dis-
cussion of directing groups and stereoselec-
Class Conditions tivity to the next two chapters of this book.
Esters KOH, H2O (base hydrolysis); HCl, H2O (acid hydrolysis);
LiAlH4, Et 2O (reduction); H2, Pd-C (Cbz esters)
15.6 Protection of Alcohols
Ethers BBr3, CH2Cl2; TiCl4, CH2Cl2, –78°C;
Ce4+, EtOH (PMB ethers); H2, Pd-C (benzyl ethers)
The O–H group is acidic, with typical pKa
Acetals and ketals H2SO4, H2O, THF; Bu4NF, THF (SEM ) values varying from a low of 4 to 5 in car-
boxylic acids to a high of 18 to 19 in tertiary
alcohols. As a consequence, this group often
interferes in reactions involving nucleophiles because it is deprotonated by many nucleo-
philic reagents. This can interfere with the ability of the chemist to use particular reagents
during a synthesis. Moreover, proton transfers from oxygen are among the fastest reac-
tions known, so that it is almost impossible to avoid the reaction by attempting to exploit
differences in reaction rates. Consequently, if a basic reagent is used, it is frequently neces-
sary to add excess reagent to allow the initial reaction with the alcohol proton to proceed.
Using a Grignard reagent under these circumstances, for example, requires an additional
equivalent of the reagent to be used, so that the reaction actually proceeds via the magne-
sium alkoxide.
The protection of alcohols always involves the replacement of the acidic hydrogen by a
less reactive surrogate. Prior to the last three decades of the 20th century, a variety of pro-
tecting groups in the form of esters and ethers were used to accomplish the selective pro-
tection of alcohols. A catalogue of widely used protecting groups for alcohols and phenols,
along with their acronyms, is given in Table 15.5, and the common conditions for their
removal are given in Table 15.6.
Esters
Their easy preparation and their (generally) simple removal by acid or base hydrolysis or
ammonolysis has made esters popular as protecting groups for the hydroxyl groups of alco-
hols and phenols, especially in oxidation reactions. Selective formation of esters from pri-
mary alcohols has been accomplished by the use of hindered esters such as the pivalate ester
(Example 15.50). These highly hindered esters also address the susceptibility of simpler
esters such as the acetate or benzoate toward acid or base hydrolysis. Mixed carbonate
esters are sometimes used as protecting groups for alcohols (although carbonic acid deriv-
atives are much more widely used for the protection of amines as carbamates). The three
48. Brown, H.C.; Ramachandran, V. Pure Appl. Chem. 1991, 63, 307.

most commonly used mixed carbonates are the alkyl tert-butyl carbonate (Boc), the alkyl
benzyl carbonate (Cbz), and alkyl 9-fluorenylmethyl carbonate (Fmoc). The Fmoc group
may be cleaved by base by an E1cb elimination pathway using triethylamine in pyridine
(taking advantage of the aromatic character of the fluorenyl anion).
Me3COCl
base O
KOH
R (15.50)
ROH O ROH
LiAlH4, Et2O
Representative conditions for the removal of ester-protecting groups from alcohols are
gathered in Table 15.7. All esters can be cleaved by complex metal hydride reducing agents,
but the use of these reagents is obviously restricted to the cleavage of esters in compounds
without other reducible functional groups. Of the common esters in Table 15.6, the Boc
ester is unique in being cleaved by anhydrous trifluoroacetic acid (TFA), and the Cbz ester
is unique in being cleaved by catalytic hydrogenolysis. As referred to above, the hindered
pivalate ester is resistant to acid or base hydrolysis, but it may be cleaved by reduction
using complex metal hydrides such as lithium triethylborohydride. In general, benzoate
esters react more slowly with nucleophiles than the acetate esters, so it is often possible to
hydrolyze an acetate ester selectively in the presence of a benzoate ester.
Despite their ease of formation and cleavage, esters present one major drawback in
their use as protecting groups: they exhibit a propensity to isomerize by internal migra-
tion of the ester group from one hydroxyl group to another under acid or base conditions.
Such isomerizations compromise the integrity of the protection afforded by the ester
group, which limits their usefulness.
Ethers
Generally, the least reactive derivative of an alcohol or phenol that one can make is a
simple alkyl ether, which ought to make ethers ideal protecting groups for alcohols in a
wide range of reactions. However, ethers are not easily cleaved under mild conditions,
except for certain aryl methyl ethers. This makes the removal of the protecting group
problematic in multifunctional molecules. The simplest method for cleaving simple alkyl
ethers involves treating the ether with boron tribromide in dichloromethane, a reaction
that works especially well for the cleavage of methyl ethers.
The difficulty inherent in using simple ethers to protect alcohols and phenols arises from
the need to use strong Lewis acids for their cleavage, and this spurred the search for ethers
that could be cleaved under milder conditions. One option is the benzyl ether, because the
Table 15.7 Representative Conditions for the Removal of Ester-Protecting Groups
LiEt 3BH,
KOH, H2O RNH2 H2SO4, H2O THF H2, Pd-C TFA
R–OAc R–OH R–OH R–OH R–OH — —

R–OCOPh R–OH R–OH R–OH R–OH — —
R–OCOBut — — — R–OH — —
R–OBoc R–OH R–OH R–OH R–OH — R–OH
R–OCbz R–OH R–OH R–OH R–OH R–OH —
R–OFmoc R–OH R–OH — R–OH — —

benzyl group can be removed by hydrogenolysis over palladium (Example 15.51). In fact,
because this group can be removed under very mild conditions, it has become a very popular
protecting group for alcohols, amines, and amides. A wide range of benzyl ethers, benzyl
esters, and benzylamines is now available commercially. The benzyl group has been espe-
cially widely used in the solid-state synthesis of proteins. The trityl (triphenylmethyl) ether
can be used for the selective protection of primary alcohols in the presence of secondary al-
cohols; it is readily removed in acid or by hydrogenolysis.
PhCH2Br, NaH
OR
ROH (15.51)
H2, Pd-C
The protection of alcohols as ethers that can be cleaved by oxidation is a relatively

modern development, with the p-methoxybenzyl (PMB) ether being the prototypical ex-
ample of this type of protecting group. Cleavage of PMB ethers is accomplished fairly
simply by oxidation with ceric ammonium nitrate (CAN) or 2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone (DDQ) (Example 15.52).
Br
MeO OR
base
ROH (15.52)
CAN, EtOH
OMe
(PMB ether)
Acetals and Ketals

An alternative approach to solving the problem of cleaving the ether under mild condi-
tions has been to use an acetal or ketal as the protecting group. Formaldehyde acetals can
be readily prepared by treatment of the alcohol or phenol with a suitable chloromethyl
ether and a base, and these compounds can then be cleaved by protic acids or Lewis acids
under very mild conditions. Among the formaldehyde acetals used in synthesis, the me-
thoxymethyl (MOM) ether (e.g., Example 15.53) and the (2-methoxyethoxy)methyl
(MEM) ether (e.g., Example 15.54) are probably the most widely used.
MeO O Cl
base O
(15.53)
ROH O OMe
R
HCl, MeOH
(MOM ether)
O Cl
MeO
base O
(15.54)
ROH O
R OMe
TiCl4, CH2Cl2
–78°C (MEM ether)
The cyclic acetals formed by the acid-catalyzed addition of the alcohol to dihydropy-
ran have also been widely used to protect the alcohol. The only disadvantage that these
tetrahydropyranyl (THP) ethers (Example 15.55) have is that their formation involves the
generation of a new chiral center in the molecule, and this often results in mixtures of
diastereoisomers. Nevertheless, the ease of their formation and cleavage, combined with
their robustness in the presence of strong nucleophiles and strong bases, has made them
popular protecting groups. In similar fashion, the addition of the alcohol to ethyl vinyl

Table 15.8 Stability of protecting groups toward various reagents
Conditions→ Aqueous Aqueous Lewis Strong Metal Fluoride Hydrogen, Hydride

Group↓ acid base TFA acid base alkyls anion catalyst reductant Oxidation
—OR a
—OCH2Ar a b c
—OTr d a b
—OCOR e f g h h
—OCbz e f h b h
—OFmoc e f i h b h
—OBoc e f k a h h
—OSiR 3 e f l m
—OMOM e a
—OMEM e a
—OTHP e
—OSEM n
Where no indication is given, one may assume that the group is generally stable under the conditions specified.
a. Susceptible to strong Lewis acids (BBr3, TiCl4, etc.)
b. Susceptible to hydrogenolysis, especially over Pd
c. Electron-rich benzyl ethers can be cleaved by oxidation with reagents such as CAN and DDQ
d. Usually used with trifluoroacetic anhydride
e. Susceptible to acid-catalyzed hydrolysis or alcoholysis
f. Susceptible to base-promoted hydrolysis or alcoholysis
g. Only esters that have an α hydrogen; generally a problematic side reaction in reactions of ester enolates
h. Reduced by complex metal hydrides (LiBH4, LiAlH4, etc.); not generally susceptible to reduction by NaBH4
i. Cleaved by Grignard reagents, alkyllithiums, etc.
j. Cleaved by bases, including tertiary amines; mechanism is E1cb
k. Isobutylene is formed in the E1 elimination of the tert-butyl group
l. Cleaved by alkyllithiums, but not by Grignard reagents
m. Ease of cleavage is slowed by increased steric bulk of the groups on silicon
n. Silyl fluoride and ethylene are formed in this fragmentation by the E1cb or E2 mechanism
ether gives a 1-ethoxyyethyl ether (a mixed acetaldehyde acetal) that can also be cleaved
under mild conditions. Like the THP ether, the preparation of this ether generates a new
chiral center in the molecule. A summary of protecting groups for monohydric alcohols
and their susceptibility to reaction conditions is gathered in Table 15.8.
, TsOH
O
ROH (15.55)
R
H2SO4, H2O O O
H
THF
(THP ether)
1,2- and 1,3-Diols

Ketals are much less widely used as protecting groups for monohydric alcohols, but the
mixed ketals of acetone, formed by acid-catalyzed addition to methyl isopropenyl ether,
known as MEP ethers, have been used. In contrast to the situation with monohydric alco-
hols, ketals are the protecting groups of choice for 1,2- and 1,3-diols. In fact, the acetonides

of 1,2-diols are frequently commercially available. As shown in Example 15.56, their syn-
thesis by ketal exchange is usually straightforward.
Me2C(OMe)2
TsOH
HO O
(15.56)
n n
HO H2SO4, H2O O
THF
The protection of diol components of polyhydric alcohols is an important feature of

carbohydrate chemistry, and the choice of the carbonyl component for the formation of
the protected diol can be critical in determining exactly what protected derivative is
formed. For example, the protection of d-glucose with acetone leads to the formation of
the bis-acetonide where the six-membered pyranose ring of the glucose has contracted
to the five-membered furanose form (Example 15.57), whereas the same reaction with
d-galactose, which also exists predominantly in the six-membered pyranose form, forms
the bis-acetonide where the galactose ring remains in the six-membered pyranose form
(Example 15.58). The same protecting group thus leaves the 3-hydroxyl group free in
d-glucose and the 6-hydroxyl group free in d-galactose. This example also serves as some-
thing of a cautionary tale. Often, exactly which isomeric product will be formed on incor-
porating a particular protecting group must be determined by experiment and cannot
always be easily predicted. One of the general rules to come from the formation of aceton-
ides from 1,2-diols in cyclic systems is the requirement that the two hydroxyl groups be cis
to each other on the ring; the trans diols form a five-membered ring that is too strained.
OH
O OH O H
Me2CO, H2SO4 O
O O (15.57)
HO OH H
HO O
OH
OH
OH
O O
O OH
Me2CO, H2SO4 (15.58)
O
HO OH O
O
OH
Wiesner’s Synthesis of (±)-13-Desoxydelphonine: A Case Study Before

the Widespread Use of Silyl Groups
OH C OH
H OMe OMe
OMe
OMe H OH D
MeO E MeO OH
H OH
(15.59)
Me N H A B
OH N OMe N OMe
Me Me
OMe
OMe OMe F
OMe
One of the most instructive examples of the manipulation of protecting groups in synthe-
sis is provided by the “fourth generation” synthesis of the alkaloid (±)-13-desoxydelpho-
nine (Example 15.59), reported by Canadian chemist Karel Wiesner in 1979.49 This
49. (a) Wiesner, K. Pure Appl. Chem. 1979. 51, 689. (b) Tsai, T.Y.R.; Nambiar, K.P.; Krikorian, D.; Botta, M.;
Marini-Bettole, R.; Wiesner, K. Can. J. Chem. 1979, 57, 2124.

OCHO OMOM OMOM

OMe OMe H
O OMe 1) K2CO3, H2O O OMe 1) LiBH4, THF O OMe (20.63)

2) ClCH2OMe, K2CO3 2) DCC, Me2SO, THF, 30-35°C
AcHN THF-CH2Cl2 AcHN py, CF3CO2H AcHN (87%)
O Ph O Ph (87%) O Ph
(15.60) (89%) (15.61) (15.62)
OMOM OMOM
OH OAc OMOM
H2, Pd-C OAc
OMe OMe Ac2O, py OMe OMe MeOH CrO3•2py
OMe OMe
(95%) (quant.) CH2Cl2
AcHN AcHN
O O Ph O O Ph AcHN
OH OH
Ph Ph
(15.64) (15.65) (15.66)
OMOM OMOM
OAc OH
K2CO3
MeOH, ∆ Ph O
OMe OMe OMe
(89%) MgBr
MeO
AcHN HN
O O O (15.63)
MeO Ac
(15.67) (15.68)
Figure 15.18 The use of protecting groups in Wiesner’s synthesis of 13-desoxydelphonine
molecule contains a hexacyclic skeleton (rings A–F) adorned with 13 chiral centers (al-
though only 4 are independent of the requirements imposed by the hexacyclic skeleton).
The complete synthesis, which is well worth reading as an example of strategy in synthesis,
required over 50 steps. Here, let us examine the use of protecting groups in a middle sec-
tion of the sequence. Because this synthesis was carried out shortly before the rise of silyl
ether protecting groups, it provides a “state of the art” view of the use of non-silyl protect-
ing groups. The sequence in Figure 15.18 involves the protection of functional groups
during the construction of the precursor containing the progenitors of the A, B, E, and F
rings of the polycyclic framework of the target molecule.
In the first step of the sequence, the formate ester 15.60 (obtained by the Dakin oxida-
tion50 of the aromatic aldehyde) is selectively hydrolyzed with aqueous potassium carbon-
ate. Neither the methyl ester nor the amide is hydrolyzed by this reagent, illustrating the
greater reactivity of the formate ester toward hydrolysis. The phenol that is revealed is
converted to the MOM ether 15.61, which renders the phenol resistant to nucleophilic and
basic reagents before the methyl ester is reduced with lithium borohydride to the corre-
sponding primary alcohol. Lithium aluminum hydride cannot be used here because it
would also reduce the amide functional group, whereas sodium borohydride does not
reduce esters. The benzyl ether is resistant to the subsequent Moffatt oxidation51 of the al-
cohol to give the aldehyde 15.62.
The next reagent in the sequence (15.63) is an interesting one in its own right, because
a Grignard reagent nucleophile was required that carried the MOM group of the final
50. (a) Dakin, H.D. Am. Chem. J. 1909, 42, 477. (b) Dakin, H.D. Organic Syntheses. 1923, 3, 28. For recent
examples, see: (c) Bernini, R.; Coratti, A.; Provenzano, G.; Fabrizi, G.; Tofani, D. Tetrahedron, 2005, 61, 1821.
(d) Varma, R.S.; Naicker, K.P. Org. Lett., 1999, 1, 189. (e) Alamgir, M.; Mitchell, P.S.R.; Bowyer, P.K.; Kumar, N.;
Black, D.St.C. Tetrahedron 2008, 64, 7136.
51. Reviews: (a) Moffatt, J.G. In Augustine, R.L.; Trecker, D.J., Eds. Oxidation (Dekker: New York, 1971), vol.
2, 1. (b) Tidwell, T.T. Org. React. 1990, 39, 297. (c) Lee, T.V. Comp. Org. Syn. 1991, 7, 291.

product and a group that could be converted to a ketone carbonyl group at a later stage in
the synthesis. The benzyl ether served this latter purpose. When the Grignard addition is
complete, the product (15.64) has two benzyl ethers that can be deprotected at the same
time to give the diol 15.66. The new hydroxyl group generated by the Grignard addition
needed to be protected because the next major step in the sequence involved oxidation of
15.66 to give the diketone (15.67) required for the intramolecular aldol condensation. This
protection was accomplished by conversion to the acetate ester, which is resistant both to
the hydrogenation conditions needed to remove the benzyl groups, and to oxidation using
Collins reagent.52 Note how in Wiesner’s strategy, the two carbons needed for the intramo-
lecular aldol condensation to give the enone 15.68 are both protected as benzyl ethers in
15.65 so that they can be removed under conditions that do not compromise the integrity
of any other protected hydroxyl group.
Silyl Ethers
Since the 1970s, silyl ethers have become by far the most common groups used for the
protection of alcohols. In part, this is because of the ability to fine-tune the reactivity of
the silyl ether by simply varying the size of the substituent groups on silicon. The range of
commonly used silyl ethers for the protection of alcohols is given in Table 15.9, along with
their relative reactivities in acidic and basic media. It is worthwhile noting that although
larger alkyl groups on silicon do confer increased stability on the silyl ether toward acids
and bases due to their steric bulk, the same steric bulk also makes the ethers more difficult
to form. This has partly been overcome by means of the use of the more reactive silyl tri-
flates, as shown in Table 15.9.53 Similar data (in the form of reaction half-lives) is available
for the acid- and base-promoted methanolysis of n-hexyl silyl ethers54 and n-hexyl silyloxy
ethers.55
Silyl ethers are formed by treating an alcohol with a silyl chloride or silylamine and a
base. The rates of formation of the silyl ether and the ease of recovery of the hydroxyl group
Table 15.9 Relative Stabilities of Silyl Ether-Protecting Groups
Silyl Ether Introduction In Acid In Base
R–OSiMe3
Me3SiCl, imidazole, DMF 1 1
(R–OTMS)
R–OSiEt 3
Et 3SiCl, imidazole, DMF 64 10–100
(R–OTES)
R–OSiMe2But ButSiMe2Cl, imidazole, DMF
R–OTBS ButSiMe2OTf, 2,6-lutidine, CH2Cl2 2 × 104 2 × 104
R–OSi(Pri)3 (i-Pr)3SiCl, imidazole, DMF

R–OTIPS (i-Pr)3SiOTf, 2,6-lutidine, CH2Cl2 7 × 105 1 × 105
R–OSi(Ph)2But
t-Bu(Ph)2SiCl, imidazole, DMF 2 × 104 5 × 106
R–OTBDPS
52. (a) Collins, J.C.; Hess, W.W.; Frank, F.J. Tetrahedron Lett. 1968, 9, 3363. (b) Collins, J.C.; Hess, W.W. Org.
Synth. 1988, Coll. Vol. 6, 644. (c) Ratcliffe, R.; Rodehorst, R. J. Org. Chem. 1970, 35, 4000.
53. Wuts, P.G.M.; Greene, T.W. Greene’s Protective Groups in Organic Synthesis, 4th ed. (Wiley-Interscience:
New York, 2007).
54. Davies, J.S.; Higginbotham, L.C.L.; Tremeer, E.J.; Brown, C.; Threadgold, R.S. J. Chem. Soc., Perkin Trans.
1 1992, 3043.
55. Gillard, J.W.; Fortin, R.; Motron, H.W.; Yiakim, C.; Quesnelle, C.A.; Daignault, S.; Guindon, Y. J. Org.
Chem. 1988, 53, 2602.

from the silyl ether both depend on the alkyl groups on silicon. Trimethylsilyl ethers are
formed readily from all alcohols by treating the alcohol with trimethylsilyl chloride and a
base such as triethylamine, imidazole, or hexamethyldisilazane (Me3SiNHSiMe3), and they
are cleanly hydrolyzed by dilute aqueous acid or base. They are the most labile of the silyl
ethers.
Following their initial use for enols reported by Stork 56 and the use of imidazole in
DMF as the base catalyst during their introduction,57 the tert-butyldimethylsilyl (TBDMS)
ethers have become extremely popular as protecting groups for alcohols due to their en-
hanced resistance to aqueous hydrolysis.58 The TBDMS group has the added advantage
that the steric hindrance around the silicon permits the selective silylation of primary al-
cohols with TBDMS chloride in the presence secondary alcohols59 or the selective silyla-
tion of the less hindered of two hydroxyl groups. In fact, one of the most important
advantages of silyl ethers is the way that they can be used for the selective protection and
deprotection of the less hindered hydroxyl groups in polyhydric alcohols.
TBDMS ethers are resistant to hydrolysis by aqueous acids or bases, but the free alco-
hol can be recovered from the silyl ether by treatment with fluoride ion (the formation of
the strong silicon-fluorine bond probably provides the driving force for this reaction). Like
protection of hydroxyl groups as TBDMS ethers, deprotection of the least hindered hy-
droxyl group usually occurs most rapidly. For example, in compound 15.69 it is the
TBDMS ether group flanked by only one branched chain (a) that is cleaved to give the
monosilyl ether 15.70; the silyl ether flanked by two branched chains (b) is not.60
OTBDMS OH
O O
O O
O H TBAF, THF O H
O H N3 r.t. O H N3
TBDMSO (90%) TBDMSO
MeO2C MeO2C
(15.69) (15.70)
An excellent model for the modern use of protecting groups for alcohols is provided by
part of the synthetic sequence used in the early stages of Hashimoto’s total synthesis of
zaragozic acids A and C (Figure 15.19).61 This sequence begins with a protected d-erythronic
acid derivative. The three alcohol groups of the erythronic acid skeleton must eventually be
converted into three different moieties, which means that they must be differentially pro-
tected from an early stage in the synthesis.
OH
HO2C OH
OH
D-erythronic acid
The starting compound for the sequence is the ester 15.71, in which the terminal
diol is protected as the acetonide. Protection of the remaining hydroxyl group as the
56. Stork, G.; Hudrlik, P.F. J. Am. Chem. Soc. 1968, 90, 4462. See also: (b) Lalonde, M.; Chan, T.H. Synthesis
1985, 817.
57. Corey, E.J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
58. For a discussion of the unusual stability of tert-butylmethylsilyl compounds, see: Sommer, L.H.; Tyler,
L.J. J. Am. Chem. Soc. 1954, 76, 1030.
59. (a) Ogilvie, K.K.; Shifman, A.L.; Penney, C.L. Can. J. Chem. 1979, 57, 2230. (b) Kinzy, W.; Schmidt, R.R.
Liebigs Ann. Chem. 1987, 407.
60. Nakaba, T.; Fukui, M.; Oishi, T. Tetrahedron Lett. 1988, 29, 2219, 2223.
61. Hirata, Y.; Nakamura, S.; Watanabe, N.; Kataoka, O.; Kurosaki, T.; Anada, M.; Kitagaki, S.; Shiro, M.;
Hashimoto, S. Chem. Eur. J. 2006, 12, 8898.

CCl3
O
MeO NH OH
H O H O 10% HCl, H2O
MeO2C OH
TBDPSCl
MeO2C O MeO2C O
imidazole
Ph3CBF4, Et2O, 0°C THF
OMPM CH2Cl2
OH (93%) OMPM (90%)
(86%)
(15.71) (15.72) (15.73)
CO2H O O
OH OMOM O OMOM DDQ, CH2Cl2 O OMOM

MeO2C OTBDPS MeO2C OTBDPS MeO2C OTBDPS
EDCI, DMAP phosphate
OMPM CH2Cl2 OMPM buffer OH
pH 7
(80%)
(15.74) (15.75) (99%) (15.76)
O O
DMP O OMOM N2 CO2Et N2 O OMOM (Me3Si)2NH

CH2Cl2 MeO2C OTBDPS LiHMDS, THF OTBDPS imidazole
EtO2C THF
(97%) –78°C
O HO CO2Me
(70%)
(15.77) (15.78)
N2 O OMOM
OTBDPS
EtO2C
TMSO CO2Me
(15.79)
Figure 15.19 Sequence from Hashimoto’s synthesis of the zaragozic acids
p-methoxybenzyl ether (or p-methoxyphenylmethyl, or MPM, ether) gave the ester (15.72).
Unlike ester or silyl ether protecting groups, the MPM ether does not migrate under acid
or base conditions. Hydrolysis of the acetonide gave the terminal diol (15.73), which was
selectively monoprotected as the tert-butyldiphenylsilyl (TBDPS) ether. Like the TBDMS
ether, the TBDPS ether of a primary alcohol can be formed selectively in the presence of a
secondary hydroxyl group. This alcohol (15.74) now has only a single hydroxyl group left,
so the chemical differentiation of the three hydroxyl groups is now accomplished, allow-
ing their straightforward, selective transformation. Esterification of the free hydroxyl
group of 15.74 with MOM-protected 3-hydroxypropanoic acid gave the ester 15.75, which
was next selectively deprotected with DDQ to give the α-hydroxyester 15.76. Oxidation of
the revealed alcohol with the Dess-Martin periodinane gave the α-ketoester 15.77, which
was then treated with the conjugate base of ethyl α-diazoacetate to give the addition prod-
uct 15.78 as a mixture of diastereoisomers. Protection of the new hydroxyl group as the
trimethylsilyl ether completed this part of the synthesis. Note how, in this densely func-
tionalized molecule, all the alcohol hydroxyl groups are protected differently, and all three
esters are also different.
Problems
15-7 What will be the major organic product formed when the alcohol below is treated
with the reagents in the list below it? Unless otherwise specified, assume that the
amount of the reagent is sufficient to react with all the hydroxyl groups that will
react with it.

OH OH
OH
(a) Ac2O, py
(b) TBDMSCl (1 eq), imidazole, DMF
(c) NaH, PhCH2Br
(d) Ph3CBr, py
(e) (1) TBDMSCl (2 eq), imidazole, DMF; (2) AcCl, PhNMe2; (3) TBAF, THF
(f) (1) Ph3CBr, py; (2) PMBCl, NaH; (3) DHP, TsOH; 4) DDQ
(g) Me3COCl, py, DMAP
(h) (1) TBDMSCl (2 eq.), imidazole, DMF; (2) TBAF (1 eq), THF
(i) MOMCl, K 2CO3, THF
(j) (1) TBDMSCl (1 eq), imidazole, DMF; (2) MEM-Cl, K 2CO3, MeCN; (3) TBAF,
THF
15-8 When acyclic 1,2,3-triols are protected as the acetone ketals (acetonides), the
major product is almost always has a five-membered ring, and when benzalde-
hyde is used, the ring is usually six-membered. Suggest a reason why this should
be the case.
15-9 Provide a reasonable rationalization for the observation that the acetonides of
d-mannose and d-glucose are constitutional isomers, as shown, and not simply
stereoisomers of each other.
O O
HO O HO
HO HO O
H H H H
HO O
HO O HO O O O
HO OH O O HO OH O OH
D-glucose D-mannose
15-10 Provide the missing reagents from the following synthesis of citreoviral (J. Org.
Chem. 1987, 52, 5067). Note that more than one step may be required for each
transformation.
Ph
Ph Ph MEMO
a b MEMO O I2 O c
O MEMO O
O NaHCO3 HO
HO
I
MEMO MEMO
O d MEMO e MEMO f
O O O
PhCO2 PhCO2
PhCO2 PhCO2
CHO
I
CO2Et
HO HO HO
O O O
g h i
PhCO2 HO HO
CO2Et OH CHO

Reaction Synopses
Protecting Groups for Alcohols
O
R' R OH R'
R OH
R O R O
Alkyl Ethers
Formation: RX, base; R=Me, PhCH2, p-MeOC6H4CH2; etc.
Cleavage: BBr3, CH2Cl2; H2, Pd-C (allyl, benzyl); DDQ, CAN (PMB
ethers); HCO2H (trityl ethers)
Silyl Ethers
Formation: R 3SiX, EtN(i-Pr)2; X=Cl, OTf
Cleavage: TBAF, THF; etc.
Acetals/Ketals
Formation: ROCH2-Cl, base; R=Me, Me(OCH2CH2)2, DHP, TsOH; etc.
Cleavage: H3O+; TiCl4, CH2Cl2, etc.
Carboxylic Esters
Formation: Ac2O, Py; Me3COCl, py; PhCOCl, KOH, H2O; etc.
Cleavage: K 2CO3, MeOH; NaOH, H2O, THF; NH3, H2O; etc.
Mixed Carbonate Esters
Formation: Boc2O, Py; CbzCl, Py, etc.
Cleavage: TFA (Boc); H2Pd-C (Cbz); etc.
15.7 Protection of Aldehydes, Ketones, and Carboxylic Acids
The carbonyl group is arguably the most versatile functional group in organic synthesis. A
quick examination of the preceding 10 chapters of this book will reveal that more than half
the reactions discussed involve carbonyl compounds as reactants, reagents, or products.
Of course, this very reactivity presents a problem, and the protection of carbonyl groups
has long been an important facet of multistep syntheses.
Protection of Aldehydes and Ketones

Acetals and Ketals
The simplest and most widely used protecting groups for aldehydes and ketones are the
acetals and ketals. Although acetals and ketals derived from simple monohydric alcohols
can be prepared and used, the corresponding compounds prepared from ethylene or pro-
pylene glycol derivatives are by far the most widely used.
The preparation of acetals is easier than the preparation of ketals, as should be expected
given the difference in reactivity between the carbonyl precursors toward nucleophiles. Thus,
the conversion of aldehydes to dialkyl acetals is usually straightforwardly accomplished by
heating the aldehyde and the alcohol in the presence of an acid catalyst (e.g., Example 15.80).
When the alcohol is something other than methanol, provision must usually be made to remove
the water formed in the equilibrium reaction either azeotropically or by means of a water scav-
enger. As the steric requirements of the alcohol and the carbonyl compound increase, the equi-
librium for the formation of an acetal, and more so a ketal, becomes much less favorable.
CHO MeO OMe
H H
MeOH, HCl
(15.80)
AcO (60%) AcO

OMe
O
H
O R OMe
(MeO)3CH, TsOH (15.81)
MeOH, 3-5 d
OMe
(70-80%)
R
OMe
OMe
OMe
OMe
(15.82)
A more general method for preparing dialkyl acetals and ketals is to treat the carbonyl
compound with the trialkyl orthoformate (Example 15.81)62 or with the alcohol and
2,2-dimethoxypropane63 (Example 15.83) in the presence of an acid catalyst, which may be
a Lewis acid catalyst. In these reactions, the orthoformate or the acetone ketal functions as
the water scavenger. These two reactions also illustrate another property of the ketaliza-
tion reaction. The reaction in Example 15.81 is believed to proceed through the enol ether
15.82, which accounts for the observation that both isomers of the diketone give the same
cis-decalin derivative. Changing the alcohol in Example 15.83 to isopropyl alcohol leads to
exclusive formation of the enol ether 15.84.
PrOH, Me2C(OMe)2 OPr
(15.83)
TsOH, hexane, ∆
OPr
O
i-PrOH, Me2C(OMe)2
O-i-Pr (15.84)
TsOH, hexane, ∆
The replacement of open-chain alcohols by 1,2- or 1,3-diols has a dramatic effect on the
position of the equilibrium for the formation of ketals from ketones. In part, this can be
traced to the effects of entropy. In the conversion of a ketone to a dialkyl ketal (Example
15.85), three molecules are converted to two, resulting in ∆S < 0 for the reaction. This leads
to an algebraic increase in the value of ∆G°, and a reduction in the value of Keq for the re-
action. When a diol is used to form a cyclic ketal (Example 15.86), the entropy change is
much smaller and is due mainly to the loss of conformational freedom in the alkyl chain
between the hydroxyl groups.
R R
OR'
O + 2 ROH + H2O ∆Sreact<0
OR'
R R
(15.85)
R R
HO O
O + + H2O ∆Sreact 0
HO O
R R
(15.86)
Problem
15-11 The formation of the cis-diketal in Example 15.89 may be rationalized in terms of
both kinetic control and thermodynamic control. Which model gives the stron-
ger rationalization and why?
62. Wijnberg, J.B.P.A.; Kesselmans, R.P.W.; de Groot, A. Tetrahedron Lett. 1986, 27, 2415
63. Rigby, H.L.; Lewis, D.E. Synth. Commun. 1993, 23, 993.

Table 15.10 Relatives rates for Hydrolysis of Cyclic Ketals by 0.003 M HCl in Dioxane-Water (70:30)
Ketal Rate Ketal Rate Ketal Rate
Me
O O
O
1 13.0 8.02
O O
O
Me
O O
O
30.6 172 259
O O
O
Me Me
O
O O
2.01 16.5 23.0
O
O O
Me
O O
O
0.888 7.65 11.3
O O
O
Me
O O O
0.335 2.67 3.28
O O O
The rate of acid hydrolysis of ketals is strongly affected by the nature of the substituents
on the ketal carbon64 and in cyclic ketals by the size of the ring.65 These effects are summa-
rized in Table 15.10. From the data in the table, a number of generalizations can be drawn:
1. Cyclohexanone ketals are generally more resistant to hydrolysis than the correspond-
ing cyclopentanone ketals.
2. 1,3-Dioxanes are more readily hydrolyzed than 1,3-dioxolanes.
3. Substitution at the α carbon of the ketone increases the rate of ketal hydrolysis.
4. 5,5-Dialkyl-1,3-dioxanes are more resistant to hydrolysis than simple 1,3-dioxanes,
and the larger the substituents at the 5- position, the more stable the dioxane toward
acid hydrolysis.
Table 15.11 Relative Rate Constants (L mol−1 s−1) for the Acid- Not surprisingly, given how much more reactive alde-
Catalyzed Hydrolysis of 1,3-Dioxolane and its Derivatives at 25°C hydes are toward nucleophiles than ketones, the acetals
are generally more stable toward hydrolysis than the
Dioxolane k Dioxolane k Dioxolane k
structurally similar ketals. Thus, the rate constants for the
O O O hydrolysis of acetals are significantly lower than the rate
1 5130 54,300 constants for the hydrolysis of structurally similar ketals,
O O O
as is illustrated by the rate constants for the dioxolanes in
O O
7540* O Table 15.11.66 These data show that (1) acetaldehyde acetals
1.52 55,100
O O 1910† O hydrolyze more than two orders of magnitude faster than
the corresponding formaldehyde acetals and that (2) the
O O acetone ketals hydrolyze another order of magnitude or
0.223 713
O O more faster still. The same generalizations about the ef-
fects of ring size and substitution pattern in acetals can be
*cis isomer. made as were drawn for ketals: in general, 1,3-dioxolanes
†
trans isomer. are more resistant to hydrolysis than are 1,3-dioxanes.
64. Satchell, D.P.N.; Satchell, R.S. Chem. Soc. Rev. 19990, 19, 55.
65. (a) Newman, M.S.; Harper, R.J., Jr. J. Am. Chem. Soc. 1958, 80, 6350. (b) Smith, S.W.; Newman, M.S. J. Am.
Chem. Soc. 1968, 90, 1249, 1253.
66. Salomaa, P.; Kankaanperä, A. Acta Chem. Scand. 1961, 15, 871.

As the most widely used derivatives for the protection of ketones, the 1,3-dioxolanes
have received a huge amount of attention in regard to both formation and hydrolysis. In
compounds with two saturated carbonyl groups, the less hindered is preferentially pro-
tected with ethylene glycol and an acid catalyst, as illustrated by Example 15.87.67 When one
of the two carbonyl groups is conjugated, the non-conjugated carbonyl group is selectively
protected, as illustrated by Example 15.88;68 the formation of dioxolanes from α,β-unsatu-
rated ketones is often accompanied by migration of the double bond into the β,γ-position,
as shown in Example 15.89.69 The use of a weaker acid catalyst (e.g., oxalic acid) results in
substantially less double bond migration during ketal formation.
O H O O HO
O
(CH2OH)2, C6H6
(15.87)
TsOH, 80°C
H H
O O
(CH2OH)2, TsOH
(15.88)
r.t. 23 min O
O (93%) O
(CH2OH)2, TsOH
O (15.89)
O O
Dithioacetals and Dithioketals70

The dithioacetals and dithioketals are more robust toward aqueous acids than the corre-
sponding acetals and ketals, which makes these protecting groups useful for the protection of
aldehydes and ketones in these circumstances. The dithioketals are most commonly formed
by the reaction between a dithiol and the carbonyl compound in the presence of a Lewis acid,
as illustrated by reaction 15.90, which is one step in Isobe’s synthesis of the BCDE fragment of
ciguatoxin 1B.71 In a subsequent paper,72 the BF3 etherate was replaced by zinc triflate.
SH
O O , BF3•Et2O S S O
SH
Me O O Me
O O IO CH2Cl2 O O O O IO
O O
SiEt3 SiEt3
Ph (90%) Ph
Ph Ph
(15.90)
The traditional methods for the removal of dithioketal and dithioacetal protecting
groups require the use of mercury and cadmium compounds, but these methods are now
generally avoided on environmental grounds. Instead, strategies for removal of the func-
tional group now focus on oxidation or alkylation to generate sulfonium or sulfoxide spe-
cies that are more easily hydrolyzed by dilute acid or base. The limitations of many of these
reagents were exposed by the attempted deprotection of the dithiane in Example 15.91.73
Although the desired product was obtained only in low yield and as part of complex mix-
tures using oxidative and alkylation methods, it could be obtained pure, albeit still in low
yield, by means of mercuric perchlorate.
67. Crimmins, M.T.; DeLoach, J.A. J. Am. Chem. Soc. 1986, 108, 800.
68. Ciceri, P.; Demnitz, F.W.J. Tetrahdedron Lett. 1997, 38, 389.
69. de Leeuw, J.W.; de Waard, E.R.; Beetz, T.; Huisman, H.O. Rec. Trav. Chim. Pays-Bas 1973, 92, 1047.
70. For an extensive review of dithiane chemistry, see: Yus, M.; Nájera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147.
71. Kira, K.; Isobe, M. Tetrahedron Lett. 2001, 42, 2821.
72. Kira, K.; Hamajima, A.; Isobe, M. Tetrahedron 2002, 58, 1875.
73. Ishihara, J.; Murai, A. Synlett 1996, 363.

OMOM OMOM
S S S S
O O
O H H H O H H
OMPM OTBS
H O O H O O
H
MOMO MOMO TES
(18%) Hg(ClO4)2, CaCO3 (90%) I2, NaHCO3

THF-H2O, –15°C, 15 min Me2CO-H2O, 0°C, 15 m
OMOM OMOM
O O
O O
O H H H O H H
OMPM OTBS
H O O H O O
H
MOMO MOMO TES

(15.91) (15.92)
Based on their analysis of a range of failed reactions, the authors reasoned that the
oxygen atom at position 4 was interfering with the deprotection. They were right. By carrying
out the deprotection on the seco compound where this oxygen atom is part of an enol ether,
essentially the same deprotection was accomplished in much higher yield with iodine under
mildly basic conditions (Example 15.92). This pair of reactions also demonstrates one of the
frustrations in using protecting groups—often the correct protecting group must be deter-
mined in a rather more empirical fashion than the chemist would prefer.
Worked Problem
15-3 Design a reasonable sequence to accomplish the transformation in Example 15.44.
OH O
(15.44)
OH OH O
§Answer below.

The three hydroxyl groups in this molecule (2,9-dimethyldecane-2,4,8-triol), must be differentially pro-
tected during the sequence. The transformations involve the oxidation of the hydroxyl group at C-8, the dis-
placement of the hydroxyl group at C-4 by an acetate enolate equivalent, with inversion of configuration, and
the lactonization of the hydroxyl group at C-2. One possible approach to this problem is suggested below:
OH OH O
Me2C(OMe)2 (COCl)2, Me2SO
TsOH Et3N, CH2Cl2, –60°C
OH OH O O O O
A B C
H2SO4 O TBDMSCl (CO2H)2

H2O imidazole H2O
THF O OH DMF O OTBS THF
OH OH OH OTBS
D E F
HS(CH2)3SH TsCl, py CH2(CO2Me)2

S S S S
O OTBS BF3 DBU, CH2Cl2
OH H OH OTBS I OTs OTBS
G
O
S S S S
TBAF 1) H2SO4, H2O, ∆
2) MeI, MeCN-H2O O
OTBS O
MeO2C L
MeO2C
CO2Me O
O
J K
(continues)

Problems
15-12 Provide the missing reagents from the following steps in the synthesis of pleu-
romutilin (Angew. Chem. Int. Ed. 2009, 48, 9315). Note that more than one step
may be required for each transformation.
OTBS OH OH OH O O
Me Me Me Me
MeO2C a MeO2C b c
TBSO HO HO TBSO
O O O
Me O Me O Me O Me O
15-13 (a) The selective hydrolyses below, described in the same paper, have been re-
ported to give the same outcome. Provide a reasonable rationalization for the
fact that only one of the two acetonide groups is hydrolyzed in aqueous acetic
acid. Your response should also provide a reason why each acetonide group is
either susceptible to or resistant to hydrolysis under these conditions.
H O O H O O
O HO
HOAc, H2O
O H O HO O
R1 R R1 R
2 2
A: R1 = OCH2Ph; R2 = CH2OCH2Ph
B: R1 = CH2OCH2Ph; R2 = OCH2Ph
References: A: J. Org. Chem. 2008, 73, 1234; B: Eur. J. Org. Chem. 2008, 5715.
(b) Provide reagents to carry out each of the following transformations, which

were used in a synthesis of the marine toxin, tetrodotoxin (J. Org. Chem.
2008, 73, 1234).
Ph PhS PhS
Ph HO OH O2N SPh O2 N SPh
O O
O O
a O HO OH b O OMOM
O
O H O
H Ph O
Ph PhS HO O O
PhS O O
SPh NO2 SPh NO2 Ph Ph
Ph Ph
PhS SPh OTBDPS OTBDPS OTBDPS
O2N OMOM O2N OMOM O OMOM O OMOM

c d O
O O O O O O O O O O
O O O O O
Ph Ph Ph Ph Ph Ph
§ Answer to Worked Problem (Continued)

This process begins with protection of the 2,4-diol as the acetonide B, and this is followed by Swern oxida-
tion of the C-8 hydroxyl group to give the ketone C. Hydrolysis of the acetonide should lead to formation of the
cyclic hemiketal E as a mixture of anomers. Conversion of E to the bis-TBS ether F should be accomplished with
TBS chloride and imidazole in DMF—anhydrous acidic conditions should be avoided to prevent the formation
of the bicyclic ketal M, shown below. Mild acid hydrolysis of F should give a hemiketal, G, which could be con-
verted to the dithioketal H; it is possible that the treatment of F itself with propanedithiol and BF3 could lead
directly to H. Conversion of H to the tosylate I would be followed by SN2 displacement with the anion of di-
methylmalonate to give the diester J. The deprotection of the TBS ether in J should be accompanied by intra-
molecular transesterification to give lactone K; ester hydrolysis and decarboxylation, followed by hydrolysis of
the dithiane should complete the synthesis of the desired target L.
O
H
O O
D OH OH M

Carboxylic Acids
Esters
The acidic hydrogen of carboxylic acids is capable of interfering with a wide range of reac-
tions involving nucleophiles, and so the protection of the acid as an ester is often carried
out as a matter of course in syntheses. Although this does prevent the carboxylic acid
acting as a proton donor, it generally does not protect against reactions where the carbonyl
group is the electrophile.
The simplest esters to form are the methyl esters, which are conveniently prepared
under very mild by treatment of the carboxylic acid with diazomethane (e.g., Example
15.93). The fact that few hydroxyl groups interfere with this reaction (certain phenolic
hydroxyl groups are converted to their methyl ethers) makes it especially suitable for use
with sensitive substrates. A mild alternative to using diazomethane that can be applied to
the synthesis of esters other than methyl involves the treatment of the acid with a carbo-
diimide, and the subsequent decomposition of the N-acylisourea with the alcohol. Al-
though this reaction is not widely used in the synthesis of esters, it has become a mainstay
of solid-phase peptide synthesis, where it is applied to the formation of amides.
Boc CO2H Boc CO2Me
N CH2N2, Et2O N (15.93)
OH OH
Much of the driving force for developing esters for the protection of acids has been
O provided by the need for deprotection under mild conditions: tert-butyl esters are depro-
R tected under acidic conditions,74 whereas 9-fluorenylmethyl (Fm) esters (Example 15.94)
O
(15.94) are relatively stable to acid but cleaved by diethylamine or piperidine.75 One interesting
method for the cleavage of allyl esters is the Tsuji-Trost allylation of dimedone.76 Also,
p-methoxybenzyl esters can be deprotected by oxidation with CAN or DDQ or by hydrog-
enolysis over palladium, similar to the ethers.
1,3-Oxazolines
The 2-substituted-1,3-oxazoline ring system is a functional group in which the carboxylic
acid group is present in a masked form. In both systems, the carbonyl and hydroxyl reac-
tivity of the carboxylic acid is suppressed. Beginning around 1970, these compounds were
developed as useful carboxylic acid surrogates in the formation of carbon-carbon bonds.
Unlike esters, these compounds are resistant to the attack of Grignard reagents or lithium
aluminum hydride (25°C, 2 hr), which makes them ideal reagents for the protection of the
carboxyl functionality in the presence of strong nucleophiles. These derivatives can be
formed directly from carboxylic acids77 or acid chlorides78 and can be converted back to
R
the carboxylic acid under relatively mild conditions.
Relatively early in the development of 1,3-oxazolines as useful surrogates for carboxylic
N O
(15.95) acids, the synthetic potential of chiral oxazolines in synthesis was realized. The 1,3-oxazolines
Ph derived from (1S,2S)-1-phenyl-2-aminopropane-1,3-diol (e.g., Example 15.95) have been espe-
OMe cially successful chiral carboxylic acid surrogates in this regard.79
74. (a) Anderson, G.W.; Callahan, F.M. J. Am. Chem. Soc. 1960, 82, 3359. (b) Chandrasekaran, S.; Kluge, A.F.;
Edwards, J.A. J. Org. Chem. 1977, 42, 3972. (c) Bryan, D.B.; Hall, R.F.; Holden, K.G.; Huffman, W.F.; Gleason,
J.G. J. Am. Chem. Soc. 1977, 99, 2353.
75. Kessler, H.; Siegmeier, R. Tetrahedron Lett. 1983, 24, 281.
76. Seki, M.; Yamanaka, T.; Kondo, K. J. Org. Chem. 2000, 65, 517.
77. Meyers, A.I.; Temple, D.L. J. Am. Chem. Soc. 1970, 92, 6644.
78. Schow, S.R.; Bloom, J.D.; Thompson, A.S.; Winzenberg, K.N.; Smith, A.B., III J. Am. Chem. Soc. 1986,
108, 2662.
79. Reviews: (a) Meyers, A.I.; Mihelich, E.D. Angew. Chem. Int. Ed. Engl. 1976, 15, 270. (b) Meyers, A.I. Acc.
Chem. Res. 1978, 11, 375. (c) Meyers, A.I. In Eliel, E.L.; Otsuka, S., Eds. Asymmetric Reactions and Processes in
Chemistry. ACS Symp. Ser. 1982, 185, 83. (d) Lutomski, K.A.; Meyers, A.I. In Morrison, J.D., Ed. Asymmetric
Synthesis (Academic Press: New York, 1984), Vol. 3, 213. (e) Meyers, A.I. J. Org. Chem. 2005, 70, 6137.

Reaction Synopses
Protecting Groups for Aldehydes and Ketones
R' R' R' R'
OR" SR"
O O
OR" SR"
R R R R
Acetals and Ketals

Formation: MeOH, TsOH, PhH, ∆; HO(CH2)2OH, TsOH, PhH, ∆; etc.
Cleavage: H2SO4, H2O, THF; (CO2H)2, H2O; etc.
Dithioacetals and Dithioketals
Formation: HS(CH2)3SH, BF3; etc.
Cleavage: HgCl2, CaCO3; HgCl2, CdCO3; NBS, H2O; MeI, MeCN-H2O; etc.
Protecting Groups for Carboxylic Acids
HO R'O HO N
O O O O
R R R R
Esters
Formation: CH2N2, Et2O (R'=Me); R'OH, DCC; Me2C=CH2, H2SO4
(R=But); etc.
Cleavage: K 2CO3, MeOH; TFA (R'=But); Et2NH (R'=Fm); dimedone,
Pd(OAc)2 (R'=allyl); LiAlH4, Et2O; H2, Pd-C (R'=allyl,
benzyl); etc.
1,3-Oxazolidines
Formation: (1) (COCl)2, CH2Cl2; (2) HOCH2CMe2NH2; etc.
Cleavage: HCl, H2O; etc.
15.8 Protection of Amines
Much of the incentive to develop protecting groups for amines has come from the
solid-phase synthesis of proteins and peptides. The synthesis of these compounds carries
with it the special requirement that the reactions for incorporating and removing the pro-
tecting groups must not lead to racemization of the chiral α carbons, which places signif-
icant restrictions on the groups that can be used to protect these functional groups.
Amines are nucleophiles, and it is this reactivity toward a wide range of electrophiles
that must usually be guarded against in a synthesis. The simplest way to reduce the nucle-
ophilicity of the amine nitrogen is to convert it to an amide or an amide-like compound.
By far the most widely used protecting groups of this type are the carbamates, all of which
are obtained from the amine by treatment with an appropriate alkoxycarbonyl derivative
(e.g., a chloroformate ester; see Example 15.96). The variations available in the urethane
protecting groups are illustrated by the examples in Table 15.12, where several common
protecting groups for amines are gathered with representative conditions for their incor-
poration and cleavage. This list is by no means exhaustive, and you should consult a spe-
cialist monograph when choosing a protecting group for an amine.
O
R' O
O Cl
R NH2 R' R (15.96)
base O N
H
Unlike the carbamates, simple amides (usually acetamides) must be cleaved under
relatively forcing conditions. The susceptibility of acetamides to hydrolysis increases

Table 15.12 Carbamate-Protecting Groups for Amines
Representative Conditions for Incorporation

Protected Amine Acronym and Removal
O
But R
On: (Boc)2O, NaOH, H2O, 25°C
O N
Boc
Off: 3 M HCl, EtOAc; etc.
H
O
R
On: Cbz-Cl, Na 2CO3, H2O
Ph O N
Cbz, or Z
Off: H2, Pd-C
H
O
R
O N On: Fmoc-Cl, NaHCO3, dioxane-H2O
H Fmoc
Off: Piperidine, DMF; etc.
O
R
On: Troc-Cl, py
Cl3C O N
Troc
Off: Zn, THF, H2O (pH 4.2); etc.
H
O
Me3Si R
On: Teoc-O-succinimide, NaHCO3, dioxane-H2O
O N
Teoc
Off: TBAF, KF, MeCN
H
O
R Aloc On: H2C=CHCH2OCOCl, py
O N Off: (Ph3P)4Pd, dimedone, THF
H
with substitution by halogens at the α carbon.80 The rates of hydrolysis follow the
order:
CH3CONHR < ClCH2CONHR < Cl2CHCONHR < Cl3CONHR < CF3CONHR
Although acetamides require heating for several hours with hydrochloric acid, trifluo-
roacetamides can be hydrolyzed by sodium or potassium carbonate in aqueous methanol.
(In fact, the N-trifluoroacetyl group can be hydrolyzed in the presence of a methyl ester81!)
The hydrolysis of amides can also be facilitated by neighboring group participation by a
hydroxyl group, as in 2-acyloxymethylbenzamides82 (e.g., Example 15.97). Primary amines
can also be protected as the corresponding N-alkylphthalimides (e.g., Example 15.98).
These compounds, which are also intermediates in the Gabriel synthesis of primary
amines,83 can then be cleaved by hydrazinolysis in ethanol or base hydrolysis.
O
O
R O
N NaOMe, MeOH
H (15.97)
20°C, 2 min
+
OAc H2N R
O O
R NH2, CHCl3, 70°C
O N R (15.98)
NH2NH2, EtOH, 25°C
O O
80. Goody, R.S.; Walker, R.T. Tetrahedron Lett. 1967, 289.

81. Boger, D.L.; Yohannes, D. J. Org. Chem. 1989, 54, 2498.
82. Cain, B.F. J. Org. Chem. 1976, 41, 2029.
83. Review: Gibson, M.S.; Bradshaw, R.W. Angew. Chem. Int. Ed. Engl. 1968, 7, 919.

As an alternative to simple chemical hydrolysis or cleavage, the selective hydrolysis of

a variety of simple amide can also be accomplished by means of acylases. This provides the
opportunity to accomplish optical resolution of the amine at the same time, because the
enzyme generally shows a marked preference for the cleavage of one of the two enantio-
meric amides. For example, the hydrolysis of the ω-trifluoro-α-amino acid amides in Ex-
ample 15.99 with hog kidney acylase results in hydrolysis of the S amide in 97% yield and
81% e.e., with the unhydrolyzed R amide being recovered in 92% yield and 78% e.e.84
NH2
F3C
n OH
NHAc hog kidney acylase (97%, 81% e.e.)

F3C (15.99)
n CO2H pH 7, H2O +
(±) NHAc
F3C
n CO2H
(92%, 78% e.e.)
Problems
15-14 (a) There are two ways to deprotect the bicyclic alcohol below. What are the
products of the two reactions specified below?
H
H
TFA, CH2Cl2 (1:1) HO H 1.0 M aq. LiOH, THF (4:1)
Boc N
0°C to 25°C, 30 min 0°C to 25°C, 3 h
(99%) MeO2C (99%)
(b) What is the product of the deprotection reaction below?

H
CO2Me
H 1) TFA (32 eq.), CH2Cl2,
N 0°C to 25°C, 1.5 h
H 2) Et3N (5 eq.), CH2Cl2,
HO O N
OH 0°C to 25°C, 15 h
Boc H
(77%)
15-15 Suggest a reason why phthalimides might be easier to hydrolyze with aqueous
base than acetamides.
Reaction Synopses
Protecting Groups for Amines
O
O
N R R NH2 R
N X
H
O
(continues)
84. Tsushima, T.; Kawada, K.; Ishihara, S.; Ucjida, N.; Shiratori, O.; Igaki, J.; Hirata, M. Tetrahedron 1988,
44, 5375.

Amides
Formation: RCOCl, (RCO)2O; etc.
Cleavage: HCl, H2O, ∆; KOH, H2O-EtOH, ∆; etc. or acylases, buffer
Carbamates
Formation: ROCOCl, base (R=t-Bu, PhCH2, etc.)
Cleavage: HCl, H2O; KOH, EtOH; etc. or TFA (R=t-Bu); H2, Pd-C
(R=PhCH2); etc.
Phthalimides
Formation: phthalic anhydride, CHCl3, ∆; etc.
Cleavage: H2NNH2, EtOH, 25°C; KOH, H2O, EtOH, ∆; etc.
Worked Problem
15-4 (a) Provide the missing reagents in the following steps from Sato’s synthesis of
tetrodotoxin (J. Org. Chem. 2008, 73, 1234).
O OH
HO O H O O O H O O O H O O
a b c
HO OH O O O O O
O
HO HO
OH OH
O H O O HO H O O O O
OHC
d O e HO O f O g
O
O O Ph O Ph
Ph O O
O
Ph Ph Ph
SPh
O2N SPh PhS O OH
HO O O O O PhS O O
O2N h O i j OH
O
O Ph O Ph
O NO2 O O
O O NO2 O O
Ph
Ph Ph Ph Ph
Ph
SPh OTBDPS
SPh PhS OMOM Ph OMOM Ph
PhS OH Ph
k l m
O2N O O2N O
O2N O O O
O
O O Ph O O Ph
HO OH Ph
§Answers below.

(a) Me2CO, H+; the authors actually used I2 as a Lewis acid.
(b) (i) (CF3CO)2O, DMSO, DBU; (ii) Ph3P=CH2. The first step is a version of the Moffatt oxidation, and is the
best suited to oxidation of such a highly functionalized substrate. A Swern oxidation [(COCl)2, Me2SO,
Et 3N, CH2Cl 2, –60°C] would also work well here.
(c) (1) m-CPBA, (CH2Cl)2; (ii) NaOH, H2O-THF. In this reaction, the epoxidation occurs from the less hin-
dered exo face of the 1,3,5-trooxabicyclo[3.3.0]octane ring system, and the basic nucleophile attacks at the
primary carbon to give the exo alcohol as the major product.
(d) NaH, PhCH2Br, DMF (Williamson ether synthesis).
(e) HOAc, H2O. This reagent hydrolyzes only the ketal derived from the 1,2-diol, and not the ketal whose
hydrolysis would reveal the aldehyde.
(f) NaIO4, MeOH-H2O.
(g) MeNO2, NaOMe, MeOH. This reaction gives Na+ salt of nitromethane, which is a good carbon nucleop-
hile that adds to the carbonyl group of the aldehyde. Since the next step of the sequence is dehydration, the
stereochemistry of the new chiral center does not matter. This addition is known as the Henry reaction.

15.9 Protecting Groups for Hydrocarbons
The plethora of protecting groups for oxygenated functional groups and amines stands in
stark contrast to the number of protecting groups available for protecting the π bonds of
alkenes and alkynes. The strategy for protecting these functional groups is essentially the
same as that used in protecting aldehydes and ketones as acetals and ketals: the reactive π
bond is converted to a less reactive derivative by addition, which is then reversed at a later
stage of the synthesis.
Alkenes
In contrast to the carbonyl π bond, the π bond of an alkene reacts with electrophiles and
not with nucleophiles, so the protecting group needs to be resistant to the attack of an
electrophile rather than the attack of a nucleophile. The most obvious derivative is the
vicinal dibromide, formed by addition of bromine to the alkene. The alkene π bond can
then be regenerated by reductive elimination, as shown in Example 15.100.
Br2, CH2Cl2 Br
(15.100)
Zn, HOAc Br
In 1984, Ganem proposed epoxides as protecting groups for alkenes, following his
discovery that diazomalonate esters act as mild deoxygenating agents that preserve
the stereochemistry of the original alkene in the presence of a rhodium catalyst (e.g.,
Example 15.101). In a similar vein (e.g., Example 15.102), a combination of epoxidation
by alkaline hydrogen peroxide and subsequent deoxygenation by Mo(CO)6 provides a
convenient method for the protection of the alkene π bond of conjugated enones and
esters.
O N2=C(CO2Me)2
H H 85
H Rh2(OAc4), C6H6, ∆ H (15.101)
(85%)
cis:trans = 1.7:1 cis:trans = 1.7:1
85. Martin, M.G.; Ganem, B. Tetrahedron Lett. 1984, 25, 251.
§ Answer to Worked Problem (Continued)

(h) MsCl, Et 3N, CH2Cl 2. The mesylate (any sulfonate would) is formed, and then undergoes E1cb elimination
from the anion of the nitroalkane. Although the dehydration can be effected using stronger bases without
making the sulfonate ester first, this two-stage approach is better suited to sensitive substrates.
(i) (PhS)2CH2, LDA, THF. The dithiane anion is formed first, and then it is added to the nitroolefin. The con-
jugate addition proceeds ≈10:1 in favor of the diastereoisomer shown. In the conformation drawn for the
nitroolefin, this would correspond to addition to the less hindered face of the alkene.
(j) HOAc, H2O, ∆. Under these more vigorous conditions than in (e), the aldehyde ketal is hydrolyzed.
(k) NaHCO3, H2O-MeOH. This is another Henry reaction, and previous work had shown that sodium bicar-
bonate was a sufficiently strong base to close the six-membered ring.
(l) (i) Me2C(OMe)2, TsOH, CH2Cl 2; (ii) CH2(OMe)2, P2O5, CH2Cl 2. There are two groups to be protected in this
step: the cis-1,2-diol, and the secondary alcohol. They are protected in that order. The authors give no
reason for the use of P2O5 as the acid catalyst in the second step to form the MOM ether, but it is worth-
while noting that P2O5 almost always contains some polyphosphoric acid, and that the hydroxyl group at
this position is susceptible to elimination under E1cb conditions, which would preclude forming the
MOM ether under the more usual basic conditions.
(m) (i) NBS, MeCN-H2O; (ii) NaBH4, MeOH. The aldehyde formed by hydrolysis of the dithioacetal is reported
to be unstable, so both steps were carried out without isolating the aldehyde.

SO2Ph SO2Ph
H2O2, KOH 86
H H (15.102)
Mo(CO)6, PhH O
H CO2Me ∆ H CO2Me
Yet another method for protecting alkenes involves their conversion to 1,2-diols by
oxidation with osmium tetroxide. These diols can be protected as acetonides, for example,
and after the transformations have been completed, the diol can be revealed and recon-
verted to the alkene by means of the Corey-Winter reaction.87
A more recent method for the selective protection of the more reactive π bond of a
non-conjugated diene, thus allowing selective hydrogenation of the less reactive π bond,
has been developed by Goess.88 In this method, the diene is treated with 9-borabicy-
clo[3.3.1]nonane (9-BBN), which reacts with the more reactive π bond to give the alkylbo-
rane and the less reactive π bond is then reduced. Treatment of the borane with
2-methyl-2-nitrosopropane then returns the alkene (e.g., Example 15.103).
B
9-BBN, THF
(15.103)
Me3C—NO
Another approach to the protection of alkene π bonds during synthesis has been to
use a Diels-Alder adduct as a protecting group and then to reveal the alkene by flash
vacuum pyrolysis. Although this method does work well, it suffers from the drawback
that the Diels-Alder adduct is itself an alkene (unless the diene used was anthracene or a
higher acene); thus, it is susceptible to the same reactions as the original alkene (e.g.,
Example 15.104).
X X
+ Y (15.104)
∆
Y (FVP)
Alkynes
The protection of alkynes falls in two major areas: (1) protection of the terminal C—H
bond, which is done using many of the same silane protecting groups as were used for
alcohols and (2) protection of the C—C π bond. The protection of alkyne C—C π bonds
relies, for the most part, on the formation of a transition metal complex of the alkyne
from which the triple bond is later released by suitable means (as shown in Example
15.105). The most common method for protecting the alkyne π bond involves the forma-
tion of a stable dicobalt hexacarbonyl complex of the alkyne,89 from which the triple bond
can be released by oxidation.90 This approach has been especially successful in the
synthesis of ethers from propargyl alcohols—the metal complex forms a very stable car-
86. Patra, A.; Bandyopadhyay, M.; Mal, D. Tetrahedron Lett. 2003, 44, 2355.
87. Corey, E.J.; Winter, R.A.E. J. Am. Chem. Soc. 1963, 85, 2677.
88. Graham, T.J.A.; Poole, T.H.; Reese, C.N.; Goess, B.C. J. Org. Chem. 2011, 76, 4132.
89. Greenfield, H.; Sternberg, H.W.; Friedel, R.A.; Wotiz, J.H.; Markby, R.; Wender, I. J. Am. Chem. Soc. 1956,
78, 120.
90. (a) Nicholas, K.M.; Pettit, R. Tetrahedron Lett. 1971, 3475. (b) Seyferth, D.; Nestle, M.O.; Wehman, A.T.
J. Am. Chem. Soc. 1975, 97, 7417.

bocation (a Nicholas cation91) that can be trapped by alcohol nucleophiles; intramolecular

application of the Nicholas reaction leads to the formation of oxygen heterocycles. In a
later report, a platinum complex of the alkyne was shown to be able to protect the alkyne
π bond selectively in the presence of an alkene π bond, allowing the selective hydrogena-
tion of the alkene.92
1) Co2(CO)8 (OC)3Co Co(CO)3

OH O
2)
OH, BF3•OEt2
CAN, Me2CO
93
(15.105) O
Reaction Synopses
Protecting Groups for Alkenes
Halogen and Halogen-like Adducts
Br
A B X2, CH2Cl2 A B
D C M, H-acid D C
Br
Protection: Br2, CH2Cl2; etc.

Deprotection: Zn, HOAc; Mg, Et2O; etc.
Epoxides
A B [O] A B
O
D C [H] D C
Protection: m-CPBA (simple alkenes); or H2O2, KOH (conjugated enones

or esters)
Deprotection: N2=C(CO2Me)2, Rh2(OAc)4, PhH, ∆; or Mo(CO)6, PhH, ∆; etc.
Vicinal Diols and Acetonides
OH B
A B OsO4 A B Me2C(OMe)2, TsOH A O
D C 1) Im2C=S D C H2SO4, H2O, THF D O

2) (MeO)3P C
OH
Protecting Groups for Alkynes

Co2(CO)8 (OC)3Co Co(CO)3
R1 R2
[O] R1 R2
Protection: Co2(CO)8, CH2Cl2; etc.

Deprotection: K 3Fe(CN)6; or CAN; etc.
91. Nicholas, K.M. Acc. Chem. Res. 1987, 20, 207.

92. Haskel, A.; Keinan, E. Tetrahedron Lett. 1999, 40, 7861.
93. Díaz, D.D.; Martín, V.S. Tetrahedron Lett. 2000, 41, 9993.

Problems
15-16 (a) Complete the following sequence of reactions by providing the structures of
the missing species.
OH 1) Co2(CO)8 OsO4, NMMO BF3•OEt2
A B
2) BF3•OEt2 THF-H2O CH2Cl2
O
?
C
(b) How does one account for the regioselectivity of the reaction (B→C) to form
the ketone?
Reference: Tetrahedron Lett. 1999, 40, 2815.
15-17 Complete the following reaction sequence by providing the structures of the
missing compounds.
NO2 1) NaOMe, MeOH, ∆ ∆
D E F
o-C6H4Cl2 2) CO2Me, H2O
∆ C16H13NO2 C20H19NO4 C6H9NO4
Reference: J. Org. Chem. 1955, 20, 650.
Chapter Summary
This chapter introduces organic synthesis along with the terminology of retrosynthetic
analysis. A synthesis can be assessed in terms of the increasingly sophisticated levels of se-
lectivity: chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity. The
tools of retrosynthetic analysis are transforms, which are intellectual constructs that convert
a target compound to one or more potential precursors, known as synthons. The sequence of
reactions in the synthesis may be linear, where the steps all follow in a single pathway from
starting material to product, or convergent, where two separate paths are used to construct
intermediates that are then coupled. Convergent syntheses often have higher overall yields.
Polyfunctional compounds may be subjected to the Evans-Lapworth analysis. This
reveals consonant and dissonant difunctional relationships in the target compound. Al-
though consonant relationships are easy to form, dissonant difunctional relationships can
become a source of difficulty in a synthesis. One way to overcome this is to use reagents
with charge-type inversion, or umpolung.
Modern synthesis of polyfunctional compounds almost always requires the use of
protecting groups, and such species for alcohols (including 1,2- and 1,3-diols), amines, al-
dehydes, ketones, carboxylic acids, and hydrocarbons were introduced in this chapter.
Key Terms
acetal/ketal dissonant difunctional regioselectivity

chemoselectivity relationships retrosynthetic analysis
consonant difunctional dithioacetal/dithioketal silyl ethers
relationships enantioselectivity synthon
convergent synthesis Evans-Lapworth analysis tetrahydropyranyl ethers
deconvolution linear synthesis transform
diastereoselectivity protecting group umpolung

Additional Problems
15-18 (a) Carry out a Lapworth-Evans analysis of each of the following target mole-
cules. Indicate any dissonant difunctional relationships that might be present
in each target molecule and suggest key intermediates that might be used to
introduce these dissonant relationships.
(b) Carry out a complete retrosynthetic analysis of each of the target molecules
that would permit them to be prepared (in racemic form unless otherwise
specified) from the indicated starting material. You may assume that any
other reagents may be used unless limitations are imposed.
(c) Specify one sequence of reactions that would constitute a rational synthesis of
each of the target compounds from the starting material given. Unless explic-
itly prohibited from doing so, you may use any other organic or inorganic
compounds needed to accomplish the transformation requested. Where the
relative configurations of chiral centers is not given, you may assume that a
mixture of stereoisomers is permissible in the final product.
Me
(a) from cyclohexanol (b) from cyclohexene
OH
Me
(c) (d) from cyclohexanol
from O
OH
(e) from ethanol (f) CH2 from cyclohexene
OH
Br
(g) Br from benzene (h) from benzyl alcohol
OH O
from K*CN
(i) * 14 (j) from cyclohexanone
Me (*C = C)
OH OEt
(k) from cyclohexene (l) from cyclohexene
OEt OH
O
CN
(m) from 2-cyclohexenone (n) from
O O
O
H
H O CN
MeO Me
(o) HO
from (p) from anisole
1-dodecyne from compounds

(q) (r) from benzene
with four or less carbon atoms
H
(s) (t) from cyclohexene

from cyclohexanol
OMe O
H

OH
O
(u) from (v) CN
from benzyl bromide
O OH
H H
(w) CN
from benzyl bromide (x) from
H H
O OH
H O
Br CO2H OH
from O O
(y) H (z) OH from compounds with
six or less carbons
H
O O O
O
HN
from compounds with

(aa) six or less carbons (bb) from bromobenzene
HN
O H
Ph
(cc) N from cyclopentadiene
O H
15-19 The compounds shown are all important industrial chemicals: bisphenol A is a
key raw material in the epoxy resin industry, BHT and BHA are important pre-
servatives, adipic acid is a key intermediate in the manufacture of nylon-6,6, and
caprolactam is a key intermediate in the manufacture of nylon-6. Design a syn-
thesis of each from the starting material indicated or from a phenol.
OH OH
HO OH
OMe
bisphenol A BHT BHA
NH
HO2C O
CO2H
adipic acid caprolactam
(from benzene) (from benzene)
15-20 What is the major organic product of each of the following reactions or reaction
sequences?
OH
NHBoc
TBDMSCl, imidazole WO2010026122
(a) DMAP, CH2Cl2
N (Novartis)
Cbz
HO NH2
Boc2O, Et3N, CH2Cl2 WO2010001169
(b)
N (AstraZeneca)
Cbz

1) NaHMDS; THF, -78°C J. Am. Chem. Soc. 2011,

(c)
O N 2) TBDMSCl 133, 7704.
Me
H 1) Me3CCOCl, DMAP
TBSO H Me Et3N, CH2Cl2, 0°C
O J. Am. Chem. Soc. 1999,
(d) OMe 2) TBAF, THF
HO 121, 6563.
H
HO Ph 1) MOM-Cl, i-Pr2NEt
(e) O
2) H2, Pd-C, MeOH Org. Lett. 2004, 6, 3533.
OTIPS
F
OMe
WO2010026122
(f) N BBr3, CH2Cl2
(Novartis)
N F
H 1) Co2(CO)8, CH2Cl2
H O 2) BF3•OEt2 (0.1 eq) Tetrahedron 2011, 67,
(g) O
OH
TMS CH2Cl2, -78°C 9809.
H 3) CAN, MeOH
H O TBAF (1.0 eq), AcOH (1.0 eq)

(h) TBDPSO Org. Lett. 2008, 10, 1247.
THF-CH2Cl2 (1:1)
OTBS
O
TIPS-OTf, 2,6-lutidine J. Am. Chem. Soc. 2008,
(i) H H CH2Cl2, -20°C
H
130, 2783.
HO
HO NHBoc
H2, Pd-C, MeOH WO2010001169
(j)
N (AstraZeneca)
Cbz
MOMO BCl3, CH2Cl2

(k) Org. Lett. 2004, 6, 3533.
I
OTIPS
OMe
Me
N
H BBr3 (5 eq), CH2Cl2
(l) OMe Org. Lett. 2007, 9, 1461.
H H -80°C to 0°C, 2 h
Me
H
Me
MeO2C
O O J. Org. Chem. 1975, 40,
(m) Br
PhH, TsOH, 18 h 150.
O
MeO OMe
H 1) TBAF, THF, 24 h
(n) NC 2) Dess-Martin, CH2Cl2, 12 h Org. Lett. 2007, 9, 1461.
Me 3) (CH2OH)2, CSA, PhH, ∆, 10 h
OTBS
Me

OHC (MeO)3CH
N OH J. Org. Chem. 2002, 67,
(o) HCl, MeOH
O 4337.
Ph
CHO
Me3SiO
CO2Me
O (MeO)3CH, TsOH J. Am. Chem. Soc. 1993,
(p)
HO MeOH, 15 min 115, 3146.
OO
15-21 (a) Provide the missing reagents from the following steps in the synthesis of he-
mibrevetoxin B (J. Am. Chem. Soc. 2003, 125, 7822). Note that more than one
step may be required for each transformation.
O
AcO HO HO
a b
AcO HO HO
O CO2Me O CO2Me O CO2Me
H H H H H H
O OH
Ph O Ph O
c d e
O O OH
O CO2Me O
H H H H
OH OH OMOM
Ph O OH f Ph O O g TESO O
O OH O O TfO O
O O O
H H H H H H
(b) Why was the hydrolysis of the diester in step a necessary before the forma-
tion of the epoxide in step b? (c) Why was the benzylidene acetal chosen in
step c instead of the acetonide?
(d) Why were the operations in steps d and e carried out in the order shown?
(e) In step g, three hydroxyl groups are revealed, and all three are converted to
different functional groups. Provide a reasonable rationale for the order in
which the various operations are carried out.
15-22 (a) What are the intermediate compounds in the transformation shown (Org.
Lett. 2003, 5, 4815)? (Hint: the mechanism of the first step should provide a
strong clue here.)
1) HS(CH2)3SH, NaOEt
EtOH-THF, –10°C to r.t. S
CO2Me
2) LiAlH4, THF, 0°C, 4h
TIPSO S
3) TIPSCl, imidazole, THF, 12 h
(b) Is there an alternative approach to this same compound?

15-23 Provide the missing reagents in the reaction sequence shown (J. Am. Chem. Soc.
2003, 125, 9554). Note that more than one step may be necessary to complete each
transformation.
OTBDPS OTBDPS
CHO
a b
THPO THPO
EtO2C
15-24 What will be the stereochemistry of the organic product of the reaction shown?
How could predominantly one diastereoisomer of the product be obtained
(J. Org. Chem. 2007, 72, 4098)?
Br Ph Ph
O
HO OH
TsOH

15-25 (a) Complete the following reaction sequence taken from Nicolaou’s total syn-
thesis of Taxol (J. Am. Chem Soc. 1995, 117, 634, 645).
EtO2C Me
O PhB(OH)2 Me2C(CH2OH)2 TBS-OTf
+ A B C
PhH, ∆ ∆ 2,6-lutidine
O DMAP
OH C18H19BO6 C12H16O6 C24H44O6Si2
OH CH2Cl2
TBDPS-Cl
LiAlH4 CSA, MeOH imidazole KH, PhCH2Br
D E F G
Et2O CH2Cl2 DMF Bu4NI (cat.)
C22H42O5Si2 C16H28O5Si C32H46O5Si2 Et2O C39H52O5Si2
TPAP
LiAlH4 Me2C(OMe)2 NMMO
H I J
Et2O CSA, CH2Cl2 MeCN
C33H42O5Si C36H46O5Si C36H44O5Si
(b) What is the reason for using phenylboronic acid to give compound A?
(c) What is the role played by the neopentyl glycol in the transformation of
A to B?
(d) Only one of the two allylic silyl protecting groups is removed in the conver-
sion of D to E. Which one, and why?
(e) In the exhaustive reduction of G to H, one of the silyl protecting groups is
lost. Which one, and why (suggest a mechanism)?
(f) There are two isomeric compounds consistent with the molecular formula for
compound I. The isomer formed under kinetic control rearranges slowly and
completely to the thermodynamic isomer. What is the structure of the kinetic
isomer, and why is it formed more rapidly?
15-26 (a) The tetrodotoxin molecule is one of the most complex natural products whose
synthesis has been completed. Complete the following reaction sequence,
taken from Isobe’s asymmetric total synthesis of tetrodotoxin (J. Am. Chem.
Soc. 2003, 125, 8798).
OH OTBS OTBS OTBS OTBS
O a O b O c O d O
OiPr OiPr I OiPr OiPr OiPr

OH O OH TMS OH TMS O
OAc OH
O OTBS TBSO OTBS O OTBS O OTBS
e O f O Pb(OAc)4 O g O
KHCO3
OiPr OiPr OiPr OiPr
TMS TMS TMS
OH MOM OH MOM OH
OHC OH OTBS O OTBS O OTBS O OTBS
O
h O i O j H O k HO O
H H
OiPr OiPr OiPr OiPr
OTBDPS OTBDPS OTBDPS

O OTBS O O
HO H HO H
l PhCO2 O m PhCO2 O n PhCO2 O o
H H H
OiPr OMe OMe
O
OTBDPS
O OTBS OTBS OTBS
PhCO2 PhCO2
PhCO2 O p TBDPSO O q TBDPSO O

H
OMe OMe OMe
OTBS O O O Ph

(b) Write a reasonable mechanism for step m of the sequence.

(c) Does the exact order in which the operations are carried out in step i
matter? Why?
(d) Is the ring opening of the epoxide (step k) carried out under acidic or basic con-
ditions? Would the product be the same if the reaction were carried out under
the opposite (acidic instead of basic, or basic instead of acidic) conditions?
(e) step o actually required two separate reactions. Suggest a reason why.
15-27 Morphine is an intriguing natural product first synthesized in 1956 by Gates and
Tschudi [J. Am. Chem. Soc. 1956, 78, 1380]. The following convergent formal syn-
thesis is from the laboratory of David A. Evans in 1982 [Tetrahedron Lett. 1982,
23, 285]. Supply the missing reagents for each of the transformations shown. Note
that more than one step may be necessary to complete each transformation.
Br
CO2H OH Br
a b c
A
CO2H OH Br Br
OMe OMe
OMe
OMe
O
d e B
HO
N N N
Me Me Me
OMe OMe OMe
OMe OMe OMe

f g h ClO4
A + B
N N N
Me Me Me
H
Br
i
MeO MeO MeO MeO

k j Me2SO
MeO MeO H MeO MeO
HO CHO ClO4
N Me N Me N Me N
Me
MeO MeO MeO MeO
MeO MeO MeO

m n O MeO o O
N Me N Me N Me N Me
O O
15-28 Eleven years after the Evans approach appeared, Overman published a more
modern approach to the synthesis of optically active morphine derivatives
[J. Am. Chem. Soc. 1993, 115, 11028], and a formal total synthesis of enantiomeri-
cally enriched morphine. Supply the missing reagents for each of the transforma-
tions shown. Note that more than one step may be necessary to complete each
transformation.
NHPh NHPh NPh
O O O O O O O
a b O c O d
H H
O O
O R
O NH N
CHO I
g OBn ZnI2
e f
SiMe2Ph SiMe2Ph SiMe2Ph SiMe2Ph OMe

R OMe OMe OMe

MeO
N h i j
H OBn O O
BnO O
I
H R N R N OH HN
15-29 Cubane is the first of the “Platonic solids” to be prepared in hydrocarbon form
[J. Am. Chem. Soc. 1964, 86, 3157]. Supply the missing reagents for each of the
transformations shown. Note that more than one step may be necessary to com-
plete each transformation.
O
O O O O
O O
a b O c
Br
O O O
Br Br Br
Br Br Br
d
O O O
CO2—OBut CO2H Br O Br O Br O
i h g f e
ButOO2C HO2C Br
O
Why is the formation of the monoketal necessary for the synthesis to be success-
ful? Is this step a concession step or not? Why or why not?
15-30 In 1979, Samir Chatterjee published two papers describing total syntheses. Both
are now universally considered to be fabrications. The first was published in Chem.
Commun. [1979, 620] as a total synthesis of the interesting sesquiterpene hydro-
carbon, isocomene. The second was published in Tetrahedron Lett. [1979, 3249] as
the synthesis of a synthon for the C19 diterpenoid alkaloids. There are several reac-
tions described in both papers that contradict the known outcomes of such reac-
tions in other systems, thus providing the hints that the syntheses are fraudulent.
What are these reactions and what would be their expected outcome? What other
evidence could be used to support the deduction that the syntheses as published
are frauds (you should read the original papers to obtain this information)?
(a) Chem. Commun. 1979, 620.
1) BH3•THF O 1) Br O
OAc
2) Jones oxidation 2) KOH Br
3) PBr3
O O O
1) Ph3P
2) BuLi
NH
1) Br2/HBr/
t-BuOOH O
Triton B (OH—) 2) HMPA/∆
O
O O O
CF3CO2H
H
1) POCl3 1) H2/Pd-C
HO
2) Me2CuLi 2) MeMgI
3) TsOH
O O
(b) Tetrahedron Lett. 1979, 20, 3249.

OMe
1) K2Cr2O7, H2SO4, 1) p-MeOC6H4MgBr
COCl Me2CO, H2O Et2O
N O O
2) CH2N2, Et2O 2) POCl3, py
CHO CO2Me

OMe OMe OMe

1) H2, Pd-C 1) SOCl2, py
2) saponification 2) AlCl3, CH2Cl2
CO2Me CO2Me MeO

MeO MeO O
OMe OMe 1) saponification

BrCH2CO2Et, NaH MeI, NaH 2) Li, NH3
DME DME THF, t-BuOH
CO2Et CO2Et 3) HCl, H2O

MeO MeO
O O
OMe OMe OMe

1) (CH2OH)2 1) NaOH
TsOH 2) (COCl)2
2) CH2N2 O O
O CO2H Et2O CO2Me COCl
O O O O O
OMe 1) hν, THF, c-C6H12 OMe

2) NH2NH2, KOH, ∆
CH2N2, Et2O 3) H3O+
O N2
O O
O O O

Chapter sixteen
Organic Reactions V
Condensations and Cascade Reactions
of Carbon Nucleophiles
16.1 Addition, Condensation, and Cascade Reactions: Definitions
Condensations differ from addition reactions in one very important aspect: during a
condensation reaction, a small molecule (often water or an alcohol but occasionally a more
complex species) is eliminated from the initial adduct. Condensation reactions occur by
an addition-elimination sequence, so the product retains a π bond. Cascade reactions
occur by an addition-intramolecular substitution sequence, so the product is net addition
to the π bond (Example 16.1); such reactions are also often called condensations. Either of
the two steps may be rate determining, which can make it more difficult to control the
stereochemistry, especially if the addition step is reversible. Questions of stereochemistry
in condensation reactions are most often expressed in terms of E/Z or cis/trans instead of
R/S or syn/anti.
Nu X
condensation
R Y products
intramolecular Z
displacement
Z X
Z
X Z Nu Nu
Nu X (16.1)
R Y addition R Y
R Y elimination
16.2 The Aldol Condensation and Related Reactions1
Although the aldol addition has become the more common form of this reaction in the
past several decades, the aldol condensation, where the product is a conjugated carbonyl
compound, still remains an important reaction. The aldol condensation is a two-stage
reaction that involves initial aldol addition, followed by dehydration of the resultant
β-hydroxycarbonyl compound under acidic or basic conditions to give the conjugated
enone. Because modern methods for quantitative enolate generation make the aldol addi-
tion a much simpler reaction than before, the aldol condensation is now usually carried
out in two separate steps: (1) aldol addition, followed by (2) acid- or base-catalyzed dehy-
dration of the aldol. The acid-catalyzed dehydration is generally accepted to occur by the
E1 mechanism, and the base-promoted elimination almost certainly involves an enolate
anion and so occurs by the E1cb mechanism.
1. For a somewhat dated but still extremely useful review, see: House, H.O. Modern Synthetic Reactions
(Benjamin/Cummings: Menlo Park, CA, 1972), ch. 10.
647

648 Advanced Organic Chemistry | Chapter sixteen
O
O R' CHO
R G R' (16.2)
G base
R
The Claisen-Schmidt Reaction

The reaction between a ketone enolate and an aldehyde is known as the Claisen-Schmidt
condensation, after the two chemists (Ludwig Claisen and J. Gustav Schmidt) who reported
it independently in 1881.2 The product of the Claisen-Schmidt reaction is a conjugated
enone. As with the aldol condensation, the Claisen-Schmidt reaction is most easily carried
out today as a two-step process; it also works best when the aldehyde partner does not have
an α-hydrogen—typically an aromatic aldehyde, as shown in Example 16.3.3
MeO
1) LDA, THF, –78°C
O H
2) MeO CHO
O (16.3)
3) H2SO4, H2O
(87%)
The Knoevenagel Condensation

When the source of the enolate anion is an active methylene compound—a compound
where the CH2 group is flanked by a pair of electron-withdrawing groups such as carbonyl
groups, cyano groups, or nitro groups, so that it is acidic enough to be quantitatively con-
verted to the enolate anion by alkoxide anion bases—the aldol condensation is frequently
referred to as the Knoevenagel condensation.4 The reaction follows the same course as the
aldol condensation (aldol addition followed by dehydration), but the presence of two
groups capable of conjugating with the double bond renders the dehydration step much
more facile. In 1902, Doebner5 introduced a modification of the original Knoevenagel con-
densation in which an amine (usually piperidine or pyridine) and acetic acid replace more
strongly basic catalysts.6 The Doebner modification is now probably the most commonly
used form of the reaction (as in Example 16.47). Alkylammonium carboxylate salts are
known to be low-melting solids that can function as ionic liquids, which has led to the
exploration of these salts as solvents for the Knoevenagel reaction. The results of some
early work in this area are promising.
2. (a) Claisen, L.; Claparède. A. Ber. dtsch. chem. Ges. 1881, 14, 2460. (b) Schmidt, J.G. Ber. dtsch. chem. Ges.
1881, 14, 1459. (c) Claisen, L. Ber. dtsch. chem. Ges. 1887, 20, 655.
For biographical details of Claisen see Chapter 6. Biographical details about Schmidt are difficult to find; he
was a friend of Traugott Sandmeyer at the ETH in Zurich.
3. Seo, B.-I.; Wall, L.K.; Lee, H.; Buttrum, J.W.; Lewis, D.E. Synth. Commun. 1993, 23, 15.
4. Knoevenagel. E. Ber. dtsch. chem. Ges. 1898, 31, 2596.
Heinrich Emil Albert Knoevenagel (1865–1921) was educated in Hannover (PhD, 1889). After working with
Viktor Meyer at Göttingen and Heidelberg, he was appointed Extraordinary Professor at Heidelberg in 1896.
He remained there until his death from peritonitis due to a burst appendix at age 56. For more biographical
details, see Angew. Chem. 1922, 35, 29.
5. Oscar Doebner (1850–1907) was educated in Munich and Tübingen (Dr rer nat, 1873). After 18 months as
Otto’s assistant in Braunschweig, he moved to Berlin to work with Hofmann. He was made Professor at Halle
in 1884. Doebner’s accomplishments include the discovery of the two reactions that bear his name as well as the
dye malachite green. For more information, see: Schotten, C. Ber. dtsch. chem. Ges. 1907, 40, 5131.
6. Doebner, O. Ber. dtsch. chem. Ges. 1902, 35, 1136.
7. Erdman, P.J.; Gosse, J.L.; Jacobson, J.A.; Lewis, D.E. Synth. Commun. 2004, 34, 1163.

Organic Reactions V 649
CO2Et
CHO
NCCH2CO2Et (1.0 eq) CN
piperidine (0.16 eq.)
(16.4)
NH4OAc (0.4 eq)
HOAc (1.25 eq)
OH PhMe, ∆
(87%) OH
In a recent example of this reaction (Example 16.5), the synthesis of either the E or Z
isomers of nitroalkenes can be accomplished by appropriately choosing the solvent and
temperature for the reaction.8 In this example, the initial reaction is the nitro-aldol addi-
tion, or Henry reaction of nitromethane with aldehydes.9 The use of molecular sieves is
critical to the stereochemical outcome: in the absence of molecular sieves, the diastereose-
lectivity is poor.
piperidine (6 mol %)
CH2Cl2, 4Å MS, 30 m
(90%) O2N
CHO (16.5)
NO2 piperidine (6 mol %)

PhMe, ∆, 4Å MS, 4 h
(87%) NO2
The Perkin Condensation

When an aromatic aldehyde is heated with an acid anhydride and the alkali metal salt of
the acid, a cinnamic acid derivative is formed. This reaction was discovered by William
Henry Perkin10 and is now known by his name.11 The reaction is thought to involve the
formation of the enolate anion of the anhydride, which then reacts with the aldehyde to
give a β-hydroxyacid that is acetylated and then undergoes elimination to give the cin-
namic acid. However, this interpretation of the available evidence has recently been
thrown into question.12 More recent variants of the reaction use a tertiary amine as the
base catalyst for the reaction.
Intramolecular Aldol Condensations via Enamines

Dibenzylamine trifluoroacetate was introduced as a reagent for the intramolecular aldol
condensation by converting a dialdehyde to an enamine that would then undergo an in-
tramolecular addition and subsequent dehydration. The reagent converts dialdehydes to
conjugated cycloalkenecarboxaldehydes, as in Examples 16.6 and 16.7.
8. Fioravanti, S.; Pellacani, L.; Tardella, P.A.; Vergari, M.C. Org. Lett. 2008, 10, 1449
9. Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265.
10. Sir William Henry Perkin (1838–1907) was educated at the Royal College of Chemistry under Hofmann.
Aged 17, he prepared “mauveine,” the first commercially successful synthetic dye; before graduating, he left the
College and set up a company to manufacture this dye; and at 36 he sold his company and became inde-
pendently wealthy. He was elected FRS in 1866 and knighted in 1906. For more details, see: (a) Brightman, R.
Nature 1956, 177, 805; (b) Holme, I. Color. Technol. 2006, 122, 235.
11. (a) Perkin, W.H. J. Chem. Soc. 1868, 21, 181; 1877, 31, 660. Reviews: (b) Johnson, J. R. Org. React. 1942, 1,
210. (c) Rosen, T. in Trost, B.M.; Fleming, I., Eds. Comprehensive Organic Synthesis (Pergamon: Oxford, 1991),
vol. 2, p. 395.
12. Chandrasekhar, S.; Karri, P. Tetrahedron Lett. 2006, 47, 2249.

THPO CHO THPO

CHO (PhCH2)2NH2 CHO
H CF3CO2
H 13
(16.6)
PhH, 50°C, 1h
O (64%) O
MEMO MEMO
O OTBS O OTBS
(PhCH2)2NH
CHO CF3CO2H
O O (16.7)14
CHO PhH, 60°C
(94%) CHO
Worked Problem
Ph
O O
O
I CHO (PhCH2)2NH Ph NaOH
(a) CF3CO2H
(b) O MeOH
CHO CHO
O
§Answers below
16.3 Condensations Where the Initial Adduct Is Intercepted
The initial adduct of an enolate anion and an aldehyde or ketone is an alkoxide that can be
intercepted by an appropriately located electrophile such as a halide or an ester group (e.g.,
Example 16.8). Both these types of reactions are known. Interception of the aldolate with an
alkyl halide gives an epoxide in a reaction known as the Darzens glycidic ester condensation,
and interception by an ester group gives the Stobbe condensation. The Corey-Chaykovsky
reaction between a sulfonium ylide and an aldehyde to give an epoxide is closely related
(mechanistically, at least) to the Darzens condensation.
13. Corey, E.J.; Danheiser, R.L.; Chandrasekharan, S.; Siret, P.; Keck, G.E.; Gras, J.-L. J. Am. Chem. Soc. 1978,
100, 8031.
14. Birman, V.B.; Danishefsky, S.J. J. Am. Chem. Soc. 2002, 124, 2080.
O O O
(PhCH2)2NH O
I CHO
(a) CF3CO2H
I
CHO
CHO
Ph Ph
O O
Ph NaOH, MeOH Ph
(b) O O
CHO O
O
References: (a) J. Org. Chem. 2008, 73, 8049. (b) J. Org. Chem. 2007, 72, 4098.

O
O O
CO2R CO2R CO2R (16.8)
R R
R H
X X
The Darzens Condensation15

The Darzens condensation is a reaction of α-haloesters and aldehydes in the presence of
base to give an α,β-epoxyester (a glycidic ester), first reported by French chemist Auguste
Georges Darzens16 in 1904.17 The reaction is known to proceed through a reversible initial
addition of the enolate anion to the carbonyl group, followed by a rate-determining intra-
molecular displacement of the halide by the alkoxide anion18 rather than the alternative
mechanism, as was demonstrated by Zimmerman and Ahramjian.19 The alternative mech-
anism involves formation of a carbene that then adds to the carbonyl group. In their study,
they also found that the reaction in Example 16.9 gives predominantly the product with
the two phenyl groups cis. The conformation of the intermediate alkoxide suggests that the
major product is formed by addition of the E(O) enolate of the ester to the aldehyde
through a six-membered Zimmerman-Traxler transition state.
Cl H
PhCHO O
CO2Et
KOBut CO2Et
(16.9)
Cl
Cl Ph H
OEt OEt
Ph
O O O
M
M
As with other reactions, efforts to control the stereochemistry of the Darzens conden-
sation have become focused on absolute, as well as relative, control of the stereochemistry
of the reaction. In this reaction, stereoselectivity must be managed at two levels: diastereo-
selectivity, which controls the cis/trans ratio, and enantioselectivity, which controls the en-
antiomer ratio. Particular success in the asymmetric Darzens condensation (e.g., Example
16.10) has been achieved using chiral phase transfer catalysts20 or chiral crown ethers.21
15. Reviews: (a) Newman, M.S.; Magerlein, B.J. Org. React. 1949, 5, 413. (b) Rosen, T. In Trost, B.M.; Fleming,
I., Eds. Comprehensive Organic Synthesis (Pergamon: Oxford, 1991); vol 2, 409.
16. Auguste Georges Darzens (1867–1954) was born to French parents in Moscow, and educated in Paris at
the École Polytechnique under Grimaux. He remained after graduation (1888; MD, 1890) to begin his career.
Darzens eventually rose to Professor of Chemistry in 1913. Darzens and Grimaux were among the few at the
École (a military school) who defended Alfred Dreyfus, and Grimaux lost his Professorship over it. Darzens
remained as Professor at the École until his retirement in 1937. For more biographical details, see: Laszlo,
P. Bull. Hist. Chem. 1994, 15/16, 59.
17. Darzens, G. Compt. Rend. 1904 139, 1214.
18. (a) Ballester, M.; Bartlett, P.D. J. Am. Chem. Soc. 1953, 76, 2042. (b) Ballester, M. Chem. Rev. 1955, 55, 283.
(c) Ballester, M.; Perez-Blanco, D. J. Org. Chem. 1958, 23, 652.
19. Zimmerman, H.E.; Ahramjian, L. J. Am. Chem. Soc. 1960, 82, 5459.
20. (a) Arai, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2145. (b) Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Tetrahedron
1999, 55, 6375. (c) Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T. Chem. Commun 1999, 49. (d) Arai, S.; Tokumaru, K.;
Aoyama, T. Tetrahedron Lett. 2004, 45, 1845. (e) Arai, S.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1998, 39, 8299.
(f) Arai, S.; Shioiri, T. Tetrahedron 2002, 58, 1407.
21. Bakó, P.; Szöllõzy, A.; Bombicz, P.; Tõke, L. Synlett 1997, 291–292.

Cl
CHO H
H OH N (16.10)
O H
Ph O PTC (10 mol %) PTC:
LiOH (2 eq), Bu2O Ph O CF3
117 h, 4°C Br
(82%; 57% e.e.) N
Ph Ph Ph
N Ph N2=CHCO2Et H N
(16.11)
H TfOH (0.25 eq) O CO2Et
O
O H EtCN, –78°C, 6 h O H
(73%, dr >95:5)
The aza-Darzens reaction, which gives aziridines as the final product, has been carried
out using α-diazoketones under conditions of acid catalysis (Example 16.11).22 In this re-
action, it is possible that the diazoketone becomes protonated to give a diazonium ion
(Example 16.12), which contains an excellent leaving group (N2+) that is displaced by the
imine nitrogen to give iminium ion (Example 16.14). This ion in turn is deprotonated to
give an azomethine ylide (Example 16.13; see Section 6.5: 1,3-dipolar cycloadditions, for
more about these reagents). This ylide undergoes conrotatory ring closure. In an alterna-
tive pathway, the imine is protonated to give the iminium ion (Example 16.16), which then
reacts with the diazoalkane as a nucleophile to give the intermediate (Example 16.18)
carrying the leaving group.
CO2R CO2R CO2R R1
R1 R1 R1 conrotatory
N N
N2 N N CO2R
R2
R2 R3 R 2
R3
R 2
R3
R 3
(16.12) (16.13) (16.14) (16.15)
R1 H
R1 R1 N2 NH R1 N
N NH 2 N2
R CO2R
R2 R3 R2 R3 CO2R 3 R2
R CO2R R3
(16.16) (16.17) (16.18) (16.19)
The Corey-Chaykovsky Reaction23

A sulfur ylide is a species where the group stabilizing the carbanion center may also act
as a leaving group, thus making it (in a formal sense, at least) analogous to the enolate
anion of an α-halocarbonyl compound. Thus, when one replaces the α-haloester enolate
of the Darzens condensation with a sulfur ylide, one also obtains an epoxide by the two-
step process of addition to the aldehyde carbonyl group followed by intramolecular dis-
placement of the dialkyl sulfide (Example 16.20). The reaction can also be applied to the
synthesis of aziridines from imines and to cyclopropane formation from α,β-unsaturated
carbonyl compounds. The mechanism of all these reactions follows a common course:
addition to the carbonyl group, followed by intramolecular displacement of the leaving
group. Recently, an “instant sulfur ylide”—a dry mixture of the sulfonium or sulfoxo-
nium salt and sodium hydride or potassium tert-butoxide—has been found to be stable
for more than a year when dry, making it especially convenient for this reaction (e.g.,
Example 16.21).24
22. Williams, A.L.; Johnston, J.N. J. Am. Chem. Soc. 2004, 126, 1612.
24. (a) Ciaccio, J.A.; Drahus, A.L.; Meis, R.M.; Tingle, C.T.; Smrtka, M.; Geneste, R. Synth. Commun. 2003,
33, 2135. (b) Ciaccio, J.A.; Aman, C.E. Synth. Commun. 2006, 36, 1333.

X
R'
R' R' X R' R' R'
R X (16.20)
R S R
Y
R R
R S
Y X = O, NR", CR"—COR"
R
Y = –:, O, NR"
O
O Me3S+i-, NaH
O (16.21)
O THF, 0-25°C, 16 h
O (55%) O
O H O
Me3S(O)I-NaH
(16.22)
Me2SO, r.t., 50 m
(86%)
The course of the reaction with conjugated ketones, especially, is decided by the struc-
ture of the sulfur ylide. Sulfonium ylides, where the group Y on sulfur is a lone pair, are
harder nucleophiles, and show a strong tendency to add to the carbonyl carbon of conju-
gated ketones, giving allylic epoxides. In contrast to this, sulfoxonium ylides (where the
group Y on sulfur in Example 16.20 is oxygen) are softer nucleophiles, and tend to add to
the β-carbon, giving cyclopropyl ketones as the major product (Example 16.22).
The Stobbe Condensation

When the source of the enolate anion in an aldol condensation is a dialkyl succinate, the
reaction is known as the Stobbe condensation, first reported by German chemist Hans
Stobbe25 in 1893.26 In the Stobbe condensation, as in the Darzens condensation, the interme-
diate alkoxide (16.25) is intercepted to form a lactone (16.27). The subsequent E1cb elimina-
tion of the carboxylate anion gives the half-ester of an alkylidenesuccinate, in which the
ester group, rather than the carboxyl group, is conjugated with the double bond (Figure 16.1).
Figure 16.1 The course of the

O
Stobbe condensation
RO H R'
R'
H CO2R CO2R
CO2R
O
RO2C RO2C RO
(16.23) (16.24) O
(16.25)
OR
R' H R'
CO2R CO2R
R' CO2R
O O
O
RO
O O O
(16.28) (16.27) (16.26)
25. Hans Stobbe (1860–1938) was educated at Heidelberg, Munich, Strasbourg, and then Leipzig, where he
studied under Wislicenus. He remained at Leipzig, eventually succeeding Wislicenus in 1903. Stobbe was a
pioneer in physical organic chemistry and in polymer chemistry. For more information, see his obituary
(nekrolog): Weygand, C. Kolloid-Z. 1939, 87, 1.
26. Stobbe, H. Ber. Dtsch. Chem. gs. 1893, 26, 2312; Justus Liebigs Ann. Chem. 1894, 282, 280.

The stereochemistry of the Stobbe condensation is typically E with aldehydes, as in

Example 16.29,27 but with ketones (e.g., Example 16.30), a mixture of both stereoisomers
(e.g., Examples 16.31 and 16.32) is almost always obtained, as shown below.28 Its ability
to differentiate between the two groups of the symmetrical succinate diester makes the
Stobbe condensation especially useful.
CO2Et 1) PhCHO, NaOEt

CO2Et
EtOH, ∆ HO2C
(16.29)
CO2Et 2) H , H2O
Ph H
O R1 R2
1) (CH2CO2Et)2, KOBut, t-BuOH
O OMe OMe
60°C, 5 h O
O OMe 2) H , H2O O OMe

(16.30) OMe R1=CH2CO2Et, R2=CO2H: (16.31) (41%) OMe
R1=CO2H, R2=CH2CO2Et: (16.32) 33%)
Reaction Synopses
Claisen-Schmidt Reaction
O O
R'CHO, base
R R R'
R R
Reagents: NaOH, EtOH; KOH, EtOH; NaOEt, EtOH; etc.

Works best if the aldehyde is aromatic
Knoevenagel Condensation
R
O
E—CH2—E'
E'
R acid or base R
R E
E, E' = COR', CO2R', CN, NO2, SO2R', etc.
Reagents (all Doebner modification):
CH2(CO2Et)2, NH4OAc, piperidine, AcOH, ∆; N ≡ CCH2CO2Et,
NH4OAc, piperidine, AcOH, ∆; MeCOCH2CO2Et, NH4OAc,
piperidine, AcOH, ∆; etc.
Perkin Condensation
R Ac2O, base R
O
∆ R CO2H
R
Reagents: Ac2O, NaOAc, ∆; Ac2O, Et3N, ∆; etc.

Reaction proceeds more slowly with other anhydrides to give α-substituted
cinnamic acids.
27. Plattner, J.J.; Marcotte, P.A.; Kleinert, H.D.; Stein, H.H.; Greer, J.; Bolis, G.; Fung, A.K.L.; Bopp, B.A.;
Luly, J.R. J. Med. Chem. 1988, 31, 2277.
28. For a typical example, see: Smissman, E.E.; Portoghese, P.S.; Mode, R.A. J. Org. Chem. 1961, 26, 3628.

Darzens Condensation
X
R O R' H R O
base R'
X G X G
G=R, Ar, OR;

X=O, NR, C(R)—E (E=CO2R, COR, CN, NO2, etc,)
Reagents: RCH(Cl)CO2Et, ArCHO, KOBut, THF; etc.
Corey-Chaykovsky Reaction
R' R' R' R' R'
R' O
S O S R'
O R R E R R E
R R R R
R'
R R R R
Reagents: Me3S+I–, NaH, Me2SO; Me3S+I–, KOBut, THF; etc.

or Me3S(O)+I–, NaH, Me2SO; Me3S(O)+I–, KOBut, THF; etc.
Stobbe Condensation
R CO2R' R CO2H
R'O2C
O base
R R CO2R
Reagents: (CH2CO2Et)2, NaOEt, EtOH, ∆; etc.

Stereochemistry: with aldehydes, E isomer predominates; with ketones product
is close to stereorandom
Worked Problem
16-2 What is the product of the following reaction?
O (Me3SO)I (2.2 eq)

C10H16O
NaH, Me2SO
11 h
§Answer below

This Corey-Chaykovsky reaction almost certainly proceeds in two stages. In the first stage, the cyclopropyl
ketone is formed as expected from a sulfoxonium ylide, and this cyclopropyl ketone then reacts more slowly
with the second equivalent of the nucleophile to give the observed product. The bulky isopropyl group controls
the stereochemistry of the second addition. It had been noted that when the reaction time was shorter, and the
excess of the ylide less, a substantial amount of starting material was recovered. This presumably arises from
the deprotonation of the ketone by the ylide before addition (a problem that often occurs in cyclopentanone
derivatives).
O
O O

Problem

O
H
ClCH2CO2Et, KOBut [epimerization occurs
(a) PhH, ButOH, r.t. during this reaction]
H
O
Ph
1) N
N
Li
(b) ClCH2CO2But
2) PhCHO, THF, -100°C
3) MeOH, –20°C
O
CHO
(CH2CO2Et)2, KOBut (CH2CO2Et)2, NaOMe
(c) mechanical grinding (d)
O I NaOH, MeOh-H2O
(no solvent)
O
Me
References: (a) J. Am. Chem. Soc. 1958, 80, 5006. (b) Chem. Pharm. Bull. 1995, 43, 1821. (c) Green
Chem. 2000, 2, 303. (d) Tetrahedron Lett. 2001, 42, 437.
16.4 The Claisen Condensation and Related Reactions
The Claisen Condensation

The name of Ludwig Claisen has become attached to the prototypical base-promoted con-
densation of esters to give β-ketoesters.29 However, the first observation of such a reaction—
the condensation of ethyl acetate by sodium metal to give ethyl acetoacetate—was actually
made by Frankland and Duppa30 and further clarified by Geuther,31 who first used an alkox-
ide anion as the base. In this reaction, the ester is converted to a small equilibrium concen-
tration of the enolate anion (16.34) that then adds to the carbonyl group of a second molecule
of ester to give an intermediate (16.35). This then loses the alkoxide (Figure 16.2) to give the
β-ketoester (16.36), which is much more strongly acidic than the starting ester, and it is
Figure 16.2 The path of the R

Claisen condensation R'O O
O O
OR' R'O O O
H
OR' OR' OR'
R R R R
(16.33) (16.34) (16.35)
O O O O
OR' OR'
R R R R H
OR'
(16.37) (16.36)
29. The first of a long series of papers by Claisen on the preparation and use of β-ketoesters in synthesis
appeared in 1887: (a) Claisen, L.; Lowman, O. Ber. dtsch. chem. Ges. 1887, 20, 651. (b) Claisen, L. Ber. dtsch. chem.
Ges. 1887, 20, 655. (c) Beyer, C.; Claisen, L. Ber. dtsch. chem. Ges. 1887, 20, 2178. (d) Claisen, L.; Stylos, N. Ber.
dtsch. chem. Ges. 1887, 20, 2188. (e) Claisen, L.; Fischer, L. Ber. dtsch. chem. Ges. 1887, 20, 2191.
Biographical information about Claisen can be found in Chapter 6.
30. (a) Frankland, E.; Duppa, B.F. J. Chem. Soc. 1866, 19, 395. (b) Frankland, E.; Duppa, B.F. Justus Liebigs
Ann. Chem. 1866, 138, 204, 328.
31. Geuther, A. Z. Chem. 1868, 4, 652.

quantitatively deprotonated by the alkoxide base in the final step of the reaction. Note that
all previous the steps of the mechanism are reversible.
A B
O O
CO2Et CO2Et
CO2Et
(16.38) NaOEt
EtOH, ∆
O O
CO2Et
CO2Et CO2Et
(16.39)
C D
The Claisen condensation gives a mixture of products if both esters have α-methylene
groups. However, if one can arrange the conditions such that only one of the possible prod-
ucts has a hydrogen atom flanked by two carbonyl groups, the reaction will ultimately pro-
ceed to give the conjugate base of that product alone. For example, if a 1:1 mixture of esters
16.38 and 16.39 is treated with base, there are four possible products: A, B, C, and D. How-
ever, neither of the esters C and D has a hydrogen atom flanked by two carbonyl groups, so
both can revert to starting material in a retro-Claisen condensation. If the reaction mixture
is heated long enough to go to completion, the anion B will be the major organic product of
the reaction. This situation is even simpler when one of the two esters cannot form an
enolate—for example, a carbonate ester (Example 16.40), a benzoate ester (Example 16.41),
or a formate ester (Example 16.42). Before the advent of methods to form simple enolates
quantitatively using strong amide bases, the Claisen condensation between a carbonyl com-
pound and ethyl formate, diethyl carbonate, or diethyl oxalate were used as a means to acti-
vate the α position of the carbonyl compound, because the activating group could be simply
removed after the reaction by hydrolysis and decarboxylation, or a similar process.
O O
(EtO)2CO, NaH CO2Et 32
DME, 85°C (16.40)
(53%)
CO2Me
CO2Me O
CO2Me
CO2Me 33
CO2Me (16.41)
NaH, DMF
MeO MeO
HCO2Et, NaH H 34
H O (16.42)
O Et2O, 18 h
(73%)
OH
The Dieckmann Condensation

The intramolecular version of the Claisen condensation is known as the Dieckmann
condensation after its discoverer, German chemist Walter Dieckmann,35 who disclosed it
32. Coates, R.M.; Shaw, J.E.J. J. Am. Chem. Soc. 1970, 92, 5657.
33. Conover, L.H.; Butler, K.; Johnston, J.D.; Korst, J.J.; Woodward, R.B. J. Am. Chem. Soc. 1962, 84, 3222.
34. Coates, R.M.; Sowerby, R.L. J. Am. Chem. Soc. 1972, 94, 5386.
35. Walter Dieckmann (1869–1925) took his PhD under Bamberger at Munich. He remained at Munich
after graduation as Private Assistant to Adolf von Baeyer, before moving to industry, working for Badische
Anilin- und Sodafabrik (BASF). He returned to academia in 1894 and completed his habilitation, which con-
tained the reaction that now bears his name, in 1898. On completing his habilitation, he was appointed Extra-
ordinary Professor of Chemistry at Munich.

in a series of papers between 1894 and 1901.36 The Dieckmann condensation is a useful
method for the production of cyclic ketoesters (e.g., Example 16.43, where sodium metal is
used as the base37). However, the reversibility of the reaction limits its use, in practical
terms, to the formation of five- and six-membered rings.
O
CO2Et 1) Na, PhMe, ∆
(16.43)
CO2Et 2) HOAc, H2O
CO2Et
(74-81%)
The Thorpe and Thorpe-Ziegler Reactions

A reaction analogous to the Claisen condensation based on nitriles instead of esters is
known as the Thorpe reaction.38 In this case, the product is a β-amino-α,β-unsaturated
nitrile. However, the reaction is hampered by the propensity of metalated nitriles to un-
dergo rapid intermolecular proton transfer and for nitriles to undergo oligomerization
during the reaction.39 Therefore, the reaction is usually used in an intramolecular form,
known as the Thorpe-Ziegler cyclization,40 which is the nitrile analog of the Dieckmann
condensation. The one case where intermolecular condensation does not lead to oligomer-
ization of the nitrile occurs when the electrophile used is a protected cyanohydrin (e.g.,
Example 16.44); this allows the synthesis of densely functionalized products.41 It is inter-
esting to note that the Dieckmann condensation of the diester corresponding to the dini-
trile in Example 16.45 fails to give more than 5% yield of product.
OEt
O
CN 1) BuLi, THF, –78°C
NH2 (16.44)41
2) EtO O CN
CN
(51%)
OMe
OMe
O
O H H
H H
add over 22 h
to LiHMDS H 42
H H H (16.45)
THF, ∆
(63%)
NC
NC CN NH2
Decarboxylation of β-Ketoacids
Carboxylic acids carrying a carbonyl group in the β position are susceptible to decarboxyl-
ation on heating. It is this facility that has made these compounds popular as a means to
carry out monoalkylation of ketones by means of the sequence in Example 16.46: (1) crossed
Claisen condensation with diethyl carbonate or a similar compound, (2) alkylation of the
36. Dieckmann, W. Ber. dtsch. chem. Ges. 1894, 27, 102; 1900, 33, 595, 2670; Justus Liebigs Ann. Chem. 1901,
317, 51, 93.
37. Pinckney, P.S. Org. Synth. 1937, 17, 30; Org. Synth. 1943, Coll. Vol. 2, 116.
38. (a) Baron, H.; Remfry, F.G.P.; Thorpe, J.F. J. Chem. Soc. 1904, 85, 1726. (b) Schaefer, J.P.; Bloomfield, J.J.
Org. Reactions 1967, 2, 1.
39. Reynolds, G.A.; Humphlett, W.J.; Swamer, F.W.; Hauser, C.R. J. Org. Chem 1951, 16, 165.
40. For a review of this and other nitrile anion cyclizations, see: Fleming, F.F.; Shook, B.C. Tetrahedron
2002, 58, 1.
41. Kobayashi, K.; Hiyama, T. Tetrahedron Lett. 1983, 24, 3509.
42. Luyten, M.; Keese, R. Tetrahedron 1986, 42, 1687.

resultant β-ketoester, (3) acid hydrolysis of the product β-ketoester, and (4) decarboxylation.
The hydrolysis step must generally be carried out under acidic, rather than basic, conditions.
The reversibility of the Claisen condensation can lead to fragmentation of the β-ketoester
instead of hydrolysis and decarboxylation.
O (EtO)2CO O CO2Et
NaOEt, EtOH, ∆
R R R R
1) NaOEt
(16.46) 2) R'X
O R' 1) H2SO4, H2O,∆ O CO2Et

R'
2) ∆ (–CO2)
R R R R
The decarboxylation is known to involve the formation of the enol, and the kinetics of
the reaction suggest that the reaction is unimolecular, corresponding to a retro-ene reac-
tion to eliminate carbon dioxide via an activated complex similar to Example 16.47. There
is evidence43 that both the acid and carboxylate forms of the acid participate in the reac-
tion concurrently.
R O ‡
H
O (16.47)
R
O
A useful variant of the decarboxylation reaction was introduced by Krapcho in 1982.44
In this variant of the reaction, the ester is cleaved by halide in a dipolar aprotic solvent
at elevated temperature, conditions under which the β-ketoacid decarboxylates as it is
formed, as shown in Example 16.48.45
MeO2C O
O NaCl, DMF
MeO2C (16.48)
H2O, ∆
N
N
Reaction Synopses
Claisen Condensation
O O
R CO2R R CO2R R CO2R
R R
Reagents: (1) NaOEt, EtOH, ∆, then (2) HCl, H2O; etc.

Equilibrium is favored by deprotonation of β-ketoester product.
Crossed Claisen condensation works best when only one product can deprotonate
to shift equilibrium.
(continues)
43. Hall, G.A., Jr. J. Am. Chem. Soc. 1949, 71, 2691.
44. Krapcho, A.P. Synthesis 1982, 805, 893.
45. Stevens, R.V.; Lee, A.W.N. J. Am. Chem. Soc. 1979, 101, 7032.

Dieckmann Condensation
CO2R CO2R
n n
CO2R
O
n=1, 2, 3, >11
Reaction works well to form 5- and 6-membered rings—and large rings.
Reaction does not work well to form medium-sized rings.
Thorpe-Ziegler Condensation
CN CN
n n
CN
NH2

Reaction can be used to form medium-sized rings.
Decarboxylation
R O R O R O
∆
R CO2R' R CO2H R
Reagents: (1) H2SO4, H2O, ∆, then (2) ∆; etc. or LiI, DMF, ∆;

LiBr, Me2SO, H2O, ∆; etc. (Krapcho)
Worked Problem
16-3 Give a reasonable mechanism for the transformation below.
O 1) NaOEt, EtOH O
2) MeI Et
CO2Et Me CO2Et
3) NaOEt, EtOH, ∆
4) EtI
§Answer on the next page.
Problem
H H H H O
HCO2Et, NaOMe
(a)
PhH, r.t.
H H H H
OTES
CO2Me
TBSO LDA, THF, –78°C

(b) O
O H
O O
O

Ac
N
CO2Me
NaOMe, MeOH, ∆
(c) CO2Me
CN KOBut, t-BuOH
(d) 85°C, 2.5 h
O
H CN
References: (a) J. Am. Chem. Soc. 2004, 126, 15664. (b) J. Am. Chem. Soc. 1994, 116, 1597, 1599.
(c) Tetrahedron 1963, 19, 247. (d) J. Am. Chem. Soc. 2000, 122, 4526.
16.5 The Wittig, Horner-Wadsworth-Emmons,

and Related Reactions
The regiochemical control of the location of the alkene π bond in reactions such as the
aldol condensation and its analogs is a result of the fact that one product (the conjugated
ketone or aldehyde) is stabilized by conjugation and the isomeric products are not.
When forming a new alkene π bond in a molecule where there is not this possibility of
conjugation, control of regiochemistry is often problematic. A good example is provided
by the synthesis of methylene-cyclohexane by an elimination reaction. If one attempts
to prepare this alkene by an E1 or E2 reaction (as in Example 16.49), the major product
formed is 1-methyl-cyclohexene (as predicted by Zaitsev’s rule). Similarly, acid-catalyzed
dehydration of cyclohexylmethanol also gives 1-methylcyclohexene as the major
§ Answer to Worked Problem

This reaction is deceptively simple. The first step must result in removal of the most acidic proton—from
between the two carbonyl groups—to give anion B and not the removal of the less acidic α proton from the
ketone to give the isomeric anion B' (even though this would appear to be the simplest way to get the
alkylation pattern required). The alkylation of this anion will now put the methyl group between the car-
bonyl groups, in ketoester C. This means that somehow the ester and ketone carbonyl groups must be ex-
changed before the final product is obtained. This is, in fact, fairly straightforward when one remembers
that the Dieckmann condensation—like the Claisen condensation—is reversible, and that it is the depro-
tonation of the β-ketoester that renders the reaction effectively irreversible. Consequently, the addition of
ethoxide anion to the first alkylated product will lead to opening of the ring to give enolate E, which will
undergo proton transfer (either intramolecularly or intermolecularly) to the enolate F, which closes to the
β-ketoester H. Deprotonation of H gives the anion I, which then reacts with the ethyl iodide to give the
observed product J.
I
O O Me EtO O O H
Me EtO Me CO2Et
CO2Et CO2Et CO2Et CO2Et
CO2Et
H
A OEt B C D Me
O E
NOT CO2Et
B'
EtO2C
I
O Et O O O OEt
EtO2C Me EtO2C Me EtO2C Me EtO2C Me O
Et H
OEt
J I H G Me
EtO
F

product. In fact, the only elimination reaction guaranteed to give the desired methy-
lenecyclohexane is the base-promoted E2 elimination of a cyclohexylmethyl halide or its
equivalent (Example 16.50).
Me X Me CH2OH
E1 or E2 H2SO4, ∆
(16.49)
CH2X CH2
KOBut (16.50)
t-BuOH
The solution to this problem lies in using a nucleophile that carries with it a leaving
group that can be eliminated in an E2 reaction following the initial addition. As reported
by Wittig46 in the mid-1950s,47 phosphonium ylides, or phosphoranes, are just such a class
of nucleophiles. These reagents, which we discussed at some length in Section 11.3, are
stabilized carbanions where the stabilization of the carbanion center may be due to dπ -pπ
backbonding, or to delocalization of the lone pair on carbon into the low-lying σ* orbitals
of the adjacent C—P bonds (Figure 16.3). The product of the reaction between a phospho-
nium ylide and an aldehyde or ketone is an alkene, where the new C—C double bond is
formed between the carbonyl carbon and the ylide carbon of the phosphorane. The reac-
tion has been reviewed.48
The first stage of the Wittig reaction involves the formation of a four-membered cyclic
compound called an oxaphosphetane. In the classical mechanism for the reaction, the for-
mation of the oxaphosphetane is preceded by addition of the phosphorane to the carbonyl
compound to give a betaine.49 The mechanism of oxaphosphetane formation is still open to
interpretation today,50 and both concerted and stepwise mechanisms have been proposed.
Based on extensive nuclear magnetic resonance studies of the reaction, Vedejs has pro-
posed that the oxaphosphetane is formed by an asynchronous, concerted [2 + 2] cycload-
dition through a puckered transition state (16.51) that minimizes the steric hindrance
between the two largest groups in the activated complex (Figure 16.4). In this model, the
two larger groups are located to minimize the steric crowding of the phenyl groups on
phosphorus, which places the group R of the aldehyde in a quasi-bowsprit p osition in the
Figure 16.3 The models of the

C—X bond in heteroatom-
R R
stabilized carbanions. The X
X R 3P R3P
resonance description of the R R
bonding is shown to the right
of the orbital diagrams. dπ-pπ σ-σ*
46. Georg Wittig (1897–1987) completed his graduate studies at Marburg (habilitation 1926) after returning
from internment as a prisoner of war in England. He also began his independent career there before moving to
to Braunschweig (1932), Freibourg (1937), Tübingen (1944), and Heidelberg (1956). He retired in 1967. Wittig
shared the Nobel Prize in Chemistry for 1980 with H.C. Brown. More biographical information is available in
his obituary (Tochtermann, W. Liebigs Ann. 1997, I-XXI) and at the web site of the Nobel Foundation.
47. (a) Wittig, G.; Schöllkopf, U. Chem. Ber. 1954, 87, 1318. (b) Wittig, G.; Haag, W. Chem. Ber. 1955, 88, 1654.
48. (a) Maercker, A. Org. React. 1965, 14, 270. (b) Maryanoff, B.E.; Reitz, A.B. Chem. Rev. 1989, 89, 863.
(c) Edmonds, M.; Abell, A. In Takeda, T., Ed. Modern Carbonyl Olefination (Wiley-VCH: Weinheim, 2004); 1.
49. Reviews: (a) Trippett, S. Quart. Rev. 1963, 17, 406. (b) Trippett, S. Pure Appl. Chem. 1964, 9, 255. (c) Wittig, G.
Pure Appl. Chem. 1964, 9, 245.
50. For studies of the mechanism of the Wittig reaction, see: (a) Vedejs, E.; Marth, C.F.; Ruggeri, R. J. Am.
Chem. Soc. 1988 110, 3940. (b) Vedejs, E.; Marth, C.F. J. Am. Chem. Soc. 1988, 110, 3948. (c) Vedejs, E.; Meier,
G.P.; Snoble, K.A.J. J. Am. Chem. Soc. 1981, 103, 2823. (d) Vedejs, E.; Fleck, T.J. J. Am. Chem. Soc. 1989, 111, 5861.
(e) Vedejs, E.; Marth, C.F. J. Am. Chem. Soc. 1990, 112, 3905.

R' ‡ Figure 16.4 Rationalizing

O R the stereochemistry of the
R' concerted mechanism for
H H H R H
P H Ph the Wittig reaction
O R R' R
H Ph P Ph3P O R' H
Ph H
(16.52) (16.53)
(16.51)
four-membered ring, and the group R' of the phosphorane in a quasi-flagpole position, anti
to one phenyl group. The net result of this transition state model is that the Z alkene is pre-
dicted to be the major product of the reaction, which is what is observed. In one particu-
larly interesting application of the Wittig reaction, White used the phosphorane first as a
nucleophile to displace an allylic halide and then converted the resultant phosphonium salt
to the phosphorane. He then carried out a Wittig olefination with that phosphorane to
obtain the Z alkene during a synthesis of a number of related epothilones (16.54).51
S
N
S
N 1) Ph3P=CH2, THF, –78°C
2) LiHMDS, THF, –78°C
TBSO (16.54)
MeO2C
TBSO TBSO O
3) MeO2C
O
Br
TBSO CHO TBSO OTBS
(73% overall)
O
H H
Ph3P=CH2
(16.55)52
(96%)
H H H H
CO2Et CO2Et
CHO
Ph3P=CHMe 53
(16.56)
O O THF, –78 to 20°C O O
(69%)
O
CO2Me CO2Me
H Ph3P=CH2
H 54
Et2O, 0°C to r.t., 6h (16.57)
(59%)
The Wittig reaction has become the method of choice for forming alkenes. Its syn-
thetic importance is due to its generality and to the fact that the alkene is formed with
the double bond located in a predictable position—between the carbonyl carbon of the
51. White, J.D.; Carter, R.G.; Sundermann, K.F.; Wartmann, M. J. Am. Chem. Soc. 2001, 123, 5407.
52. Ramig, K.; Kuzemko, M.A.; McNamara, K.; Cohen, T. J. Org. Chem. 1992, 57, 1968.
53. Calo, F.; Richardson, J.; Barrett, A.G.M. Org. Lett. 2009, 11, 4910.
54. Srinivasa Reddy, D. Org. Lett. 2004, 6, 3345.

aldehyde or ketone and the carbanion carbon of the ylide. As illustrated by Examples 16.55
and 16.57, it remains one of the best methods for the introduction of a terminal methylene
group into a molecule.
When the aldehyde can form a cyclic hemiacetal, the compound will preferentially
exist as the hemiacetal if the ring is five- or six-membered. Even so, when such aldehydes
are treated with a phosphorane, the product formed is just what one would predict if the
aldehyde existed as the open-chain hydroxyaldehyde form. Note, again, that the stereo-
chemistry of the alkene double bond is Z, just as one would predict for the reaction of the
open-chain hydroxyaldehyde with the phosphorane—as shown by a step in the synthesis
of thromboxane B2 (reaction 16.58).55
H MeO OH
MeO O CO2H
OH CO2H Br O
O Ph3P
H (16.58)
NaCH2SOMe, Me2SO
(78%, mixture of isomers)
HO C5H11 HO C5H11
The ylides we have discussed to this point are stabilized only by the adjacent phospho-
nium group and are known as unstabilized ylides. If the carbanion center is conjugated
with an electron-withdrawing group such as a carbonyl group, a stabilized ylide is ob-
tained. This relatively small change in the electronic structure of the ylide leads to pro-
found changes in the outcome of the reaction: stabilized ylides strongly favor the formation
of the E alkene, as illustrated by Example 16.59.56
CHO
H CHO
O Ph3P CHO Br H
O (16.59)
H
BuLi, Et2O H
CO2Me
CO2Me
The Schlosser Modification

The propensity of unstabilized ylides to give the Z alkene can be reversed by carrying out
the reaction in the presence of an excess of a soluble salt and one equivalent of an alkyl-
lithium (preferably phenyllithium) at low temperature (where the fragmentation of the
oxaphosphetane occurs only very slowly). This reaction was first described by Schlosser
and Christmann.57
The rationalization of the Schlosser modification (Figure 16.5) is that adding the alkyl-
lithium to the oxaphosphetane (16.60) leads to the formation of a β-oxidophosphorane
(16.61) that on treatment with an electrophile (which may be a proton58 or another electro-
phile59) gives the stereoisomeric oxaphosphetane (16.62), This then fragments normally to
give the E alkene. The effect may be exaggerated by the addition of a soluble lithium salt,
which is believed to open the oxaphosphetane to give a lithium betaine (16.64) that does not
55. Nelson, N.A.; Jackson, R.W. Tetrahedron Lett. 1976, 3275.

56. Baker, S.R.; Clissold, D.W.; McKillop, A. Tetrahedron Lett. 1988, 29, 991.
57. (a) Schlosser, M.; Christmann, K.F. Angew. Chem. Int. Ed. Engl. 1966, 5, 126.
For reviews, see: (b) Gosney, I.; Rowley, A.G. In Cadogan, J.I.G, Ed. Organophosphorus Reagents in Organic
Synthesis (Academic Press: New York, 1979) 17. (c) Maryanoff, B.E.; Reitz, A.B. Chem. Rev. 1989, 89, 863.
(d) Vedejs, E.; Peterson, M.J. Top. Stereochem. 1994, 21, 1.
58. Wang, Q.; Deredas, D.; Huynh, C.; Schlosser, M. Chem. Eur. J. 2003, 9, 570.
59. (a) Schlosser, M.; Christmann, K.F. Synthesis 1969, 38. (b) Corey, E.J.; Yamamoto, H. J. Am. Chem. Soc.
1970, 92, 226, corrigendum, 3523. (c) Hodgson, D.M.; Arif, T. J. Am. Chem. Soc. 2008, 130, 16500. (d) Hodgson,
D.M.; Arif, T. Org. Lett. 2010, 12, 4204.

H R H X Figure 16.5 The possible

H R' R
H H outcomes of the Schlosser
Ph3P Ph3P (16.64)
R H R' modification of the
O R' OLi Wittig reaction
(16.65)
LiX RLi
R
R R' R H
H RLi H
Ph3P (16.61)
Ph3P low T R'
H H O R' O
(16.60) E , low T
E R' E R
H
Ph3P (16.62)
R H O R'
(16.63)
proceed to the alkene but can then be deprotonated to give the β-oxidophosphorane (16.61).
Reprotonation of the β-oxidophosphorane, or trapping with an aldehyde59b and subsequent
reprotonation, gives the oxaphosphetane (16.65). It then fragments to the alkene with the
alkyl groups from the phosphorane and the aldehyde trans to each other. The same stereo-
chemical outcome is obtained when the electrophile is a bromomethyl ester.59d
When the β-oxidophosphorane is trapped by a halogen donor (e.g., Example 16.66) or
by a carbon electrophile larger than formaldehyde (e.g., Example 16.67), E-haloalkenes are
obtained unless the original ylide was ethylidenetriphenylphosphorane. The origins of
this size-dependent reversal of stereochemistry on changing the electrophile are not yet
understood, but the reaction does provide an excellent source of E-haloalkenes by this
reaction.59c
1) PrCH=PPh3 (1.0 eq.), LiBr (2 eq).
THF, –78°C Br
Ph (16.66)
Ph CHO
2) PhLi (1.0 eq.), Bu2O, –78°C to r.t.
3) BrCF2CF2Br, Bu2O, –78°C to r.t.
(59%; Z/E 92:8)
1) PrCH=PPh3 (1.0 eq.), LiBr (2 eq).

THF, –78°C Ph
Ph CHO (16.67)
2) PhLi (1.0 eq.), Bu2O, –78°C to r.t.
3) BrCH2OAc, Bu2O, –78°C to r.t. OAc
(71%; Z/E 92:8)
The stereochemistry of the Schlosser modification of the Wittig reaction is provided by

the computational finding, using density functional theory, that the β-oxidophosphorane
is not computationally stable at the B3LYP/6-311++G(2df,p) level, but minimizes to the
oxaphosphetane anion. In that anion (Figure 16.6), the four-membered ring is close to
planar, with the oxygen atom and one of the phenyl groups in the axial positions on the
pentacoordinate phosphorus. The two equatorial phenyl groups are arranged approxi-
mately symmetrically about the plane of the four-membered ring. In this structure, the
nucleophilic carbon is rigorously planar, so the adjacent alkyl group (derived from the al-
dehyde) directs the electrophile to the opposite face of the oxaphosphetane, which leads to
the alkyl group from the aldehyde and the electrophile becoming trans to each other in the
product alkene.60
60. Lewis, D.E. unpublished results.

Figure 16.6 The
computational model of an
oxaphosphetane
conjugate base
The Horner-Wadsworth-Emmons Reaction

One practical drawback of the Wittig reaction is the fact that the by-product, triphenyl-
phosphine oxide, can be difficult to remove from the alkene. For this reason, considerable
effort went into the development of alternative alkene-forming reactions in which the
product was much easier to purify. One way to accomplish this was by means of an anionic
phosphorus reagent that would give an anionic, water-soluble phosphorus-containing
product. In addition, many ylides, especially stabilized ylides, are not as nucleophilic as
one might expect, which also limits their usefulness. A carbanion stabilized by an adja-
cent neutral phosphorus-based group was expected to be a stronger nucleophile and this
was, in fact, found to be the case.
The most widely used of this type of variant of the Wittig reaction is the Horner-
Wadsworth-Emmons reaction, often referred to as the HWE reaction,61 in which the nuc-
leophile is the anion of a phosphonate ester instead of a phosphorus ylide (Examples 16.68
and 16.69). The original reaction was described by Horner,62 but the scope of reaction was
much expanded by Wadsworth and Emmons.63 The reaction was originally known as the
Wadsworth-Emmons reaction, but today it bears all three names. In contrast to the reac-
tions of unstabilized phosphorus ylides, which tend to give the Z alkene, the HWE reaction
usually gives the E isomer of the alkene as the predominant product (e. g., Example 16.70).
OPMB O OPMB
MeO2C P(OMe)2
(16.68)64
KHMDS
O CO2Me
61. Reviews: (a) Wadsworth, W. S., Jr. Org. React. 1977, 25, 73. (b) Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74,
87. (c) Kelley, S.E. In. Trost, B.M.; Fleming, I., Eds. Comprehensive Organic Synthesis (Pergamon: Oxford, 1991);
vol. 1, 729. (d) Maryanoff, B.E.; Reitz, A.B. Chem. Rev. 1989, 89, 863. (e) Walker, B.J. In Cadogan, J.I.G., Ed.
Organophosphorus Reagents in Organic Synthesis (Academic Press: New York, 1979), 155. (f) Nicolaou, K.C.;
Härter, M.W.; Gunzner, J.L.; Nadin, A. Liebigs Ann./Recueil 1997, 1283.
Biographical sketches of Horner, Wadsworth, and Emmons can be found in Section 11.3 of this book.
62. (a) Horner, L.; Hoffmann, H.M.R.; Wippel, H.G. Chem. Ber. 1958, 91, 61. (b) Horner, L.; Hoffmann, H. M.
R.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499.
63. Wadsworth, W.S., Jr.; Emmons, W.D. J. Am. Chem. Soc. 1961, 83, 1733; Org. Synth. 1973, Coll. Vol. 5, 547.
64. Menche, D.; Hassfels, J.; Li, J.; Mayer, K.; Rudolph, S. J. Org. Chem. 2009, 74, 7220.

O CO2Me
CHO (EtO)2P CO2Et
(16.69)65
N3 BuLi, THF, –78°C
(75%) N3
CO2Me
O
O O
CHO (MeO)2P CO2Me (71%) 66
(16.70)
NaH, THF, r.t.; then
add aldehyde, 0°C O
CO2Me
(17%)
Phosphorus-based Condensation Reactions to Give Alkynes

The reaction between an α-diazophosphonate and a carbonyl compound in the presence of
a base gives an alkyne (e.g., Example 16.7167). This reaction is generally known today as the
Seyferth-Gilbert homologation.68 The strongly basic conditions of this reaction can be circum-
vented by using the Bestmann reagent, which allows the reaction to be carried out in methanol
solution, using potassium69 or cesium70 carbonate as the base (Example 16.7271). Less reactive
aldehydes require the use of cesium carbonate. The mechanism of the Bestmann variant of the
reaction is shown in Figure 16.7. The addition of the Bestmann reagent (16.73) to the carbonyl
compound gives a zwitterion (16.74) that closes to the oxaphosphetane (16.75). Fragmentation
of the oxaphosphetane gives the vinyldiazonium ion 16.76, which then undergoes a fragmenta-
tion by base, with concomitant loss of dinitrogen, to give the vinylalkylidene 16.77. The rear-
rangement of this carbene then gives the alkyne product (Example 16.78). The acetyl group,
which is lost as methyl acetate, facilitates the addition to the aldehyde or ketone.
TMSO TMSO
O
(MeO)2PCH=N2
(16.71)
OTBS CHO KOBut, THF, –30°C OTBS
(91%)
H
O
(MeO)2P
O
N2
K2CO3, MeOH, r.t. H (16.72)
O N CHO O N
(92%)
Another reaction sequence that can be used to convert an aldehyde into an alkyne is the
Corey-Fuchs72 or Ramirez-Corey-Fuchs reaction.73 In this reaction, the aldehyde is first
65. Hudlicky, T.; Frazier, J.O.; Seoane, G.; Tiedje, M.; Seoane, A.; Kwart, L.D.; Beal, C. J. Am. Chem. Soc. 1986,
108, 3755.
66. Snowden, R.L. Tetarhedron 1986, 42, 3277.
67. Marshall, J.A.; Bourbeau, M.P. J. Org. Chem. 2002, 67, 2751.
68. (a) Seyferth, D.; Marmor, R.S.; Hilbert, P. J. Org. Chem. 1971, 36, 1379. (b) Gilbert, J.C.; Weerasooriya, U.
J. Org. Chem. 1982, 47, 1837. (c) Brown, D.G.; Velthuisen, E.J.; Commerford, J.R.; Brisbois, R.G.; Hoye, T.R.
J. Org. Chem. 1996, 61, 2540.
69. (a) Müller, S.; Liepold, B.; Roth, G.; Bestmann, H.J. Synlett 1996, 521. (b) Roth, G.; Liepold, B.; Müller, S.;
Bestmann, H.J. Synthesis 2004, 59.
70. Bondarenko, L.; Dix, I.; Hinrichs, H.; Hopf, H. Synthesis 2004, 2751.
71. Torssell, S.; Wanngren, E.; Somfai, P. J. Org. Chem. 2007, 72, 4246.
72. (a) Corey, E.J.; Fuchs, P.L. Tetrahedron Lett. 1972, 13, 3769. (b) Mori, M.; Tonogaki, K.; Kinoshita, A. Org.
Synth. 2005, 81, 1. (c) Marshall, J.A.; Yanik, M.M.; Adams, N.D.; Ellis, K.C.; Chobanian, H.R. Org. Synth. 2005, 81, 157.
73. Desai, N.B.; McKelvie, N.; Ramirez, F. J. Am. Chem. Soc. 1962, 84, 1745.

Figure 16.7 The reaction path R O

of the Bestmann O O R'
modification of the Seyferth- N N N N O N2
Gilbert homologation O P(OMe)2 O P(OMe)2 O P(OMe)2
(16.73)
(16.74)
OMe R O
R O R'
R R' R N2
O
R' P OMe
(16.78) R' N2 MeO O
(16.77)
(16.76) (16.75)
converted into a 1,1-dibromoalkene, which is then treated with two equivalents of butyllith-
ium to give the lithium alkynide. This may be protonated to give the terminal alkyne or
trapped with another electrophile to give an internal alkyne, as shown in Example 16.79,74
where the original Seyferth-Gilbert reagent was ineffective.75
1) Ph3P (2.2 eq), CBr4 (1.1 eq)
CH2Cl2, 0°C
(16.79)
2) n-BuLi, THF, —78°C
CHO 3) ClCO2Me, –78°C to r.t.
(57% overall)
CO2Me
Reaction Synopses
Wittig Reaction
R3
PPh3
R' R' R3
R2
O
base
R R R2

Stereochemistry: R=alkyl, predominantly Z; R = COR, CO2R, CHO, CN, Ph,
etc.; predominantly E
Horner-Wadsworth-Emmons Reaction
R3 O
P X
R' R' R3
R2 X
O
base
R R R2

X = alkyl, Ph (Horner); X = alkoxy (Wadsworth-Emmons)
Stereochemistry: predominantly E
74. Lewis, D.E.; Rigby, H.L. Tetrahedron Lett. 1985, 26, 3437.
75. Rigby, H.L. Ph.D. Dissertation, Baylor University, 1985.

Schlosser Modification of the Wittig Reaction

H H R'
O
R R H
Reagents: (1) Ph3P=CHR', –78°C; (2) BuLi, –78°C; (3) HCl, Et2O
Stereochemistry: predominantly (almost exclusively) E
Intermediate anion that can be intercepted by electrophiles (H2C=O; BrCH2CO2Et;
BrCF2CF2Br; etc.).
Seyferth-Gilbert Homologation
R'
O R R'
R
Reagents: (MeO)2P(O)CH=N2, KOBut, THF; or (MeO)2P(O)C(=N2)COMe,

K2CO3, MeOH
Corey-Fuchs Homologation
H
O R H
R
Reagents: (1) Ph3P, CBr4, CH2Cl2; (2) BuLi, THF, –78°C

Alkynide anion may be intercepted by a variety of electrophiles.
Worked Problem
16-4 What is the major organic product of each of the reactions involving isobutyral-
dehyde in the list below?
(a) (1) MeCHCH2PPh3Br, n-BuLi, THF, –30°C; (2) Me2CHCHO, –30°C;
(3) warm to 20°C
(b) (1) MeCHCH2PPh3Br, BuLi, LiBr (2 eq), Et2O, –30°C; (2) Me2CHCHO, –30°C;
(3) warm to 20°C
(c) (1) MeCHCH2PPh3Br, BuLi, LiBr (2 eq), Et2O, –30°C; (2) Me2CHCHO, –78°C;
(3) PhLi, Et2O, –78°C; (4) HCl, Et2O, –78°C to r.t.
(d) (1) MeCHCH2PPh3Br, BuLi, LiBr (2 eq), Et2O, –30°C; (2) Me2CHCHO, –78°C;
(3) PhLi, Et2O, –78°C; (4) CH2O, –78°C; (5) HCl, Et2O, –78°C to r.t.
(e) (1) MeCHCH2PPh3Br, BuLi, LiBr (2 eq), Et2O, –30°C; (2) Me2CHCHO, –78°C;
(3) PhLi, Et2O, –78°C; (4) BrCF2CF2Br, –78°C to r.t.
Worked Problem
16-5 Provide the missing reagents a to e in the diagram below. Where there is more
than one alternative for a reagent to complete the transformation, give at least
two alternative reagents to complete the transformation.
(continues)

O
a b
CHO
e c
H d
CO2Me
‡Answers below.
Problem
16-3 What is the major organic product expected from each of the reactions below?
NHBoc
O
(EtO)2P SMe
(a) NaH, THF
CHO
N
PMB

H H H H
H H
(a) (b) and (c)
H H
H H
Br
(d) (e)
OH
(a) This is a simple Wittig reaction between an aldehyde and an unstabilized ylide. The major product will
be the Z isomer.
(b) The added lithium bromide will degrade the stereoselectivity of this reaction; the product will be a mix-
ture of the E and Z isomers.
(c) This is the Schlosser modification of the Wittig reaction. It will give the E alkene as the major product.
(d) This is an intercepted Schlosser reaction, where the electrophile is formaldehyde. The major product will
be the primary alcohol where the alkyl groups from the aldehyde and the ylide are trans to each other—the Z
isomer in this case.
(e) This is an intercepted Schlosser reaction where the electrophile is a halogen. In these reactions, the prod-
uct is the E-haloalkene.
‡ Answer to Worked Problem

(a) Ph3PCH2CH2CH2CH3Br, BuLi, THF, –30°C. The Z isomer is required, so the Wittig reaction with an
unstabilized ylide is the best choice.
(b) EtCOCH=PPh 3, CH 2Cl 2, r.t. or EtCOCH 2P(O)(OEt)2, NaH, THF. The E isomer of the conjugated
ketone can be formed by a Wittig reaction with a stabilized ylide or by the Horner-Wadsworth-
Emmons reaction.
(c) 1) Ph3PCH2CH2CH2CH3Br, BuLi, THF, –78°C; 2) BuLi, THF, –78°C; 3) HCl, Et 2O, –78 to –20°C. The E
isomer is required, so the Schlosser modification of the Wittig reaction with an unstabilized ylide is the
best choice.
(d) MeOCOCH=PPh 3, CH 2Cl 2, r.t. or MeOCOCH 2P(O)(OEt)2, NaH, THF. The E isomer of the conjugated
ester can be formed by a Wittig reaction with a stabilized ylide or by the Horner-Wadsworth-Emmons
reaction.
(e) (MeO)2P(O)CH=N2, KOBut or (MeO)2P(O)C(Ac)=N2, K 2CO3, MeOH, or (1) Ph3P, CBr4, CH2Cl 2; (2) BuLi,
THF, –78°C; (3) HCl, Et 2O, –78°C to r.t. The alkyne may be obtained using the Seyferth-Gilbert reagent, the
Bestmann reagent, or by the Corey-Fuchs procedure.

OTBS
CHO O
(F3CH2CO)2P CO2Me
(b) HMDS, 18-crown-6
OPMB
O O
(F3CH2CO)2P
(c) KOBut
CHO
OH
MeO Ph3P=C(Me)CO2Me
(d)
O
CHO Ph3P=CH2, THF, 23°C

(e)
N OMe
N CHO [Ph3PCH2CH2CCl3]Cl
O
(f) NaHMDS, THF
(exces reagent)
CHO
1) Ph3P=CH2, THF, 0‚C

2) s-BuLi, –78°C
(g)
O 3) H2C=O, 0°C to r.t.
4) H2O, hexane
O H OPMB
H NaHMDS
(h) O THF, –78 to 0°C
P(OEt)2
PMBO CHO O O
O
1) Ph3P (6 eq), CBr4 (3 eq)

K2CO3 (1 eq), CH2Cl2
(i)
Ph CHO 2) BuLi (2.4 eq), –78°C
OMe OMe O
MeO
Me (MeO)2PCH=N2
(j) Me H
O KOBut
OMe
HO
References: (a) J. Am. Chem. Soc. 2009, 131, 13606. (b) J. Org. Chem. 2009, 74, 7220. (c) J. Am. Chem.
Soc. 2008, 130, 4421. (d) Org. Lett. 2007, 9, 4619. (e) J. Am. Chem. Soc. 2006, 128, 8734. (f) J. Am.
Chem. Soc., 2006, 128, 12656. (g) Org. Lett. 2005, 7, 4803. (h) J. Am. Chem. Soc. 2003, 125, 13022.
(i) Org. Lett. 2004, 6, 3245. (j) Angew. Chem. 2005, 117, 3551.
Silicon-based Olefination: The Peterson Reaction76

Much of the chemistry of silicon-stabilized carbanions was discussed in Chapter 11, so this
discussion will be rather abbreviated, and you are referred to that chapter for more detail.
One of the major uses of these anions is a two-step process involving sequential addition
76. (a) Peterson, D.J. J. Org. Chem. 1968, 33, 780.

Reviews: (b) Birkofer, L.; Stiehl, O. Top. Curr. Chem. 1980, 88, 58. (c) Ager, D. J. Synthesis 1984, 384. (d) Ager,
D. J. Org. React. 1990, 38, 1. (e) Chan, T.H. Acc. Chem. Res. 1977, 10, 442.
Biographical information about Peterson is provided in Section 11.3.

to the carbonyl group and elimination to give the alkene; the reaction is known as the
Peterson olefination. The initial adduct will fragment under either acidic or basic condi-
tions, and the fact that the stereochemistry of the two reactions differs allows one to obtain
a single stereoisomer of the alkene from the Peterson reaction provided that the two dias-
tereoisomeric adducts can be separated. The Peterson olefination is less affected by steric
hindrance than the Wittig reaction, so it offers a useful alternative to the Wittig reaction
in reactions of hindered ketones (e.g., Example 16.8077).
O PhS H
1) PhSCH2SiMe3/BuLi, THF
–23°C to 0°C, 3 h (16.80)
OH OH
TIPSO 2) NaHCO3, H2O TIPSO
Me N N Me (64%) Me N N Me
E:Z = 1.5:1
When the β-hydroxyalkylsilane is treated with strong base in the second step of the
Peterson olefination, the elimination occurs by a concerted mechanism with syn stereo-
chemistry. Conversely, when the adduct is treated with acid, there is a silicon-assisted E1
elimination that leads to overall anti elimination. The Peterson olefination has been used
recently as a method for the introduction of enal functionality into a molecule by means
of an intermediate β-hydroxy-α-silylimine, as shown in Example 16.81.78 Note how the
trifluoroacetic acid serves both as the acidic reagent to generate the alkene π bond, as well
as the acid catalyst for the hydrolysis of the imine.
Me N-c-C6H11, s-BuLi
1)
Me3Si H
CHO CHO (16.81)
2) CF3CO2H, H2O
Ph Ph
(81% overall)
Sulfur-based Olefination
The Julia-Lythgoe reaction79
The Julia-Lythgoe olefination is a two-step sequence involving sequential nucleophilic
addition of a sulfone anion to the carbonyl compound and reductive elimination of the
β-hydroxysulfone. The reaction shows a strong propensity to give the alkene where the
two largest groups are trans to each other. The mechanism of the reductive elimination is
believed to occur by two sequential single-electron transfers, although the mechanism
depends on the exact identity of the reducing agent.80
A more useful variant of this reaction, that avoids the need for the reducing agent, is
the Julia-Kocieńsky olefination,81 whose mechanism is shown in Figure 16.8. In the reac-
tion, the initial nucleophilic addition of the sulfone anion (16.82) to the carbonyl group is
followed by intramolecular addition of the alkoxide anion (16.83) to the C—N π bond of
77. Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura, N.; Morihira, K.; Kuwajima,
K. J. Am. Chem. Soc. 2000, 122, 3811.
78. Zeng, X.; Zeng, F.; Negishi, E. Org. Lett. 2004, 6, 3245.
79. (a) Julia, M.; Arnould, D. Bull. Soc. Chim. Fr. 1973, 743. (b) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973,
49, 4833. (c) Julia, M.; Launay, M.; Stacino, J.-P.; Verpeaux, J.-N. Tetrahedron Lett. 1982, 23, 2465. (d) Kocienski,
P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin Trans. 1 1978, 829. (e) Kocienski , P.J. ; Lythgoe, B.; Waterhouse,
I. J. Chem. Soc., Perkin Trans. 1 1980, 1045.
Reviews: (f) Kocieński, P.J. Phosphorus and Sulfur 1985, 24, 97. (g) Kelley, S.E. In. Trost, B.M.; Fleming, I.,
Eds. Comprehensive Organic Synthesis (Pergamon: Oxford, 1991); vol. 1, 729.
80. Keck, G.E.; Savin, K.A.; Weglarz, M.A. J. Org. Chem. 1995, 60, 3194.
81. (a) Baudin, J.B.; Hareau, G.; Julia, S.A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175. (b) Blakemore, P.R.; Cole,
W.J.; Kocieński, P.J.; Morley, A. Synlett 1998, 26.

R4 Figure 16.8 Mechanism of

O R4 N R3 O
S the Julia-Kocieński reaction
R2
R3 S R2
R1 S S N
R1
O O O O
(16.82) (16.83)
O
O S R3 R R4
4
S R3 O S
(16.85) R1 O
R2 R2
N S N
R1
O O
(16.84)
R2 R4
R1 R3
the heterocycle to give a cyclic orthocarbonic acid derivative (16.84) that then eliminates
a sulfinic acid as the leaving group. Fragmentation of the β-alkoxysulfinate (16.85) then
gives the product alkene. The conditions of this reaction allow it to be used with substrates
sensitive to reduction, as illustrated by Example 16.86.82
H
H CHO H
H
H H
H H NaHDMS, THF H H
H DMF, –60°C H
H H (16.86)
H (92%)
TIPSO H O O H H
H H
S S
H H
H
N
TIPSO H
The Ramberg-Bäcklund Reaction83

In 1940, Swedish chemists Ludwig Ramberg and Birger Bäcklund reported that the treat-
ment of α-halosulfones with strong base led to the formation of an alkene. This product
arises from intramolecular displacement of the halide, followed by extrusion of sulfur
dioxide from the resultant thiirane dioxide. The reaction usually yields a mixture of both
E and Z isomers. In the modern procedure, the sulfone is treated with a halogenating
agent (often CF2Br2) and strong base. The reaction can be applied to the synthesis of both
small and large rings, as illustrated by Examples 16.87 and 16.88.
Cl
O2S
KOBut, THF, 0°C (16.87)84
(54%)
Boc Boc
N t
N
KOBu , THF
(16.88)85
(97%)
S
Cl O2
82. Charette, A.B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327.
83. Review: Paquette, L. Org. React. 1977, 25 1.
84. Paquette, L.A.; Philips, J.C.; Wingard, R.E., Jr. J. Am. Chem. Soc. 1971, 93, 4516.
85. MaGee, D.I.; and Beck, E.J. Can. J. Chem. 2000, 78, 1060.

Transition Metal-based Reagents for Olefination

The strongly basic reaction conditions for generating methylene-triphenylphosphorane
or phosphonate anions led to the investigation of methods involving transition metals,
especially titanium, as an alternative to the Wittig reaction and its analogs. Two re-
agents, in particular, have come out of this work. One is the Tebbe reagent,86 which is
converted by a modest Lewis base to a titanium carbenoid derivative that condenses
with carbonyl groups to give methylene groups. The other is Lombardo’s reagent,87
which is an aged zinc carbenoid-titanium tetrachloride reagent that performs much the
same task.
The Tebbe Reaction

In 1978, Tebbe and coworkers reported a reaction in which a titanium complex reacted
with a carbonyl compound to give an alkene in a regiospecific reaction formally analogous
to the Wittig reaction (Figure 16.9). The initial complex (16.89) is prepared by the reaction
between titanocene dichloride and trimethylaluminum in toluene,88 followed by activa-
tion by treatment with a Lewis base (a tertiary amine or an ether solvent such as tetrahy-
drofuran) to liberate the active Schrock metallocarbene (16.90). An alternative method for
the preparation of the reagent from titanocene dichloride and methyllithium or methyl-
magnesium halides gives the Petasis reagent,89 Cp2TiMe2, which loses methane on heat-
ing to give the same Schrock metallocarbene as the Tebbe reagent. This carbene complex
then adds to the carbonyl group to give an oxatitanocyclobutane (16.91); this immediately
eliminates the titanocene oxide to give the alkene (16.92).90 Because the titanocene oxide
product reacts with the active methylenation reagent to give the heterodimer 16.93, two
equivalents of these reagents are usually required.91 Although the reaction is cleaner when
the purified Tebbe reagent is used, the reaction has been carried out using the reagent
generated in situ.92
Figure 16.9 Olefination with R

methylenetitanocene H2 Me O R
C R' R
reagents Ti CH2
Ti Al Ti H2C
Cl O R'
Me R'
(16.89) (16.90) (16.91) Cp2Ti O (16.92)
H2
Cp C Cp
Ti Ti
Cp O Cp
(16.93)
86. (a) Tebbe, F.N.; Parshall, G.W.; Reddy, G.S. J. Am. Chem. Soc. 1978, 100, 3611.
Reviews: (b) Hartley, R.C.; Li, J.; Main, C.A.; McKiernan, G.J. Tetrahedron 2007, 63, 4825. (c) Pine, S.H. Org.
React. 1993, 43, 1. (d) Beadham, I.; Micklefield, J. Curr. Org. Syn. 2005, 2, 231.
87. (a) Lombardo, L. Tetrahedron Lett. 1982, 23, 4293. (b) Lombardo, L. Org. Synth. 1987, 65, 81.
88. (a) Herrmann, W.A. Adv. Organomet. Chem. 1982, 20, 195. (b) Strauss, D.A. “μ-Chlorobis(cyclopentadi-
enyl)(dimethylaluminium)-μ-methylenetitanium.” In Encyclopedia of Reagents for Organic Synthesis. (John
Wiley: London, 2000).
89. (a) Petasis, N.A.; Bzowej, E.I. J. Am. Chem. Soc. 1990, 112, 6392. (b) Payack, J.F.; Hughes, D.L.; Cai, D.;
Cottrell, I.F.; Verhoeven, T.R. Org. Synth. 2002, 79, 19.
90. (a) Meurer, E.C.; Santos, L.S.; Pilli, R.A.; Eberlin, M.N. Org. Lett. 2003, 5, 1391. (b) Meurer, E.C.; da
Rocha, L.L.; Pilli, R.A.; Eberlin, M.N.; Santos, L.S. Rapid Commun. Mass Spectrom. 2006, 20, 2626.
91. (a) Hughes, D.L.; Payack, J.F.; Cai, D.; Verhoeven, T.R.; Reider, P.J. Organometallics 1996, 15, 663.
(b) Payack, J.F.; Huffman, M.A.; Cai, D.W.; Hughes, D.L.; Collins, P.C.; Johnson, B.K.; Cottrell, I.F.; Tuma, L.D.
Org. Process Res. Dev. 2004, 8, 256.
92. Cannizzo, L.F.; Grubbs, R.H. J. Org. Chem. 1985, 50, 2386.

CO2Me
OMe
Tebbe reagent
(16.94)
THF, –40°C
N N
Boc Boc
The strongly oxophilic nature of the titanium atom appears to provide the driving force for
this reaction, which allows the methylenation of ketones, and aldehydes, but also (in contrast
to the Wittig and HWE reactions) the methylenation of esters to enol ethers,93 as shown in
Example 16.94,94 and amides to enamines. Generally speaking, the reactivity of carbonyl com-
pounds toward the Tebbe reagent is as expected for reactions with a carbon nucleophile:
RCH=O > R 2C=O > RCO2R > RCONR 2
The mild conditions of the reaction mean that chiral aldehydes and ketones can be
converted to the alkene without racemization. It also means that compounds with sensi-
tive functionality can be converted to alkenes under conditions where the Wittig and sim-
ilar reactions lead to undesired side reactions. Example 16.95, which is taken from Evans’
synthesis of (+)-azaspiracid-1,.95 illustrates the use of these reagents with such a substrate.
H Teoc H Teoc
O O
O N O N
O Tebbe reagent O
O H H
pyridine, PhMe, –40°C (16.95)
O O
PhSO2 PhSO2
Lombardo’s reagent reacts rapidly with ketones to give methylene compounds. Like the
Tebbe reagent, it is a very mild reagent that tolerates sensitive functionality well, as shown
by Example 16.96.96 With unhindered aldehydes, the reaction is often accompanied by pin-
acol coupling in a McMurry-type reaction, so the reaction is much more useful in reactions
with ketones, or with hindered aldehydes, where the pinacol dimerization is slower.
CHO
MeO Zn, CH2Br2, TiCl4 MeO (16.96)
MeO CH2Cl2 MeO
O CO2Me O CO2Me
(63%)
Reaction Synopses
Peterson Olefination
R3
R2 SiMe3
R'
M R' R3 acid or R' R3
O R R2 base
R HO SiMe3 R R2
M = Li, Mg, etc.

(continues)
93. Pine, S.H.; Kim, G.; Lee, V. Org. Synth. 1993, Coll. Vol. 8, 512.
94. Mann, E.; Moisan, L.; Hou, J.-L.; Rebek, J., Jr. Tetrahedron Lett. 2008, 49, 903.
95. (a) Evans, D.A.; Dunn, T.B.; Kværnø, L.; Beauchemin, A.; Raymer, B.; Olhava, E.J.; Mulder, J.A.; Juhl, M.;
Kagechika, K.; Favor, D.A. Angew. Chem. Int. Ed. 2007, 46, 4698. (b) Evans, D.A.; Kværnø, L.; Dunn, T.B.;
Beauchemin, A.; Raymer, B.; Mulder, J.A.; Olhava, E.J.; Juhl, M.; Kagechika, K.; Favor, D.A. J. Am. Chem. Soc.
2008, 130, 16295.
96. Hsu, D.-S.; Hsu, P.-Y.; Lee, Y.-C.; Liao, C.-C. J. Org. Chem. 2008, 73, 2554.

Stereochemistry: elimination by base is syn; elimination by acid is anti. Alkene
stereochemistry can be defined by choice of reagent to frag-
ment the β-hydroxysilane.
Julia-Lythgoe Olefination
R' O R1 R' R1
O
O + S
R G R2 R R2
G = Ph or substituted phenyl
Reagents: (1) BuLi, THF; (2) add aldehyde; (3) Na(Hg), THF, ROH; etc.
or (1) BuLi, THF; (2) add aldehyde; (3) SmI2, DMPU, THF; etc.
Stereochemistry: mainly E, with two largest groups trans to each other
Julia-Kocieńsky Olefination
R' O R1 R' R1
O
O + S
R X R2 R R2
X X
X
X = N, S (tetrazoles, thiazoles, benzothiazoles)

Reagents: strong, non-nucleophilic base (LDA, BuLi, etc.)
Reduction step: not needed with this reaction
Stereochemistry: as for the Julia-Lythgoe olefination
Ramberg-Bäcklund Reaction
O O O O O O
R R
R S R R S R S
R R
X R R
R R R R R R
Reagents:
from unsubstituted sulfone: KOBut, THF, CF2Br2; etc.
from α-halosulfone: KOBut, THF
Stereochemistry: mixture of E and Z isomers obtained
Tebbe, Petasis, and Lombardo Olefinations
G Cp G
O + Ti CH2
R Cp R
G = H, R', OR', NR'2, etc.
Reagents:
Tebbe: Cp2TiCl2, Me3Al, PhMe, THF; etc.
Petasis: Cp2TiMe2, PhMe, ∆
Lombardo: Zn, CH2Br2, TiCl4, PhMe (age 3 days)

Worked Problem
16-6 In step above from the synthesis of azaspiracid-1 (Example 16.95), what would be
the possible problems if the Wittig reagent were used instead of the Tebbe reagent?
§Answer below.
Problem
16-4 What is the major organic product expected from each of the reactions below?
OHC O OMe
Zn, CH2Br2, TiCl4
(a) O
Ph
O Cp2TiMe2
(b) NC
PhMe-THF (3:2)
O
75°C, 4 h
1) Et3SiCH(Me)CH=N-c-C6H11
s-BuLi
(c) CHO
2) CF3CO2H
OTBS
polymer
1) BuLi (5 eq), PhMe, r.t., 30 min
S 2) Me2C=CHCHO (2 eq), THF, 5 h
O O
(d) 3) PhCOCl (6 eq), 15 h
4) SmI2 (9 eq), DMPU (30 eq)
H
TBSO
References: (a) J. Org. Chem. 2007, 72, 7125. (b) Org. Lett. 2008, 10, 1477. (c) Org. Lett. 2008, 10, 3223.
(d) Molecules 2006, 11, 655.
16.6 Cascade Reactions Initiated by Carbon Nucleophiles
Cascade reactions initiated by carbon nucleophiles are important synthetic methods for
the construction of complex molecules. Among the most important of these reactions are
the Robinson annelation (or Robinson annulation), the Morita-Baylis-Hillman reac-
tion, and the benzoin condensation.
§ Answer to Worked Problem

This ketone has a pair of alkoxy groups at the β position, which would make the α hydrogens of the ketone
significantly more acidic due to the inductive effect. Thus, the strongly basic ylide could, potentially, deproton-
ate the α carbon, resulting in the loss of the carbonyl group required for the methylenation. In addition, the
neopentyl-like nature of the ketone carbonyl group makes it highly hindered, a situation in which the classical
Wittig reaction frequently fails. In this case, the β-elimination to give an enone must also be considered, as
must isomerization at the anomeric carbon of the sulfone.
N SO2Ph N SO2Ph N SO2Ph

Teoc H Teoc H Teoc H
O O O O O O
O O O
H O H O H O
O O O
will not form alkene

Michael-Initiated Ring Closure

By incorporating a suitable electrophile (e.g., an alkyl halide) and a Michael acceptor at
appropriate locations in the same molecule (e.g., Example 16.97), one is able to prepare
cyclic products by a nucleophile-initiated domino reaction known as Michael-initiated
ring closure (MIRC).97 Essentially the same reaction occurs when a nucleophile carrying
a leaving group (e.g., Example 16.98) is used with a simple Michael acceptor—in the
Corey-Chaykovsky reaction,98 the leaving group (the sulfoxonium ion) and the nucleop-
hile (the enolate) are generated in the Michael addition step.
E R X E R
Nu: Nu (16.97)
CN , R2Cu(CN)Li2, enolate, etc.

E: CN, COR, CO2R; X: Cl, Br, I, OTs, epoxide, etc.
E E E
R' R'
R' (16.98)
R R
X X R
E: CN, COR, CO2R, etc.

X: SMe2, S(O)Me2, Cl, Br, I, OTs, epoxide, etc.
The Robinson annelation is an MIRC in which a cyclohexenone ring is fused onto an

existing ketone by treatment of the ketone with a base and an enone. The reaction pro-
ceeds by initial Michael addition of the enolate anion to the enone to give a new enolate
anion (16.99) that undergoes a proton shift to give the isomeric enolate 16.100. This eno-
late undergoes an intramolecular aldol addition to give the alkoxide anion 16.101, which
then gives the aldol 16.102. Dehydration then gives the new enone (16.103; Figure 16.10). In
the Robinson annelation, the enolate anion nucleophile may be replaced by an enamine,
and this occasionally improves the yield by suppressing side reactions. Two sequential
Figure 16.10 The mechanism R3

of the Robinson annelation R4 R3 R2 R4 R3 R2
Rc Rb R2 Rc Rc
R4
Rb Rb
O O
Ra O O Ra Ra
O O
R1 R1 R1
(16.99) (16.100)
R4 R3 R4 R3 R4 R3
Rc Rc Rc
R2 R2 R2
Rb Rb Rb
Ra Ra
Ra O O O
HO O
R1 R1 R1
(16.103) (16.102) (16.101)
97. (a) Little, R.D.; Dawson, J.R. Tetrahedron Lett. 1980, 21, 2609. (b) Amputch, M.A.; Matamoros, R.; Little,
R.D. Tetrahedron 1994, 50, 5591. (c) Nakache, P.; Ghera, E.; Hassner, A.P. Tetrahedron Lett. 2000, 41, 5583.

Robinson annelations were key steps in building the tetracyclic framework (Example
16.106) in Johnson’s synthesis of testosterone.99
OMe
O OMe
OMe O
NMe3
NaOMe, NaOMe,
PhH, ∆ O
O PhH, ∆ O
(16.104) (64%) (16.105) (16.106)
(34% over 2 steps)
The Morita-Baylis-Hillman and Benzoin Condensation Reactions

The Morita-Baylis-Hillman Reaction100
One fascinating variant of enolate nucleophile chemistry is provided by the Morita-Baylis-
Hillman reaction.101 In this reaction, a Michael acceptor and an aldehyde react in the pres-
ence of a tertiary amine or phosphine catalyst to form an adduct that is densely
functionalized. The mechanism of the reaction has been intensely studied, and recently
McQuade has proposed the mechanism in Figure 16.11 based on the kinetics of the reac-
tion.102 The reaction is initiated by conjugate addition of the amine or phosphine nucleop-
hile to the Michael acceptor to give a betaine (16.107), which then adds to the aldehyde to
give a new zwitterion (16.108). The reaction of this zwitterion with another molecule of the
aldehyde gives yet another new zwitterion (16.109), which now undergoes an intramolec-
ular E2 elimination to give a hemiacetal (16.110); this then eliminates a molecule of alde-
hyde to give the product (16.111).
Figure 16.11 The mechanism

O
of the Morita-Baylis-
H Ar Ar Hillman reaction
E
E E O
H
R R H Ar
N N N
R R R R O
R R R
(16.107) (16.108)
Ar Ar
E O
Ar Ar Ar H O
R.D.S.
E OH E O R
H O N
R
R
(16.111) (16.110) (16.109)
99. Johnson, W.S.; Szmuszkovicz, J.; Rogier, E.R.; Hadler, H.I.; Wynberg, H. J. Am. Chem. Soc. 1956, 78, 6285.
100. Reviews: (a) Basavaiah, D.; Rao, A.J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811. (b) Masson, G.;
Housseman, C.; Zhu, J. Angew. Chem. Int. Ed. 2007, 46, 4614. (c) Declerck, V.; Martinez, J.; Lamaty, F. Chem.
Rev. 2009, 109, 1. (d) Basavaiah, D.; Reddy, B.S.; Badsara, S.S. Chem. Rev. 2010, 110, 5447. (e)
101. (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Japan 1968, 41, 2815. (b) Baylis, A.B.; Hillman,
M.E.D. Offenlegungsschrift 2155113, 1972; U.S. Patent 3,743,669, 1972; Chem. Abstr. 1972, 77, 34174q.
For reviews, see: (c) Basavaiah, D.; Rao, J.A.; Satyanarayana, T. Chem. Rev. 2003, 103, 811. (d) Ciganek, E. Org.
React. 1997, 51, 201. (e) Basavaiah, D.; Rao, P. D.; Hyma, R.S. Tetrahedron 1996, 52, 8001. (f) Drewes, S.E.; Roos,
G.H.P. Tetrahedron 1988, 44, 4653.
102. (a) Price, K.E.; Broadwater, S.J.; Jung, H.M.; McQuade, D.T. Org. Lett. 2005, 7, 147. (b) Price, K.E.; Broad-
water, S.J.; Walker, B.J.; McQuade, D.T. J. Org. Chem. 2005, 70, 3980.

Inherently, the reaction is slow, and obtaining high yields of products can take weeks.
Nevertheless, its general lack of side reactions has made this reaction a popular method for
synthesis—especially given the dense functionalization of the products formed. Efforts to
accelerate the reaction by means of catalysts have led to observations that the reaction can
be accelerated by protic additives, such as water or alcohols and by Lewis acids (often lan-
thanides).103 Aggarwal has subsequently shown that a molecule of alcohol replaces the
second molecule of aldehyde in the transition state of the reaction in protic solvents.104
This change in the kinetic order of the reaction has been confirmed with glycol additives.
The increase in the rate constant depends, unexpectedly, on the number of hydroxymethyl
groups, rather than the number of hydroxyl groups, in the additive.105 As with the aldol
and Michael addition reactions, much of the modern focus on this reaction has now
shifted to being able to carry out the reaction in an asymmetric manner. In reaction 16.112,
for example, the chiral catalyst derived from the quinine skeleton gives the R allylic alco-
hol in high enantiomeric excess.106
O O
H2C=CHCO2CH(CF3)2 (16.112)
O O
OH
O HO O
CHO H CH(CF3)2
N
O
N
(47%, >97% e.e.)
The Morita-Baylis-Hillman reaction has been expanded more recently by the use a
relatively wide range of second acceptor molecules in place of the aldehyde, including
imines and conjugated carbonyl compounds (in an intramolecular setting). One example
of this is provided by a key cyclization step (Example 16.113) in the synthesis of the spi-
nosin A nucleus.107
O
H H
O
H H PMe3, EtCMe2OH (16.113)
H H
Br 23°C, 46 h
Br
(86%) H
CO2Me
MeO2C
The Benzoin Condensation

The benzoin condensation is one of the oldest synthetic reactions known.108 It is a di-
merization reaction between two aldehydes to give an α-hydroxyketone (Example 16.114).
It is not formally a condensation reaction as we defined it in Section 16.1 because no small
molecule is lost in the reaction. However, the reaction name is so long-standing that it is
unlikely to be changed. In the original form of the reaction, the catalyst was cyanide ion,
but in the modern variant, an N-heterocyclic carbene or thiazolium ylide acts as the cata-
lyst. In the classic form of the reaction, the initial cyanohydrin anion (Example 16.115)
103. (a) Aggarwal, V.K.; Mereu, A.; Tarver, G.J.; McCague, R. J. Org. Chem. 1998, 63, 7183. (b) Aggarwal, V.K.;
Dean, D.K.; Mereu, A.; Williams, R. J. Org. Chem. 2002, 67, 510. (c) Ameer, F; Drewes, S.E.; Freese, S.; Kaye, P.T.
Synth. Commun. 1988, 18, 495. (d) Drewes, S.E.; Freese, S.D.; Emslie, N.D.; Roos, G.H.P. Synth. Commun., 1988,
18, 1565. (e) Basavaiah, D.; Sarma, P.K.S. Synth. Commun., 1990, 20, 1611. (f) Auge, J.; Lubin, N.; Lubineau, A.
Tetrahedron Lett., 1994, 35, 7947. (g) Rafel, S.; Leahy, J.W. J. Org. Chem. 1997, 62, 1521.
104. (a) Robiette, R.; Aggarwal, V.K.; Harvey, J.N. J. Am. Chem. Soc. 2007, 129, 15513, and references therein.
(b) Aggarwal, V.K.; Fulford, S.Y.; Lloyd-Jones, G.C. Angew. Chem. Int. Ed. 2005, 44, 1706–1708.
105. Mirzaei, J.; Lewis, D.E. unpublished results.
106. Iwabuchi, Y.; Furukawa, M.; Esumi T.; Hatakeyama, S. Chem. Commun. 2001, 2030.
107. Mergott, D.J.; Frank. S.A.; Roush, W.R. Org. Lett. 2002, 4, 3157.
108. (a) Wöhler, F.; Liebig, J. Ann. Chem. Pharm. 1832, 3, 249. (b) Zinin, N. Ann. Chem. Pharm. 1839, 31, 329.

first isomerizes by a protonation-deprotonation sequence to give the isomeric nitrile

α-anion (Example 16.116). This nucleophile adds to a second molecule of aldehyde to give
the alkoxide 16.117, which also isomerizes to the cyanohydrin conjugate base (Example
16.118). This then eliminates cyanide anion to regenerate the ketone carbonyl group (Ex-
ample 16.114). Example 16.119 shows the use of an N-heterocyclic carbene as the catalyst.109
NC
O CN R O R CN
H O
R (cat) HO R HO R
(16.114) (16.118)
H
O
H O OH R R CN
NC NC OH
R R O R
(16.115) (16.116) (16.117)
O TBSO O
O
H O
TBSO H N
O N C6F5 BF4 OH
N
Et3N, CH2Cl2, 45°C, 4 h MeO O (16.119)
MeO CHO
(78%)
OMe
OMe
O Ph
O Ph
Reaction Synopses
Robinson Annulation (Robinson Annelation)
R3 R4 R3
Rc
Rc Rb Rc Rb R2 R2
R4 Rb
or +
Ra NR2 Ra O O Ra O
R1 R1
Reagents:
from ketone: KOBut, THF; NaOEt, EtOH; etc.
from enamine: PhH, ∆; etc.
Enone: may be replaced by Mannich base
Morita-Baylis-Hillman reaction
OH
E E
CHO R
+
R
R1 R2 R1 R2
E: CO2R, CN, COR, NO2, etc.

Reagents: DABCO; DMAP; R 3P; etc.
Reaction: accelerated by protic solvents and by Lewis acids (e.g., Y+3)
(continues)
109. Nicolaou, K.C.; Li, H.; Nold, A.L.; Pappo, D.; Lenzen, A. J. Am. Chem. Soc. 2007, 129, 10356.

Benzoin Condensation
HO R
CHO
R
R O
Reagents: KCN, EtOH, ∆; NHC, CH2Cl2, ∆; etc.
Chapter Summary
Condensations proceed by a multistep mechanism that requires the elimination of a small

molecule from the initial addition product. In the aldol condensation, the Henry reaction,
and the Wittig and HWE reactions, a π bond is replaced by another π bond. The Stobbe
condensation gives a conjugates half-ester of an alkylidenesuccinic acid, with the ester
group conjugated to the alkene. With aldehydes, the stereochemistry of the double bond is
E. The Claisen condensation is a net nucleophilic acyl substitution of an ester by an enolate
anion to give a β-ketoester. The Claisen-Schmidt, Knoevenagel, and Doebner reactions are
modifications of the original Claisen motif. The Dieckmann condensation is an intramo-
lecular Claisen condensation to give a five- or six-membered β-ketoester. The related cy-
clization of dinitriles is the Thorpe-Ziegler cyclization; it is less subject to steric effects than
the Dieckmann condensation and can be used to prepare medium-sized rings. Hydrolysis
of β-ketoesters gives β-ketoacids that can be decarboxylated by heat; direct decarboxyl-
ation of the β-ketoesters can be accomplished using the Krapcho decarboxylation.
Alkenes can be formed using the Wittig, HWE, Peterson, Ramberg-Bäcklund, Julia,
and Tebbe reactions, along with their derivative reactions. The Wittig reaction tends to
produce the Z alkene when unstabilized ylides are used as the nucleophile and E alkenes
when stabilized ylides are used. E alkenes are also the major product in the Schlosser mod-
ification of the Wittig reaction with unstabilized ylides. The HWE reaction gives the E
isomer as the major product. The Peterson reaction is much less susceptible to steric hin-
drance than the Wittig reaction, and the stereochemistry of the alkene can be controlled
by choosing the conditions under which the β-hydroxysilane is decomposed. The Julia-
Lythgoe and Julia-Kocieńsky olefinations allow stereocontrolled synthesis of trisubsti-
tuted alkenes. The Ramberg-Bäcklund reaction leads to alkenes by extrusion of sulfur
dioxide from intermediate thiirane dioxides. The Tebbe reaction is the prototypical syn-
thesis of alkenes from carbonyl compounds using a metal-carbene complex. It permits the
synthesis of enol ethers from esters and lactones.
The synthesis of alkynes by Wittig-type condensations can be accomplished by the
Seyferth-Gilbert reaction or by the Corey-Fuchs procedures. The Seyferth-Gilbert reac-
tion is facilitated by using the Bestmann reagent.
Cascade reactions are reactions where the product of the first reaction becomes a reac-
tant in a second reaction to give the isolated product. Cascade reactions initiated by nucle-
ophiles include the Robinson annelation (Robinson annulation), which is a Michael-initiated
ring closure; the Morita-Baylis-Hillman reaction, which is a Michael-initiated aldol addi-
tion; and the benzoin condensation.
Key Terms
aldol condensation Claisen condensation Corey-Fuchs reaction

benzoin condensation Claisen-Schmidt reaction Darzens condensation
Bestmann reagent condensation reaction Decarboxylation
cascade reaction Corey-Chaykovsky reaction Dieckmann condensation

Doebner reaction MIRC Schlosser modification

Henry reaction Morita-Baylis-Hillman Seyferth-Gilbert
Horner-Wadsworth- reactionPerkin homologation
Emmons reaction condensation Stobbe condensation
Julia-Kocieńsky olefination Petasis reagent Tebbe olefination
Julia-Lythgoe olefination Peterson reaction Tebbe reagent
Knoevenagel condensation Ramberg-Bäcklund reaction Thorpe-Ziegler
Krapcho decarboxylation Robinson annelation condensation
Lombardo reagent (annulation) Wittig reaction
Additional Problems
O
NH
CHO
HN
O [Angew. Chem. Int.
(a)
N piperidine, 110°C Ed. 2011, 50, 1402]
H
(36%)
Me 1) (c-C6H11)2BOTf, Et3N, Et2O, 0°C
MeO
[J. Org. Chem.
(b) 2) , -78°C
I O PMBO 2009, 74, 7220]
OHC TBS
3) Ac2O, THF, DMAP, 0°C

4) DBU, THF
H
KOH, Bu4NOH [Angew. Chem. Int.
(c) O
THF-Et2O, ∆ Ed. 2003, 42, 5855]
OHC H
O H O
H
[J. Am. Chem. Soc.
(d)
Ph 2002, 124, 9974]
H H O
1) LDA, THF, 50°C
CO2H
OHC [Tetrahedron Lett.
(e) 2) H , –78°C
Me2N
1990, 31, 2517]
O
3) HOAc, (MeO)2CHNMe2, ∆
O
NaH, PhMe, ∆, 18 h [J. Am. Chem. Soc.
(f)
O 1984, 106, 6690]
CO2Me
O
NaOH, THF-H2O
O
r.t., 10 h [J. Org. Chem.
(g) MeO
OH O
OH 1999, 64, 7871]
O Me

HO CO2Me
N O NH, HOAc
O N [Pure Appl. Chem.
(h) MeOH 1968, 17, 519]
O
O
O
O
O KOBut, THF, ∆ [J. Org. Chem.
(i) O 1995, 60, 7387]
H piperidine, HOAc [J. Org. Chem.

(j) PhMe, ∆, 48 h
CHO 1987, 52, 2960]
O
H CHO
NaOH
dibenzo-18-crown-6 [J. Am. Chem. Soc.
(k) O
PhH, ∆ 1982, 104, 872]
O
CHO TsOH, PhH, ∆ [J. Am. Chem. Soc.

(l) H
1987, 109, 6199]
O
O OH Ph3P=C(Me)CO2Me [J. Org. Chem.

(m)
PhH, 90°C, 90 min 2002, 67, 9443]
O [Beilstein J. Org.
CHO (MeO)2PCH=N2 Chem. 2007, 3, 29;
(n) N
KOBut, THF, –78°C to r.t. doi:10.1186/
H 1860-5397-3-29]
O
P(OEt)2
MeO
COPh [Tetrahedron Lett.
(o) N
N 2004, 45, 3783]
NaH, THF, r.t.
CHO
O Ts
Tebbe reagent
[Proc. Natl. Acad.
(p) polymer O N
pyridine, THF Sci., U.S.A. 2011,
Ph 108, 6769]
But O
Si O Tebbe reagent
But O O [Tetrahedron Lett.
(q) pyridine, PhMe, –40°C
2000, 41, 7589]
O
NHBoc
O
MeO H
O Cp2TiMe2, PhMe
[Org. Biomol. Chem.
(r)
O TBSO
80°C 2009, 7, 4582]
MeO
OTBS

Zn, CH2Br2, TiCl4 [Tetrahedron Lett.

(s) CH2Cl2, 0°C to r.t., 3 h
O
2006, 47, 2103]
O
Ph O [Pure Appl. Chem.
(t) Zn, CH2Br2, TiCl4
2007, 79, 629]
OAc
O O
N CF3
O Cp2TiMe2, THF, PhMe
Ph [Org. Proc. Res. Dev.
(u) PhCH2CMe2OAc (0.75 eq)
2004, 8, 256]
CF3
O O
S S 1) LHMDS, THF, –78°C
[Tetrahedron Lett.
(v) N
CO2Me 2) CHO 2009, 50, 4874]
TESO H
O
c-C6H11CHO, PhPMe2 (0.05 eq) [Synthesis
(w)
MeOH-CHCl3 (3:2), r.t., 22 h
2005, 3035]
16-6 Suggest a mechanism for the step from MacMillan’s synthesis of strychnine
[Nature 2011, 475, 183] shown.
N N
H CH2(CO2H)2, AcOH H
N NaOAc, Ac2O, 120°C N
H H H
HO O O O
H
16-7 Suggest reasons for the different stereochemical outcome of the two reactions
shown [Tetrahedron Lett. 2007, 48, 2961].
ClCH2CONPh2, NaOH O
H CONPh2
Ar H
O
Ar
H
BrCH2CONPh2, NaOH O
H H
Ar CONPh2
16-8 Complete the following transformations by supplying the missing reagent,

sequence of reagents, or starting structure.
Ph
O
O OH
[J. Am. Chem. Soc.
(a) O H O H
O CHO O O 2003, 125, 11510]
O
H
TBSO TBSO

O
O
[Chem. Commun.
(b) O O
1996, 2411]
Ph
O O
R CO2R R CO2R R CO2R [J. Chem. Soc.,
(c) Perkin Trans. 1
R R
1998, 689]
OH
n-Bu N N Me NTf2 MeO CO2Me
[J. Org. Chem.
(d) ?
DABCO (2 eq), r.t., 66 h
MeO 2010, 75, 4183]
H2C=CH–CO2Me
OMe
16-9 Suggest a reasonable mechanism for the tandem transformation shown (NHC is
an N-heterocyclic carbene, and DBU is the non-nucleophilic amidine base,
1,8-diazabicyclo-[5.4.0]undec-7-ene.) [Tetrahedron Lett. 2012, 53, 453]
Ph CN
1) NHC, DBU
ClCH2CH2Cl, 70°C
Ph CHO Ph NH2
2) PhCH=C(CN)2 O O
ClCH2CH2Cl, 70°C
Ph
16-10 (a) Provide the missing reagents from the following steps from the total synthesis
of morphine by Mulzer [Angew. Chem. Int. Ed. 1996, 35, 2830].
Cl
Cl Cl
a b CHO KOH, dioxane
MeO
MeO MeO MeO
MeO O MeO O OH
O
A B C
Cl Cl
Cl
H c H d DMF
MeO MeO Br 140°C
MeO
MeO MeO OMe
O
O OTMS
D E F
Cl
MeO O
O
G
Suggest mechanisms for the conversions from compound C to compound D, and

from compound E to compound F.
16-11 Provide the missing reagents from the steps in Wender’s total synthesis of taxol,
shown below [J. Am. Chem. Soc. 1997, 119, 2755, 2757].
OTMS OTMS
CHO
a b
OH
O O
CO2Et CO2Et

16-12 Rationalize the reasons for the different outcomes of the attempted Perkin con-
densations below [Tetrahedron Lett. 2003, 44, 7119].
RF RF H F3C AcO
O O Ac2O, AcONa CF3
Ac2O, AcONa
X X CO2H ∆
∆
X = m-CF3; RF = CF3 (75%) E/Z = 91:9

X = p-Cl; RF = CF3 (78%) E/Z = 95:5
X = H; RF = CF3 (67%) E/Z = 93:7
16-13 The alkaloid, yohimbine, has had a reputation among African natives as potent
aphrodisiac since antiquity. The synthesis of (±)-yohimbine by van Tamelen
[J. Am. Chem. Soc. 1969, 91. 7315] begins with the steps below. Provide the struc-
tures, including stereochemistry, of the intermediates A-D. Compound C exists
as a mixture of two diastereoisomers. What are the structures of these two diaste-
reoisomers, and why were they not separated during the synthesis?
O
(1.3 eq) Zn, HOAc ClCH2CO2Et 1) NaOH, H2O, ∆
A B C
C6H6, 14-21 d C10H10O2 C10H12O2 KOBut, C6H6 C14H18O4 2) HCl, H2O
O
CHO
H
D Cu, 220°C
C12H14O2
H
O

Chapter seventeen
Organic Reactions VI
Metal-Catalyzed Reactions for C—C Bond Formation
17.1 Catalysis and “Green” Chemistry
Monty Python, the British comedy team from the 1970s, often used a phrase for bridg-
ing segments of their television show that could easily serve as the subtitle for this
chapter: “. . . And now for something completely different.” In the previous chapters of
this book, we have discussed the reactions of organic compounds and distilled much
of this chemistry into a series of generalizations. The truth can now be told. Many of
those generalizations are oversimplifications, and many should have appended to
them the statement, “except if a transition metal complex is involved in the reaction.”
Two such generalizations for which this is especially true are, “In the absence of
electron-w ithdrawing groups to activate the molecule toward nucleophilic displace-
ment, the nucleophilic displacement of a vinyl halide or aryl halide will not occur
except under extreme reaction conditions,” and “Unless activated by an adjacent
electron-w ithdrawing group, simple alkenes do not react with nucleophiles.” In other
words, this chapter is not so much an end as it is a beginning—a launching point from
which one can begin to explore what modern organic chemistry has become and where
it may be going.
The holy grail of organic synthesis is to prepare the target molecule with absolute
control over regiochemistry and stereochemistry, and with perfect atom economy, a
concept that was first defined by Trost during the early development of “green" chem-
istry.1 In the ideal case, the target molecule is formed as a single, pure stereoisomer (or
enantiomer, if it is chiral), and every atom used in the reactions of the synthetic se-
quence is incorporated into the target. Achieving this level of atom economy would,
of course, restrict the synthetic chemist to using addition and rearrangement reac-
tions only, because atoms are lost during substitution and elimination reactions. Ob-
viously, this ideal is unattainable—even living cells, the most accomplished synthetic
chemists of all, use substitution and elimination reactions in synthesizing complex
molecules.
Nevertheless, the concept of atom economy has driven the move, begun during the
last two decades of the 20th century, toward an increased use of catalysis as a means to
reducing the environmental impact of organic synthesis. In 1999, the journal Green
Chemistry was launched by the Royal Society of Chemistry to provide a place for the
publication of articles addressing questions of environmentally friendly chemistry.
1. (a) Trost, B.M. Science 1991, 254, 1471. (b) Trost, B.M. Angew. Chem. Int. Ed. Engl. 1995, 34, 259. (c) Trost,
B.M. Acc. Chem. Res. 2002, 35, 695.
689

690 Advanced Organic Chemistry | Chapter seventeen
The Twelve Principles of Green Chemistry2 have been formalized as follows:
1. It is better to prevent waste than to treat or clean up waste after it is formed.

2. Synthetic methods should be designed to maximize the incorporation of all materials
used in the process in the final product.
3. Wherever practical, synthetic methodologies should be designed to use and generate
substances that possess little or no toxicity to human health and the environment.
4. Chemical products should be designed to preserve efficacy of function while reduc-
ing toxicity.
5. The use of auxiliary substances (e.g., solvents, separation agents) should be made un-
necessary whenever possible and innocuous when used.
6. Energy requirements should be recognized for their environmental and economic im-
pacts and should be minimized. Synthetic methods should be conducted at ambient
temperature and pressure.
7. A raw material feedstock should be renewable rather than depleting whenever techni-
cally and economically practical.
8. Unnecessary derivatization (blocking group, protection-deprotection, temporary
modification of physical/chemical processes) should be avoided whenever possible.
9. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.
10. Chemical products should be designed so that at the end of their function they do not
persist in the environment and break down into innocuous degradation products.
11. Analytical methodologies need to be further developed to allow for real-time in-process
monitoring and control prior to the formation of hazardous substances.
12. Substances and the form of a substance used in a chemical process should be chosen so
as to minimize the potential for chemical accidents, including releases, explosions,
and fires.
Not only do these principles explicitly (Principle 9) and implicitly (Principle 8) urge
the use of catalytic chemistry, but they also promote the concept of atom economy
(Principle 2).
Until the last third of the 20th century, catalytic reactions in organic chemistry had
been largely restricted to catalytic hydrogenation. Then, in 1980, the whole field exploded
as catalysts for asymmetric epoxidation3 and hydrogenation4 reactions were developed,
work that resulted in the award of the 2001 Nobel Prize in Chemistry to Sharpless, Noyori,
and Knowles. Since then, the Nobel Prize in Chemistry has been awarded twice more for
catalysis applied to C—C bond-forming reactions.
The adoption of catalytic reactions for forming carbon-carbon bonds followed a slower
path than that of the asymmetric redox reactions. Both the Sharpless asymmetric epoxi-
dation and the asymmetric hydrogenation of α-amidoacrylates using a chiral 2,2'-bis-
(diphenylphosphino)-1,1'-binaphthyl (BINAP) complex as catalyst appeared in 1980. Two
decades later, both reactions were routine synthetic methods.
17.2 Bonding in Organometallic Complexes
One is unlikely to spark any controversy at all by asserting that few areas of modern
organic chemistry have undergone the explosive growth that organometallic chemistry—
especially catalysis—has. What is more, few areas of organic chemistry are showing such
promise for new developments—and few have shown just how dangerous it is to make
2. Anastas, P.T.; Warner, J.C. Green Chemistry Theory and Practice. (Oxford University Press: New York, 1998).
3. Sharpless, K.B.; Katsuki, T. J. Am. Chem. Soc. 1980.
4. (a) Knowles, W.S. J. Am. Chem. Soc. 1980, (b) Noyori, R. J. Am. Chem. Soc. 1980.

Organic Reactions VI 691
generalizations about the reactivity of organic compounds. Transition metal catalysis has
become an important part of much modern industrial chemistry, as we shall see in the R M
course of this chapter.
Organometallic compounds are all characterized by the presence of one or more metal-
carbon bonds in the molecule. We have already discussed the chemistry of the Group IA R M
and Group IIA metal alkyls such as the alkyllithiums and Grignard reagents, and we have
also discussed, albeit briefly, the chemistry of the simple metal alkyls of the Group IB and
(17.1)
Group IIB such as the dialkylzinc and organocuprate reagents. Although many of these
organometallic compounds exist as aggregates, much of their chemistry can be rational-
ized in terms of a simple resonance picture (Example 17.1) of a polar metal-carbon σ bond
in which the carbon atom is the nucleophile.
These metal alkyls and metal “ate” complexes share several chemical properties. All
these metal ions have a filled d subshell, so the metal d orbitals are not part of the carbon-
metal bond, which is a more or less typical σ bond (although the alkali metal alkyls do
form aggregates). They are all strong Lewis bases sensitive to protic acids, with which
they react with to give the hydrocarbons. Most react with carbon electrophiles to form
carbon-carbon bonds, as illustrated by the addition reactions between carbonyl com-
pounds and Grignard (Example 17.2), organolithium (Example 17.3), organozinc
(Example 17.4) and organocopper compounds (Example 17.5). Of course, as the electro-
negativity of the metal increases, the percent ionic character of the carbon-metal bond
decreases and the nucleophilic strength and the base strength of the organometallic
compound decreases.
OH
O CHO O
MeMgBr, Et2O 5
(17.2)
O Br (93%) O Br
OH (1 eq),
O Br t-BuLi (2 eq) OH
6
(17.3)
Et2O, 0°C OH
(73%)
Et2Zn (1.1 eq), Et2O

(17.4)7
(92%)
COCl
O
O OCMe3 O OCMe3
Cl Et2CuLi 8
(17.5)
(>65%)
O O
5. Ziegler, F.E.; Schwartz, J.A. J. Org. Chem. 1978, 43, 985.

6. Corey, E.J.; Widiger, G.N. J. Org. Chem. 1975, 40, 2976.
7. Wiberg, K.B.; Hess, B.A., Jr. J. Org. Chem. 1966, 31, 2250.
8. Dauben, W.G.; Ahlgren, G.; Leitereg, T.J.; Schwarzel, W.C.; Yoshioko, M. J. Am. Chem. Soc. 1972, 9, 8593.

Worked Problem
17-1 What is the major organic product of the following reaction?
OTMS H 1) BuLi (1 eq.), THF, –78°C
A
CO2Me (C22H40O7Si2)
2) O CO2Me, Me3SiCl
O
§Answer below.
Problem
CO2Me
Me
Et O CO2Me
MeMgBr (1 eq.), Et2O B
(a) O (C25H34O9)
–78°C, 60 min
O
OCOPh
H O
H MeMgBr, Et2O (C9H19)2CuLi
(b) TfO (c) Ac2O
O –20°C, 2 h THF-Et2O, –40°C
MeO O H
References: (a) Can. J. Chem. 1985, 63, 2810. (b) J. Am. Chem. Soc. 2005, 127, 11958. (c) J. Am. Chem.
Soc. 1974, 96, 3654.
Transition Metal Organometallic Compounds

When the metal involved is a transition metal with vacant d orbitals, the chemistry of
organometallic compounds frequently offers a stark contrast with the chemistry of those
that have figured prominently in our discussions so far. The bonding in these compounds
can be very different from that of the Group I and II organometallic compounds because
the metal d orbitals are intimately involved in the formation of the metal-carbon bonds,
which may be either σ bonds or π bonds or both.
These organometallic compounds are characterized by much more covalent character
in the carbon-metal bond, so one generally finds that they are much weaker bases than the
alkyllithiums or Grignard reagents. The alkyl groups bonded to the metal in these

In the initial step in this reaction, the alkyne is deprotonated to give the lithium alkynide, a powerful nucle-
ophile. The other reactant has three carbonyl groups—all esters—capable of undergoing nucleophilic addition
by the alkynide ion. When faced with this type of choice, it is worthwhile remembering that esters prefer to
adopt a syn conformation, whereas the lactone is locked in the anti conformation, making its energy higher
than in simple esters. Therefore, one would predict that the major product will be that formed by attack on the
lactone carbonyl group [Can. J. Chem. 1985, 63, 2810].
CO2Me
OTMS H 1) BuLi (1 eq.), THF, –78°C TMSO
CO2Me
OTMS
CO2Me O
2) O CO2Me, Me3SiCl
O

compounds also tend to be poorer nucleophiles than in the alkyllithiums and Grignard
reagents, and, in fact, the metal atom may actually function as the nucleophile in these
compounds.
The first synthetic organometallic complex of a transition metal was isolated by W.C.
Zeise in Copenhagen around 1827.9 The compound, K[C2H4PtCl3]•H2O (now known as
Zeise’s salt), was isolated from the reaction between potassium tetrachloroplatinate and
ethanol in the presence of acid. Despite concerted efforts to elucidate the structure and
bonding in this salt, more than a century would elapse before its true character was de-
termined. During this same period, more organotransition metal complexes were iso-
lated, but they were generally viewed as curiosities until after World War II, when the
work of Reppe’s group began to appear in the chemical literature.10 Within 3 years of the
publication of the first reports of the Reppe acetylene cyclooligomerizations to cyclooc-
tatetraene, benzene, styrene, and other useful cyclic compounds (these papers began to
appear in 1948), the field of organotransition metal chemistry had blossomed. In 1951, one Fe
of the most intriguing organometallic compounds known—ferrocene (Example 17.6)—
was discovered11 (although its correct structure was not proposed until a year later12). The
ensuing decades have seen the discovery of a multitude of organometallic compounds (17.6)
whose reactions have altered forever the way in which organic chemists view their
discipline.
Of course, along with the mushrooming of the field comes the impossibility of covering it
adequately in a single chapter. This chapter can only serve as an appetizer for the banquet
that awaits those who are willing to consult one of the many textbooks13 and comprehensive
review series14 devoted just to the subject of organotransition metal chemistry.
Electron Bookkeeping and the “18-Electron Rule”

Discussions of the structure and bonding in simple organic compounds were greatly sim-
plified by the development of the concept of the valence-shell octet developed by G. N.
Lewis. Based on this simple model, it became possible to rationalize the bonding in or-
ganic compounds and to correlate reactivity with structure. Of course, the theory has its
limitations, and it has gradually been augmented (replaced) by molecular orbital theory,
especially in compounds with extended π-bonding systems. Advances in computers have
9. Zeise, W.C. Ann. Phys. 1831, 97, 497.

William Christopher Zeise (1789–1847): for biographical information on Zeise and the history of the con-
formation of his proposed structure of this complex, see Hunt, L.B. Platinum Metals Rev. 1984, 28 (2), 76.
10. (a) Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. Justus Liebigs Ann. Chem. 1948, 560, 1. (b) Reppe, W.;
Schlichting, O.; Meister, H. Justus Liebigs Ann. Chem. 1948, 560, 93. (c) Reppe, W.; Schwekendiek, W.J. Justus
Liebigs Ann. Chem. 1948, 560, 104.
Walter Julius Reppe (1892–1969) was a major figure in the German chemical industry (I.G. Farbenindus-
trie) during the Nazi period, and he continued at BASF after the war. His close association with the Nazi regime
may have cost him the Nobel Prize in chemistry. Biographical information can be found at: (a) Oesper, R.A. J.
Chem. Educ. 1950, 27, 648. See also: (b) Firmen- und Personennachrichten Eur. J. Lipid Sci. Technol. 1969, 71,
743; and (c) “Reppe, Julius Walter.” Complete Dictionary of Scientific Biography. 2008. The article is available
online: http://www.encyclopedia.com/doc/1G2-2830906041.html (accessed January 14, 2012).
11. (a) Kealy, T.J.; Pauson, P.L. Nature 1951, 168, 1039. (b) Miller, S.A.; Tebboth, J.A.; and Tremaine, J.F. J.
Chem. Soc. 1952, 632.
12. (a) Wilkinson, G.; Rosenblum, M.; Whiting, M.C.; Woodward, R.B. J. Am. Chem. Soc. 1952, 74, 2125.
(b) Fischer, E.O.; Pfab, W. Z. Naturforsch. B 1952, 7, 377.
13. (a) Crabtree, R.H. The Organometallic Chemistry of the Transition Metals, 3rd ed. (Wiley-Interscience:
New York, 2000). (b) Spessard, G.O.; Miessler, G.L. Organometallic Chemistry, 2nd ed. (Oxford University
Press: New York, 2009). (c) Collman, J.P.; Hegedus, L.S.; Norton, J.R.; Fincke, R.G. Principles and Applications
of Organotransition Metal Chemistry (University Science Books: Mill Valley, CA, 1987). (d) Hartwig, J. Organo-
transition Metal Chemistry. From Bonding to Catalysis. (University Science Books: Mill Valley, CA, 2010).
14. Crabtree, R.H.; Mingos, D.M.P., Eds. Comprehensive Organometallic Chemistry, 3rd . ed. (Elsevier:
Amsterdam, 2007).

allowed the use of ab initio or density functional theory to largely supersede the Lewis
structures, but, as pointed out in the early chapters of this book, the Lewis model, which
is really little more than electron bookkeeping, still retains an attractive simplicity in
terms of actually using it.
There is a similar electron bookkeeping model for the bonding in organotransition
metal complexes, known as the “18-electron rule.” The basic tenet of the 18-electron rule is
the same as the Lewis octet rule: species are most stable once all the atoms involved have
attained the outer electron configuration of a noble gas. The electron configuration of
every transition metal corresponds to a set of core electrons with the configuration of the
immediately preceding noble gas, with a valence shell composed of five d orbitals, one s
orbital, and three p orbitals. Filling the valence shell to generate the electron configuration
of the next noble gas requires a total of 18 electrons—hence the name. Organotransition
metal complexes in which the metal atom has 18 valence electrons are described as coordi-
natively saturated: like saturated organic molecules, their reactivity tends to be restricted
to substitution reactions. Organotransition metal complexes in which the metal atom has
less than 18 valence electrons are termed coordinatively unsaturated. The metal atom in
these complexes frequently participates in addition reactions that lead to the metal acquir-
ing enough electrons to complete its valence shell.
To apply the 18-electron rule, one totals the number of valence electrons on the metal,
adds the number of electrons contributed by the ligands, and then adjusts the total for the
charge on the complex. The bonding between carbon and the metal in metal complexes
may be either σ bonding or π bonding. Ligands bonded to the metal through σ bonds
usually contribute either one or two electrons to the metal. The number of electrons do-
nated by each π-bonded ligand is equal to the number of carbon atoms directly bonded to
the metal, a number designated as the hapto number, η. The hapto numbers of several
common π-type ligands are shown in Figure 17.1.
Thus, in Zeise’s salt, the two carbons of the ethylene are both simultaneously bound to
the platinum: the alkene is an η2 ligand. In ferrocene, each of the two cyclopentadienyl
(frequently abbreviated as Cp) rings is simultaneously bound to the iron through all five
carbon atoms, and the cyclopentadienyl groups are η5 ligands. Although its use is wide-
spread, the hapto nomenclature is by no means universal yet. Certain π-bonded ligands
are known by trivial names that are much more widely used than the hapto names. One of
the more common examples of the survival of a less systematic nomenclature for organo-
metallic complexes concerns complexes containing η3 ligands, which are widely referred
to as π-allyl ligands.
To apply the 18-electron rule, one must know just how many electrons each ligand
contributes to the metal in the complex. This can be determined fairly simply by noting
that most ligands bonded to the metal through σ bonds donate one or two electrons and
that π-bonded ligands donate a number of electrons equal to the hapto number of the
ligand. The numbers of electrons donated by various ligands are given in Table 17.1, where
the ligands are treated as neutral groups attached to a metal center, and Table 17.2, where
the ligands are treated as ions bound to the metal center. Which convention is chosen will
depend on the complex under study.
π-Allylpalladium complex 17.7 illustrates the use of this model for electron bookkeep-
ing in metal complexes. This complex is neutral overall, and because the ligands are all
Figure 17.1 Hapto numbers η2 η3 η4 η5 η7 η6 η8

for a series of
common ligands
H2C CH2
Cl Pt Cl Co Fe Cr Cr Ti
OC CO OC CO OC CO
Cl CO CO CO

treated as monoanions, the metal atoms must each carry Table 17.1 Electrons Donated by Neutral Ligands for Electron
a +2 charge. In this version of the 18-electron rule, there- Accounting by the 18-Electron Rule
fore, the configuration of the metal atom is d8, and each Electrons Typical Examples of Ligands
metal atom carries 16 electrons. Both palladium atoms of
the complex are coordinatively unsaturated, and both are 1 Alkyl, aryl, alkynyl, H, halogen
in the +2 oxidation state—the complex is a palladium 2 CO, phosphines, η2 alkene, η2 alkyne
(II) complex.
3 η3 allyl, NO
4 η4 diene (e.g., 1,3-butadiene; cyclobutadiene;
Carbon-Metal Bonding in Organotransition norbornadiene)
Metal Complexes
5 η5 dienyl (e.g., cyclopentadienyl, Cp;
The bonding between a transition metal and an organic cyclohexadienyl)
ligand depends on both the metal and the nature of the
6 η6 arene (e.g., benzene; mesitylene)
organic ligand. When the ligand is a simple alkyl group,
aryl group, or acyl group, the carbon-metal bond is a 7 η7 trienyl (e.g., cycloheptatrienyl)
typical σ bond, which may be viewed as a pair of elec- 8 η8 tetraenyl (e.g., cyclooctatetraenyl)
trons shared between the carbon and the metal. In
these complexes, the carbon-metal σ bond is formed by
coaxial overlap of the metal orbital and the hybrid or-
bital on carbon to give σ and σ* orbitals (Figure 17.2).
In Figure 17.2, the process of bond formation is repre- Table 17.2 Electrons Donated by Ionic Ligands for Electron
Accounting by the 18-Electron Rule
sented as being due over lap of the ligand highest energy
occupied molecular orbital (HOMO) and the metal Electrons Typical Examples of Ligands
lowest energy unoccupied molecular orbital (LUMO). 2 Halide ion, alkoxide ion, carboxylate ion
In terms of their reactivity, metal-carbon σ bonds
behave as typical covalent bonds between carbon and 4 η3 allyl anion, η4 diene
an electropositive element. 6 η5 dienide anion, η6 arene, η7 trienyl cation
The description of π bonding in organotransition metal
8 η8 tetraenyl (e.g., cyclooctatetraenyl)
complexes is less straightforward because the exact nature
of the bonding depends on the exact type of the ligand. In Cl
the vast majority of cases, ligands that form π bonds with Pd Pd (17.7)
Cl
transition metals are themselves u nsaturated—alkenes;
arenes; and delocalized, conjugated radicals. The bonding Pd2+ (3d8) 8
between the metal and the ligand in these compounds is not
simple two-center bonding, and the bonds cannot be de- C3H5(allyl anion 4 e ) 4
−
scribed in terms of the simple Lewis electron pair model. Cl (anion, 2 @ 2e )−

4
Depending on the ligand, the metal may be simultaneously
Total 16
bonded to as few as two carbon atoms (η2 ligands) or as
many as seven or eight (η7 or η8 ligands). The X-ray crystal
structure analysis of many organotransition metal complexes containing polyhapto alkene
ligands has shown that the carbon atoms of the ligand are, where geometrically possible,
Figure 17.2 Orbital overlap

between a metal atom lowest
M R σ* energy unoccupied
molecular orbital and a
ligand highest energy
M R occupied molecular orbital to
give the σ and σ* orbitals of
a metal-carbon bond
M R σ

Figure 17.3 Metal-alkene
(top) and metal-alkyne
(bottom) σ bonding (left) M M
and dπ -pπ
backbonding (right)
σ dπ-pπ
R R
M M
R R
Figure 17.4 Bonding in

carbonyl (top) and phosphine
(bottom) complexes M C O M C O
dπ-pπ
σ
dπ-dπ
M PR3 M PR3
equidistant from the metal. This means that all the carbons are equally involved in the bond-
ing to the metal, which may be illustrated by the simplest example, a metal-alkene bond.
The metal–alkene bond (Figure 17.3) is rather more complex than the simple bonds
that we have discussed to date because there are two components to the bonding process.
Bonding in the “forward” direction involves the overlap of the ligand HOMO with an
empty d orbital on the metal. Such bonds are almost invariably σ bonds. However, be-
cause most metal complexes of this type are formed by low-valent metals, the metal atom
also has electrons available for donation. In addition, there is a component to the metal-
carbon bonds that is due to overlap between the ligand LUMO and a filled d orbital ion
the metal. The donation of electron density from the metal to the ligand is known as
back-donation because the normal direction of electron donation in metal complexes is
from the ligand to the metal; this type of bonding is called backbonding, and it forms an
important part of the bonding in many alkene complexes of transition metals. Backbond-
ing is almost always π bonding, and because it involves the overlap of a metal d orbital
and ligand p orbitals, it is often referred to as (d-p) π bonding or dπ ‑pπ bonding. The
bonding in alkyne complexes of transition metals is basically identical to the bonding in
the alkene complexes.
Two important two-electron ligands for transition metals are carbon monoxide and
trialkyl- or triarylphosphines. The compounds formed between a metal and carbon
monoxide are known as carbonyl complexes. In transition metal carbonyls, carbon
monoxide acts as a two-electron donor, and it participates readily in backbonding
through the C—O π* orbital (Figure 17.4). The bonding between a phosphine and a
metal is almost identical to the bonding in a metal carbonyl, with the exception that the
ligand orbital involved in the backbonding is an empty 3d orbital on phosphorus (so this
bond is a dπ -dπ bond).

Worked Problem
17-2 Is the following metal complex coordinatively saturated or not? What is the oxi-
dation state of the metal? Give your reasons.
Ph3P OEt2
Rh
Cl PPh3
§ Answer below.
Problem
17-2 Which of the following complexes is(are) coordinatively unsaturated, and which
is(are) coordinatively saturated? What is the oxidation state of the metal in
each case?
PR3
H Cl
Br
OC Me Ru
(a) Co CO (b) Ni (c) Fe CO (d) Cl
OC O
O CO PPh3
H2C CH2
Me
17.3 Basic Organometallic Reactions I: Reactions at the Metal
Ligand Substitution
Many of the reactions of organotransition metal complexes are due to the presence of ac-
cessible d orbitals on the transition metal. The simplest reactions of organometallic com-
pounds are ligand substitution reactions where one ligand is replaced by another. These
reactions may occur by either an associative mechanism (analogous to the SN2 substitu-
tion) or a dissociative mechanism (analogous to the SN1 substitution). Ligand substitution
by a dissociative mechanism occurs through coordinatively unsaturated intermediates,
and this reaction is therefore often a critical step in catalytic processes. A good example is
provided by the initial stages of the hydroformylation reaction (Example 17.8), an import-
ant method for the homologation of 1-alkenes into aldehydes by carbon monoxide using a
cobalt catalyst.15 Industrially, this reaction is known as the oxo process.
H H H
OC OC
Co CO Co Co CO (17.8)
OC OC CO OC
CO CO
R
18 e 16 e 18 e
15. For a discussion of the mechanism of this reaction, see: (a) Heck, R.F.; Breslow, D.S. J. Am. Chem. Soc.
1961, 83, 4023. (b) van Leeuwen, P.W.N.M. Homogeneous Catalysis: Understanding the Art (Kluwer Academic:
Dortrecht, Netherlands, 2004), ch. 7.

This complex has at least one ionic ligand (Cl–), so we use the values in Table 17.2 to determine the total
number of electrons. Because the overall complex is uncharged, this means that the rhodium must be in the form
of Rh(I). It has 16 total electrons: Rh (8) + P (2 × 2) + Cl (2) + O(2), which makes it coordinatively unsaturated.

Figure 17.5 Metal Cl Cl Cl Cl Cl Cl
H2O H2O
substitution can dramatically Pd Pd Pd Pd
affect ligand reactivity. Cl Cl OH2 OH2
(17.9) (17.10) HO
(17.13)
H2O
Cl Cl 2– Cl Cl
H2C=CH2
Pd Pd
Cl Cl Cl
(17.11) (17.12)
Ligand substitution can have a dramatic effect on the reactivity of a metal complex,
and ligand substitution is an important method for modulating the reactivity of a metal
complex. Thus, by appropriately choosing the ligands on the metal, one can stabilize reac-
tive species (e.g., one can render air-sensitive complexes inert to all but the strongest
oxidizing agents), or one can render ligands susceptible to attack by reagents toward which
they are normally inert. These effects are well illustrated by the example in Figure 17.5. In
the dimeric palladium complex (17.9), the alkene ligand is labile toward displacement but
is not reactive toward nucleophilic attack. In the monomeric complexes (17.11, 17.12),
however, incorporating one water ligand and one alkene ligand gives a complex (17.10)
where the alkene π bond is quite susceptible to attack by nucleophiles (e.g., water, as
in 17.13), as in the Wacker-Smidt16 and related reactions.
Oxidative Addition and Reductive Elimination

Certain coordinatively unsaturated complexes react with neutral molecules to give coordi-
natively saturated products, a reaction accompanied by an increase in the formal o xidation
number of the metal center. A lone pair on the metal is critical for this reaction to occur.
This reaction is known as oxidative addition (Example 17.14), and the reverse is known as
reductive elimination (Example 17.15). I have found it useful to write simple mechanisms,
as shown, to rationalize electron movement in these reactions, but the involvement of the
transition metal also means that these are almost c ertainly oversimplified.
R R R R
X :MLn MLn (17.14) MLn R :MLn (17.15)
X R
oxidative addition reductive elimination
Examples of both types of reaction are provided by the catalytic cycle of hydrogena-
tion using Wilkinson’s catalyst (Figure 17.6).17 In the first step of the catalytic cycle, the
coordinatively unsaturated rhodium (I) complex (17.16) reacts with hydrogen to give the
coordinatively saturated rhodium (III) hydride complex (17.17). In the last step of the cat-
alytic cycle, the coordinatively unsaturated rhodium (I) complex is regenerated by reduc-
tive elimination of the alkane from the saturated alkyl complex (17.18).
16. (a) Smidt, J.;Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Rütlinger, R.; Kojer, H. Angew. Chem. 1959, 71,
176. (b) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, S. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
17. (a) Tolman, C.A.; Meakin, P.Z.; Lindner, D.L.; Jesson, J.P. J. Am. Chem. Soc. 1974, 96, 2762. (b) Halpern,
J.; Okamoto, T.; Zackiriev, A. J. Mol. Calat. 1976, 2, 65. (c) Collman, J.P.; Hegedus, L.S.; Norton, J.R.; Fincke,
R.G. Principles and Applications of Organotransition Metal Chemistry (University Science Books: Mill Valley,
CA, 1987), pp. 531–535. (d) Spessard, G.O.; Miessler, G.L. Organometallic Chemistry, 2nd ed. (Oxford University
Press: New York, 2010), pp. 353–358.

Figure 17.6 Oxidative
Rh(I) [16 e–] Rh(III) [18 e–]
addition and reductive
H elimination
Ph3P Solv H H Ph3P H
Rh Rh
Cl PPh3 [oxidative Cl PPh3
addition] Solv
(17.16)
(17.17)
re
d uc
tiv
e
el
H R
im
in
at
H
io
n
Ph3P R
Rh
Cl PPh3
Solv
(17.18)
Many simple molecules participate in oxidative addition reactions, and these may be
divided into three broad classes: polar covalent molecules (e.g., alkyl or acyl halides;
Example 17.19), non-polar molecules (e.g., H2 gas or C—H σ bonds; Example 17.20), and
unsaturated compounds (Example 17.21). The overall result of the oxidative addition reac-
tion is to form two new σ bonds to the metal, and to increase its oxidation number by two
at the same time.
H
H MLn
MLn
H
H
R R R
R MLn Ar
MLn Ar MLn R R MLn
X MLn
X H M
H Ln
R O R
R O O O R R
MLn R O MLn
MLn or MLn MLn R R
X MLn M
X X H Ln
H
(17.19) (17.20) (17.21)

Insertion Reactions
Another reaction of organotransition metal complexes that is important in organic syn-
thesis is known as migratory insertion (Example 17.22). This reaction results in the inser-
tion of one ligand into the metal-ligand bond of another. Two types of migratory insertion
are commonly observed; in both cases, the migrating group formally adds to a π bond. In
the one case, the bonding between the non-migrating ligand and the metal remains unal-
tered. In the second, the metal migrates to the other end of the π bond to give a net addi-
tion and conversion of a π complex to a σ complex. One of the most common examples of
migratory insertion is the migratory insertion of carbon monoxide into a carbon-metal
bond to give an acyl-metal bond that can be converted in turn into a variety of acyl com-
pounds, including aldehydes, ketones, and carboxylic acids (as well as carboxylic acid de-
rivatives such as amides and esters). The migratory insertion into carbon monoxide is
assisted by external carbon monoxide, which maintains the coordination number of the
metal atom. An excellent example of this reaction is provided by the carbonylation of allyl
bromide by carbon monoxide in the presence of nickel tetracarbonyl (Figure 17.7). The
migratory insertion step converts the tetracoordinate nickel carbonyl 17.24 into a

Figure 17.7 Carbonylation of oxidative addition

allyl bromide by carbon CO Br
monoxide in the presence of Br
Ni Ni
nickel tetracarbonyl OC CO CO
CO CO
2 CO
(17.23) (17.24)
OMe
migratory
HBr reductive insertion
O elimination
MeOH, 2 CO
Br Br
Ni CO Ni
CO CO
CO
O O
(17.26) (17.25)
coordinatively unsaturated tricoordinate acylnickel complex (17.25), which then reacts

further with carbon monoxide.
R R
MLn MLn MLn R MLn
X R X (17.22)
X X
Y
Y
migratory insertion migratory insertion
Migratory insertion is also an important step in the mechanism proposed18 for the
Ziegler-Natta polymerization reaction that proceeds through an η2 titanium or vanadium
alkene complex (Figure 17.8). In this mechanism, the polymer chain is extended by means
of a migratory insertion reaction of the alkene into the metal-carbon σ bond of 17.28 to give
17.30. Similar migratory insertion reactions of an alkene into a metal-hydrogen σ bond are
believed to be critical steps in the mechanism of homogeneous catalytic hydrogenation.
The reverse of the migratory insertion reaction in Figure 17.7 (i.e., where a small mole-
cule is extruded from a metal-carbon σ bond) is also important in organic synthesis, espe-
cially when that small molecule is carbon monoxide. This reaction is known as
decarbonylation. Decarbonylation of aldehydes by Wilkinson’s catalyst is an important
synthetic method, as well as being a significant (almost always undesirable) side reaction
during hydrogenation of conjugated aldehydes with this catalyst. Decarbonylation occurs
with retention of configuration (e.g., Example 17.31).19
Ph (Ph3P)3RhCl Ph
Et Et (17.31)
CHO PhCN, 160°C H
Me Me
R only S (81% ee)
β-Hydride Elimination
The β-elimination of hydride from transition metal-alkyl σ-bonded complexes to give a
metal hydride complex (or an η2 alkene–metal hydride complex, as in Example 17.32) and
the unsaturated hydrocarbon also belong, in a formal sense, to this class of organometallic
18. (a) Cossee, P. J. Catal. 1964, 3, 80. (b) Arlman, E.J.; Cossee, P. J. Catal. 1964, 3, 99.
19. (a) Tsuji, J.; Ohno, K. Synthesis 1969, 157. (b) Walborsky, H.M.; Allen, L.E. J. Am. Chem. Soc. 1971, 93, 5465.

R Figure 17.8 Migratory
migratory ‡ insertion in the Ziegler-Natta
R R
insertion polymerization. The asterisk
* MLn MLn R *
MLn MLn is used here (and elsewhere)
(17.27) (17.28) to denote a vacant
(17.29) (17.30) coordination site on the
metal atom.
reactions. The step of the Wacker process that converts Example 17.33 to the acetaldehyde
enol η2 complex of the palladium hydride (Example 17.34) is a good example of this type
of reaction.
H
H MLn MLn
(17.32)
R R
β-hydride elimination
Cl Cl Cl
H2O Pd Cl H2O Pd * H2O Pd H
Cl
HO
OH OH
(17.13) (17.33) (17.34)
Transmetallation and Exchange with Metalloids

In Section 11.2, in the discussion of the metal alkyls of the alkali and alkaline earth metals,
we considered the concept of metal exchange reactions and the formation of metal alkyls
of the transition metals by metal-halogen exchange. This exchange is quite facile in these
systems, but it also occurs quite easily when one or both of the metals involved is a transi-
tion metal. Thus, transmetallation is the key step of the Stille coupling, a palladium-cata-
lyzed reaction between a vinylstannane20 (17.38, M=Sn) or alkylmercury compound
(Example 17.38, M=Hg)21 and an alkenyl or aryl halide to give a conjugated diene or a
styrene derivative. The reaction with carbon monoxide and methanol gives methyl es-
ters.22 Transmetallation can also be used with metal alkyls of magnesium,23 zinc,24 and
aluminum.25 We will consider these reactions in more detail at appropriate places later in
this chapter. The exchange of palladium with boron in the boronic acids is the basis of the
Suzuki coupling,26 and the exchange with silicon in tetraalkylsilanes is the basis of the
Hiyama coupling.27
20. Milstein, D.; Stille, J.K. J. Am. Chem. Soc. 1978, 100, 3636.
21. Reviews: Beletskaya, I.P. J. Organomet. Chem. 1983, 250, 551; Pure Appl. Chem. 2002, 74, 1327.
22. Stille, J.K.; Wong, P.K. J. Org. Chem. 1975, 40, 335.
23. Yamamoto, Y.; Kohara, T.; Yamamoto, A. Chem. Lett. 1976, 1217.
24. (a) King, A.O.; Okukado, N.; Negishi, E.-i. J. Chem. Soc. , Chem. Commun. 1977, 683. (b) Tamaru, Y.;
Ochiai, H.; Yamada, Y.; Yoshida, Z. Tetrahedron Lett. 1983, 24, 3869.
25. Bumagin, N.A.; Ponomaryov, A.B.; Beletskaya, I.P. Tetrahedron Lett. 1985, 39, 4819.
26. Reviews: (a) Suzuki, A. Pure Appl. Chem. 1991, 63, 419; J. Organomet. Chem. 1999, 576, 147. (b) Mi-
yaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron
2002, 48, 9633.
27. Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 563, 918.

Figure 17.9 The catalytic reductive oxidative

cycle for metal-catalyzed elimination addition
coupling reactions
R R' R X
LnPd0
(17.35)
L L
R Pd L R Pd L
R' X
(17.40) (17.36)
cis-trans cis-trans
isomerization isomerization
L L
R Pd R' R Pd X
(17.39) L L (17.37)
X M R' M
(17.38)
transmetalation
The foregoing discussion of reactions at the metal atom provides the backdrop for an
introduction to the important synthetic reactions involving coupling of ligands on a
metal. In most coupling reactions, it is a reductive elimination step involving two adjacent
carbon ligands from the metal that leads to carbon-carbon bond formation. Metal-catalyzed
coupling reactions all follow a general pattern where the final product arises in a reductive
elimination reaction from a coordinatively saturated metal complex. The general catalytic
cycle for coupling reactions is given in Figure 17.9. Beginning from the coordinatively un-
saturated LnPd (0) intermediate (17.35), the cycle consists sequentially of oxidative addi-
tion of the halide, isomerization to the trans isomer (if necessary), transmetallation,
isomerization of the trans complex 17.39 to the cis isomer 17.40 (if necessary), and reduc-
tive elimination of the coupled product.
Reaction Synopses
Ligand Substitution
L'
LnM L LnM L'
Reaction may proceed by a dissociative or an associative mechanism.

Oxidative Addition
R
R X
MLn MLn
X
Reaction converts coordinatively unsaturated complex to coordinatively satu-

rated complex by effectively inserting metal into R—X σ bond.

Reductive Elimination
R R X
MLn MLn
X
Reaction eliminates σ-bonded product from a coordinatively saturated complex

to give a coordinatively unsaturated complex.
Migratory Insertion
R R
L MLn L MLn
L L
Reaction results in coordinatively unsaturated complex in migration step; reac-

tion is almost always assisted by additional ligand to satisfy need for coordinative
saturation. It is most common with η2 alkene or carbonyl ligands. With carbonyl
ligands, the reaction may be reversible.
β-Hydride Elimination
H
R' R H
MLn MLn
R R
Reaction may lead to direct loss of alkene and formation of hydride complex, or
to hydride complex with a bound to η2 alkene ligand.
Transmetallation
Y
R
R' MLn
R X R' MLn
X: MgX, MgR, ZnX, ZnR, HgX, HgR, SnR 3, AlR 2, Cu, SiR 3, B(OH)2 etc.
Problem
17-3 The reaction cycle diagram below is a common one for cross-coupling reactions
catalyzed by transition metals (especially palladium). This particular example
is for the Heck coupling reaction. Designate each of the steps of the cycle as
belonging to one of the classes of reactions summarized in the Reaction Synopses
immediately above. What is the oxidation state of the metal in each of the subse-
quent complexes, if complex A is Pd(0), and L is a neutral 2-electron ligand?
HBr ArBr
H Ar
L Pd L L Pd L L Pd L
Br A Br
Ar R F B H R
R R R R
L
L
H Ar Ar H Ar
R L H R
R
L Pd L Pd L Pd
R
Br R R
Br R Br R R
L L
E C
D

17.4 Basic Organometallic Reactions II: Reactions at the Ligand
In the reactions we have just discussed, the reagent attacks the metal atom directly. How-
ever, there is a rich chemistry of organic compounds coordinated to transition metal
atoms where the attack of the reagent is at the coordinated ligand, instead of the metal. In
the introductory section of this chapter, it was hinted that reactions in which transition
metals play a role often disobey rules that have come to be viewed as axiomatic in intro-
ductory textbooks. In large part this is true: transition metal organometallic compounds
exhibit many avenues of reactivity that are forbidden to simple organic compounds. This
is nicely illustrated by the Wacker reaction. The first step of this reaction is a nucleophilic
addition of water to the η2 alkene ligand—and in introductory organic chemistry text-
books, the authors take great pains to make it clear that the activation energy of nucleop-
hilic addition to the π bond of simple alkenes is prohibitively high. The major use of
organotransition metal compounds in modern synthetic organic chemistry is, in fact, the
formation of carbon-carbon bonds during the synthesis of complex organic compounds
where the unusual reactivity of the ligands allows the construction of those bonds under
extremely mild conditions (and often in violation of the “normal” reactivity).
Synthetic Reactions Involving Electrophilic Attack on Ligands

As might be expected, the nature of the metal atom (especially its oxidation state) profoundly
affects the type of reactions that typically occur at the bound ligands. In general, metals in
higher oxidation states render bound polyhapto ligands (η2-alkene, η3-allyl, η4-dienyl, and
so on) electrophilic and therefore susceptible to attack by nucleophilic species. In contrast,
metals in lower oxidation states tend to render the same types of ligands (especially η4-
dienyl) more nucleophilic and therefore susceptible to attack by electrophiles. This is illus-
trated by the coordinatively saturated iron complexes 17.4128 and 17.42.29 In Example 17.41,
the iron atom is in the +2 oxidation state, and the ligand reacts with an enamine nucleop-
hile. In Example 17.42, the iron atom is in oxidation state zero, and the ligand reacts with an
acylium ion electrophile. The treatment of the η3-allyl product in Example 17.38 with a
base—a general reaction of η3-allyliron (II) complexes—leads to deprotonation and regen-
eration of an η4 diene complex; the net effect is electrophilic acyl substitution of the diene.
N 1) MeCN, 0°C
Fe CO O (17.41)
2) HCl, H2O Fe CO
CO + (48% overall)
H CO
MeCOCl, AlCl3 Me (17.42)

Fe(CO)3 (OC)3Fe O
Synthetic Reactions Involving Nucleophilic Attack on Ligands

Alkene and alkyne complexes of iron (II), palladium (II), and platinum (II) are especially
useful in reactions where a nucleophile attacks the hapto ligand. In the process, an η2
28. (a) Rosenblum, M. Acc. Chem. Res. 1974, 7, 122. (b) Lennon, P.; Rosan, A.M.; and Rosenblum, M. J. Am.
Chem. Soc. 1977, 99, 8426.
29. Greaves, E.O.; Knox, G.R.; Pauson, P.L.; Toma, S.; Sim, G.A.; Woodhouse, D.I. J. Chem. Soc., Chem.
Commun. 1974, 257.

ligand is converted to a σ ligand (Example 17.43), and the hapto number of higher order
hapto ligands is reduced by one (e.g., Examples 17.44 and 17.45). The cationic (η2-alkyne)
iron (II) complex 17.46, for example, reacts with a wide variety of nucleophiles, including
malonic ester anions (e.g., Example 17.47) and organocuprates (e.g., Example 17.48) to give
a σ-alkene complex by addition of the nucleophile anti to the iron.30 The stereochemistry
of addition in the corresponding complexes, in which the phosphine is replaced by a
second carbonyl ligand, depends on the base strength of the nucleophile.31
Nu MLn (17.43)
MLn
Nu
η 2 σ
Nu MLn
MLn (17.44)
η3 Nu η2
Nu MLn
MLn (17.45)
Nu
η4 η3
NaCH(CO2Et)2 Fe COMe
THF, –78°C to r.t. EtO2C PPh3
(86%) Me
Me CO2Et (17.47)
Fe CO
PPh3
Me Li2Cu(CN)Ph2
Me Fe CO
THF, –78°C to r.t. PPh3
(17.46) (87%)
Ph Me (17.48)
One of the most versatile applications of nucleophilic attack on the ligand occurs
in π-allylpalladium (II) complexes, where the attack of a soft nucleophile occurs at the
η 3 ligand from the face opposite the metal atom. This reaction, which can be repre-
sented by the catalytic cycle in Figure 17.10, quickly became an important synthetic
reaction thanks to the pioneering contributions 32 of Jiro Tsuji 33 and Barry M. Trost, 34
30. Reger, D.L.; Belmore, K.A.; Mintz, E.; McElligott, P.J. Organometallics 1984, 3, 134.
31. Akita, M.; Kakuta, S.; Sugimoto, S.; Terada, M.; Tanaka, M.; Moro-oka, Y. Organometallics 2001, 20, 2736.
32. (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 4387. (b) Trost, B.M. Tetrahedron 1977,
33, 2615. (c) Trost, B.M. Acc. Chem. Res. 1980, 13, 385. (d) Tsuji, J. Organic Synthesis with Palladium Compounds
(Springer-Verlag: New York, 1980). (e) Trost, B.M. In Bartmann, W.; Sharpless, K.B., Eds. Stereochemistry of
Organic and Bioorganic Transformations (VCH: New York, 1986. (f) Trost, B.M. Pure Appl. Chem. 1981, 53, 2357.
(g) Trost,B.M.; Verhoeven, T.R. In Wilkinson, G., Ed. Comprehensive Organometallic Chemistry (Pergamon
Press: Oxford, 1982), Vol. 8, Ch. 57. (h) Tsuji, J. Pure Appl. Chem. 1982, 54, 197. (i) Tsuji, J. Tetrahedron 1986, 42,
4361. (j) Trost, B.M. Angew. Chem. Int. Ed. Engl. 1989, 28, 1173. (k) Godleski, S.A. In Trost, B.M.; Fleming, I.,
Semmelhack, M.F. Eds. Comprehensive Organic Synthesis (Pergamon Press: Oxford, 1991); Vol. 4, Ch. 3.3. (l)
Tsuji, J. Transition Metal Reagents and Catalysts. Innovations in Organic Synthesis (John Wiley & Sons: Chich-
ester, U.K., 2000). (m) Tsuji, J. Palladium Reagents and Catalysts. New Perspectives for the 21st Century. (Wiley:
print-on-demand, ISBN 978-0-470-85032-9; 2004).
33. Jiro Tsuji (1927–) was educated at Kyoto (BS), Baylor (MS), and Columbia (PhD, 1960). After 14 years in
industry, he joined the Tokyo Institute of Technology in 1974 as professor. In 1988, he moved to Okayama Uni-
versity of Science. Brief biographies are available: Acc. Chem. Res. 1973, 6, 8; 1987, 20, 140.
34. Barry M. Trost (1941–) was educated at the University of Pennsylvania (BA, 1962) and the Massachusetts
Institute of Technology (PhD, 1965). He joined the University of Wisconsin, becoming Professor in 1969, and
he moved to Stanford University in 1987. More details are available in Acc. Chem. Res. 2002, 35, 695.

Figure 17.10 The catalytic PdL4

cycle of the Tsuji-Trost
reaction with soft
(17.49)
nucleophiles
2L
X
(17.52) R PdL2
R Nu
(17.50) (17.54)
X
L L
R R
L PdII L PdII Nu
Nu H
H
(17.51) (17.53)
L = PPh3, etc.
X = Cl, Br, OAc, OCOPh, etc.
for whom the reaction is often named. Much of the work to adapt this reaction to
asymmetric synthesis has been done by the Trost group.35 The L 2Pd0 complex (17.50)
is formed from a coordinatively saturated palladium (0) complex, 17.49—often
(Ph 3P)4Pd0. The catalytic cycle is then initiated by an oxidative addition with the
a llylic halide or acetate (17.52).
The addition of alkyllithium reagents to carbon monoxide gives extremely unstable
acyllithium reagents that are not useful reagents in organic synthesis. It is for this reason
that many organic chemists have sought to generate “acyl anion equivalents” or umpoled
reagents for use where an acyl anion would be useful.36 In contrast to the acyllithium re-
agents, acyl complexes of transition metals are both stable enough to be useful reagents
and also readily formed by the addition of alkyllithium reagents to coordinated carbon
monoxide in metal carbonyls.
Unlike alkali metal acyl complexes, the transition metal acyl complexes have a
resonance-stabilized structure, with both the acylmetal anion (Example 17.55) and the
metallocarbene (Example 17.56) contributing to the resonance hybrid. The bond lengths
of the C—O and C—M bonds in these complexes support this interpretation of the bond-
ing in acylmetal complexes of the transition metals.
O R O R
OC OC
Fe CO Fe CO
OC OC
CO CO
(17.55) (17.56)
Like an enolate anion, an acylmetal anion is also an ambident nucleophile. With pro-
tons and soft Lewis acids, the predominant reaction of these complexes is through the
metal to give the product of oxidative addition. In the example in Figure 17.11, we see that
35. Reviews: (a) Trost, B.M.; Van Vranken, D.L. Chem. Rev. 1996, 96, 395. (b) Trost, B.M.; Crawley, M.L.
Chem. Rev. 2003, 103, 2921.
36. For a useful compilation of early references to acyl anion equivalents, see: Hase, T.A.; Koskimies, J.K.
Aldrichimica Acta 1981, 14, 73.

O R Figure 17.11 Acylmetal
CO complexes react with soft
OC RLi OC electrophiles to give a metal-
Fe0 CO Fe0 CO
OC OC acyl product.
CO CO
(17.57) (17.58)
O R E X
O R X
CO
E OC E
FeII
OC CO
CO
(17.59)
O R O R MeO R
Figure 17.12 Formation of
CO metal alkylidene complex
OC CO RLi OC CO OC CO [Me3O][BF4] OC CO
Cr Cr Cr Cr from an acylmetal anion and
OC CO OC CO OC CO OC CO
CO CO CO a hard electrophile
CO
(17.60) (17.61) (17.62)
these complexes (e.g., 17.54) are formed quite readily by the addition of alkyllithium
reagents to metal carbonyls (e.g., 17.57). The resultant anionic acyl complexes react as
metal-centered soft nucleophiles with a range of electrophiles to give a neutral complex
(e.g., 17.59) that gives the final carbonyl compound by reductive elimination. When a
harder Lewis acid, such as a triflate or Meerwein’s salt, is used to trap the anionic complex,
the reaction occurs at the oxygen atom, the harder site, to give a metallocarbene, known
as a Fischer complex, after E. O. Fischer,37 who first described them. One of the more syn-
thetically useful Fischer complexes (17.62) is derived from chromium hexacarbonyl, as
Synthetic Reactions Involving Electrophilic Attack on Ligands

Electrophilic substitution on η n carbocyclic ligands has been known for decades. It is
well illustrated by the acylation of the cyclobutadiene and cyclopentadienyl ligands in
Examples 17.6338 and 17.64.39 Otherwise, the attack of electrophiles on ligands in tran-
sition metal complexes is less common, with the most frequent examples of the reac-
tion being electrophilic substitution on the ligand, as in the earlier example of
acylation of the η4-butadieneiron tricarbonyl complex.40 One interesting application
of electrophilic addition to a metal complex is the formal [3 + 2] cycloaddition reac-
tion between a σ-allyliron complex and diethyl methylenemalonate. The reaction pro-
ceeds by initial electrophilic addition of the very electron-deficient alkene (17.65) to
37. Ernst Otto Fischer (1918–2007) was a Nobel Prize-winning (1973) chemist. His education at the Tech-
nische Universität München (PhD, 1952) was delayed by “work service” under the Nazis and military service
during World War II. He spent his career at the University of Munich (1957–1964) and then at the Technical
University, where he retired in 1984. For more details, see the Nobel Foundation website.
38. Broadhead, G.B.; Osgerby, J.M.; Pauson, P.L. J. Chem. Soc. 1958, 650.
39. Fitzpatrick, J.D.; Watts, L.; Emerson, G.F.; Pettit, R. J. Am. Chem. Soc. 1965, 87, 3524.
40. Greaves, E.O.; Knox, G.R.; Pauson, P.L.; Toma, S.; Sim, G.A.; Woodhouse, D.I. J. Chem. Soc., Chem.
Commun. 1974, 257.

the allyl group, with concomitant conversion of the σ- complex to an η 2-alkene com-
plex, and formation of the malonate anion (17.66). This complex then undergoes a
subsequent intramolecular addition of the nucleophile to the η 2-alkene complex to
give a new σ complex (17.67) with a cyclopentane ring. The mechanism for this reac-
tion is shown in Figure 17.13.
HCON(Me)Ph CHO
Fe Fe (17.63)
POCl3
Me
MeCOCl, CS2 O (17.64)
Fe 20°C, 45 min Fe
OC CO OC CO
CO (60%) CO
Oligomerization of Alkene and Alkyne η2 Ligands

In 1940, German chemist Walter Reppe discovered that alkynes oligomerize to cyclic
polyenes, often in high yields, in the presence of nickel catalysts. One of the earliest exam-
ples of this reaction—the nickel-catalyzed cyclopolymerization of acetylene to cyclic
polyenes, especially cyclooctatetraene (Example 17.68)—became an integral part of the
German research efforts to use acetylene to circumvent the need for petroleum and rubber.
The nickel-catalyzed reactions of acetylenes, now known collectively as Reppe chemistry,
were first reported after the end of World War II in three papers41 occupied the first 116
pages of volume 560 of Justus Liebigs Annalen der Chemie! Although details of the reac-
tion remain unclear, this reaction appears to be an example of a template reaction, where
all four alkynes are preassembled on the metal atom as a template (Example 17.69) prior to
the oligomerization. By using ligands on the nickel (e.g., triphenylphospine) that can com-
pete with the acetylene for the metal, it is possible to use the reaction to prepare benzene
derivatives instead of the cyclooctatetraene (Example 17.70). In more recent forms of the
reaction (e.g., starting from 17.71, taken from the elegant synthesis of (±)-estrone by Funk
and Vollhardt42), the nickel catalyst has been replaced by CpCo(CO)2. Under these condi-
tions, the reaction has generally been carried out with two of the alkyne groups within one
of the two reactants.
EtO2C CO2Et
Fe η2
OC Fe σ
Fe CHO2Et OC
OC CO
CO
CO σ
CO2Et CO2Et
EtO2C
(17.65) (17.66)
(17.67)
Figure 17.13 Formation of a cyclopentane by sequential electrophilic addition to a σ-allyl complex

and intramolecular nucleophilic addition to an η2-alkene complex
41. (a) Reppe, W.; Schlichting, O.; Klager, K.; Toepel, T. Justus Liebigs Ann. Chem. 1948, 560, 1. (b) Reppe, W.;
Schlichting, O.; Meister, H. Justus Liebigs Ann. Chem. 1948, 560, 93. (c) Reppe, W.; Schwekendiek, W.J. Justus
Liebigs Ann. Chem. 1948, 560, 104.
42. Funk, R.L.; Vollhardt, K.P.C. J. Am. Chem. Soc. 1979, 101, 215.

H
Ni(acac)2
(17.68) Ni (17.69)
Ni (17.70)
L
H OO
Me3Si
(17.72)
(57%)
Me3Si
H OO
Me3SiCCSiMe3 (high yield) ∆
OO
CpCo(CO)2
H (17.73)
Me3Si (30%)
(17.71) H H
Me3Si
A related reaction is the Pauson-Khand reaction,43 in which an alkene and an

alkyne react with carbon monoxide under catalysis by a transition metal carbonyl
such as Co2(CO)8 to give a cyclopentenone. The catalytic cycle of the reaction is given
in Figure 17.14. It involves the complexation of the alkyne replacing the two μ-CO
ligands of the Co2(CO)8 to give 17.75, followed by displacement of one CO ligand by
the alkene to give the η 2 complex 17.76, which then undergoes migratory insertion
of the η 2 ligand to give a cobaltocycle 17.77. The mechanism as shown in Figure 17.14
then passes through migratory insertion into a carbonyl ligand with concomitant
carbonylation to give the complex 17.78, and a second carbonylation to give the co-
baltocyclopropane 17.79. This then reacts with a molecule of alkyne to release the
enone (17.80) and regenerate the complex 17.75. The formation of the cobalt carbonyl
alkyne complex 17.75 changes the geometry about the triple bond and allows the re-
action between remote groups on the chain that are not permitted while the triple
bond is present.
Nucleophilic cyclizations promoted by Lewis acids on the alkyne complex of dinu-
clear cobalt carbonyls are known as the Nicholas reaction.44 An example of this is pro-
vided by the tandem Nicholas cyclization—Pauson-Khand cyclization of the propargyl
ether 17.81 to give the tricyclic ether 17.84.45 Originally, the Pauson-Khand reaction’s
utility was limited by the need for stoichiometric amounts of the highly toxic, pyrophoric
dicobalt octacarbonyl, the vigorous reaction conditions, and the low yields. Continued
43. (a) Khand, I.U.; Knox, G.R.; Pauson, P.L.; Watts, W.E. J. Chem. Soc. D, Chem. Commun. 1971, 36a.
(b) Khand, I.U.; Knox, G.R.; Pauson, P.L.; Watts, W.E.; Foreman, M.I. J. Chem. Soc., Perkin Trans. 1 1973, 977.
(c) Pauson, P.L.; Khand, I.U. Ann. N.Y. Acad. Sci. 1977, 295, 2. Reviews: (d) Schore, N.E. Org. React. 1991, 40, 1.
(e) Gibson, S.E.; Stevenazzi, A. Angew. Chem. Int. Ed. 2003, 42, 1800. (f) Blanco-Urgoiti, J.; Añorbe, L.; Pérez-
Serrano, L.; Domínguez, G.; Pérez-Castells, J. Chem. Soc. Rev. 2004, 33, 32. (g) Gibson, S.E.; Mainolfi, N. Angew.
Chem., Int. Ed. 2005, 44, 3022.
44. For reviews, see: (a) Teobald, B.J. Tetrahedron 2002, 58, 4133. (b) Caffyn, A.J.M.; Nicholas, K.M. In Com-
prehensive Organometallic Chemistry II; Abel, E.W.; Stone, F.G.A.; Wilkinson, G. Eds. (Pergamon: Kidlington,
1995); Vol. 12, p 685.
45. Quintal, M.M.; Closser, K.D.; Shea, K.M. Org. Lett. 2004, 6, 4949.

Figure 17.14 A catalytic cycle (17.74) (17.75) (17.76)

for the Pauson-
Khand reaction O O O
O O O O R' O O
Co R R Co Co
O O R R R R
Co Co Co
O O 2 CO O O CO O
O O O R'
R R R R
O O O O O
O O O O O
CO CO
R' O Co Co O Co R Co R
(17.80) R R
O O Co Co
O
R' O
R' O O O R'
(17.79) (17.78) (17.77)
research, however, has resulted in a reaction that can be carried out under catalytic con-
ditions, using rhodium, titanium, cobalt, iridium, and ruthenium carbonyl complexes as
catalysts—under much milder reaction conditions. By appropriate use of chiral ligands
(e.g., Example 17.87), the reaction can be used to prepare chiral cyclopentenones such as
Example 17.86.46
(OC)3Co Co(CO)3
Co2(CO)8
HO MeO
MeO
OH
(17.81) (17.82)
BF3•Et2O
CH2Cl2
O (OC)3Co Co(CO)3
c-C6H11-NH2
O
(CH2OMe)2
O
(17.84) (17.83)
46. Kim, D.E.; Kim, I.S.; Ratovelomanana-Vidal, V.; Genêt, J.-P.; Jeong, N. J. Org. Chem. 2008, 73, 7985.

Me
[Rh(CO)2Cl2]2 Ph Me
17.87 (0.1 eq)
O Ph O O PPh2
AgOTf, CO (0.1 atm.) PPh2
THF, 18-20°C H
(95%; 94% e.e.) Me
(17.85) (17.86)
Me
(17.87)
Metathesis and Metallocycle Formation

Olefin metathesis47 has been known since the middle of the 20th century,48 but it is only
since the 1990s that its use has become widespread. The currently accepted mechanism of
the reaction49 was proposed in 1971 by Yves Chauvin,50 who shared the 2005 Nobel Prize in
Chemistry for the development of the reaction. The mechanism, shown in Figure 17.15,
involves an initial [2 + 2] cycloaddition of a metallocarbene complex (17.88) to the first
alkene to give a metallocyclobutane (17.89). This is followed by a retro-[2 + 2] cyclorever-
sion to give a new metallocarbene complex (17.90) that then adds to the second alkene to
give a second metallocyclobutane (17.91). This then expels the product alkene as a mixture
of stereoisomers. The reaction proceeds most favorably when both participating alkenes
are terminal, so that one of the alkene products is ethylene.
R1 Figure 17.15 The catalytic

R2 H2C MLn R1 cycle of the Chauvin
retro- mechanism for olefin
(17.88) [2+2]
[2+2] metathesis
MLn MLn
R2 R1 R1
(17.91) (17.89)
retro-
[2+2] [2+2]
R1 CH2
MLn H2C
R2
(17.90)
47. Reviews: (a) Hoveyda, A.H.; Zhugralin, A.R. Nature 2007, 450, 243. (b) Nicolaou, K C.; Bulger, P.G.;
Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490. (c) Grubbs, R.H. Tetrahedron 2004, 60, 7117. (d) Chatterjee,
A.K.; Choi, T.-L.; Sanders, D.P.; Grubbs, R.H. J. Am. Chem. Soc. 2003, 125, 11360. (e) Connon, S.J.; Blechert, S.
Angew. Chem. Int. Ed. 2003, 42, 1900. (f) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013. (g) Grubbs, R.H.;
Chang, S. Tetrahedron 1998, 54, 4413. (h) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371.
48. Anderson, A.W.; Merking, N.G. U.S. Patent No. 2.721,189 [Oct. 18, 1955]
49. Hérisson, J.-L.; Chauvin, Y. Makromol. Chem. 1971, 141, 161.
50. Yves Chauvin (1930–2015), who shared the Nobel Prize in Chemistry for 2005, spent his career with the
Institut Français du Pétrole, from which he retired in 1995. His autobiography is available at the Nobel Founda-
tion web site.

Figure 17.16 The catalytic H2C=CH2

cycle of the enyne
metathesis reaction (17.92) R2C MLn H2C MLn (17.88)
"priming H2C=CH2
R1 R3 cycle"
(17.99) H R2
R2 C MLn (17.94)
retro- R4
R4 [2+2] R1
[2+2] (17.93)
R4 R4
MLn MLn
R1
R3 R2 R1
R2
R4 (17.95)
(17.98)
[2+2] retro-electro-
R4 MLn
cyclization
R4
(17.97) R3 R2 R1
(17.96)
A similar mechanism, shown in Figure 17.16, can be written for the related enyne me-
tathesis reaction to give conjugated dienes. This reaction requires an initial priming cycle
that generates the actual metallocarbene catalyst from the alkene partner in the reaction. By
carrying out the reaction under an atmosphere of ethylene, the reaction is accelerated due to
formation of the methylene complex51 in a pre-equilibrium before entering the catalytic cycle.
The initial [2 + 2] cycloaddition gives a metallocyclobutene (17.95) that then under-
goes a retro-electrocyclization to give a new metallocarbene (17.96). This then participates
in the metathesis with the second alkene to give the diene (17.99). Note how, in contrast to
olefin metathesis, this reaction leads only to reorganization of the atoms of the starting
materials—all the atoms of the reactants end up in the product, and no molecule of a
second alkene is produced.
The first work to show that a metal-alkylidene complex may be involved in the metath-
esis reaction was published by Casey,52 and it was subsequently investigated by Katz53 and
then Schrock.54 Catalysts such as 17.100,55 based on tungsten or molybdenum, are now
generally referred to as Schrock catalysts.
In parallel with Schrock’s work, Grubbs had been investigating the use of Tebbe’s re-
agent56 (Example 17.101) as a catalyst for olefin metathesis. Although it showed activity (and
was important in elucidating the mechanism of the reaction), its reactivity limited its useful-
ness as a catalyst. Subsequently, Grubbs turned his attention to complexes of ruthenium, and
this has provided a wide range of highly active catalysts.57 The first truly active catalyst for
general use developed by the Grubbs group is the alkylidene complex 17.102, now known
as the first-generation Grubbs catalyst (Grubbs I).58 Subsequent research found that the
51. Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082.
52. Casey, C.P.; Burkhardt, T.J. J. Am. Chem. Soc. 1974, 96, 7808.
53. (a) Katz, T.J.; Lee, S.J.; Acton, N. Tetrahedron Lett. 1976, 4247. (b) Katz, T.J.; Acton, N. Tetrahedron Lett.
1976, 4251. (c) Katz, T.J.; Lee, S.J.; Shippey, M.A. J. Mol. Catal. 1980, 8, 219.
54. (a) Schrock, R.; Rocklage, S.; Wengrovius, J.; Rupprecht, G.; Fellmann, J. J. Mol. Catal. 1980, 8, 73.
(b) Rocklage, S.M.; Fellmann, J.D.; Rupprecht, G.A.; Messerle, L.W.; Schrock, R.R. J. Am. Chem. Soc. 1981, 103, 1440.
55. Oskam, J.H.; Fox, H.H.; Yap, K.B.; McConville, D.H.; O’Dell, R.; Lichtenstein, B.J.; Schrock, R.R. J. Or-
ganomet. Chem. 1993, 459, 185.
56. Tebbe, F.N.; Parshall, G.W.; Reddy, G.S. J. Am. Chem. Soc. 1978, 100, 3611.
57. Review of catalyst development by the Grubbs group: Grubbs, R.H. Tetrahedron 2004, 60, 7117.
58. Schwab, P.; Grubbs, R.H.; Ziller, J.W. J. Am. Chem. Soc. 1996, 118, 100.

c omplex 17.103, which carries an N-heterocyclic carbene ligand, is an even more active cata-
lyst; this catalyst is now known as the second-generation Grubbs catalyst (Grubbs II).59 A
more stable (if less reactive) form of the Grubbs catalyst is the Hoveyda-Grubbs catalyst,60 in
which the metal carries a chelating alkylidene ligand (Example 17.104). Within a short time,
a second-generation Hoveyda-Grubbs catalyst (Example 17.105) had also been reported.61
Ph Cy3P Cl
H2
N C Me
Ru
Mo Ti Al
CF3 Cl PCy3
O Cl Me
O CF3
F3C CF3
(17.101) (17.102)
(17.100)
Me Me
Me Me Cy3P Cl N N
N N
Cl
Cl Ru Me Me Me
Me Me Me Ru
Me Ru Me
Cl O Cl O
Cl PCy3
(17.103) (17.104)
(17.105)
The original patent describing the reaction was for what is now known as ring-opening
polymerization (ROMP) of norbornene. However, the major use of the reaction in modern
synthesis is for the opposite task: closure of rings by elimination of a small alkene (usually
ethylene). Ring- closing metathesis (RCM) has become a very powerful tool for the closure of
medium to large rings, especially in active pharmaceuticals.62 This is nicely illustrated by the
closure of the 13-membered ring in Overman’s synthesis of the marine alkaloid sarain-A,
shown in Example 17.106.63 Although the regiochemistry of the enyne metathesis reaction is
well defined, the stereochemistry of the intermolecular reaction is often poorly controlled.64
For this reason, the intramolecular reaction, as illustrated in E
xample 17.107,65 is often preferred.
O O
TIPSO O TIPSO O
N N
OTBS Grubbs I OTBS
N CH2Cl2, ∆ N
(17.106)
[E:Z 2:1]
(82% after hydrogenation of double bond)
CO2Me CO2Me
Grubbs II (5 mol %)
N CH2Cl2, 40°C, 3 h N (17.107)
(91%)
59. Scholl, M.; Trnka, T.M.; Morgan, J.P.; Grubbs, R.H. Tetrahedron Lett. 1999, 40, 2247.
60. Garber, S.B.; Kingsbury, J.S.; Gray, B.L.; Hoveyda, A.H. J. Am. Chem. Soc. 2000, 122, 8168.
61. Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41, 9973.
62. Reviews: (a) Phillips, A.J.; Abell, A.D. Aldrichimica Acta 1999, 32, 75. (b) Vernall, A.J.; Abell, A.D. Aldri-
chimica Acta 2003, 36, 93.
63. Becker, M.H.; Chua, P.; Downham, R.; Douglas, C.J.; Garg, N.K.; Hiebert, S.; Jaroch, S.; Matsuoka, R.T.;
Middleton, J.A.; Ng, F.W.; Overman, L.E. J. Am. Chem. Soc. 2007, 129, 11987.
64. For an extensive review, see: Diver, S.T.; Giessert, A.J. Chem. Rev. 2004, 104, 1317.
65. Yang, Q.; Alper, H.; Xiao, W.-J. Org. Lett. 2007, 9, 769.

Worked Problem
17-3 The following olefin metathesis reaction could give several possible products, but
in practice, only one is isolated. What is that product and why is it preferred?
H H
OTES
O
H Grubbs-I
O O CH2Cl2, ∆
H
O O
H
§Answer below.
All metathesis reactions involving Grubbs or Hoveyda-Grubbs catalysts face the same
problem: it can be difficult to remove the catalyst from the product, which often leads to
C
further undesired metatheses during product isolation. Diver66 has found a creative solu-
N tion to this problem by using an isocyanide to stop the metathesis; by using an ionic iso-
CO2K cyanide (Example 17.108) in methanol, the metal could be removed quantitatively from
(17.108) the reaction mixture by simple chromatography.
Reaction Synopses
Nucleophilic Attack on Ligands
Nu
Nu Nu
MLn MLn MLn MLn MLn MLn
η2 σ η3 η2 4
η η3
Reagents: RLi, RMgX, R 2Zn, etc.; enolate anions; oxyanions; etc.

This converts an ηn ligand to an ηn−1 ligand (η2 to σ) by attack of the nucleophile
on the ligand.
RLi O O
O C MLn MLn MLn
R R
Attack on carbonyl ligands gives acylmetal complexes that are resonance-stabilized

ambident nucleophiles.
Electrophilic Attack on Ligands
E E
E
MLn MLn MLn
66. Galan, B.R.; Kalbarczyk, K.P.; Szczepankiewicz, S.; Keister, J.B.; Diver, S.T. Org. Lett. 2007, 9, 1203.

In this reaction, the preferred metathesis reaction occurs between the two monosubstituted alkene groups,
which leads to the formation of ethylene as the other product. Since the ethylene is a volatile product that can
escape, this route is also favored by Le Châtelier’s Principle. [J. Am. Chem. Soc. 2006, 128, 15960].
H H H H
OTES OTES
O O
H Grubbs-I H
O O O O
H CH2Cl2, ∆ H
O O (73%) O O
H H

Reagents: RCOCl, AlCl3; HCONMe2, POCl3; etc.

Reaction usually proceeds by conversion of the ηn complex to the cationic ηn−1
complex, and elimination of the proton to give the new ηn complex with a substi-
tuted ligand.
Oligomerization
R R R
R
R R R R
A B
R R R R
R
R R R
Reagents: A. Ni catalyst, frequently Ni(CO)4

B. Ni catalyst with a strongly binding ligand (e.g., Ph3P)
Reaction of alkynes with diynes in the presence of CpCo(CO)2 gives benzenes.
Metathesis and Metallocyclobutane Formation
R3
R1 R3 cat. R1 R3 R3
+ R1
cat.
+ R1
R2 R4 R2 R4
R2
C2H4 R4
R2 R4
Reagents: catalyst is a ruthenium (Grubbs-type), or tungsten or molybde-

num (Schrock-type) carbene complex carrying hindered ligands
Ar Ph
Cy3P Cl N Cl Ph Ar N
Ph
Ru Ar Ru Ar Mo
Cl PCy3 Cl N O O
Ar
Grubbs I Grubbs II Schrock
Problem
17-4 What is the major product formed in each of the following reactions?
(a) O O Grubbs-II
TBSO CH2Cl2
N Grubbs I
(b) CH2Cl2, ∆, 2 h
O
OTBDMS
O
H2C=CH(CH2)11CH3
(c) HO H O Grubbs-II, CH2Cl2, ∆
(continues)

(Problem continued)
CO2Me
N Cbz Grubbs I
(d)
CH2Cl2, r.t.
References: (a) Tetrahedron 2011, 67, 9376. (b) J. Am. Chem. Soc. 2005, 127, 8398. (c) Tetrahedron 2011,
67, 9283. (d) J. Am. Chem. Soc. 2002, 124, 13342.
17.5 Hydrometallation: Making the Organometallic Reagents

by Addition
The recurring motif in cross-coupling reactions is one of metathesis between an organic

derivative of a metal or metalloid and a hydrocarbon or halide equivalent (Example
17.109). One key step in most of these reactions involves the transfer of an alkyl group
from the metalloid or a metal to the transition metal at some point during the catalytic
cycle. These transmetallation (metal exchange) reactions proceed, in most cases, with
retention of configuration of the migrating organic ligand (as in Example 17.110). There
are two major ways for preparing the organometallic reagents required as reactants in
the cross-coupling reactions: (1) transmetallation between less reactive metal halides
and more reactive alkali metal organometallic reagents and (2) hydrometallation and
carbometallation of unsaturated hydrocarbons with metal hydrides and metal alkyls
(e.g., Example 17.111).
H M H M'
R R R R
(17.110)
R M R R'
(17.109) M' X M X
M=Li, Mg, etc
R' X M X M'=Zn, Al, Cu, Sn, Hg, Zr, Si, etc.
R' M
R' M
R H (17.111)
R R
R'=H, alkyl
M=Al, Mg, Zr, Sn, etc.
The transmetallation of alkali metal alkyls by transition metal halides was discussed
in detail in Section 11.2. It involves the formation of a metal alkyl of a more active metal,
followed by the exchange with a halide salt of a less active metal. The method can be used
to prepare not only transition metal alkyls such as cuprates and zincates but also alkyl
derivatives of non-metals and metalloids (e.g., the formation of phosphines and arsines
from phosphorus or arsenic trihalides and Grignard reagents).
Hydrometallation involves the addition of a metal (or metalloid) hydride across the π
bond of an alkene or an alkyne in a process that is formally the reverse of the β-hydride
elimination. The reactive σ bond to hydrogen is polarized such that the hydrogen is δ– and

the heteroatom is δ+. The closely related carbometallation reaction involves the addition
of a similarly polarized metal-carbon σ bond across the π bond of an alkene or alkyne. It
is somewhat ironic that the prototypical addition reaction of this type does not involve the
addition of a metal-hydrogen σ bond across a C—C π bond at all. It involves, instead, the
addition of a B—H σ bond across the C—C π bond: hydroboration. The hydroboration
reaction, however, exhibits many of the fundamental characteristics of hydrometallation:
(1) the addition gives syn addition of B–H across the π bond, (2) the regiochemistry of
addition is generally anti-Markovnikov (in the formal sense, based on the location of the
hydrogen atom), and (3) the resultant borane can be used in a wide variety of synthetic
reactions. It is instructive to note how organoboranes have undergone a resurgence of
importance in organic synthesis with the development of metal-catalyzed cross-coupling
reactions such as the Suzuki-Miyaura and Sonogashira reactions.
A wide range of metal and metalloid hydrides will add to C—C π bonds. The most
important among these are the hydrides of silicon, tin, zirconium, and aluminum
(Example 17.112). All these hydrides will react with alkenes to give saturated organo-
metallic compounds and with alkynes to give vinyl derivatives with well-defined ste-
reochemistry. In the absence of a directing (usually chelating) group, the addition of
the M—H bond is usually syn, and the regiochemistry of the addition is anti-
Markovnikov. This is in keeping with the metal atom being the electrophilic end of
the M—H bond.
δ− δ+ δ− δ+
H M H M
R D H M H M
R D R D (17.112)
R R R R R D
M=Mg, Al, Si, Zr, Sn, etc.
Hydroboration
The discovery that the hydroboration of alkenes is catalyzed by ethers and other modest
Lewis bases67 was followed by decades of research into the synthesis and reactions of bo-
ranes. Early on, much of the importance of hydroboration in organic synthesis was due to B
the facile conversion of the resultant boranes to alcohols, amines, and halides. These reac- H
tions all occur with anti-Markovnikov regiochemistry and are stereospecific, giving the Sia2BH
syn adduct (amines and alcohols), or the anti adduct (halides).
Hydroboration-oxidation is the longest used variant of the reaction. It is an extremely H
B
useful method for the formation of alcohols due to its regiochemical control and its ste-
H
reospecificity (all additions of borane are syn). Historically, the oxidation of the interme-
diate trialkylborane was effected by alkaline hydrogen peroxide, but organic oxidants ThBH2
such as tert-butyl hydroperoxide and base, and triethylamine N-oxide (TEAO) or N-meth-
ylmorpholine N-oxide (NMMO) have become popular; the amine N-oxides avoid the ne- BH
cessity for strongly basic reagents.
The regiochemical preferences of the BH3 reagent can be enhanced by incorporating
9-BBN
one or more sterically demanding groups on the boron. There are three borane derivatives
that have been particularly widely used in organic synthesis (17.113). (17.113)
1. Disiamylborane (Sia2 BH), which is formed in situ by the addition of two equiva-
lents of 2-methyl-2-butene to BH3•THF prior to the hydroboration of the alkene
of interest
67. Review: Brown, H.C. Tetrahedron 1961, 12, 117.

2. Thexylborane (ThBH2), formed in situ by the addition of one equivalent of 2,3-dimethyl-

2-butene to BH3•THF prior to the hydroboration of the alkene of interest
3. 9-Borabicyclo[3.3.1]nonane [9-BBN], which is a stable, commercially available solid
prepared from 1,5-cyclooctadiene by hydroboration with BH3•THF and subsequent
thermal equilibration of the product mixture
The high levels of both regioselectivity and diastereoselectivity attainable with

these hindered borane reagents led to the study of asymmetric hydroboration. These
early efforts identified the diisopinocampheylborane (Ipc 2 BH) system, a chiral analog
of disiamylborane available as either enantiomer from α-pinene, as a useful reagent
for the enantioselective synthesis of secondary alcohols from cis alkenes.68 In these
reactions, e.e’s are often greater than 99%. The major enantiomer formed using diiso-
pinocampheylborane may be predicted on the basis of the simple model for the hyd-
roboration of cis-2-butene given in Figure 17.17. It is important to recognize that this
model is a simple mnemonic (much like the Cram’s rule model)—useful for prediction
but not necessarily representative of the actual transition state structure in the hyd-
roboration reaction. In this model, the conformation of the borane is written so that
the large and small groups (R L , R S) are arranged with the large group on one isopino-
campheyl group approximately eclipsing the hydrogen on the other. The alkene now
approaches the boron to give approximate sp3 hybridization at boron, with the methyl
groups oriented away from R L, which brackets the two hydrogens. This leads to the
borane from 1S-α-pinene giving the S alcohol from a symmetrical Z alkene. This
model also predicts that lower levels of enantioselectivity should be expected for the
E-alkene due to increased interference between the methyl group of the alkene and R L
of the borane.
In the ensuing decades, other chiral hydroborating agents have been developed, most
noteworthy among them being Masamune’s chiral borolane,69 although the lengthy syn-
thesis required to generate the reagent has limited its use. In 2008, Soderquist reported the
synthesis (Figure 17.18) of a new class of chiral cyclic boranes70 (10-alkyl-9-borabicyclo[3.3.2]
decanes, 17.118) and their use in hydroboration of 1,1-disubstituted alkenes with high
levels of enantioselectivity. These alkenes had previously given poor results in asymmetric
hydroboration reactions. The results in Table 17.3 are typical of those obtained with chiral
borane reagents. Soderquist reported that the in situ generation of the active hydroborat-
ing agent from the borohydride was the most convenient method for carrying out hydrob-
orations with these reagents.
Figure 17.17 A model for H

predicting the RS H Me
stereochemistry of addition H H
B RS B Me
of diisopinocampheylborane
to cis-2-butene (a H RS RL R2B
H H Me
representative Z alkene) RL Me
RL
H
68. Reviews: (a) Srebnik, M.; Ramachandran, P.V. Aldrichimica Acta 1987, 20, 9. (b) Brown, H.C.; Ramachan-
dran, P.V. Pure Appl. Chem. 1991, 63, 307.
69. Masamune, S.; Kim, B.M.; Petersen, J.S.; Sato, T.; Veenstra, S.J.; Imai, T. J. Am. Chem. Soc. 1985, 107, 45–49.
70. (a) Gonzalez, A.Z.; Romàn, J.G.; Gonzalez, E.; Martinez, J.; Medina, J.R.; Matos, K.; Soderquist, J.A.
J. Am. Chem. Soc. 2008, 130, 9218. (b) Burgos, C.H.; Canales, E.; Matos, K.; Soderquist, J.A. J. Am. Chem. Soc.
2008, 130, 8044. (c) Canales, E.; Ganeshwar, P.; Soderquist, J.A. J. Am. Chem. Soc. 2005, 127, 11572.

Ph Figure 17.18 The synthesis of

the Soderquist boranes
OMe MeO H HO
R Me O
B RiCH=N2 B R
Ph NHMe H N B
hexane Me
(17.114) (17.115) (17.116)
LiAl(OEt)3H
Et2O, 0–25°C
H R R
HB Me3SiCl H2B
(17.118) (17.117)
Table 17.3 Hydroboration with Chiral Boranes: Effects of Alkene and Borane Structure on
Enantioselectivity
BH2
BH2 Ph H Me3Si H
B BH BH
H
Representative 2
Alkene Ipc2BH IpcBH2 DMB
Me H
14 73 99.5 96 95
H Me
Me Me
99.1 24 97.6 32 84
H H
Me Me
15 53 97.6 74 —
H Me
Me H
32 — 1.5 38 52
H
Me H
— 5 — 78 66
Ph H
Values are e.e.
The stereochemistry of the product of hydroboration with the Soderquist reagents can
be predicted relatively straightforwardly using the model in Figure 17.19. In this model, the
alkene approaches the boron from the direction opposite the substituent at the 10- position,
with the large group oriented away from the bicycle (17.119). In this model, the 1R

Figure 17.19 Model for RS R ‡

predicting the R
stereochemistry of addition (R) RL
(S) B H
of the Soderquist borane to a
1,1-disubstituted alkene (R) BH RS
RL
(17.119) B
H
RL Rs
H R
H2O2 H
RS RS
HO B
RL base
RL
(17.121) (17.120)
enantiomer of the borane is predicted to give the R enantiomer of 2-methyl-1-butanol

(17.121, R L=Et, RS=Me) from 2-methyl-1-butene. Thomas and Aggarwal subsequently re-
ported high levels of asymmetric induction in the hydroboration of 2-alkyl-1-alkenes with
the Soderquist boranes and the Suzuki-Miyaura coupling of the intermediate boranes.71
With the advent of these new chiral hydroborating agents, the enantioselective synthesis of
chiral alcohols by hydration of alkenes has now been raised to levels similar to those ob-
tainable with asymmetric epoxidation and dihydroxylation reactions. The origins of the
enantioselectivity have been explored computationally for both diisopinocampheylborane72
and the Soderquist reagent.73
A recent application of boranes in synthesis has been their use as a protecting group
for alkenes to allow the selective semihydrogenation of dienes.74 In this approach, the less
hindered double bond of the diene reacts with one equivalent of a hindered borane such as
9-BBN, and the resultant unsaturated borane is subjected to catalytic hydrogenation. The
oxidation of the saturated product with a tertiary nitroso compound returns the original
alkene. As Examples 17.122 and 17.123 show, the reaction can be applied to either conju-
gated or non-conjugated dienes.
1) 9-BBN, THF
2) H2, Pd-C, THF, 0-25°C (17.122)
3) (Me3C—NO)2
(89%)
1) 9-BBN, THF
2) H2, Pd-C, THF, 0-25°C
(17.123)
3) (Me3C—NO)2
(57%)
H
Migration of Groups from Boron

Despite the fact that boranes are generally (but not always!) stable with respect to rear-
rangements, the migration of groups from boron is a key feature of most organoborane
chemistry and is essential to the formation of useful products from boranes. The
71. Thomas, S.P.; Aggarwal, V.K. Angew. Chem. Int. Ed. 2009, 48, 1896.
72. Houk, K.N.; Rondan, N.G.; Wu, Y.D.; Metz, J.T.; Paddon-Row, M.N. Tetrahedron 1984, 40, 2257.
73. Ess, D.H.; Kister, J.; Chen, M.; Roush, W.R. J. Org. Chem. 2009, 74, 8626.
74. Graham, T.J.A.; Poole, T.H.; Reese, C.N.; Goess, B.C. J. Org. Chem. 2011, 76, 4132.

driving force for these migrations almost invariably comes from the elimination of the
formal negative charge on boron in an “ate” complex by migration of an alkyl group
from boron to an acceptor electrophile. These reactions can occur in either an intramo-
lecular or an intermolecular sense. In the absence of other factors, intramolecular
reactions (Example 17.124) generally proceed with retention of configuration at the
migrating carbon, whereas intermolecular reactions usually proceed with inversion at
the migrating carbon (Example 17.125).
R' R'
R' B Y B Y
R' Y R' R R'
R' B X B X R
R R' R X X X
retention of configuration at R inversion of configuration at R
(17.124) (17.125)
Trialkylboranes react slowly with halogens, but the reaction is accelerated by the addi-
tion of an alkoxide base, which leads to an intermediate “ate” complex (Example 17.129)
that then reacts rapidly with the halogen.75 The reaction in this case proceeds with net
inversion of configuration, as illustrated by the conversion of an exo-2-norbornylborane
(Example 17.128) to endo-2-bromo-norbornane (Example 17.127).76 As shown in this ex-
ample, the stereochemistry is consistent with the halogen attacking the borate from the
back side (i.e., with inversion of configuration at the migrating carbon).
1) BH3•THF
(17.127)
2) NaOMe, Br2,
(17.126) THF-MeOH, 0°C Br
(75%)
MeO
OMe
(17.129)
BR2 BR2
(17.128)
Br
Br
When one of the groups on boron is unsaturated, the reaction of a trialkylborane with
iodine in the presence of base takes a dramatically different course. On treatment with
iodine and base, the borane undergoes a rearrangement with concomitant formation of a
carbon-carbon bond, rather than a carbon-iodine bond to give cis alkenes from trans vi-
nyldialkylboranes and conjugated dienes from divinylalkylboranes.77 In this reaction,
Zweifel and his coworkers found that replacing the iodine by cyanogen bromide resulted
in a reversal of the stereochemistry of the double bond in the product.
75. (a) Brown, H.C.; Rathke, M.W.; Rogic, M.M. J. Am. Chem. Soc 1968, 90, 5038. (b) Brown, H.C.; Lane, C.F.
J. Am. Chem. Soc. 1970, 92, 6660.
76. Brown, H.C.; Lane, C.F. J. Chem. Soc., Chem. Commun. 1971, 521.
77. (a) Zweifel, G.; Arzoumanian, H.; Whitney, C.C. J. Am. Chem. Soc. 1967, 89, 3652. (b) Zweifel, G.; Polston,
N.L.; Whitney, C.C. J. Am. Chem. Soc. 1968, 90, 6243. (c) Zweifel, G.; Fisher, R.P.; Snow, J.T.; Whitney, C.C.
J. Am. Chem. Soc. 1971, 93, 6309. (d) Zweifel, G.; Fisher, R.P.; Snow, J.T.; Whitney, C.C. J. Am. Chem. Soc. 1972,
94, 6560. (e) Evans, D.A.; Crawford, T.C.; Thomas, R.C.; Walker, J.A. J. Org. Chem. 1976, 41, 3947.

Figure 17.20 Variation of

stereochemistry in
iodination of 1) I2
I2, NaOH, 0°C
vinylboronic acids I I
Et2O, H2O 2) NaOH
I
(90%) B(OH)2 B(OH)2
B(OH)3
(17.130)
OH
(17.131)
(17.132)
RH I H
I H
H
I B(OH)2 R B(OH)2
(17.133) (17.134)
R, B(OH)2 R, B(OH)2
I aproximately gauche
anti I
(17.135)
(17.136)
The situation with terminal vinylboronic acids (Figure 17.20) is more interesting be-
cause, depending on the exact order of the addition of the base and the electrophile (almost
always iodine), one may obtain either geometric isomer of the vinyl iodide.
Thus, when the base is added to E-1-octeneboronic acid (17.130) first, followed by
iodine, the product is the E iodide (17.135).78 When the iodine is added first, followed by
the base, Z-1-iodo-1-octene (17.136) is obtained.79 The stereochemistry of these reactions is
rationalized in terms of the timing of the cleavage of the B—C bond. When the iodine and
base are added simultaneously, the cleavage occurs at the iodonium ion stage (17.133),
leading to apparent retention of configuration at carbon, whereas when excess halogen is
added first, it is proposed that the B—C bond is cleaved in a concerted anti elimination
from the diiodide (17.134). A variant of this reaction that gives 2-iodo-1-alkenes as the
major product involves the initial iodoboration of a terminal alkyne with 9-iodo-9-BBN,
followed by protonolysis of the B—C bond,80 as illustrated by a key step in Overman’s
synthesis of alcyonin, shown as Example 17.137. 81
I
1) B I
H H
TBDMSO OTBDMS 2) AcOH, NaBO3 TBDMSO OTBDMS (17.137)

O O
O O
t-Bu t-Bu
Hydroalumination82
Aluminum is located directly below boron in the periodic table, so one might reasonably
expect that compounds of aluminum could exhibit some of the chemical properties of the
78. Brown, H.C.; Hamaoka, T.; Ravindran, N. J. Am. Chem. Soc. 1973, 95, 5786.
79. Brown, H.C. Pure Appl. Chem. 1976, 47, 49.
80. Hara, S.; Dojo, H.; Takinami, S.; Suziki, A. Tetrahedron Lett. 1983, 24, 731.
81. Corminboeuf, O.; Overman, L.E.; Pennington, L.D. Org. Lett. 2003, 5, 1543.
82. Reviews and monographs: (a) Dzhmenilev, U.M.; Ibragimov, A.G. In Andersson, P.G.; Munslow, I.J.
Modern Reduction Methods (Wiley-VCH: Weinheim, 2008), ch. 18, p. 447.

analogous boron compounds. Lithium aluminum hydride does add to unsaturated hydro-
carbons, but these addition reactions typically require high temperatures and pressures,
and ether solvents. The neutral aluminum hydrides (e.g., diisobutylaluminium hydride
[DIBAL-H]), on the other hand, are electrophilic and add much more easily to terminal
alkynes, with syn stereochemistry to give the E-vinylalanes.83 The regioselectivity with
internal alkynes is generally poor unless there is a bias in the form of the electronic char-
acteristics of the two groups bonded to the triple bond.84
The stereochemistry of the hydroalumination reaction depends markedly on the
formal charge on aluminum. Neutral alanes lead to syn addition of the Al—H bond, while
anionic aluminates lead to anti addition of the Al—H bond. The stereochemistry of the
addition of neutral alanes to terminal alkynes is most easily interpreted in terms of a con-
certed addition through a four-membered cyclic transition state, as in Example 17.138. The
stereochemistry with aluminates, on the other hand, requires a two-step mechanism, with
hydride addition as the first step to give the anion 17.139, which is in equilibrium with its
cis isomer (Example 17.140), and trapping of the vinyl anion by the neutral alane as the
second. Because the intermediate vinyl anion exists preferentially as the trans isomer, the
overall addition becomes trans (Example 17.141).
H AlR2 ‡ H
R H AlR2 (17.138)
R
R H
H
AlR3
H AlR3
R
R R R R
R
H H
(17.139) (17.140)
AlR3
R (17.141)
R
H
The one drawback of hydroalumination of terminal alkynes comes in the form of

competing deprotonation to generate the corresponding alkynylaluminum species. This
can be suppressed, in part, by using the trimethylsilyl group as a surrogate for the acety-
lenic hydrogen (e.g., as in Example 17.142). Interestingly, by changing the solvent from
heptane (a non-coordinating solvent) to N-methylpyrrolidine (a good Lewis base), the
stereochemistry of the hydroalumination can be reversed. In heptane, the major product
is from syn addition (Example 17.144), whereas in mixed heptane–N-methylpyrrolidine,
the isomer from anti addition (Example 17.143) predominates. With diethyl ether as the
solvent (a weaker Lewis base than N-methylpyrrolidine), a mixture of stereoisomers is
83. (a) Wilke, G.; Müller, H. Chem. Ber. 1956, 89, 444. (b) Eisch, J.J.; Kaska, W.C. J. Am. Chem. Soc. 1963, 85,
2165. (c) Bundens, J.W.; Francl, M.M. Organometallics 1992, 12, 1608.
84. Eisch, J.J.; Gopal, H.; Rhee, S.-G. J. Org. Chem. 1975, 40, 2064.

formed.85 The unexpected stereochemistry of the addition in heptane was ascribed86 to

catalysis of the cis-trans isomerization by the alane itself. Researchers found that this
isomerization also required the trialkylsilyl group in order to occur: the simple vinylal-
anes did not isomerize under the same conditions. Obviously, these results mandate cau-
tion in making predictions about the stereochemistry of this reaction in systems other
than simple hydrocarbons.
DIBAL-H H Al(i-Bu)2 H SiMe3

Ph SiMe3 +
solvent
Ph SiMe3 Ph Al(i-Bu)2
(17.142) (17.143) (17.144)
solvent = heptane 4 : 96
solvent = heptane, N-Me-pyrrolidine) 96 : 4
solvent = Et2O 65 : 35
Hydrozirconation87
Organozirconium compounds have emerged over the past four decades as extremely
useful reagents in the functionalization of alkenes and alkynes and as key intermedi-
ates in transmetallation reactions to give the organometallic partner in a wide range
of cross-coupling reactions. One of the most important zirconium complexes is the
Schwartz reagent88 (Example 17.145), which reacts with alkenes and alkynes to give
products of syn addition. Unlike many other hydrometallations, hydrozirconation
H generally proceeds under very mild conditions. The relatively facile transmetallation
Zr thus makes a wide range of organometallic complexes with defined stereochemistry
Cl readily available. As an example, although hydroalumination of alkenes generally re-
quires elevated temperatures and pressures, the addition of small amounts of zirco-
nium chloride or of Schwartz reagent allows the reaction to be carried out at room
(17.145) temperature.
One of the interesting features of the hydrozirconation of alkenes is the facile re-
arrangement of the initially formed alkylzirconocene chloride (regardless of the
alkene used initially) by Zr–H elimination and subsequent addition to give a less hin-
dered alkylzirconocene chloride. By simply warming a tetrahydrofuran, or THF, solu-
tion of the alkene and Schwartz reagent to 50°C, an internal alkylzirconocene chloride
rearranges quantitatively to the terminal alkylzirconocene chloride. A similar rear-
rangement occurs in the addition of Schwartz reagent to internal alkynes (e.g.,
E xample 17.146) in THF, provided that the Schwartz reagent is present in excess. In
the presence of one equivalent of the Schwartz reagent, the kinetic product mixture of
Examples 17.147 and 17.148 is obtained.89 With excess Schwartz reagent at 50°C in
THF, the addition is syn, with zirconium bonded to the carbon bearing the smaller
substituent (17.148).
85. Eisch, J.J.; Foxton, M W. J. Org. Chem. 1971, 36, 3520.

86. Eisch, J.J.; Rhee, S.-G. J. Am. Chem. Soc. 1975, 97, 4673.
87. Reviews: (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853. (b) Wipf, P.; Takahashi, H.; Zhuang, N. Pure
Appl. Chem. 1998, 70, 1077. (c) Wipf, P. Top. Organomet. Chem. 2005, 8, 1.
88. (a) Hart, D.W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115. (b) Schwartz, J.; Labinger, J.A. Angew. Chem.
Int. Ed. Engl. 1976, 15, 333. (c) Hart, D.W.; Blackburn, T.F.; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679.
(d) Buchwald, S.L.; LaMaire, S.J.; Nielsen, R.B.; Watson, B.T.; Kin, S.M. Org. Synth. 1998, Coll. Vol. 9, 162.
89. Panek, J.S.; Hu, T. J. Org. Chem. 1997, 62, 4912.

Cl
Me H Me Zr
MeO MeO
MeO Me
Zr H
Ph Ph
Cl
Ph
(17.146) (17.147) (17.148)
Cp2Zr(H)Cl (1.2 eq), PhMe, 45°C, 2 h 37 63
Cp2Zr(H)Cl (1.4 eq), THF, 50°C, 1 h 0 100
Hydrostannylation and Hydrosilation

Silicon frequently serves as a hydrogen surrogate in organic synthesis, and this reactivity
extends to the addition of Si—H bonds across an alkene or alkyne π bond. Thus, although
hydrosilation is a slow reaction in the absence of a metal catalyst, in the presence of a pal-
ladium catalyst, the reaction proceeds at a useful rate to give alkyl or vinylsilanes, depend-
ing on the unsaturated hydrocarbon partner.
The stereochemistry of the addition in the metal-catalyzed hydrosilation is depen-
dent on the metal catalyst chosen. With platinum catalysts,90 the overall addition is syn
and is thus analogous to catalytic hydrogenation. A catalytic cycle proposed by Chalk
and Harrod in 196591 involved sequential addition of the silane to the coordinatively
unsaturated metal to give the hydride 17.150, coordination of the alkene (alkyne) to
give 17.152, migratory insertion into the M—H bond to give 17.153, and reductive elim-
ination of the final alkane (alkene) product (17.154). Later work by Roy and Taylor,92
using 1,5-cyclooctadiene as a non-reactive ligand toward the silane, led to the proposal
of the alternative catalytic cycle shown in Figure 17.21. The key change from the origi-
nal catalytic cycle is that the active form of the catalyst (17.150), formed from the
pre-catalyst by multiple hydrosilations, already carries multiple silyl groups. The only
irreversible step in this catalytic cycle is the reductive elimination step leading to for-
mation of the product.
The reaction catalyzed by other metals (Ru, Rh, Ir) leads to overall anti addition, and
a slight modification of the original Chalk and Harrod mechanism has been proposed to
account for this observation. In this mechanism (Figure 17.22), the initial syn adduct
(17.157) undergoes isomerization (presumably driven by relief of steric crowding between
the alkyl substituent and the metal) prior to the reductive elimination step. The re-
giochemistry can be controlled by the electronic nature of the substituents on the π
bond. In the absence of strongly orienting groups, the tendency is for the silicon to
become bonded to the less hindered carbon, which usually corresponds to anti-
Markovnikov addition. Although there are studies on the mechanism of this reaction
and on the factors affecting its stereochemistry, the overall stereochemical control is still
somewhat situation-specific.
In similar vein, addition of Sn—H bonds across an alkene or alkyne π bond can also
be catalyzed by palladium. Hydrostannylation is the addition of the Sn—H bond across
an alkene or alkyne π bond. The reaction can be carried out under free radical conditions
90. (a) Speier, J.L.; Webster, J.A.; Barnes, G.H. J. Am. Chem. Soc. 1957, 79, 974. (b) Speier, J.L. In Stone, F.G.A.;
West, R., Eds. Advances in Organometallic Chemistry ( Academic Press: New York, 1979) Vol. 17, p. 407.
91. Chalk, A.J.; Harrod, J.F. J. Am. Chem. Soc. 1965, 87, 16.
92. Roy, A.K.; Taylor, R.B. J. Am. Chem. Soc. 2002, 124, 9510.

Figure 17.21 Roy and Taylor MXn

mechanism for hydrosilation
of alkynes SiR3 HSiR3
H
H HSiR3
(17.154) L
R
L Pt SiR3
SiR3
L L SiR3 (17.149)
L SiR3
R3Si Pt SiR3
L Pt SiR3
H H
H SiR3
R (17.150)
(17.153)
L L SiR3 H
R3Si Pt SiR3
R
H R
(17.151)
L L (17.152)
H
Figure 17.22 A modified SiR3

Chalk and Harrod
R R3SiH
mechanism that accounts for H
(17.159)
the formation of the Z-
H [M]
vinylsilane from an alkyne
H H SiR3
[M] M=Ru, Rh, Ir, etc. [M]
SiR3
H
R
(17.155)
(17.158)
H H SiR3 H
R [M]
SiR3 (17.151)
[M] H R
R
H
(17.157) (17.156)
or under metal (usually palladium) catalysis.93 Under free radical conditions, the re-
giochemistry of the addition is controlled by the relative stability of the two possible
radicals, but stereochemical control is often problematic—in direct contrast to the metal-
catalyzed reaction, which is reliably syn. One reaction that can be used to form C—Sn
bonds is stannylmetallation-protonolysis (Example 17.160). The second metal may be alu-
minum, zinc, magnesium, or boron,94 but copper (I) is by far the most popular choice. In
93. Review: Smith, N.D.; Mancuso, J.; Lautens, M. Chem. Rev. 2000, 100, 3257.
94. (a) Hibino, J.; Matsubara, S.; Morizawa, Y.; Oshima, K. Tetrahedron Lett. 1984, 25, 2151. (b) Matsubara, S.;
Hibino, J.; Morizawa, Y.; Oshima, K. J. Organomet. Chem. 1985, 285, 163. (c) Aksela, R.; Oehlschlager, A.C.
Tetrahedron 1991, 47, 1163. (d) Nonaka, T.; Okuda, Y.; Matsubara, S.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Org.
Chem. 1986, 51, 4716.

stannylcuprations, the regiochemistry of the addition can be controlled by the choice of

the stannylcopper reagent (as in Example 17.161).95 Note how using the higher order cu-
prate leads to higher levels of the 1-stannyl-1,3-diene from terminal alkynes.
R3SnM M SnR3 NH4Cl H SnR3

R R
R R R R
M = Cu, Al, Zn, Mg, BR2
(17.160)
1) (Bu3Sn)nCu(CN)Lin SnBu3
THF, –40°C SnBu3
2) NH4Cl +
n=1 19 : 81
n=2 3 : 97
(17.161)
SnBu3
1) (Bu3Sn)nCu(CN)Lin Bu3Sn
THF, –40°C
+
2) NH4Cl
HO HO HO
n=1 38 : 62
n=2 18 : 82
Carbometallation96
The addition of a carbon-metal σ bond across a carbon-carbon π bond is most widely used
in the preparation of vinylmetal complexes with defined stereochemistry. Many carbo
metallation reactions involve copper, either in the form of a stoichiometric organocopper
reagent or as a catalyst.97 In the carbocupration of alkynes, the stereochemistry is almost
universally syn, and the regiochemistry tends to place the metal at the terminal carbon,
although the regioselectivity in simple alkynes is not always good. In contrast, the inclu-
sion of a group capable of complexing the copper (e.g., a propargyl ether) leads to high
levels of regioselectivity, as shown in Example 17.162.98
1) Me2CuLi, Et2O, –45°C
O O 2) ICH2CO2Et, HMPA, O CO2Et
–55°C to r.t. (17.162)
O
(30-55%)
H Me
H
The combination of an aluminum alkyl and titanium or zirconium chloride provides
an active catalyst for the Ziegler-Natta polymerization of alkenes. A similar catalyst can
be generated from an aluminum halide and a zirconocene. In the initial reaction, there is
95. (a) Barbero, A.; Cuadrado, P.; Fleming, I.; Gonzalez, A.M.; Pulido, F.J. J. Chem. Soc., Perkin I 1992, 351.
(b) Aksela, R.; Oehlschlager, A.C. Tetrahedron 1991, 47, 1163. (c) Betzer, J.- F.; Delaloge, F.; Muller, B.; Pancrazi,
A.; Prunet, J. J. Org. Chem. 1997, 62, 7768.
96. Review: Basheer, A.; Marek, I. Beilstein J. Org. Chem. 2010, 6, 77.
97. Review: Normant, J.F.; Alexakis, A. Synthesis 1981, 841.
98. Magnuson, S.R.; Sepp-Lorenzino, L.; Rosen, N.; Danishefsky, S.J. J. Am. Chem. Soc. 1998, 120, 1615.

Figure 17.23 The Cossee ‡

R R R R
mechanism for the Ziegler- R
Natta polymerization R
of an alkene L L L
M M M
L L L L L L
L L L
(17.163) (17.164) (17.165)
R R
M = Ti, V, Zr
R R
(17.167)
H
L L
M M
L L L L
L L
(17.168) (17.166)
an alkyl transfer from aluminum to the Group IVB metal, and this alkylzirconium or
alkyltitanium species reacts with the alkene to give the polymeric product. As illustrated
in Figure 17.23, the currently accepted mechanism of the Ziegler-Natta polymerization,
first proposed by Cossee,99 involves the initial formation of a coordinatively unsaturated
metal alkyl (e.g., 17.163) that then actively catalyzes the addition polymerization. Com-
plexation of the alkene to the vacant site on the metal gives the species 17.164, which then
undergoes migratory 1,2-insertion through a four-membered transition state (17.165) to
generate a new coordinatively unsaturated complex (17.166). By repetition of these steps,
one can obtain a high polymer bound to the metal. During polymerization, the reaction
may be terminated by β-hydride elimination to give an alkene (17.167) and a metal hy-
dride complex (17.168) capable of adding to a new alkene to begin a new polymer chain.
In 1978,100 Negishi reported a zirconium-catalyzed single-stage carboalumination
of alkynes to give a vinylalane by syn addition of the C—Al bond across the alkyne. For
many years, the mechanism of the reaction was assumed to proceed by a carbozircona-
tion, followed by transmetallation. However, later work by Negishi demonstrated
that—with trialkylaluminum reagents bearing alkyl groups larger than methyl, at
Cp Zr Al Et least—the mechanism is rather more complicated 101 and probably involves direct car-
Cp Cl Et boalumination of the alkyne, catalyzed by a zirconium species. One such species is the
metallocycle 17.169, in which there is both an electrophilic zirconium and a nucleop-
(17.169) hilic aluminum.
Why Are These Hydrometallation Reactions Important?

Much of the usefulness of hydrometallation with hydrides of zirconium, aluminum, and
tin, especially, derives from the stereospecific replacement of the C—metal bond by a
99. (a) Cossee, P. J.Catal. 1964, 3, 80. (b) Arlman, E.J.; Cossee, P. J. Catal. 1964, 3, 99. An alternative mecha-
nism proposed by Green and Rooney [(c) Ivin, K.J.; Rooney, C.D.; Stewart, C.D.; Green, M.L.H.; Mahtab, J.R. J.
Chem. Soc., Chem. Commum. 1978, 604. (d) Green, M.L.H. Pure Appl. Chem. 1978, 100, 2079] was later ruled
out in an ingenious isotope effect/stereochemistry experiment by Grubbs [(e) Clawson, L.; Soto, J.; Buchwald,
S.L.; Steigerwald, M.L.; Grubbs, R.H. J. Am. Chem. Soc. 1985, 107, 3377].
100. (a) Van Horn, D.E.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252. (b) Negishi, E.; Van Horn, D.E.;
Yoshida, T. J. Am. Chem. Soc. 1985, 107, 6639. (c) Negishi, E. Pure Appl. Chem. 1981, 53, 2333.
101. Negishi, E.-i.; Kondakov, D.Y.; Choueiry, D.; Kasai, K.; Takahashi, T. J. Am. Chem. Soc. 1996, 118, 9577.

C—X bond by simple treatment with the halogen. The reaction proceeds with retention of
configuration with vinylmetal compounds, which allows the preparation of vinyl halides
of known stereochemistry for the formation of C—C bonds by palladium-catalyzed
cross-coupling reactions.
Problem
OH
OH 1) AlMe3, Cp2ZrCl2
CH2Cl2 MgBr
(a) (b) CuI (cat.), Et2O
2) I2, THF
OH
1)Cy2BH, hexanes
1) Red-Al, THF 2) Me2Zn, PhMe
(c) Ph 2) I2, EtOAc (d) 3) PhCHO, PhMe
O
[step 2 is a B—Zn exchange reaction]
References: (a) Org. Lett. 2005, 6, 4297. (b) J. Org. Chem. 1998, 63, 7945. (c) J. Am. Chem. Soc. 2010,
132, 8219. (d) J. Org. Chem. 2007, 72, 5935.
Reaction Synopses
Hydroboration
R R HBR'2 R R HBR'2 H BR'2
H BR'2 R R
R R R R R R
Reagents:
for alkenes: BH3•THF; Sia2BH, THF; ThBH2, THF;
9-BBN, THF;
for alkynes: [o-C6H4O2]BH, THF; (Me2CO)2BH, THF; etc.
Regiochemistry: Markovnikov; regiochemical control is improved with
bulky boranes.
Stereochemistry: strictly syn
Reaction may be carried out asymmetrically using IpcBH2, Ipc2BH, and Soder-
quist boranes:
H
B R
BH2 BH
Hydroalumination
R R R H
R R
R'2Al H R'3Al R
syn addition: DIBAL-H, PhMe; DIBAL-H, Et2O; DIBAL-H,

Reagents:
MeN(CH2)4, etc.
anti addition: LiAlH4, Et2O; LiEt3AlH, Et2O; etc.
(continues)

Regiochemistry: Markovnikov with electrophilic aluminum reagents, but can
be altered by complexation of Al with a strong Lewis base
prior to the hydrometallation to give a more nucleophilic alu-
minum reagent
Hydrozirconation
Cp2Zr(Cl)H R R
R R
solvent H ZrCp2
Cl
Solvent: PhMe (mixture of regioisomers); THF (Zr bonds to less hin-

dered carbon); etc.
Stereochemistry: syn
Hydrostannylation
R3SnH R R
R R
H SnR3
Reagents: R 3SnH, AIBN, hν; etc. (free radical mechanism); R 3SnH, Pd

(not widely used)
R3SnM M SnR3 NH4Cl H SnR3
R R
R R R R
M = Cu, Al, Zn, Mg, BR2
Copper: most widely used metal

Hydrosilation
R3SiH R R
R R
H2PtCl6 H SiR3
Stereochemistry: syn when Pt catalysts are used

Carbometallation
R'O
OR' R"—M R
R
R" M
M = Cu, Al, Zr, Ti, etc.
Reagents: R"2CuLi, THF; R"2Cu(CN)Li2, THF (carbocupration); R"3Al, ZrCl4;
R 3Al, Cp2Zr(Cl)H, (carboalumination); etc.
17.6 Palladium-Catalyzed Substitution: Tsuji-Trost

and Buchwald-Hartwig Reactions
Despite the fact that no textbook chapter can keep up with developments as rapid as those
taking place in modern catalytic organic synthesis, such a chapter is not without value. It
can still serve as a jumping-off point for your own reading about organic synthetic

reactions catalyzed by transition metal complexes. Let us, therefore, begin by looking at
palladium-catalyzed analogs of simple nucleophilic displacement reactions.
One of the oldest coupling reactions of this type is the Tsuji-Trost reaction.102 The
reaction between an allylic compound and a nucleophile catalyzed by a palladium com-
plex, discovered by Jiro Tsuji and developed by Barry M. Trost, relies on the oxidative ad-
dition of an allylic ester, halide, or similar species to a palladium (0) precursor to generate
an electrophilic η3-allylpalladium (II) species. The reactivity of common leaving groups
follows the general order:
Cl, Br > OCO2R > OCOR
Allylic carbonate esters have achieved popularity as precursors to the electrophile be-
cause the oxidative addition of these esters to the palladium leads to an anion that loses
carbon dioxide to make the addition irreversible. The usual regiochemistry of the reaction
gives the product with the nucleophile bound to the allyl group at the less substituted end.
The stereochemistry of the reaction depends on the nature of the nucleophile. Hard
nucleophiles (e.g., R 2Zn) attack the η3 allyl complex at the metal atom first, giving a com-
plex (17.176) that lead to inversion of configuration, whereas soft nucleophiles (e.g., eno-
lates) attack the ligand first, giving a complex (17.174) that leads to retention of configuration.
The two divergent stereochemical outcomes can be accommodated by the catalytic cycles
in Figure 17.24.
R Nu Figure 17.24 Catalytic cycles

of the Tsuji-Trost allylation
H Me reaction with hard and soft
(17.178) nucleophiles, showing
(inversion) LnPd0 R Nu reversal of stereochemistry
R (17.170) H Me
H Me (17.175)
(retention)
Nu
PdLn
(17.177) R Nu
R X
R X
Me
Me H
H Me H
(17.171) PdLn
PdLn
(17.172) (17.174)
R Me
LnPd Nu X
(17.176)
R Me Nu
Nu (addition at
PdLn ligand)
(addition at metal)
"Hard (17.173) "Soft
nucleophiles" nucleophiles"
102. (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 4387. (b) Trost, B.M. Tetrahedron 1977,
33, 2615. (c) Trost, B.M. Acc. Chem. Res. 1980, 13, 385. (d) Trost, B.M. Pure Appl. Chem. 1981, 53, 2357. (e) Tsuji,
J. Pure Appl. Chem. 1982, 54, 197. (f) Tsuji, J. Tetrahedron 1986, 42, 4361. (g) Trost, B.M. Angew. Chem. Int. Ed.
Engl. 1989, 28, 1173. (h) Tsuji, J. Palladium Reagents and Catalysts. New Perspectives for the 21st Century. (Wiley:
print-on-demand, ISBN 978-0-470-85032-9; 2004).

The allylpalladium (II) species are susceptible to attack by a wide range of anionic
nucleophiles, as illustrated by Examples 17.179,103 17.180,104 and 17.181.105 The Tsuji-Trost
allylation has been the subject of several modifications, some to allow its use with or-
ganocatalysis, where the enolate anion becomes replaced by an enamine generated in
situ, and also by a creative combination with the Morita-Baylis-Hillman reaction to
form cyclized enones (Example 17.180). Using allylic epoxides in the reaction is illus-
trated by Example 17.181, which is an early coupling step in Fukuyama’s synthesis of
strychnine.
O OAc O
Pd(PPh3)4 (0.05 eq)

(17.179)
NH (0.3 eq), Me2SO, r.t.
O O O O
(82%)
OCO2Et
Pd(PPh3)4 (1 mol %)
(17.180)
Bu3P (1.0 eq), t-BuOH
60°C O
O
(83%) O
O
OTBS
HO
MeO2C CO2Me H O H
OTBS CO2Me
NH CO2Me
H (17.181)
Pd2(dba)3, P(3-furtyl)3
OTBS PhMe, r.t. NH
(86%) OTBS
More recent work 106 has led to the development of useful chiral ligands for use in
asymmetric allylation, especially of ethers.107 A typical example of a chiral diphosphine
ligand suitable for asymmetric allylation is given as Example 17.182. With C2 -symmetric
diphosphine ligands such as 17.182, Trost has established a mnemonic to predict the ste-
reochemistry of the alkylation of meso-diesters.108
Ph2P
H
N H P
HN N
O
N
O H P
(17.182)
PPh2
In this mnemonic, shown in Figure 17.25, the diphosphine is viewed along the axis
between the two phosphines, and the direction of rotation is determined to be clockwise
or counterclockwise. (In this example, it is counterclockwise.) The initial η2 complexation
103. Ibrahem, I.; Córdova, A. Angew. Chem. Int. Ed., 2006, 45, 1952.
104. Jellerichs, B.G.; Kong, J.-R.; Krische, M.J. J. Am. Chem. Soc. 2003, 125, 7758.
105. Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2004, 126, 10246.
106. Review: Trost, B.M.; Crawley, M.L. Chem. Rev. 2003, 103, 2921.
107. Trost, B.M.; Toste, F.D. J. Am. Chem. Soc. 2003, 125, 3090.
108. (a) Trost, B.M.; Van Vranken, D.L. Chem. Rev. 1996, 96, 395. (b) Trost, B.M.; Lee, C. In Ojima, I, Ed.
Catalytic Asymmetric Synthesis, 2nd Ed. (Wiley-VCH: New York, 2000), pp. 593–649.

Figure 17.25 The mnemonic

X X X X for predicting
LnPd PdLn stereochemistry in the
"counter-
"clockwise" PdLn clockwise" asymmetric allylation of
meso substrates using C2 -
symmetric “Trost”
diphosphine ligands
Nu X X Nu
of the alkene to the metal occurs on the face opposite to the leaving groups. The alkene is
oriented so that the metal is above the plane of the π bond. The initial complexation cen-
ters the palladium above the alkene, and conversion of the η2-alkene complex to the η3-al-
lyl complex requires movement of the palladium to the left (clockwise) or the right
(counterclockwise) to center the metal atom above the ligand.
The clockwise ligand leads to clockwise movement of the palladium. The nucleophile
then attacks the bottom face of the ligand to give the observed product (e.g., Example
17.183). There is one caveat in this mnemonic: when the nitrogen and carbonyl groups of
the amides are reversed (i.e., the diamide of a diamine is replaced by the isomeric diamide
of a dicarboxylic acid; Example 17.184), the stereochemistry of the reaction is also re-
versed, despite the phosphines having the same relative disposition (here, counterclock-
wise). There is, as yet, no general model that one can use to predict the stereochemistry in
this reaction.
O
O
O O Pd2(dba)3-CHCl3
dioxane (17.183)
Me
17.182 Me
(94%; 88% e.e.)
Ph2P
O
O N
H
NH
(17.184)
PPh2
The Tsuji-Trost reaction has also been useful in the asymmetric construction of qua-
ternary centers. One useful example of this process is given by the allylation reaction in
Example 17.185.109 In this reaction, a ketone is first converted to a mixed enol allyl carbon-
ate, which is then treated with a palladium catalyst in the presence of a chiral phosphine.
A range of phosphine ligands has been used, with the PHOS ligands, especially t-Bu-
PHOS, being the most effective. The reaction also applies to intermolecular reactions
using enol trimethylsilyl ethers and diallyl carbonate.110 Interestingly, these workers also
found that the best ligands for this reaction were not chiral diphosphines but rather the
chiral PHOS ligands, with the enantioselectivity rising as the steric bulk of the group on
the PHOS ligand increased. The scope of the reaction has been further extended since the
first report, with its application to acyclic enol allyl carbonates.111,112
109. McFadden, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 7738.
110. Behenna, D.C.; Stoltz, B.M. J. Am. Chem. Soc. 2004, 126, 15044.
111. Trost, B.M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180.
112. Mohr, J.T.; Stoltz, B.M. Chem. Asian J. 2007, 2, 1476.

Pd2dba3
O THF, 23°C, 20 min
O (17.185)
O O O
N
PPh2
(83%, 91% e.e.
In contrast to the palladium-catalyzed allylation, which gives the less substituted re-
gioisomer, Hartwig has reported113 that the use of an iridium-based catalyst leads to the
formation of the more substituted allyl regioisomer with hard nucleophiles, as illustrated
in Example 17.186. The active catalyst (Example 17.187) is formed by treating [Ir(cod)Cl]2
with a chiral phosphoramidite ligand and an amine.
NH2
H
S N (17.186)
S
OCO2Me catalyst (2 mol %)
(86%; 98% ee)
stereochemistry not specified
Ar
O N
P Ar
O
Cl (17.187)
O O
Ir Ir P
PrNH2 or DABCO
Cl N Ar
Ir
Ar
The Buchwald-Hartwig and Related Cross-Coupling Reactions

The amination of aryl halides catalyzed by palladium complexes was described early in
the 1980s but was not really developed until the mid-1990s, when Buchwald and
Hartwig independently began the work that defined the scope of the reaction. The re-
action is now known by both chemists’ names.114 The catalytic cycle of the Buchwald-
Hartwig coupling (Figure 17.26) follows a fairly standard scheme for palladium-catalyzed
coupling at sp2 carbon: (1) oxidative addition of the aryl halide to a coordinatively
unsaturated Pd0 complex (17.188) to give a saturated complex (17.189), followed by
(2) replacement of the halide ligand by the other coupling partner to give the complex
17.191 (this may require more than one step), and (3) a final reductive elimination of the
product (17.192). In its most widely used form, the nucleophile is a primary amine, al-
though simple ammonia has proved to be problematic, requiring the use of surrogates
for ammonia in the reaction due to the very strong complexation of the palladium by
ammonia itself.
Like most palladium-catalyzed cross-coupling reactions, the Buchwald-Hartwig
coupling is tolerant of a wide range of functional groups—esters, nitriles, tertiary
113. (a) Shu, C.; Hartwig, J.F. Angew. Chem. Int. Ed. 2004, 43, 4794. (b) Shu, C.; Leitner, A.; Hartwig, J.F.
Angew. Chem. Int. Ed. 2004, 43, 4797. (c) Leitner, A.; Shu, C.; Hartwig, J.F. Org. Lett. 2005, 7, 1093.
114. Reviews: (a) Hartwig, J.F. Synlett 1997, 4, 329. (b) Hartwig, J.F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(c) Wolfe, J.P.; Wagaw, S.; Marcoux, J.F.; Buchwald, S.L. Acc. Chem. Res. 1998, 31, 805. (d) Hartwig, J.F. Acc.
Chem. Res. 1998, 31, 852. (e) Hartwig, J.F. Pure Appl. Chem. 1999, 71, 1416. (f) Muci, A.R.; Buchwald, S.L. Top.
Curr. Chem. 2002, 219, 131. (g) Hartwig, J.F. Acc. Chem. Res. 2008, 41, 1534. (h) Surry, D.S.; Buchwald, S.L.
Angew. Chem. Int. Ed. 2008, 47, 6338. (i) Surry, D.S.; Buchwald, S.L. Chem. Sci. 2011, 2, 27.

(17.192) Ar—X
Figure 17.26 The catalytic
Ar Nu L cycle of the Buchwald-
L Pd Hartwig coupling reaction
(17.188)
L L
L Pd Ar L Pd Ar
Nu X
(17.189)
(17.191)
L NaOCMe3
L Pd Ar
Me3COH NaX
OCMe3
Nu H
(17.190)
amines, and ethers—which makes this reaction an excellent method for the formation
of highly functionalized aniline derivatives. This is illustrated by the formation of the
carbazole ring system of (±)-murrayazoline (Example 17.193).115 The same synthesis con-
tains the intramolecular formation of an ether using the same Buchwald-Hartwig strat-
egy (Example 17.194).
Br
OMe
O Pd2dba3 (0.2 eq) OMe
ligand (0.6 eq.) O
Br Me NaO-t-Bu (17.193)
O
PhMe, 130°C, N
O 3h O
NH2
O (59%)
Pd(OAc)2, (1.0 eq)

OTf o-PhC6H4P(t-Bu)2 (2 eq) (17.194)
N O
OH N
Cs2CO3 (5 eq), PhMe
130°C, 20 h
(80%)
Considerable work has been expended in the search for suitable ligands for use in
cross-coupling reactions. The results of many investigations are summarized in structure
17.195, where the effects of each of the structural features of the ligand on its performance
in palladium-catalyzed aminations are summarized.116
large alkyl groups here
ortho- substitution in this promote reductive elimination;
ring inhibits oxidation to electron-releasing groups here
phosphine oxide and B accelerate oxidative adition
accelerates reductive
elimination
PR2 substituents here enhance
A catalyst stability by
B preventing metallocycle
formation;
substituents here A
substituents here encourage
accelerate reductive
elimination the formation of the L1Pd
(17.195) species
115. Ueno, A.; Kitawaki, T.; Chida, N. Org. Lett. 2008, 10, 1999.
116. Surry, D.S.; Buchwald, S.L. Chem. Sci. 2011, 2, 27.

Reaction Synopses
Tsuji-Trost Reaction
X Nu: , Pd0 Nu
X: Cl, Br, OAc, OCOPh, OCO2Et, etc.

Pd0: Pd(PPh3)4, etc.
Nu−: enolate anions, metal alkyls, etc.
Stereochemistry: net retention of configuration at carbon with soft nucleop-
hiles (e.g., enolates); net inversion with hard nucleophiles
(e.g., dialkylzinc reagents)
Chiral ligands: allow enantioselective reactions of meso diesters to give
chiral products
Buchwald-Hartwig Coupling
H Nu
Ar X Ar Nu
Pd, ligand
base
X: Br, OTf, I, etc. (Cl and OTs require more active catalysts)
Pd: Pd2dba3, Pd(OAc)2, etc.
Ligand: dppf, o-ArC6H4PR 2, etc.
Nu: Ar’NR, Ar’O, etc. (with stronger bases, enolate anions can be used)
Worked Problem
17-4 What is the major organic product of the following reaction? Provide a rational-
ization for the regiochemistry and stereochemistry of the reaction. How would
the reaction change if the malonate ester were replaced by a harder nucleophile
(e.g., a phenoxide anion)?
HO OAc CH2(CO2Me)2, KOBut

(Ph3P)4Pd (cat.)
§Answer below.
CH2(CO2Me)2, KOBut CO2Me

HO OAc
HO
(Ph3P)4Pd (cat.) CO2Me
This reaction proceeds by means of the η3-allyl complex, formed by displacement of the acetate with inver-
sion of configuration. The nucleophile in this reaction is a soft carbon nucleophile, so it attacks the face opposite
the metal, leading to a product whose stereochemistry corresponds to overall retention of configuration.
H H H
HO HO HO
Pd(PPh3)3 MeO2C
AcO H
H H MeO2C

Problems
O
NH (0.3 eq)
(a) O H2C=CH-CH2OAc
O (Ph3P)4Pd (0.05 eq)
Me2SO, r.t., 16 h
OSiMe3 OAc Ph
CO2Me N H
Me
(b) L= P
(η3-C3H5PdCl)2 (2 mol %) NH N O
Zn(OAc)2 (1.5 eq), L (0.1 eq) Ph
Ph
O
O Pd2dba3 (2.5 mol %)
S-t-Bu-PHOX (6.25 mol %)
(c) O Et2O, 6.5 h
N
References: (a) J. Am. Chem. Soc. 2006, 128, 4232. (b) J. Am. Chem. Soc., 2004, 126, 3690. (c) Angew.
Chem. Int. Ed., 2005, 44, 6924.
17-7 Suggest a reasonable model that will permit the rationalization of the stereo-
chemistry of the following reaction.
OTBDMS OTBDMS
OP(O)(OEt)2 P(O)Ph2
H L=
NH Pd2dba3•CHCl3 P(O)Ph2
Br Ts N
DMF, L
Br Ts
(80%; 84% ee)
References: Angew. Chem. Int. Ed. 2002, 41, 1934; J. Am. Chem. Soc. 2003, 125, 9801.
Table 17.4 Number of Metal-Catalyzed C—C Bond-

17.7 Cross-Coupling Reactions to Form C—C Bonds
Forming Reactions Cited in 2011
Now that we have discussed the general features of reactions Reaction Number of Mentions
involving organotransition metal complexes, it is time to
Suzuki-Miyaura cross-coupling 10,721
turn our attention to the ways in which these reactions have
transformed modern organic synthesis. Again, one should be Heck cross-coupling 3,157
aware of the fact that this is an extremely rapidly growing Sonogashira cross-coupling 2,302
area of organic chemistry, so the material here will almost
Stille cross-coupling 2,176
certainly be somewhat dated by the time that you read it. As
a guide to the importance of this field, you should consult Negishi cross-coupling 1,461
Table 17.4. This table lists the number of articles appearing in
Hiyama-Denmark cross-coupling 647
2011 in journals published by national chemical societies in
which the specified transition metal-catalyzed reaction was Tsuji-Trost 124
mentioned. Olefin metathesis 7,397
Replacement of the malonate ester by a phenoxide anion, which is a harder oxygen nucleophile, would lead
to the product of overall inversion of configuration.
H H H
HO HO HO
Pd(PPh3)3
AcO H
H H OAr

Table 17.5 Transition Metal–Catalyzed Cross-Coupling Reactions The rapid rise of transition metal–catalyzed synthetic
R reactions can be traced to the early work of Japanese
R Y R chemist Tsutomu Mizoroki117 and Nobel laureates Richard
X + + X Y Heck118 and Ei-ichi Negishi.119 The work of these chemists
R R R
identified one of the first truly general cross-coupling re-
R X R Y actions for forming a new carbon-carbon bond. Since the
X Reaction initial reports by these workers were published, the field of
R R R R Catalyst Name cross-coupling reactions has literally exploded, with sev-
Pd Heck eral permutations of substrate and nucleophile now being
X=I, OTf, Br [Cl] Y=H
well-known name reactions. A collection of the most
X=HgX, SnR 3, PbR 3, Y=H Pd Heck widely used reactions is gathered in Table 17.5.
X=I, OTf, Br [Cl] Y=SnR 3 Pd Stille

The Heck Coupling Reaction
X=I, OTf, Br [Cl] Y=ZnX, AlX 2, ZrLn Pd, Ni Negishi
The reaction now known as the Heck reaction120 was first
X=I, OTf, Br [Cl] Y=SiR 3, F− Pd Hiyama reported by Mizoroki121 a year before Heck’s first report,122
but Mizoroki’s untimely death meant that developing the
X=I, OTf, Br [Cl] Y=Si(OR)3, RO− Pd Hiyama-
Denmark reaction rested squarely with Heck. The Heck reaction is
the prototype general reaction involving the formal nuc-
X=I, OTf, Br [Cl] Y=MgX Ni, Pd Corriu- leophilic substitution of a halogen or triflate bonded to an
Kumada aromatic ring or a double bond, or a formal metathesis of
X=I, OTf, Br [Cl] Y=B(OR)2 Pd Suzuki- an aryl halide and an alkene to generate the hydrogen
Miyaura halide and the vinylarene.
Pd-Cu Sonogashira The reaction is catalyzed by palladium and occurs
X=I, OTf, Br [Cl] RC≡CH
through a catalytic cycle shown in Figure 17.27. The reac-
tion is usually initiated by reduction of palladium (II) ac-
etate to a palladium (0) complex (17.196) that is the functional catalyst. Oxidative addition
of the halide to this complex gives a palladium complex (17.197) that then undergoes
ligand exchange to give the η2 olefin complex (17.198). Migratory insertion of the aryl
group gives a σ alkyl complex (17.199) that undergoes β-hydride elimination to give a new
η2 olefin complex (17.200). Ligand substitution and reductive elimination of the hydrogen
halide completes the catalytic cycle. The reaction is facilitated by the addition of base to
neutralize the hydrogen halide.
For most Heck reactions, the reactivity of the substrate bearing the leaving group de-
creases in the order I > OTf > Br >> Cl. The reaction is also susceptible to steric hin-
drance: alkenes react in the approximate order:
H2C=CH2 > H2C=CHR > R 2C=CH2≈RCH=CHR > R 2C=CHR 2
117. Tsutomu Mizoroki (1933–1980) was a young Associate Professor at Tokyo Institute of Technology when
he discovered the palladium-catalyzed reaction of iodoarenes with alkenes. He died at age 47 of pancreatic
cancer, but his efforts laid the groundwork for the Nobel Prizes in chemistry three decades later.
118. Richard Fred Heck (1931–) was educated at the University of California, Los Angeles (UCLA) (BS, 1952;
PhD, 1954 with Winstein), and then, after postdoctoral study at ETH, Zurich, and at UCLA, he joined Hercules
Corporation. From 1971–1989, was at Delaware. For more biographical details see he Nobel Foundation web site.
119. Ei-ichi Negishi (1935–) was born in China, and educated at the University of Tokyo (BE, 1955) and the University
of Pennsylvania (PhD, 1963). His postdoctoral study with H.C. Brown, at Purdue, led to a permanent appointment to
the Purdue faculty, where he has spent his career. For more details, see Negishi, E.-i. Angew. Chem. Int. Ed. 2011, 50, 6738.
120. Reviews: (a) Heck, R.F. Acc. Chem. Res. 1979, 12, 146; Org. React. 1982, 27, 345. (b) de Meijere, A.; Meyer,
F.E. Angew. Chem. Int. Ed. Engl. 1994, 33, 2379. (c) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2. (d) Shibasaki,
M.; Boden, C.D.J.; Kojima, A. Tetrahedron 1997, 53, 7371. (e) Beletskaya, I.P.; Cheprakov, A.V. Chem. Rev. 2000,
100, 3009. (e) Whitcombe, N.J.; Hii, K.K.; Gibson, S.E. Tetrahedron 2001, 57, 7431. (g) Link, J.T. Org. React. 2002,
60, 157. (h) Dounay, A.B.; Overman, L.E. Chem. Rev. 2003, 103, 2945. (i) Gurry, D.J.; Kiely, D. Curr. Org. Chem.
2004, 8, 781. (j) Heck, R.F. Synlett. 2006, 2855. (k) Knowles, J.P.; Whiting, A. Org. Biomol. Chem. 2007, 5, 31.
121. Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581.
122. Heck, R.F.; Nolley, J.P., Jr. J. Org. Chem. 1972, 37, 2320.

H2O Figure 17.27 The catalytic

base cycle of the Heck reaction
HBr ArBr
H Ar
L Pd L L Pd L L Pd L
Br (17.196) Br
Ar R (17.201) (17.197) H R
R R R R
L
L
H Ar Ar H Ar
R L H R
R
L Pd L Pd L Pd
R
Br R R
Br R Br R R
L L
(17.200) (17.198)
(17.199)
The reaction is therefore most often used with monosubstituted alkenes. One of the
major features of the intermolecular Heck reaction is its high trans selectivity. The intra-
molecular form of the Heck reaction has been widely used to make cyclic compounds, as
shown by Examples 17.202123 and 17.203.124
Me
Me
Pd(OAc)2, Ph3P
Br (17.202)
Cs2CO3, DMF
N 120°C, 72 h
(82%) N
O
O
CO2Me CO2Me
Br
Pd(OAc)2, Bu4NBr
N N (17.203)
KOAc, DMF, 120°C
O O N O
N
O (78%)
Ph
Ph
As with all other reactions since the end of the 20th century, the Heck reaction has also
been the subject of intense research to develop asymmetric versions of the reaction.125 Be-
cause the reaction does not form a new chiral center at either end of the new C—C bond,
the adaptation of this reaction to asymmetric synthesis relies on the desymmetrization of
compounds with Cs symmetry, such as the diene in Example 17.204, where reaction at the
two double bonds of the cyclohexadiene ring gives opposite enantiomers of the product.
When this same diene was treated with a palladium catalyst in the presence of chiral
BINAP, the product obtained was significantly enantio-enriched (Example 17.205).126
123. Satyanarayana, D.; Maier, M.E. Tetrahedron 2012, 68, 1745.

124. Lee, H.S.; Kim, K.H.; Kim, S.H.; Kim, J.N. Tetrahedron Lett. 2012, 53, 497.
125. Reviews: (a) Shibasaki, M.; Boden, C.D.J.; Kojima, A. Tetrahedron 1997, 53, 7371. (b) Dounay, A.B.; Overman,
L.E. Chem. Rev. 2003, 103, 2945. (c) Shibasaki, M.; Vogl, E.M.; Ohshima, T. Adv. Synth. Catal. 2004, 346, 1533.
(d) McCartney, D.;Guiry, P.J. Chem. Soc. Rev. 2011, 40, 5122.
126. Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738.

H CO2Me CO2Me
(17.204)
CO2Me I H
CO2Me Pd(OAc)2 (3 mol %) CO2Me

(R)-BINAP (9 mol %)
Ag2CO3 (2.0 eq) (17.205)
I NMP, 60°C H
(74%; 46% ee)
The application of the asymmetric Heck cyclization to cascade reactions was first
demonstrated in 1989 by Overman (Example 17.206).127 More recently, the Heck coupling
has been applied to aldehydes (Example 17.207). The aldehyde hydrogen is the one lost
during this formal Heck-type reaction, which thus provides a palladium-catalyzed ap-
proach to the acylation of arenes.128 The Heck coupling of vinyl sulfides, sulfoxides, and
sulfones with aryl bromides shows that the isolated yield of the reaction is increased as the
alkene becomes more electrophilic.129
Pd(OAc)2 (0.1 eq)

(R)-DIOP (0.1 eq)
OTf (17.206)
Et3N, PhH
(90%; 45% ee)
O
O
OMe OMe
Pd2dba3 (2 mol %)
dppp (3 mol %)
H (17.207)
N
Cbz CHO
Br 4Å MS, DMF, 110°C Cbz
N O
H
(78%)
In a series of papers, Jeffrey introduced a ligand-free version of the Heck reaction that in-
volves using added quaternary ammonium salts to accelerate the reaction and control its regi-
oselectivity.130 By combining a quaternary salt with added potassium formate, one can directly
obtain the product of coupling and transfer hydrogenation, as illustrated in Example 17.208.131
A similar one-pot Heck coupling and hydrogenation cascade has also been described.132
I
H
Pd(OAc)2, HCO2K
Bu4NBr, DMF, r.t.
Me3SiO O Me3SiO O (17.208)
(79%)
OTBS OTBS
Ph Ph
127. Carpenter, N.E.; Kucera, D.J.; Overman, L.E. J. Org. Chem. 1989, 54, 5846.
128. Ruan, J.; Saidi, O.; Iggo, J.A.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 10510.
129. Battace, A.; Zair, T.; Doucet, H.; Santelli, M. Synthesis 2006, 3495.
130. (a) Jeffery, T. Tetrahedron Lett. 1994, 35, 3051. (b) Jeffery, T.; Galland, J.C. Tetrahedron Lett. 1994, 35,
4103. (c) Jeffery T. Tetrahedron, 1996, 52, 10113. (d) Jeffery, T.; David, M. Tetrahedron Lett. 1998, 39, 5751.
131. Lee, K.; Cha, J.K. J. Am. Chem. Soc. 2001, 123, 5590.
132. Geoghegan, K.; Kelleher, S.; Evans, P. J. Org. Chem. 2011, 76, 2187, and references therein.

The Stille, Negishi, Hiyama, and Kumada Coupling Reactions

In Heck’s earliest work,133 he reported the stoichiometric reaction using organomercury,
organotin, and organolead compounds where the halide (almost always an iodide or bro-
mide) is now used in the modern variant of reaction. The by-product of the reaction was a
metal hydride derivative that either decomposed to the free metal or to a reduced organo-
metallic species (Example 17.209). Within a short space of time, however, this work was
superseded by the catalytic reaction now used, which couples a halide with the alkene.
R'M MH
H R R' R
(17.209)
M=HgX, SnR3,
R R R R
PbR3
ArX MX
M R Ar R
(17.210)
M=SnR3, AlR2,
R R R R
ZnR, SiR3, MgX
Subsequent versions of these palladium-catalyzed coupling reactions have focused,
instead, on replacing the alkene by a suitable alkylmetal compound capable of metal-metal
exchange (as shown in Example 17.210). Thus, replacement of the alkene in the Heck reac-
tion by a stannane gives the Stille reaction,134 by aluminum or zinc alkyls gives the Negishi
coupling,135 and by silicon gives the Hiyama coupling.136 When a nickel catalyst is used
with a Grignard reagent as the organometallic participant, the reaction is known as the
Kumada coupling,137 or the Corriu-Kumada coupling.
Table 17.6 Substrates for the Stille Coupling Reaction

The Stille Coupling Reaction
The reaction between a stannane and a halide or triflate to Electrophile Electrophile Stannane Stannane
give coupled products was first reported by American
R2 R1
chemist John K. Stille,138 whose untimely death may well Ar X R1 SnR3
have deprived him of a Nobel Prize. Due to the wide range R3 X
of substrates that can be used and its tolerance to a wide
R2 R1 R2 R1
variety of functional groups, the Stille reaction quickly
Ar X Ar SnR3
became one of the most widely used catalytic cross-coupling R3 X R3 SnR3
reactions. (In fact, it was used in half the cross-coupling
reactions reported in 1992.) Some idea of the wide range of R1O X Cl R2 R1
substrates that can be used with this reaction can be ob- O Ar SnR3
O R2 R R3 SnR3
tained from the examples gathered in Table 17.6.
The key steps of the catalytic cycle (Figure 17.28) are R SnMe3 H SnR3
basically the same as in all other cross-coupling reactions:
(1) oxidative addition of the halide to the coordinatively X, Br, I, OTf, Cl; Ar, aromatic residue.
133. Heck, R.F. J. Am. Chem. Soc. 1968, 90, 5518.

134. Reviews: (a) Stille, J.K. Angew. Chem. Int. Ed. Engl. 1985, 25, 508. (b) Mitchell, T.N. Synthesis 1992, 803.
(c) Farina, V.; Krishnamurthy, V.; Scott, W.J. Org. React. 1998, 50, 1. (d) Espinet, P.; Echavarren, A.M. Angew.
Chem. Int. Ed. 2004, 43, 4704.
135. King, A.O.; Okukado, N.; Negishi, E.-i. J. Chem. Soc., Chem. Commun. 1977, 683.
137. (a) Corriu, R.J.P.; Masse, J.P. J. Chem. Soc., Chem. Commun. 1972, 144a. (b) Tamao, K.; Sumitani, K.;
Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374.
138. John Kenneth Stille (1930–1989) was educated at the Universities of Arizona (BA, 1952; MA, 1953) and
Illinois (PhD, 1957). He followed with faculty positions at Iowa and Colorado State University. Stille, who was one
of the victims of the United Airlines crash in Sioux City, Iowa, pioneered palladium-catalyzed stannane coupling
chemistry. More information is available at: Organometallics 1990, 9, 3007; Macromolecules 1990, 23, 2417.


R1 R3SnX R1 L R1 ‡
cycle of the Stille coupling.
S represents a molecule L
R2 Pd L R2 Pd L R2 Pd
of solvent L
(16.215) R3Sn X R3Sn X
(17.211)
X = I, Br
L
R2: sp2-hybridized
R1 R2 (17.213)
(17.217) R2 SnR3
R1
L Pd L L Pd L
(17.196) R1 X X
(17.197)
R1 R2 X = OTf S
(16.217) R2: sp3-hybridized
R1 R1 ‡ R1
LR R
L Pd R2 Pd SnR3 L Pd L
L R
L S 2
R SnR3 S
R3SnX
(16.716) S (17.214) (17.212)
unsaturated palladium (0) precursor (17.196) gives a coordinatively saturated complex

(17.197), (2) transmetallation gives the palladocycle 17.213, (3) elimination of the tin, and
finally (4) reductive elimination of the coupled product (17.217) regenerates 17.196. Alter-
natively, solvent displaces the halide in 17.197, followed by transmetallation and elimina-
tion of the tin via an activated complex similar to 17.214. Reductive elimination of the
product then regenerates 17.193. In the transmetallation step, it has been found that the
rate of ligand transfer of groups from tin to palladium is approximately:
RC≡C > RCH=CH > Ar > allyl ≈ benzyl > RCOCH2 > R
There is, however, one major difference between the Stille coupling and other metal-
catalyzed cross-coupling reactions. The mechanism of the reaction appears to depend on
both the identity of the leaving group and also on the hybridization of the electrophilic
carbon. The results of computational studies suggest that alkyl halides react through a
cyclic transition state (17.211), whereas triflates react preferentially through an open tran-
sition state (17.214). In both cases, the transmetallation step is proposed to be
associative.139
The relative order of reactivity of the tin ligands has been exploited to ensure the trans-
fer of the desired ligand from tin by using methyl or butyl groups as the non-transferring
ligands. The low reactivity of alkylstannanes, compared to vinyl-, aryl- and alkynyl-
stananes, can be overcome by using strong donor solvents such as hexamethylphosphoric
triamide (HMPT), dimethylformamide (DMF), and dioxane, which also suppress
139. (a) Nova, A.; Ujaque, G.; Maseras, F.; Lledós, A.; Espinet, P. J. Am. Chem. Soc. 2006, 128, 14571.
(b) Pérez-Temprano, M.H.; Nova, A.; Casares, J.A.; Espinet, P. J. Am. Chem. Soc. 2008, 130, 10518. (c) Álvarez,
R.; Pérez, M.; Faza, O.N.; de Lera, A.R. Organometallics 2008, 27, 3378. (d) Álvarez, R.; Faza, O.N.; de Lera, A.R.;
Cárdenas, D.J. Adv. Synth. Catal. 2007, 349, 887.

homocoupling of the stannane. Selectivity and reactivity in the Stille reaction can be im-
proved by the use of Cu (I)140 or Mn (II) salts in stoichiometric quantities (e.g., Example
17.218141). The use of Cu (I) salts also allows the use of palladium on carbon as the cata-
lyst.142 To accelerate the reaction, ligands are needed that stabilize both the nucleophilic
palladium (0) complex and the electrophilic palladium (II) complex. These two effects
require opposite donicity in the ligand. Therefore, ligands of intermediate donicity, such
as tri-(2-furyl)phosphine and triphenylarsine, have been used with success in promoting
Stille reactions that failed under the standard conditions.143 Adding lithium chloride to the
reaction mixture is often found to increase the yield of the reaction (e.g., Example 17.219144).
SnBu3 CO2Et
EtO2C
I
(17.218)
(Bu4N)(Ph2PO2), Pd(PPh3)4
HO
CO2Cu, DMF, 25°C HO
S
(91%)
H2C=CHSnBu3
(Ph3P)4Pd
(17.219)
TfO LiCl, THF, 75°C, 2 h
(98%)
The Negishi Cross-Coupling Reaction145

The corecipient of the Nobel Prize in 2010 was Ei-ichi Negishi, who developed a nickel- or
palladium-catalyzed cross-coupling reaction based on organozinc, organoaluminum, and
organozirconium reagents. The reaction rose to prominence due to its position as the first
catalytic cross-coupling reaction capable of forming unsymmetrical biaryls.
The catalytic cycle of the Negishi reaction is shown in Figure 17.29. In the reaction,
both dialkylzinc reagents and alkylzinc halides can be used. In one study, the alkylzinc
halide was found to give the cis-dialkylpalladium (II) complex (17.216) directly after the
transmetallation, and the dialkylzinc reagent gave the trans-dialkylpalladium (II) com-
plex (17.220) first, and this then underwent a slow trans→cis isomerization. These observa-
tions strongly suggest that the Negishi coupling is less susceptible to side reactions when
the alkylzinc halide is used instead of the dialkylzinc reagent.146 Perhaps one of the most
spectacular applications of the Negishi coupling was its use in the synthesis of hexa(ferro-
cenyl)benzene (Example 17.221).147 The orientations of the six ferrocenyl groups in this
molecule alternate above and below the plane of the benzene ring, giving the molecule an
140. (a) Liebeskind, L.S.; Fengl, R.W. J. Org. Chem. 1990, 55, 5359. (b) Farina, V.; Kapadia, S.; Krishnan, B.;
Wang, C.; Liebeskind, L.S. J. Org. Chem. 1994, 59, 5905. (c) Piers, E.; Romero, M.A. J. Am. Chem Soc. 1996, 118,
1215. (d) Takeda, T.; Matsunaga, K.; Kabawasa, Y.; Fujiwara, T. Chem. Lett. 1995, 771. (e) Allred, G.D.; Liebeskind,
L.S. J. Am. Chem. Soc. 1996, 118, 2748.
141. Domínguez, M.; Álvarez, S.; Álvarez, R.; de Lera, Á.R. Tetrahedron 2012, 68, 1756.
142. Liebeskind, L. S.; Peña-Cabrera, E. Org. Synth., Coll. Vol. 10 2009, 9; Org. Synth. 2000, 77, 135.
143. (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585. (b) Farina, V.; Baker, S.R.; Benigni, D.A.;
Hauck, S.I.; Sapino, C., Jr. J. Org. Chem. 1990, 55, 5833.
144. Mayer, C.D.; Allmendinger, L.; Bracher, F. Tetrahedron 2012, 68, 1810.
145. Review: Negishi, E.-i.; Hi, Q.; Huang, Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71.
146. Casares, J.A.; Espinet, P.; Fuentes, B.; Salas, G. J. Am. Chem.Soc. 2007, 129, 3508.
147. Yu, Y.; Bond, A.D.; Leonard, P.W.; Lorenz, U.J.; Timofeeva, T.V.; Vollhardt, K.P.C.; Whitener G.D.;
Yakovenko, A.A. Chem. Commun. 2006, 2572.

Figure 17.29 The catalytic RR' RX

cycle of the Negishi L Pd L
cross-coupling (17.196)
R R
L Pd R' L Pd L
L X
ZnX2 RZnX
(17.216) (17.197)
R
R2Zn
L Pd L
R' RZnX
(17.220)
S6 improper axis. Despite the extreme steric crowding in this molecule, its synthesis by
means of the Negishi coupling was still accomplished in a yield of 4%.
Fe Fe
I Zn Fe
Fe
I I
R
R (17.221)
I I Pd2(dba)3, THF, 68°C, 63h
I (4%)
Fe Fe
(R=ferrocenyl)
R R'
L Pd L L Pd L
R' R'
(17.222)
R' Zn R' R' Zn R
One of the major side reactions in the Negishi cross-coupling reaction is the formation
of homocoupled products. These products arise when the reductive elimination step is slow,
from a second transmetallation prior to the reductive elimination of the product (Example
17.222). The fact that the reductive elimination step is rapid when alkylzinc halides are used
makes these compounds the more attractive organometallic partner in the Negishi coupling.
In addition to the organometallic partner, the phosphine ligand for palladium also
exerts a strong influence over the course of the Negishi coupling. By far the most work
has been done with phosphines, with the Buchwald148 hindered biphenyldicyclohexyl-
phosphines carrying potential chelating groups at the ortho positions of the biphenyl
(e.g., Example 17.223) being especially useful for difficult couplings.
O
P (17.223)
O
148. (a) Milne, J.E.; Buchwald, S.L. J. Am. Chem. Soc. 2004, 126, 13028. (b) Barder, T.E.; Walker, S.D.;
Martinelli, J.R.; Buchwald, S.L. J. Am. Chem. Soc. 2005, 127, 4685.

Figure 17.30 Effects of group

[L—Pd—L]
size in the catalyst on the two
key stages of the Negishi
Reaction rate
coupling in reaction 17.224
transmetalation
rate
steric size of the alkyl group
Buchwald’s group has demonstrated the utility of these phosphine ligands in a wide
range of cross-coupling reactions. One of the observations from their study has been that
the steric bulk of the phosphine for the Negishi coupling must meet two criteria for
maximum efficiency. One, it must be sterically congested enough to permit a significant
quantity of the L—Pd—L species (the reactive form of palladium) to be present in the
reaction mixture. Two, it must not be so sterically bulky that the transmetallation step
becomes prohibitive. This is illustrated by the effects of substituent size in the phosphine
ligands in the sterically demanding cross-coupling in Example 17.224. Here the reaction
using ligands carrying the smaller methoxy and ethoxy groups is slower than that with the
isopropoxy groups, and the ligand carrying the sterically more demanding triisopropylsi-
lyl (TIPS) groups is now hindered enough to significantly retard the transmetallation
(Figure 17.30).
MeO Cl Pd2(dba)3
Ligand
ZnCl
THF, 70°C, 15 h
MeO
R=Me: 60% conversion
RO R=Et: 57% conversion (17.224)

P
R=i-Pr: 100% conversion
OR
R=TIPS: 25% conversion
The Hiyama and Related Cross-Couplings

The high toxicity of stannane reagents is not generally shared by their silicon analogs.
Consequently, that someone would explore the palladium-catalyzed cross-coupling of
silanes with alkenes (a silicon version of the Stille coupling) was inevitable. However, sila-
nes proved to be very unreactive under the standard Stille-type conditions, and it was not
until 1988 that the reaction became synthetically useful. This, followed Hatanaka and Hi-
yama’s discovery149 that the silane required activation by fluoride anion (or a fluoride
anion surrogate such as Me3SiF2– ion, as in Example 17.225) for the reaction to proceed.
SiMe3 (1.3 eq.)

I (17.225)
(Et2N)3S F2SiMe3 (1.3 eq)

HMPA, 50°C
(98%)

Figure 17.31 The catalytic RX R' SiR3

cycle of the Hiyama L L R
cross-coupling Pd Pd F
L X L
F
(17.196) (17.197)
R' SiR3 (17.226)
RR' F
X SiR3
L R L R
Pd Pd
L R' R' L
(17.216) (17.220)
Figure 17.32 The catalytic RX

cycle of the Hiyama-
Denmark reaction (17.196) (17.197)
O SiR'3
RR'
X
L R
(17.216) (17.220) Pd
O L
R'2Si R'
(17.227)
The catalytic cycle of the Hiyama reaction is shown in Figure 17.31. The fluoride anion
is critical to the success of the reaction because it increases the electron density at carbon
in the Si—C bond, so it resembles the Sn—C bond more closely. This is accomplished by
forming a pentacoordinate silicon anion (17.226) as the first step of silane activation. The
results of a study of the mechanism of the reaction by Denmark 150 led to the development
of the Hiyama-Denmark reaction,151 in which silyloxide anions are used as the silane
component of the reaction and in which fluoride anion is no longer needed as an activator.
Mechanistic studies have shown that a pentavalent silicon species is not involved in the
Hiyama-Denmark reaction but that the silyloxide palladium complex (17.227) undergoes
unimolecular elimination of the silicone, with concomitant migration of the alkyl group
to generate the dialkylpalladium intermediate (17.216). The catalytic cycle of the Hiyama-
Denmark reaction is shown in Figure 17.32.
The Kumada Coupling

In 1900, the Zaitsev-Wagner synthesis of alcohols from aldehydes or formate esters and or-
ganozinc reagents152 (especially alkylzinc iodides) was superseded by the Grignard synthesis,
based on the corresponding organomagnesium reagents. Thus, it was only a matter of time
before an organomagnesium analog of the Negishi cross-coupling, which is based on or-
ganozinc reagents, would be examined. The resulting reaction, discovered independently by
150. Denmark, S.E.; Wehrli, D.; Choi, J.Y. Org. Lett. 2000, 2, 2491.
151. Review: Denmark, S.E.; Regens, C.S. Acc. Chem. Res. 2008, 41, 1486.
152. Lewis, D.E. Bull. Hist. Chem. 2002, 27, 37.

Corriu and Kumada153 is now generally known as the Kumada cross-coupling. Unlike the
Negishi cross-coupling, the reaction is not widely used, although it does have applications in
the synthesis of some important drugs.
The Suzuki-Miyaura and Related Coupling Reactions

Despite its flexibility, the Stille coupling suffers from the disadvantage that toxic organotin
compounds are critical to the reaction. Recently, this problem has been addressed by de-
veloping methods where the tin is used in catalytic amounts.154 The development of poly-
meric stannane reagents155 also promises to make the reaction easier to use without
generating large quantities of difficult-to-handle, toxic organotin residues. Among the
most successful replacements for the tin compounds are alkylboron compounds, espe-
cially alkylboronic acid derivatives, in a reaction now generally referred to as the S uzuki-
Miyaura coupling.156
Suzuki-Miyaura Coupling
Based on the data in Table 17.4, the Suzuki-Miyaura coupling is the most widely used metal-
catalyzed C—C bond forming reaction in use at the present time. This reaction follows a
similar catalytic cycle to other coupling reactions. However, the presence of the oxyanion
base results in two different catalytic cycles (Figure 17.33) depending on whether it at-
tacks boron, to generate the borate complex 17.228 (cycle A), or the metal, to generate the
complex 17.229 (cycle B). The reactivity of the halide participant, Ra X, in the reaction fol-
lows the general order:
RI > ROTf > RBr >> RCl
The oxidative addition of a vinyl halide to the metal proceeds with retention of config-
uration. With allylic and benzylic halides, it occurs with inversion (by a formal displace-
ment of the halogen from carbon by an SN2-like process).157 The oxidative addition initially
gives a cis metal complex that then rapidly isomerizes to the trans (17.196).158 The reductive
elimination step also proceeds with retention of configuration.159 By far the most common
153. (a) Corriu, R.J.P.; Masse, J.P. J. Chem. Soc., Chem. Commun. 1972, 144a. (b) Tamao, K.; Sumitani, K.;
Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374.
154. Gallagher, W.P.; Malezcka, R.E., Jr. J. Org. Chem. 2005, 70, 841.
155. (a) Chrétien, J.-M.; Mallinger, A.; Zammattio, F.; Le Grognec, E.; Paris, M.; Montavon, G.; Quintard,
J.-P. Tetrahedron Lett. 2007, 48, 1781. (b) Kerric, G.; Le Grognec, E.; Zammattio, F.; Paris, M.; Quintard, J.-P.
J. Organomet. Chem. 2010, 695, 103. (c) Albeniz, A.C.; Carrera, N. Eur. J. Inorg. Chem. 2011, 2347. (d) Carrera,
N.; Salinas-Castillo, A.; Albeniz, A.C.; Espinet, P.; Mallavia, R. J. Organomet. Chem. 2011, 696, 33126.
156. Reviews: (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Chemler, S.R.; Trauner, D.; Danishefsky,
S.J. Angew. Chem., Int. Ed. 2001, 40, 4544. (c) Suzuki, A.; Brown, H.C. Organic Syntheses Via Boranes (Aldrich
Chemical Co., Inc.: Milwaukee, 2002); Vol. 3. (e) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
(d) Bellina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419. (f) Miyaura, N., Ed. Cross-Coupling Reactions. A
Practical Guide. (Springer-Verlag: Heidelberg, 2002). (g) Miyaura, N. In Diederich, F.; de Meijere, A., Eds. Metal-
Catalyzed Cross-Coupling Reactions (Wiley-VCH: New York, 2004), ch. 2. (h) Hall, D.G. In Hall, D.G., Ed. Boronic
Acids-Preparation, Applications in Organic Synthesis and Medicine (Wiley-VCH; Weinheim: 2005), pp. 1–99.
(i) Bai, L.; Wang, J.-X. Curr. Org. Chem. 2005, 9, 535.
Norio Miyaura (1946–) was educated at Hokkaido University under Suzuki and is currently Professor at the
same university. For more details, see: Chem. Rev. 1995, 95, 2457.
Akiro Suzuki (1930–) was educated at Hokkaido University and served there from 1961–1994. After retiring,
he joined the faculty of Okayama University of Science. He shared the 2010 Nobel Prize in Chemistry. More
detail may be found at the Nobel Foundation web site.
157. Stille, J.K.; Lau, K.S.Y. Acc. Chem. Res. 1977, 10, 434.
158. Casado, A.L.; Espinet, P. Organometallics 1998, 17, 954.
159. (a) Ridgway, B.H.; Woerpel, K.A. J. Org. Chem. 1998, 63, 458. (b) Matos, K.; Soderquist, J.A. J. Org.
Chem. 1998, 63, 461.


Ra Rb
cycles for the Suzuki-
L Rb L
Miyaura coupling. OY is an
oxyanion base.
Pd Pd
L Ra L
(17.216) (17.196)
Ra X
A OR
Rb B OR
OY
L Rb (17.228)
L Ra
Pd Pd
Ra L X L
(17.220) (YO)B(OR)2, X (17.197)
Ra Rb
(17.216) (17.196)
Ra X
(17.220) B (17.197)
OY
(YO)B(RO)2
X
Ra L Rb L Ra
Pd B(OR)2 Pd
L O YO L
Y RbB(OR)2
(17.230) (17.229)
catalysts are based on palladium, which has been shown in a computational study160 to be
the most reactive of the noble metals with respect to the reductive elimination step of the
Suzuki-Miyaura reaction. In this study, the order of reactivity was found to be:
Pd > Pt > Rh > Ir, Ru, Os
By far, the major applications of the Suzuki-Miyaura cross-coupling are in the synthesis
of biaryls and styrenes from aryl halides and aryl- or vinylboronic acids as illustrated by
Example 17.231.161 One of the major strengths of the reaction is the fact that in the synthesis
of styrenes, for example, the stereochemistry of the vinylborane is retained during the mi-
gration step, allowing the stereochemistry of the product to be predicted. The same holds
true in the synthesis of simple dienes by means of the Suzuki coupling between vinyl halides
and vinylboronic acid derivatives. For example, the synthesis of caparratriene (Example
17.232) by means of a Wittig reaction provided the E,E isomer only as the major component
of a 2:1 mixture. When the Suzuki-Miyaura coupling was used with the E bromide and the
160. Ananikov, V.P.; Musaev, D.G.; Morokuma, K. J. Am. Chem. Soc. 2002, 124, 2839; Organometallics
2005, 24, 715.
161. Al-Lakkis-Wehbe, M.; Roux, L.; Charrier, C.; Alavi, S.; Le Nouën, D.; Defoin, A.; Tarnus, C.; Albrecht,
S. Tetrahedron 2012, 62, 6447.

E vinylboronic acid, however, only the natural E,E isomer was produced.162 An interesting
example of the intramolecular application of the Suzuki coupling is provided by Example
17.233, from the formal total synthesis of strychnine by Bodwell and Li.163 In this case, the
required boron derivative was formed by hydroboration of an alkene immediately prior to
the addition of the catalyst.
Br I Br
PhB(OH)2, Pd(PPh3)4
(17.231)
K2CO3, H2O, THF, 70°C
(91%)
NHCbz NHCbz
O MeCH=PPh3, THF
E,E : Z,E 2:1
(17.232)
O
B Br
O
Pd(PPh3)4, NaOEt
PhH, ∆
NH NH
1) 9-BBN, THF, 12 h N
N (17.233)
N 2) Ph(PPh3)4, Cs2CO3, N
N THF, ∆, 2 d N
I (65%)
The boronic acids in the Suzuki coupling may be successfully replaced by alkyltrifluo-
roborates, which offer advantages in terms of reagent stability compared to other boronic
acid derivatives. This can permit a ligand-less version of the Suzuki coupling to be used.164
Example 17.234 gives a recent illustration of the application of these boron reagents in the
Suzuki coupling.165
O N O
Br OMe
N N OMe
N N
BF3K Pd(PPh3)4 (9 mol %) N (17.234)
PhMe, ∆, 9 h
(70%)
162. Vyvyan, J.R.; Peterson, E.A.; Stephan, M.L. Tetrahedron Lett. 1999, 40, 4947.
163. Bodwell, G.J.; Li, J. Angew. Chem. Int. Ed. 2002, 41, 3261.
164. (a) Molander, G.A.; Rodriguez Rivero, M. Org. Lett. 2002, 4, 107. (b) Molander, G.A.; Bernardi, C.R.
J. Org. Chem. 2002, 67, 8424. (c) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393. (d) Molander, G.A.; Biolatto, B.
Org. Lett. 2002, 4, 1867.
165. Math, S.K.; Mokri, H.H.; LaMunyon, J.B.; Cefalo, D.R.; Testa, C.R. Tetrahedron Lett 2012, 53, 2487.

Sonogashira Coupling
When the nucleophilic partner in the coupling reaction is a copper (I) alkynide, formed
either stoichiometrically or catalytically, the reaction is known as the Sonogashira cou-
pling.166 When both metals are used in catalytic amounts, the catalytic cycle for the reac-
tion involves two intermeshed cycles, one for the palladium, and one for the copper. The
catalytic cycle of the Sonogashira cross-coupling is shown in Figure 17.34. The palladium
cycle begins with the familiar pattern of oxidative addition of the halide to the coordina-
tively unsaturated palladium (17.196) to give the coordinatively saturated complex (17.197),
ligand exchange with copper to give the trans alkynylpalladium complex 17.235, isomeri-
zation of the complex to the cis isomer (17.236), and reductive elimination of the product.
The copper cycle involves the formation of an initial η2 alkynyl complex of the copper (I)
halide (17.237). This reacts with the base to give the corresponding copper (I) alkynide
(17.238), which then undergoes ligand exchange with the palladium to regenerate the
copper (I) halide. More recently, a nickel-catalyzed version of the reaction167 has been de-
veloped, reducing the expense associated with the palladium.
Like the Suzuki reaction, the Sonogashira reaction is highly tolerant of a wide range of
functional groups, as shown by the synthesis of the phenylalanine-biotin conjugate 17.239,
where the sulfide, ester and urethane groups are all present in the starting materials. The
order of reactivity of the halide participant in the Sonogashira cross-coupling reaction
follows the order in the Suzuki coupling, with the added observation that aryl halides and
triflates are less reactive than similar vinyl halides and triflates.
The copper in the Sonogashira coupling does occasionally lead to one undesired side
reaction: the Glaser homocoupling of the alkyne.168 For this reason, an alternative, copper-
free variant of the reaction has been developed,169 in which a very hindered phosphine
ligand, such as tri-tert-butylphosphine, is used in place of the copper; the resulting palla-
dium complex reacts directly with the alkyne to give the alkynylpalladium complex.
Figure 17.34 The catalytic R = aryl, hetaryl, vinyl

cycle of the Sonogashira X = I, Br, OTf, Cl
cross-coupling reaction R3NH2 X
R—X
Cu
R3N
R (17.196) (17.197) C
C C H
C R' C
R' (17.238) (17.237) C Cu X
R'
R L R L
Pd Pd Cu—X
C L L C
C C
(17.236) (17.235) R' H C C R'
R'
166. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467. (b) Sonogashira, K. J. Or-
ganomet. Chem. 2002, 263, 46. (c) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874. (d) Chinchilla, R.;
Nájera, C. Chem. Soc. Rev. 2011, 40, 5084.
167. Vechorkin, O.; Barmaz, D.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 12078.
168. (a) Glaser, C. Justus Liebigs Annm. Chem. 1870, 154, 137; Ber. dtsch. chem. Ges. 1869, 2, 422. (b) Johans-
son Seechurn, C.C.C.; Kitching, M.O.; Colacot, T.J.; Snieckus, V. Angew. Chem. Int. Ed. 2010, 51, 5062.
169. (a) Böhm, V.P.W.; Herman, W.A. Eur. J. Org. Chem. 2000, 3679. (b) Méry, D.; Heuzé, K.; Astruc, D.
Chem. Commun. 2003, 1934.

Boc
H N O Boc
H N O
N
S Boc Pd(OAc)2 (1.3 mol % N
H Ph3P (2.6 mol %) Boc
S H
I CuI (2.6 mol %)
Et2NH (solvent) (17.239)
(91%)
MeO2C NHBoc
MeO2C NHBoc
Reaction Synopses
Heck Reaction
Nu E
Z E
Z
X
Nu
Pd0, ligand, base

R X Nu E
R
R R
R R
E = COR, CO2R, SOR, SO2R, CN, Ar, etc.

Nu = OR, OCOR, NR 2, N(R)COR, etc.
Reagents: Pd(PPh3)4, Cs2CO3, DMF, 100°C; Pd(OAc)2, dppp, NEt3,
Me2SO, 115°C; etc.
Regiochemistry: reaction occurs β to electron-withdrawing substituents, and α
to electron-releasing substituents; reaction is much more fa-
vorable with electron-deficient alkenes.
Stereochemistry: reaction exhibits strong preference for trans product.
Stille Reaction
R" SnR'3 O R" SnR'3 O
R X R R" R R
G3P, [LiCl] X G3P, [LiCl] R"
Pd cat., THF Pd cat., THF
G = aromatic or hindered alkyl

R = aryl, vinyl, alkyl, acyl
R" = vinyl, aryl, alkyl, alkynyl
Reagents: PdCl2, (t-Bu)3P, CuI, CsF, DMF, ∆; Pd(OAc)2, DABCO, KF or
Bu4NF, dioxane, ∆; etc.
Migratory preference in stannane: vinyl, aryl > alkyl; this permits the use of re-
agents such as ArSnBu3, RCH=CHSnBu3.
Negishi Coupling
R" M
R X R R"
Pd cat., G3P
R: usually aryl
R"—M: R"2Zn, R"ZnX, R"3Al, R"ZrCp2L, etc; organozinc reagents are the most
widely used.

G3P: Ph3P, 1,1'-(diphenylphosphino)ferrocene [dppf]

o-Cy2PC6H4—2,6-(MeO)2C6H4; etc.
Reagents: RZnBr, (t-Bu3P)2Pd, dioxane; R 2Zn, Pd2dba3, dioxane; R 2Zn,
(dppf)PdCl2, THF; etc.
Hiyama and Hiyama-Denmark Couplings
R" SiR'3 R" Si(OH)R'2
R X R R" R X R R"
F , HMPA base, Pd cat.
Pd cat., G3P G3P
R'3Si: SiMe3, Si(OR')3, Me3-nSiFn, etc.

Pd cat.: PdCl2, Pd(OAc)2, Pd2dba3, [C3H5PdCl]2, etc.
Reagents: Hiyama coupling
R"Si(OMe)3, PdBr2, (t-Bu)2PMe, Bu4N+ F– (TBAF), THF;
R"Si(OMe)3, Pd(OAc)2, DABCO, TBAF, dioxane, ∆.; etc.
Reagents: Hiyama-Denmark coupling
R"Si(OK)Me2, [(t-Bu)3P]2Pd, PhMe, ∆; R"Si(OG)Me2,
Me3SiOK, Pd2dba3, dioxane; etc.
Kumada Coupling
R" MgX
R X R R"
Ni or Pd cat.
G3P
Ni cat: (dppb)NiCl2; etc. Pd cat.: (Ph3P)4Pd; etc.

Reagents: R"MgBr, Ni(acac)2, o-[MeCH(OH)]C6H4PPh2; etc.
Suzuki-Miyaura coupling
R" B(OR')2 R" BF3K
R X R R" R X R R"
Pd cat., base Pd cat.
Molander modification
X: Br, I, OTf, etc.; R':H, alkyl; R": alkyl, aryl
Reagents: (Ph3P)4Pd, Na2CO3, R—B(OCMe2)2, C6H6-EtOH, ∆; Pd(OAc)2,
o-(2,6-MeO)2C6H3—C6H4PCy2, K 3PO4, THF; etc.
Sonogashira Coupling
R" H
R X R R"
Pd cat., Cu(I), base
X: Cl, Br, I, OTf.

Reagents: (Ph3P)4Pd, CuI, n-PrNH2, PhH; (Ph3P)2PdCl2, CuI, Et3N (sol-
vent); etc.
Chapter Summary
This chapter has concerned catalytic reactions for the formation of new carbon-carbon
bonds, a field that has grown dramatically as the 12 Principles of Green Chemistry move
into the mainstream of organic synthesis. Most of these reactions involve the use of or-
ganometallic complexes as the catalytic species; reactions in these complexes, which can

be coordinatively saturated (18 electrons formally on the metal atom) or coordinatively

unsaturated (less than 18 electrons formally on the metal atom); bonding to ligands may
be σ or π—especially (d-p)π bonding. Bonding between the metal and ligands in π com-
plexes is frequently described using the hapto number, η. Reactions of these species can
involve reactions at either the metal or a ligand. Reactions at the metal include ligand ex-
change; migratory insertion, which is a rearrangement occurring at the metal atom; oxi-
dative addition, where the coordination number and the oxidation number of the metal
both increase by two; and reductive elimination, where the reverse occurs. These reactions
figure prominently in the catalytic cycles of a number of important synthetic reactions.
Addition of neutral metal hydrides across C—C π bonds is often facile and occurs
with syn stereochemistry. The addition of organometallic reagents across alkynes (carbo-
metallation) also occurs with predominant syn stereochemistry. Transition metal carbene
complexes react with both alkenes and alkynes to generate new metal carbene complexes,
with concomitant elimination of the alkene.
Important bond-forming reactions discussed in this chapter include the Tsuji-Trost
reaction; olefin metathesis; the Reppe oligomerization reactions of alkynes; Heck reaction
and its congeners (the Stille, Negishi, Kumada, Hiyama and Hiyama-Denmark couplings);
and the Suzuki-Miyaura reaction and its congener, the Sonogashira coupling.
Key Terms
Buchwald-Hartwig reaction Heck reaction olefin metathesis

carbometallation β-hydride elimination oxidative addition
carbonylation Hiyama coupling reductive elimination
coordinatively saturated Hiyama-Denmark coupling Reppe chemistry
coordinatively unsaturated hydroformylation Sonogashira coupling
decarbonylation hydrometallation Stille coupling
ene-yne metathesis Kumada coupling Suzuki (Suzuki-
Fischer complexes ligand Miyaura) coupling
“green” chemistry migratory insertion transmetallation
hapto number Negishi coupling Tsuji-Trost reaction
Additional Problems
Ph O
O (Ph3P)3RhCl [Tetrahedron Lett.
(a) OHC
PhCN, ∆
O O 2006, 47, 3905]
H
O
O
EtO2C PdCl2•2 MeCN, HCO2H [J. Am. Chem. Soc.
(b) MeO I Et3N, DMF, 60°C, 60 min 2003, 125, 3090]
(93%)
O
H O O
OAc
Pd(PPh3)4 (5 mol %) [Org. Lett.
(c) pyrrolidine (40 mol %)
CHO Me2SO, r.t. 30 min 2007, 9, 5063]

OAc O
ButO CO2Et
[J. Am. Chem. Soc.
(d) NaH, THF, r.t.
Pd2(dba)3, PPh3 1993, 115, 9293]
OCO2Me
(91%)
MeO
O
MeO
O
Pd(OAc)2, Me3NCH2Ph Cl
(e) OMe Et2NCHMe2, DMF, 80°C [Synlett 2008, 126]
I (45%)
OMe
OMe
H
H2C=CH2, CH2Cl2 [J. Am. Chem. Soc.
(f) Grubbs I, 12 h
H
H 2002, 124, 9974]
O (93%)
O
OTBS
OTf
(Ph3P)4Pd, K2CO3
[J. Am. Chem. Soc.
(g) H
MeCN, 90°C
O
(46%)
1996, 118, 2843]
O OO
O Ph
H
H2C=CH2, CH2Cl2 [J. Am. Chem. Soc.
(h) Grubbs I, 12 h
H
H 2002, 124, 9974]
O (93%)
O
O
H
PMBO Grubbs I [Org. Lett.
(i) H
CH2Cl2, ∆
O 2003, 5, 4277]
N (89%)
H
MeO N OMe
Boc
N
Grubbs I [J. Am. Chem. Soc.
(j) CH2Cl2, r.t., 18 h 2002, 124, 13342]
(90%)
OTBDPS
MeO OMe
[Org. Lett.
(k) N CO2Me
2007, 9, 3425]
S Grubbs-II, CH2Cl2,
O 40°C, 60 h
CONMe2 SnBu3 (1.5 eq.)

[Tetrahedron Lett.
(l) I (Ph3P)4Pd (3 mol %)
PhMe, ∆, 16 h
2012, 53, 4514]

Cbz
N Br
OMe
N
PCy2 [J. Am. Chem. Soc.
(m) MeO OMe
Pd(OAc)2 (2.5 mol %) 2004, 126, 706]
K3PO4 (2 eq.)
B O ligand (2.5 mol %) THF
O
89%) ligand
Br
TESO BO
O
[J. Am. Chem. Soc.
(n) H
Pd(PPh3)4 (4 mol %) 2008, 130, 16864]
MEMO
K2CO3 (3 eq), H2O, THF
OTBS
Me
OTs o-BrC6H4B(OH)2 (1.2 eq) [Org. Lett.
(o)
I Pd(PPh3)4 (0.1 eq), Na2CO3 2008, 10, 1999]
C6H6-THF-H2O, ∆
NH2
H2C=CHSO2Me (2 eq.)
Br Ph2PH2C CH2PPh2
[PdCl(allyl)]2 (0.01 eq)
(p) OMe
NaOAc (2 eq)
MeCONMe2, 130°C
Ph2PH2C CH2PPh2 [Synthesis, 2006, 3495]
ligand
ligand (0.02 eq)
OR
H
O Grubbs-II, O O [Tetrahedron 2011,

(q) RO
H ClCH2CH2Cl, 95°C 67, 10179]
O
O
O Ph
Bu3SnH, AIBN
80°C
H OH
Me OTf
Bu3Sn O [Tetrahedron 2011,
(r) CO2Me
O Ph
OH 67, 10026]
N
Pd2dba3, DMF, 50°C
O
O
O
P
O
I OMe p-MeC6H4CCH, CuI

[Tetrahedron
(s) (Ph3P)2PdCl2, i-Pr2NH
O THF, ∆ 2011, 67, 9291]
O
OAc
H H
Grubbs-II [J. Org. Chem.
(t) H2C=CH2, CH2Cl2
O O 2002, 67, 4441]
O H OH
Grubbs-Hoveyda
(u) O ClCH2CH2Cl, ∆ [Org. Lett. 2010, 12, 60]
CO2Et

O
HO
N
NHCHO Bu3SnH, THF [Org. Lett.
(v) H Pd(dppf)Cl2•CH2Cl2 2007, 9, 4619]
OTBS
1) Cp2Zr(H)Cl, THF(*)
[J. Am. Chem. Soc.
(w) 2) I2, THF, –78°C
OTBS 2007, 129, 3826]
(*made in situ from Cp2ZrCl2 + DIBAL-H)
HO
1) (PhMe2Si)2Cu(CN)Li2, THF, -10°C
2) NH4Cl, H2O
CO2Me
OB
O Br
O [J. Am. Chem. Soc.
(x) O
Pd(OAc)2, Ph3P, MeOH-THF 2005, 127, 16038]
TESO
N SiMe3 Na2CO3
O
SETO
H H
OTES Bu3Sn
O
H [J. Am. Chem. Soc.
(y) O O Ph3P, CuI, THF
H 2006, 128, 15960]
O I
O
H
TIPSO 1) 9-BBN, THF, 0°C

2) Cs2CO3, H2O
O
[Org. Lett.
(z) OTBDPS, DMF
3)
O
H
OTES
2012, 14, 3186]
OPMB
OTf
Ph3As, Pd(dppf)Cl2•CH2Cl2
H H
OTES Bu3Sn
O
H [J. Am. Chem. Soc.
(aa) O O Ph3P, CuI, THF
H 2006, 128, 15960]
O I
O
H
1) Cp2Zr(Cl)H [J. Am. Chem. Soc.

(bb) O 2) NBS
O 1997, 119, 10935]
3) AcOH
1) Bu3SnH, (Ph3P)2PdCl2, THF

[J. Org. Chem.
(cc) 2) I2, CH2Cl2, –78°C to r.t.
OH OTBS 2002, 67, 2751]
O H SiMe3
[J. Am. Chem. Soc.
(dd) Co2(CO)8
2003, 125, 11514]
Br
B(OH)2 Br [J. Am. Chem. Soc.
(ee)
(Ph3P)4Pd, Tl2CO3, THF-H2O 2006, 128, 8126]
OTBDMS
O
1) BH, THF, ∆
O
[J. Org. Chem.
(ff)
2) I OH, (Ph3P)4Pd 1998, 63, 8638]
NaOH, H2O, THF, ∆

[Rh(CO)2Cl]2 (0.1 eq)

[Org. Lett.
(gg) O CO (1 atm.), PhMe, ∆
O 2011, 13, 6304]
[Which double bond of the allene reacts?]
1) BH [Pure Appl. Chem.

(hh) 2
1991, 63, 307]
2) MeCHO
Me
F N N
Cl O, Pd(OAc)2
F
H [WO 2010/015972
(ii)
A1] (Pfizer)
MeO2C NH O
Ph2P PPh2
17-9 The following reactions from applications for international patents by pharma-
ceutical companies in 2010 illustrate the impact of transition metal- (especially
palladium-) catalyzed reactions on modern synthesis. Give the structure of the
major organic product of each reaction.
O
HN Zn(CN)2, Pd(PPh3)4 WO 2010/026110 A2
(a) H N Br
DMF (Hofmann-La Roche)
O
HN Bu3Sn—CH=CH2 WO 2010/026110 A2
(b) H N Br
Pd(PPh3)4, PhMe, ∆ (Hofmann-La Roche)
O
HN Ph—CH=CH2, Pd(OAc)2 WO 2010/026110 A2
(c) H N Br
(o-MeC6H4)3P, Et3N, MeCN (Hofmann-La Roche)
O N, Pd(OAc)2
HN WO 2010/026110 A2
(d) Br
H N
(o-MeC6H4)3P, Et3N, (Hofmann-La Roche)
DMF
O
HN B(OH)2, Pd(OAc)2 WO 2010/026110 A2
(e) H N Br
Cy3P, K3PO4, H2O, PhMe (Hofmann-La Roche)
O
HN
H N Br
Pd2dba3, NaOBut
t-BuOH, dioxane WO 2010/026110 A2
(f) H2N N CF3 (Hofmann-La Roche)
P(But)2
i-Pr i-Pr
i-Pr
CO2Et
H
MeO N N (t-Bu3P)2Pd, Pd2dba3 WO 2010/043714
(g)
O Cy2NMe, dioxane A1 (Glaxo)
Br

OTf I
WO 2010/013161
(h) BocHN CO2Me
A1 (Pfizer)
O Zn, (Ph3P)2PdCl2, DMF
NH2
Cl O OMe
PhCH2CH2ZnBr WO 2010/026075 A1
(i) N
(But3P)2Pd, dioxane (Hofmann-La Roche)
CN Br
BocHN
Br S
ZnBr
N N WO 2010/026121 A1
(j) N
N [(Ph2PC5H4)2Fe]PdCl2•CH2Cl2 (Novartis)
N THF
OMe S
ZnBr
N Cl WO 2010/026122 A1
N
(k)
N [(Ph2PC5H4)2Fe]PdCl2•CH2Cl2 (Novartis)
THF
H H N
N Boc
N N N
SnBu3 WO 2010/016005
(l) N
(Ph3P)4Pd, C6H4Me2, ∆ A1 (Pfizer)
Cl
F F N I
HC CSiMe3, Et3N WO 2010/016005
(m)
O N CuI, DMF, THF, (Ph3P)4Pd A1 (Pfizer)
Boc
N
N Zn(CN)2, Pd2dba3, DMF, H2O

NHH WO 2010/016005
(n)
N A1 (Pfizer)
PCy2
Cl N MeO OMe
N
N
N
MeO H2N WO 2010/016005
(o) N
N Cl Pd2dba3, BINAP, Cs2CO3 A1 (Pfizer)
PhMe
N
HC CSiMe3, CuI
WO 2010/016005
(p) Cl N Br (Ph3P)2PdCl2, EtN(i-Pr)2
A1 (Pfizer)
DMF
Ph
Cl O O Et2Zn, (dppf)PdCl2 WO 2010/026075 A1

(q) THF, HOCH2CH2NMe2
Br
N ∆ (Hofmann-La Roche)
CN
Ph
Cl O O Bu3SnCH2CH=CH2 WO 2010/026075 A1
(r) (Ph3P)4Pd, DMF, ∆
Br
N (Hofmann-La Roche)
CN

NH2
Cl O OMe PhCH2CH2ZnBr WO 2010/026075 A1
(s) N (t-Bu3P)2Pd, dioxane (Hofmann-La Roche)
CN Br
Cl
Cl O OMe N, CuI
WO 2010/026075 A1
(t) (Ph3P)2PdCl2, Et3N
N (Hofmann-La Roche)
CN Br
Cl
Cl O OMe BrZnCH2CH2CO2Et WO 2010/026075 A1
(u) N (t-Bu3P)2Pd, dioxane (Hofmann-La Roche)
CN Br
SnBu3
F WO 2010/020810 A1
(v) OEt
CuI, (Ph3P)2PdCl2, MeCN (AstraZeneca)
N Br
17-10 Suggest a mechanism for the reaction shown. What is the role of the pyrrolidine?
[Angew. Chem. Int. Ed., 2006, 45, 1952].
O O
OAc
(Ph3P)4Pd (0.05 eq.)
NH (0.3 eq)
Me2SO, r.t.
17-11 What does the stereochemistry in the reaction below [J. Am. Chem. Soc. 2004,
126, 10246] suggest about the mechanism of the reaction?
OTBS
HO O
MeO2C CO2Me H O H
OTBS CO2Me
CO2Me phosphine = O
NH H P
Pd2(dba)3,PhMe, r.t. O
OTBS NH
phosphine
(86%) OTBS
17-12 Suggest reagents that can be used for the conversion in each of the reactions
below. Where possible, carry out the transformation in a single step.
O Ph O Ph
H H
[Tetrahedron
(a)
OH O OH O 2011, 67, 9358]
O O
S S [J. Am. Chem. Soc

(b) I
S S 2003, 125, 350]
[Angew. Chem. Int. Ed.

(c) N
H (one step) N 2011, 50, 1402]
H
BocHN
F F F F
[WO 2010/026122 A1
(d) N N N
TfO
H
N (Novartis)]

17-13 The power of modern cross-coupling reactions in synthesis is nicely demon-

strated by two stereospecific total syntheses of the acetylenic sesquiterpene, freel-
ingyne. The two syntheses appeared within months of each other in 1997 and
show remarkable similarities. The stereospecificity of these syntheses may be con-
trasted with the lack of stereospecificity in the previous two syntheses, which also
appeared in close succession [Knight, D.W.; Pattenden, G. J. Chem. Soc., Chem.
Commun. 1974, 188. Ingham, C.F.; Massy-Westropp, R.A.; Reynolds, G.D. Aust. J.
Chem. 1974, 27, 1477]. When you have completed each synthesis by supplying the
missing reagents or reaction products, compare the two syntheses. How are they
similar and how do they differ?
(a) Katsumura’s synthesis
CO2Me CHO
1) Ph3P, CBr4
CHO 2) BuLi (2 eq) Br 1) LiAlH4
A B
O 3) ZnCl2 (PPh3)4Pd 2) MnO2 O
(C6H3ClOZn) (C11H10O3)
1) MnO2 I OH OH
1) BuLi
C D
2) Ph3P, CBr4 2) NH4Cl (PPh3)4Pd
O
(C11H8Br2O) (C11H8O)
1) MnO2
2) NaClO2 CO2H PdCl2(MeCN)2
Ph2PCH2CH2PPh2 O
Et3N O
O O
(b) Negishi’s synthesis

carboalumination route carbocupration route I
I OH OH
reagent g reagent h OH
1) TsOH, MeOH
i j 2) DMP
O O
I O O O O
H
O
CHO
k m I CO2H
L N O
(PPh3)4Pd, CuI
O Et3N O O
(C11H8Br2O) (C11H8O)
17-14 There are three steps in Somfai’s short synthesis of the alkaloid, stemoamide.
Supply the missing reagents and products in this three-reaction sequence in the
middle of the synthesis.
H
1) I B
N O BrZnCH2CO2Et Grubbs-II
P Q R
2) HOAc (Ph3P)4Pd CH2Cl2
C11H16INO THF-DMPU, ∆ C15H23NO3 C13H19NO3

Chapter eighteen
Redox Reactions I
Oxidation
18.1 Introduction
Oxidation and reduction reactions can comprise more than 25% the reactions used in the
synthesis of a complex molecule, so they are important processes in organic chemistry.
This also means that a large number of reagents have been developed for carrying out
these reactions. Oxidation and reduction may be defined a number of ways. The first is the
definition that is taught in introductory courses: oxidation is a net loss of electrons, and
reduction is a net gain in the number of electrons. An alternative, older definition still re-
mains useful: oxidation is a net gain in the number of oxygen (or other electronegative)
atoms or a net loss in the number of hydrogen (or other electropositive) atoms. Reduction is
the reverse of oxidation: a net gain in the number of hydrogen (or other electropositive)
atoms or a net loss in the number of oxygen (or other electronegative) atoms.
Based on these definitions, let us categorize a familiar reaction, the conversion of a
primary alcohol to a carboxylic acid:
R—CH2OH → R—CO2H
In this transformation, there is a net loss of two hydrogen atoms and a net gain of an
oxygen atom. The reaction is oxidation. We can also write an oxidation half-equation for
this transformation:
R—CH2OH + H2O → R—CO2H + 4H+ + 4e−
Likewise, the conversion of an alkyl halide to a Grignard reagent is a representative

reduction: there is a net loss of one electronegative atom (the halogen) and a net gain of one
electropositive element (the magnesium). Note how it is much easier to see the change in
the number of electrons when one uses the minor contributor to the resonance hybrid.
R—X + Mg → R—Mg—X (or R− Mg2+ X−)
Again, we can write oxidation and reduction half-equations for this reaction:
R—X + 2e− → R− + X− [reduction half-equation]
Mg → Mg2+ + 2e− [oxidation half-equation]
Oxidation Numbers: Use and Limitations

One convenient method for monitoring oxidation and reduction reactions is by the use of
oxidation numbers. Oxidation numbers are useful when applied to the inorganic reac-
tants in oxidation and reduction reactions. We readily refer to potassium permanganate as
761

762 Advanced Organic Chemistry | Chapter eighteen
manganese (VII) reagents and various reagents based on chromic acid as chromium
(VI) reagents.
The oxidation numbers of carbon in a series of organic compounds with a range of
commonly found functional groups are presented in Table 18.1. X, Y, and Z refer to electro-
negative elements (e.g., O, N, halogens, S); the hydrogen atoms in the structures may be
replaced by atoms of a similarly electropositive element (e.g., metals, Si, B), without affect-
ing the oxidation number of carbon. Oxidation formally corresponds to movement up or
to the right and reduction to movement down or to the left. The oxidation numbers are
calculated using the rule that hydrogen is +1 in organic compounds, halogens are −1,
oxygen is −2, and that alkyl groups contribute 0.
One consequence of this way of computing oxidation numbers, is that the substitution
of hydrogen (+1) by alkyl (0) leads to an algebraic increase in the oxidation number of
carbon of +1—formally an oxidation. This shows up in Table 18.1. The formal oxidation
Table 18.1 The Oxidation Number of Carbon in Representative Organic Compounds
Formal Oxidation Number of Carbon

−4 −3 −2 −1 0 +1 +2 +3 +4
Z
H H H H X
H H H X [O] X X Y
H H H Y Y C X
Y C X
R
R R R X
H H H X [O] X Y
H H H
R C X
R R R
H H [H] H X [H] X
R R R
R R
R H R X
R R
H H X X X X
H H H H X X
R R
H H
R R
R R
H X
H X

Redox Reactions I 763
number for a particular functional group is not constant but depends on the other groups
attached to the carbon. This is illustrated by the oxidation number of the carbon bearing
the functional group in the series of compounds in the accented boxes (e.g., alcohols or
alkyl halides): moving through this series from methanol to tertiary alcohols increases the
formal oxidation number of the carbinol carbon by +1 each step. So formally this is an
oxidation, although this structural change is seldom viewed in this way. Instead, this
series gives the potential for oxidation: carbon has a maximum oxidation number of +4,
so the difference between this and the value of the oxidation number in the compound
under scrutiny tells us something about its potential for oxidation. Methanol can be oxi-
dized all the way to carbon dioxide, primary alcohols to carboxylic acids, and secondary
alcohols to ketones. Each of these oxidations leads to a change of +2 in the oxidation
number of carbon. Tertiary alcohols resist oxidation.
Oxidizable and Reducible Groups in Organic Compounds

Carbon-based oxidizable groups in organic chemistry fall into two major classes: σ bonds
to hydrogen and C—C π bonds. Oxidation of these groups is achieved by (1) replacement
of two σ bonds to hydrogen by a π bond (Example 18.1), (2) replacement of a σ bond to
hydrogen by a σ bond to an electronegative element (Example 18.2), and (3) replacement
of a carbon-carbon π bond by two σ bonds (or π bonds) to electronegative elements
(Examples 18.3 and 18.4). Examples of the more common oxidation reactions in organic
chemistry are presented in Table 18.2.
H H R H X
R X X R G R G
R R R R
(18.1) (18.2)
X X R R R R
R R X X
R R R R R R
(18.3) (18.4)
Reducible groups in organic chemistry fall into two major classes: π bonds and σ
bonds to an electronegative atom. Reduction of these is achieved by (1) replacement of a π
bond by two σ bonds to hydrogen (Example 18.5), (2) replacement of a σ bond to an elec-
tronegative element a σ bond to hydrogen or an electropositive element (Example 18.6),
and (3) replacement of σ (or π) bonds to a pair of electronegative elements by a new C—C
π bond (Examples 18.7 and 18.8). Examples of the more common types of reduction reac-
tions in organic chemistry are presented in Table 18.3.
R H H X H
X X R G R G R
R R R R
(18.5) (18.6)
X X R R R R
R R X X
R R R R R R
(18.7) (18.8)
Problems
18-1 Using molecular formulas, verify that each of the examples in Tables 18.2 and 18.3
are actually oxidations and reductions.

Table 18.2 Some Common Oxidation Reactions
Reaction Type Example
OH O
Alcohol oxidation PCC, CH2Cl2
(18.9)
O O
SeO2, ∆ (18.10)
Dehydrogenation
Pd-C, ∆
(18.11)
HO OH
Oxidative cleavage HIO4 CHO
of glycols CHO (18.12)
O O
1) LDA, THF, –78°C (18.13)
α-Selenylation
2) PhSeSePh SePh
OH
Hydroxylation OsO4, NMMO (18.14)
OH
CCl4
m-CPBA (18.15)
Epoxidation
CH2Cl2 O
1) O3, CH2Cl2, –78°C CHO

Ozonolysis CHO (18.16)
2) Me2S
Table 18.3 Some Common Reduction Reactions
Reaction Type Example
H
Catalytic H2, PtO2 (18.17)
hydrogenation EtOH
H
Metal NaBH4, EtOH

O OH (18.18)
hydride reduction
CO2H
Reductive Mg, Et2O (18.19)
elimination O
Br O
Dissolving metal Na, NH3, EtOH

(18.20)
(Birch) reduction
Deoxygenation N2H4, KOH (18.21)

HOCH2CHH2OH, ∆
CO2H CO2H
Reductive OTs LiAlD4, Et2O, ∆ D

(18.22)
substitution

18-2 Write balanced oxidation or reduction half-equations for each of the following reac-
tions. You may use H+ or H2O to provide hydrogen or oxygen atoms as needed.
(a) MnO4− → MnO2 (f) R 2C=CR 2 → R 2C(OH)—C(OH)R 2
(b) Cr2O72− → Cr3+ (g) R 2C=CR 2 → R 2CHCHR 2
(c) RCH2OH → RCHO (h) BrCH2CH2OR → CH2=CH2 + Br−
(d) RCONH2 → RCH2NH2 (i) RCOR' → RCO2R'
(e) R 2C=CR 2 → 2 R 2C=O (j) ClCrO3− → Cr3+
18-3 Indicate the formal oxidation number of each carbon atom indicated in each of
the following compounds.
*
NC * O *
* N
(a) * (b) *N (c) * N *N *
* * * O *
*
O *
OH O
S O
O
(d) * (e) * * (f) * * O* N
O * * *
*
18-4 Classify each of the following reactions as oxidation, reduction, or neither. It may
be necessary to consider atoms within the reacting species individually to obtain
a satisfactory answer.
Zn HO H O O
(a) O
HOAc
(b) HO
O
H CHO
I
K2CO3, I2 MeLi, THF H
(c) (d) N
O HN Ar
CO2H S N2
O O O
S Ar
O
O
18.2 Overview of Oxidation1
There are a number of types of oxidations that it is important to be able to carry out selec-
tively in organic chemistry. These are shown schematically in Figure 18.1. In the diagram,
there are five different classes of oxidations shown.
1. Books on oxidation reactions: (a) Wiberg, K.B. Oxidation in Organic Chemistry. Part A (Academic
Press: New York, 1965). (b) Trahanovsky, W.S. Oxidation in Organic Chemistry. Part B (Academic Press: New
York, 1973); Part C (Academic Press: New York, 1978); Part D (Academic Press: New York, 1982). (c) Hudlicky,
M. Oxidations in Organic Chemistry (American Chemical Society: Washington, D.C., 1990). (d) Haines, A.H.
Methods for the Oxidation of Organic Compounds, Vol. 1 (Academic Press: New York, 1985); Vol. 2 (Academic
Press: New York, 1988). (e) Chinn, L.J. Selection of Oxidants in Organic Synthesis (Marcel Dekker: NewYork,
1971). (f) Augustine, R.L.; Trecker, D.J. Oxidation, Vol. 1 (Marcel Dekker: New York, 1969); Vol. 2 (Marcel
Dekker: New York, 1971). (g) Mijs, W.J.; de Jonge, C.R.J.I. Organic Synthesis, by Oxidation with Metal Com-
pounds (Plenum: NewYork, 1986). (h) Cainelli, G.; Cardillo, G. Chromium Oxidations in Organic Chemistry
(Springer Verlag: New York, 1984). (i) Arndt, D. Manganese Compounds as Oxidizing Agents in Organic
Chemistry (Open Court Publishing Company: La Salle, IL, 1981). (j) Lee, D.G. The Oxidation of Organic

Figure 18.1 Major classes of

R OH R R
oxidation reactions in
OH O (18.23)
organic chemistry R R
R CHO R CO2H
O
R R
R R
(18.24)
HO OH R R
R R O + O
R R R R
O O O
R R R R R R
X H (18.25)
H X
O O
R (18.26)
R R X R
OR O R CO2H
(18.27)
O
The first class of oxidation reactions (18.23) is the oxidation of alcohols to aldehydes,
ketones, and carboxylic acids, as well as the oxidation of aldehydes to carboxylic acids.
These reactions are oxidations that lead to the incorporation of a new π bond into the
molecule without the cleavage of any groups other than bonds to hydrogen. The second
class of oxidation reactions (18.24) is the oxidation of alkenes that lead to the cleavage of
carbon-carbon π bonds and/or carbon-carbon σ bonds. The third class of oxidation reac-
tions (18.25) includes oxidations of carbon-hydrogen bonds adjacent to carbon-carbon or
carbon-oxygen π bonds. These types of reactions always lead to products with a new func-
tional group. The fourth class of oxidation reactions (18.26) includes reactions in which a
heteroatom is inserted into a carbon-carbon σ bond. The final class of oxidations (18.27)
involves the oxidation of aromatic compounds, either in the ring, or in the side chain.
18.3 Oxidation of Alcohols to Aldehydes and Ketones

with Stoichiometric Metal-Based Reagents2
The oxidation of alcohols is perhaps one of the most studied of organic reactions due to the
importance of the oxidation products in organic synthesis. Depending on the reagent
chosen, primary alcohols may be oxidized either to aldehydes or to carboxylic acids, and
secondary alcohols are oxidized to ketones. Tertiary alcohols are generally resistant to
oxidation (indeed, tert-butyl alcohol is often chosen as a solvent for oxidations).
The oxidation of secondary alcohols to ketones is generally fairly easy to accomplish,
because the further oxidation of the ketone usually requires a powerful oxidizing agent
Compounds by Permanganate Ion and Hexavalent Chromium (Open Court Publishing Company: La Salle,
IL, 1980).
2. Monograph: Tojo, G.; Fernández, M. Oxidation of Alcohols to Aldehydes and Ketones (Springer: New
York, 2006).

under rather forcing conditions. The same cannot be said, however, for the oxidation of
primary alcohols, especially if one is attempting to stop the oxidation at the level of the
aldehyde. Oxidation of primary alcohols to carboxylic acids is generally easier than oxida-
tion to the aldehyde level. For these reasons, much of the effort behind the development of
selective oxidation of alcohols has been driven by the need for oxidizing agents and reac-
tions that will halt at the aldehyde stage.
Most reagents that can be used to oxidize a primary alcohol to an aldehyde or carboxylic
acid can be used to oxidize a secondary alcohol to a ketone. For this reason, the discussion
that follows will be focused on methods for the selective oxidation of primary alcohols to
aldehydes.
Metal-Based Reagents
Chromium (VI) Reagents
Aldehydes can be prepared by the oxidation of primary alcohols with compounds of a
high-valent metal such as chromium (VI) or manganese (VII). The mechanism currently
accepted for the chromium (VI) oxidation of alcohols was first proposed by American
chemist Frank Westheimer in 1949.3 It is given in Figure 18.2. In the first step of the mech-
anism, the alcohol reacts rapidly and reversibly with the chromium (VI) compound to
form an intermediate chromate ester. This ester is unstable and undergoes an E2-type
elimination reaction to give the carbonyl compound and a chromium (IV) by-product (A).
The identity of the base in the elimination step is not known, but there is a large hydrogen
isotope effect for the reaction,4 indicating that the C—H bond is broken in the rate deter-
mining step. The elimination may also occur by an Ei mechanism, where the anionic
oxygen attached to chromium functions as the base.
The Cr (IV) is an active oxidant that is believed to react directly with the alcohol in a
free radical reaction (B) to give the alkyl radical and a Cr (III) species. Evidence for the
direct oxidation of the alcohol by Cr (IV) was obtained by observing the polymerization
of acrylamide and concomitant reduction in the yield of acetone in the oxidation of
R O Figure 18.2 The Westheimer

R R O mechanism for oxidation of
R fast R O + Cr
H Cr R O O OH alcohols by chromium (VI)
A H O H O OH
O H [Cr(IV)]
Cr B
[Cr(VI)] O O B
O O
Cr [Cr(VI)]
O O
R R R
R + Cr
B H H O O
H O R O R O
O H [Cr(V)]
[Cr(IV)] Cr(III)
Cr
O OH
R OH
R R O
R R OH + Cr
H Cr R O O OH
C H O H O OH
OH H [Cr(III)]
Cr B
O O B
[Cr(V)
3. (a) Westheimer, F.H. Chem. Rev. 1949, 45, 419. (b) Watanabe, W.; Westheimer, F.H. J. Chem. Phys. 1949, 17,
61. (c) Holloway, F.; Cohen, M.; Westheimer, F.H. J. Am. Chem. Soc. 1951, 73, 65. (d) Cohen, M.; Westheimer,
F.H. J. Am. Chem. Soc. 1952, 74, 4387.
4. Westheimer, F.H.; Nicolaides, N. J. Am. Chem. Soc. 1949, 71, 25.

isopropyl alcohol by Cr (IV).5 The organic radical then reacts with another Cr (VI) spe-
cies to give the carbonyl compound and a Cr (V) species, which is believed to react with
another molecule of the alcohol by a mechanism like that in the first step (C) to give the
carbonyl compound and a Cr (III) species. Interestingly, the reaction between Cr (IV)
and Cr (VI) to give Cr (V) appears to be much slower than the oxidation of the alcohol
by Cr (IV).
Chromium (VI) compounds are among the most widely used oxidants for oxidizing
alcohols (e.g., Examples 18.28 to 18.30), and an idea of the variety of chromium (VI) re-
agents now available may be gauged from the entries in Table 18.4, which summarize some
of the more commonly used Cr (VI) reagents.
OH OMe CHO OMe
CrO3•2py
(18.28)
O CH2Cl2 O
OMe 90% OMe
Collins oxidation6
OH
MeO MeO CHO
OH PCC OH (18.29)
CH2Cl2, 25°C
H 80% H
Pyridinium chlorochromate 7
CN CN
PDC
CHO (18.30)
OH CH2Cl2, 12 h
67%
Pyridinium dichromate8
In the absence of water, chromium (VI) compounds can be used to oxidize primary
alcohols to aldehydes. Oxidation of primary alcohols by aqueous chromic acid almost
always results in oxidation to the carboxylic acid, presumably through the aldehyde hy-
drate. To suppress this further oxidation of the aldehyde, reagents such as the Sarett and
Collins (Example 18.28) reagents and the various pyridinium chlorochromate and di-
chromate salts (all of which are used under anhydrous conditions so that hydrate forma-
tion is prevented) were developed.
The two most widely used Cr (VI) oxidizing agents today are pyridinium chlorochro-
mate (PCC) and pyridinium dichromate (PDC), both of which were developed for the
oxidation of primary alcohols under mild conditions. Of the two reagents, PCC is the
more acidic oxidant, so PDC is often used for more sensitive applications. The acidic char-
acter of pyridinium chlorochromate is revealed in reactions where a cation might be
formed during the reaction. A good example of this is provided by the oxidation of
5. (a) Rahman, M.; Roček, J. J. Am. Chem. Soc. 1971, 93, 5455. (b) Rahman, M.; Roček, J. J. Am. Chem. Soc.
1971, 93, 5462.
6. Grieco, P.A.; Lis, R.; Zelle, R.E.; Finn, J. J. Am. Chem. Soc. 1986, 108, 5908.
7. (a) Kato, M.; Heima, K.; Matsumura, Y.; Yoshikoshi, A. J. Am. Chem. Soc. 1981, 103, 2434. (b) Kato, M.;
Matsumura, Y.; Heima, K.; Fukamiya, N.; Kabuto, C.; Yoshikoshi, A. Tetrahedron 1987, 43, 717.
8. (a) Kato, M.; Heima, K.; Matsumura, Y.; Yoshikoshi, A. J. Am. Chem. Soc. 1981, 103, 2434. (b) Kato, M.;
Matsumura, Y.; Heima, K.; Fukamiya, N.; Kabuto, C.; Yoshikoshi, A. Tetrahedron 1987, 43, 717.

(S)-(−)-citronellol to (S)-(−)-isopulegone by PCC.18 In Table 18.4 Oxidizing Agents Based on Chromium (VI)
the course of the reaction, the aldehyde formed initially Acronym
(Example 18.32) undergoes acid-catalyzed cyclization Compound or Reaction
(probably an ene reaction, as shown below) to give the Reagent Name Name Ref.
cyclized alcohol (Example 18.33) that then undergoes a
K 2Cr2O7, H2SO4, H2O Chromic acid —
second oxidation to give the ketone (Example 18.34) as
the final product. K 2Cr2O7, H2SO4, H2O, Et 2O Chromic acid Brown 9
oxidation
CrO3, H2SO4, H2O, acetone Chromic acid Jones 10
PCC oxidation
CH2Cl2
OH O CrO3, pyridine [C5H5N, py] C
hromic Sarett 11
H anhydride oxidation
CrO3•2py Chromic Collins 12
(18.31) (18.32) anhydride oxidation
pyHCrO3Cl Pyridinium PCC 13
chlorochromate
pyHCrO3F Pyridinium PFC 14
fluorochromate
PCC
(pyH)2Cr2O7 Pyridinium PDC 15
CH2Cl2 dichromate
O OH
(C5H4N)2HCrO3Cl Bipyridyl BPCC 16
[bpyHCrO3Cl] chlorochromate
(18.34) (18.33)
Me3SiOCrO2Cl Trimethylsilyl TMSCC 17
Pyridinium dichromate, on the other hand, is a much chlorochromate
less acidic (and, therefore, less aggressive) reagent. For
example, it also oxidizes citronellol, but unlike the oxidation with pyridinium chlo-
rochromate, the oxidation stops at the aldehyde stage without the subsequent acid-
catalyzed cyclization reaction.19 It can be used to oxidize primary alcohols to aldehydes
in the presence of acid-sensitive functional groups such as enol ethers (e.g., Example
18.35).20 Pyridinium dichromate also shows enhanced selectivity for oxidation of allylic
alcohols compared to saturated alcohols, as illustrated by the oxidation of the glycal in
Example 18.36. Here the secondary allylic hydroxyl group is oxidized in preference to
secondary hydroxyl group, again without affecting the acid-sensitive enol ether.21
9. Brown, H.C.; Garg, C.P.; Liu, K.-T. J. Org. Chem. 1971, 36, 387.
10. (a) Bowden, K.; Heilbron, I.M.; Jones, E.R.H.; Weedon, B.C.L. J. Chem. Soc. 1946, 39. (b) Meinwald, J.;
Cranfall, J.; Hymans, W.E. Org. Synth. 1965, 45, 77.
11. Poos, G.I.; Arth, G.E.; Beyler, R.E.; Sarett, L.H. J. Am. Chem. Soc. 1953, 75, 422.
12. (a) Collins, J.C.; Hess, W.W.; Frank, F.J. Tetrahedron Lett. 1968, 3363. (b) Ratcliffe, R.; Rodehorst, R.
J. Org. Chem. 1970, 35, 4000. (c) Collins, J.C.; Hess, W.W. Org. Synth. 1972, 52, 5. (d) Ratcliffe, R. Org. Synth.
1975, 55, 84.
13. (a) Corey, E.J.; Suggs, J.W. Tetrahedron Lett. 1975, 2647. (b) Piancatelli, G.; Scettri, A.; D’Auria, M. Synthe-
sis 1982, 245. (c) Brown, H.C.; Rao, C.G.; Kulkarni, S.U. J. Org. Chem. 1979, 44, 2809.
14. (a) Bhattacharjee, M.N.; Chaudhuri, M.K.; Dasgupta, H.S.; Roy, N.; Khathing, D.T. Synthesis, 1982, 588.
(b) Lewis, D.E.; Rigby, H.L. Tetrahedron Lett. 1985, 26, 3437.
15. (a) Coates, W.M.; Corrigan, J.R. Chem. Ind. 1969, 1594. (b) Corey, E.J.; Schmidt, G. Tetrahedron Lett.
1979, 399.
16. Guziec, F.S., Jr.; Luzzio, F.A. Synthesis 1980, 691.
17. Aizpurua, M.; Palomo, C. Tetrahedron Lett. 1983, 24, 4637.
18. Corey, E.J.; Ensley, H.E.; Suggs, J.W. J. Org. Chem. 1976, 41, 380.
19. Corey, E.J.; Schmidt, G. Tetrahedron Lett. 1979, 399.
20. Corey, E.J.; Schmidt, G. Tetrahedron Lett. 1979, 399
21. Czernecki, S.; Vijayakumaran, K.; Ville, G. J. Org. Chem. 1986, 51, 5472.

O O
PDC (18.35)
CH2Cl2 CHO
OH
O O
PDC, EtOAc
(18.36)
cat. AcOH, 12 h
HO HO
(84%)
OH O
Manganese-Based Reagents
Two manganese-based reagents are commonly used for the oxidation of alcohols: potas-
sium permanganate, which contains Mn(VII), and manganese dioxide, which contains
Mn(IV). More recently, barium manganate, BaMnO4, which contains Mn(VI), has been
used as an alternative to manganese dioxide.
Potassium permanganate is one of the most powerful of the common oxidizing agents,
and oxidations with this reagent are often difficult to control. The oxidation of alcohols by
potassium permanganate occurs reasonably readily, although it is known that other func-
tional groups, such as alkene π bonds and aldehydes, are actually oxidized more rapidly
then the alcohol. That potassium permanganate can oxidize alkene π bonds faster than a
primary hydroxyl group is illustrated by the oxidation of methyl cinnamate in 90% etha-
nol (Example 18.37), where the final product is isolated in 67% yield, despite the potential
for competition for the oxidizing agent from the solvent.22 Aldehydes are usually oxidized
much more rapidly by permanganate than alcohols, so potassium permanganate oxidizes
primary alcohols to carboxylic acids (Example 18.38). 23
CO2Me 1) KMnO4, EtOH CO2H

H2O, –40°C HO (18.37)
2) KOH, EtOH, H2O OH
Ph 67% Ph
KMnO4, Na2CO3
H2O, 4-5°C
OH (18.38)
76% CO2H
Bonds at allylic positions and α to a carbonyl group tend to be unusually reactive, and
this extends to allylic C—H bonds. Allyl alcohols can often be oxidized under very mild
conditions. Activated manganese dioxide, for example, selectively oxidizes allyl and
benzyl alcohols to the conjugated aldehydes and ketones (e.g., Examples 18.39 to 18.41).
Because this reagent does not rapidly oxidize saturated alcohols, it can be used to oxidize
allyl or benzyl hydroxyl groups in the presence of saturated primary and secondary
hydroxyl groups.24 However, this reagent is not always straightforward to use for two
22. Riiber, C.N. Ber. dtsch. chem. Ges. 1915, 48, 823.
23. It has been reported that this can be reversed by using potassium permanganate and copper (II) sulfate
pentahydrate on alumina in the absence of a solvent [Shaabani, A.; Lee, D.G. Tetrahedron Lett. 2001, 42, 5833].
The alumina has the effect of reversing the normal order of ease of oxidation, making the alcohol more easily
oxidized. The reaction in the absence of alumina leads to a mixture of aldehyde and carboxylic acid.
KMnO4, CuSO4•5H2O
OH Al2O3, no solvent CHO

(85%)
24. (a) Fatiadi, A. Synthesis 1976, 65. (b) Fatiadi, A. Synthesis 1976, 133.

reasons: (1) its activity depends on its precise mode of preparation and drying25 and
(2) large excesses of the reagent are sometimes needed.
OH OH
MnO2, CHCl3 26
(18.39)
16 h
HO 64% O
MnO2
R1 OH pentane R1 CHO
27
(18.40)
25°C
R2 R2
R1=H, R2=Et:
83%
R1=Et, R2=H: 64%
OH O
MnO2 28
(18.41)
57%
A reagent with similar selectivity is barium manganate,29 an insoluble compound

formed by the reduction of permanganate ion with iodide ion in the presence of barium
chloride. This reagent selectively oxidizes allyl and benzyl hydroxyl groups (e.g., Example
18.42) but is more reproducibly made and used than manganese dioxide. Allylic 1,4-diols
can be oxidized to lactones (e.g., Example 18.43) by large amounts of the reagent.30
O
BaMnO4 (1.5 eq) OH

(18.42)
HO CH2Cl2
OH 92% H
O
O
H BaMnO4 (10 eq) (18.43)
CH2Cl2
94% H
Other Transition Metal-Based Oxidants

Tetrapropylammonium perruthenate31 (TPAP, Pr4N+RuO4−, Ley’s reagent]) rapidly and
selectively oxidizes primary alcohols to aldehydes, as illustrated by Example 18.44.32 It can
25. (a) Attenburrow, J.; Cameron, A.F.B.; Chapman, J.H.; Evans, R.M.; Hems, B.A.; Jansen, A.B.A.; Walker,
T. J. Chem. Soc. 1952, 1094. (b) Goldman, I.M. J. Org. Chem. 1969, 34, 1979.
26. Johnson, W.S.; Vredenburgh, W.A.; Pike, J.E. J. Am. Chem. Soc. 1960, 82, 3409.
27. Chan, K.C.; Jewel, R.A.; Nutting, W.H.; Rapoport, H. J. Org. Chem. 1968, 33, 3382.
28. Boeckmann, R.K., Jr.; Enholm, E.J.; Demko, D.M.; Charette, A.B. J. Org. Chem. 1986, 51, 4743
29. Firouzabadi, H.; Ghaderi, E. Tetrahedron Lett. 1978, 839.
30. (a) Garigipati, R.S.; Freyer, A.J.; Whittle, R.R.; Weinreb, S.M. J. Am. Chem. Soc. 1984, 106, 7861. (b) Hol-
linshead, D.M.; Howell, S.C.; Ley, S.V.; Mahon, M.; Ratcliffe, N.M.; Worthington, P.A. J. Chem. Soc., Perkin
Trans. 1 1983, 1579.
31. (a) Griffith, W.P.; Ley, S.V.; Whitcombe, G.P.; White, A.D. J. Chem. Soc., Chem. Commun. 1987, 1625. (b) Ley, S.V.;
Norman, J.; Griffith, W.P.; Marsden, S.P. Synthesis 1994, 639. (c) Markó, I.E.; Giles, P.R.; Tsukazaki, M.; Chellé-Regnaut,
I.; Urch, C.J.; Brown, S.M. J. Am. Chem. Soc. 1997, 119, 12661. (d) Hinzen, B.; Lenz, R.; Ley, S.V. Synthesis 1998, 977.
32. Yang, Z.; Attygale, A.B.; Meinwald, J. Synthesis 2000, 1936.

be used catalytically with a co-oxidant such as N-methylmorpholine N-oxide (NMMO) so

that the amount of the relatively expensive ruthenium reagent needed is minimized. TPAP
oxidation frequently gives higher yields of product than the popular Swern oxidation,33
which we will discuss in the next section.
OH TPAP, NMMO
(18.44)
CH2Cl2 CHO
Ph Ph
In a series of papers beginning in 1968, Fétizon introduced silver carbonate on celite
(the Fétizon reagent) as a mild oxidizing agent for alcohols and lactols.34 The reagent is
expensive but is particularly useful for small-scale oxidations due to the ease of workup
(simple filtration of the reagent suffices to give a solution of the product that can be evap-
orated). The final step in Grieco’s synthesis of quassin (Example 18.45)35 illustrates the use
of this reagent in sensitive systems.
OMe OMe
O O
O O
Ag2CO3, celite
MeO MeO (18.45)
C6H6, ∆
H H H H
77%
O OH O O
H H H H
Vanadium (V) compounds have long been used in industry as oxidation catalysts.
(Their use in the epoxidation of alkenes will be discussed at length in the next chapter.)
Recently, however, catalytic methods that use vanadium (V) catalysts and molecular
oxygen as the stoichiometric oxidant have been developed for the oxidation of alcohols.
Vanadium pentoxide in refluxing toluene with potassium carbonate as a buffer exhibits a
preference for the oxidation of secondary alcohols or benzylic alcohols, as was shown by a
competition between cyclohexanol and 1-heptanol (Example 18.46).36
OH O
(87%)
V2O5 (3 mol %)
K2CO3 (0.5 eq.)
OH OH (18.46
O2 (1 atm),PhMe
100°C, 16 h
Oxidation of Tertiary Allylic Alcohols to Ketones:

Transposition of the Carbonyl Group
The oxidation of saturated tertiary alcohols by chromic acid requires forcing conditions
and is preceded by dehydration, so that the alkene is the compound actually oxidized.
β,γ-Unsaturated tertiary alcohols carrying a hydrogen at the γ carbon, however, are
33. Griffith, W.P.; Ley, S.V. Aldrichimica Acta 1990, 23, 13.
34. (a) Fétizon, M.; Golfier, M. Compt. rend. (C) 1968, 267, 900. (b) Fétizon, M.; Golfier, M.; Louis, J.-M. Chem.
Commun. 1969, 1102. (c) Fétizon, M.; Golfier, M.; Louis, J.-M. Chem. Commun. 1969, 1118. (d) Kakis, F.J.; Fétizon,
M.; Douchkine, N.D.; Golfier, M.; Mourgues, P.; Prange, T. J. Org. Chem. 1974, 39, 523. (e) Fétizon, M.; Moreau,
N. Compt. rend. (C) 1972, 275, 621. (f) Bastard, J.; Fétizon, M.; Gramain, J.C. Tetrahedron 1973, 29, 2867.
35. Grieco, P.A.; Ferriño, S.; Vidari, G. J. Am. Chem. Soc. 1980, 102, 7586.
36. Velusamy, S.; Punniyamurthy, T. Org. Lett., 2004, 6, 217.

smoothly oxidized by less acidic chromium (VI) reagents (which do not catalyze the dehy-
dration of the alcohol) on prolonged exposure (e.g., Examples 18.47 and 18.48).37
PCC (2eq) O
OH (18.47)
CH2Cl2
94%
OH
O
CrO3•2py
(18.48)
CH2Cl2
H H
These oxidations occur with allylic rearrangement: during the reaction, the oxygen
atom in chromate ester 18.50 becomes bonded to the other end of the allylic system to give
the molecule in Example 18.51, which then completes the oxidation to give the rearranged
ketone 18.52. The reaction is occasionally known as the Babler oxidation. The rearrange-
ment step probably occurs at the chromate ester stage of the reaction; its mechanism has
not yet been unambiguously determined, but it most likely involves the carbocation
formed by heterolysis of the carbon-oxygen bond. It may also be a [3,3] sigmatropic rear-
rangement of the chromate ester.
R2 R1
R1 R2
R 1
R2
R3
H R1 R2
R3 H O O R3
HO O R3
O Cr OH HO Cr O
(18.49) O O (18.52)
(18.50 (18.51)
Worked Problem
18-1 What is the major organic product obtained from the oxidation of the alcohol
below with each of the reagents that follow? Where appropriate, give your reasons.
HO HO HO
(g) (h) (i)
O CO2H O OH O CHO
(a) PCC, CH2Cl2, 25°C, 30 min

(b) MnO2, pentane, 25°C
(c) BaMnO4, CH2Cl2
(d) TPAP, NMMO, CH2Cl2, 25°C
(e) PCC, CH2Cl2, 25°C, 24 h
(f) Ag2CO3, celite, PhH, ∆
(g) CrO3, H2SO4, H2O, acetone
(h) MnO2, NaCN, MeOH
(i) PDC (1 eq), CH2Cl2, 30 min
37. (a) Babler, J.H.; Coghlan, M.J. Synth. Commun. 1976, 6, 469. (b) Dauben, W.G.; Michno, D.M. J. Org.
Chem. 1977, 42, 682. (c) Sundaraman, P.; Herz, W. J. Org. Chem. 1977, 42, 813.

Problem
18-5 What is the major organic product of each of the following reactions? Where the
quantity of reagent is not specified, assume that it is present in excess.
OH BaMnO4, CH2Cl2
(a) HO
OH O
OH MnO2, CHCl3 Br Br BaMnO4
(b) microwave heating
(c) CH2Cl2-THF
O CHO
OH
OH
Me3Si PCC, CH2Cl2

(d) SiMe3
OH
MeO O
H
N Me PCC O
MeO PCC
(e) H CH2Cl2
(f) CH2Cl2
OCOPh
OH
OH
O
H Me
HO
H O TPAP, NMO HO TPAP, NMO
(g) MOMO HO
CH2Cl2
(h) OH
CH2Cl2
H TBDPSO
OTIPS
References for problems: (a) Tetrahedron Lett. 1989, 30, 1173. (b) Tetrahedron Lett. 2009, 50, 6823.
(c) Can. J. Chem. 2007, 85, 352. (d) J. Org. Chem. 2003, 68, 1339. (e) J. Org. Chem. 1982, 47, 1302.
(f) J. Org. Chem. 2010, 75, 8337. (g) J. Am. Chem. Soc. 2008, 130, 2783. (h) Org. Lett. 2008, 10, 1247.

HO HO HO
(a) (b) (c)
O CHO O OH O OH
O
HO HO
(d) (e) (f)
O CHO O CHO O OH
HO HO HO
(g) (h) (i)
O CO2H O OH O CHO
Reasons: (a) Short reaction times mean that the PCC will oxidize the primary alcohol to the aldehyde and
the secondary alcohol to the ketone, but no further transformation will occur. (b) and (c) Only the secondary
allylic alcohol will oxidize. (d) TPAP will oxidize the primary alcohol to the aldehyde and the secondary alco-
hol to the ketone. (e) In this reaction, the PCC will oxidize the primary and secondary alcohol groups to the
aldehyde and ketone, respectively, but the prolonged reaction time will also permit the Babler oxidation of the
tertiary allylic alcohol. (f) and (h) The reagent is selective for oxidation of allylic alcohols. (g) Jones reagent is
aqueous and acidic; it will lead to the carboxylic acid from the primary alcohol and will oxidize the secondary
alcohol to the ketone. (i) PDC is a less aggressive reagent than PCC, so it will oxidize the primary and secondary
alcohols, but not the tertiary allylic alcohol.

18.4 Oxidations of Alcohols Using Non-Metal-Based Reagents
Although they are convenient to use, metal-based oxidants are sometimes much too powerful
to use in the synthesis of sensitive molecules. Not only can they oxidize alcohols to aldehydes
and ketones, but they can also oxidize sulfur-based functional groups (e.g., thioacetals and
thioketals), and they can cause oxidative cleavage of carbon-carbon bonds when there are two
oxidizable functional groups sufficiently close to each other (as in vicinal diols, for example,
which are cleaved by Cr (VI) reagents). As an alternative to high-valent metal oxidants, sev-
eral oxidation methods based on non-metal oxides (particularly oxides of sulfur, iodine and
nitrogen) as the oxidizing agent have been developed. More recently, catalytic methods with
molecular oxygen as the terminal oxidant have come under fairly intense study.38
Oxidations Based on Sulfoxides39

The earliest of the oxidation methods based on non-metal oxides is the oxidation of
alcohols with dimethyl sulfoxide, for which a variety of reagents are now available
(Table 18.5).
Each of these reactions follows the same basic protocol:
a solution of the alcohol in dimethyl sulfoxide is first Table 18.5 Oxidizing Agents Based on Dimethyl Sulfoxide
treated with a dehydrating agent, and then with a base.
The active oxidizing agent in all these oxidations is a triva- Reagent Name of Reaction
lent sulfonium ion carrying a sulfur-heteroatom bond (or Ac2O, Me2SO, 25°C
a sulfur-carbon bond in a sulfonium amidine). This ion is
C6H11N=C=NC6H11, CF3CO2H, C6H6,
formed by the attack of the dimethyl sulfoxide on the de-
Me2SO, py, 25°C
hydrating agent. This sulfonium ion reacts with the alco-
hol by an addition-elimination mechanism or in what may C6H11N=C=NC6H11, H3PO4, Me2SO, 25°C Moffatt (or Moffatt-
be direct SN2 displacement at sulfur to give a sulfoxonium Pfitzner)40
ion derived from the alcohol (e.g., Example 18.53). E2 py•SO3, Et3N, Me2SO, 25°C Parikh-Doering41
elimination of dimethyl sulfide as the leaving group by the
(COCl)2, Et 3N, Me2SO, CH2Cl2, −78°C Swern42
base gives the carbonyl compound.43
Me2SO + (COCl)2 → Me2S+−Cl + CO + CO2 + Cl−
Me2SO + RN=C=NR + H+ → Me2S+−[C(NHR)=NR]
Me2SO + Ac2O → Me2S+−OAc + OAc−
Me2SO + SO3 → Me2S+−OSO3−
38. (a) Lee, A.F.; Gee, J.J.; Theyers, H.J. Green Chem. 2000, 2, 279. (b) Mattal, T.; Baiker, A. Chem. Rev. 2004,
104, 3037. (c) Gangwal, V.R.; van der Schaaf, J.; Kuster, B.F.M.; Schouten, J.C. J. Catalysis 2005, 232, 432.
39. Reviews: (a) Mancuso, A.J.; Swern, D. Synthesis 1981, 165. (b) Tidwell, T.T. Org. React. 1990, 39, 297.
(c) Tidwell, T.T. Synthesis 1990, 857. (d) Moffatt, J.G. In Augustine, R.L.; Trecker, D.J., Eds. Oxidation (Marcel
Dekker: New York, 1971), p. 1.
40. (a) Pfitzner, K.E.; Moffatt, J.G. J. Am. Chem. Soc. 1965, 87, 5661. (b) Albright, J.D.; Goldman, L. J. Am.
Chem. Soc. 1967, 89, 2416.
41. Parikh, J.R.; Doering, W.v.E. J. Am. Chem. Soc. 1963, 89, 5505.
42. (a) Mancuso, A.J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43, 2480. (b) Omura, K.; Swern, D. Tetra-
hedron, 1978, 34, 1651.
Daniel A. Swern (1916–1982) was educated at the City College of New York, Columbia University, and the
University of Maryland. In 1937, he joined the East Regional Research Center of the US Department of Agri-
culture in Philadelphia, serving as a research chemist here until 1963, when he was appointed to the faculty of
Temple University. Swern was an eminent lipid chemist, and published more than 280 books and articles;
among other awards, he received the 1968 AOCS Award in Lipid Chemistry.
43. This mechanistic pathway was first proposed by: Albright, J.D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2146.

Me Me
Me X
S R S Me S Me
R O R
R Me
H O (18.53)
R OH
R
H
N H
R R N
R R R
R
The Swern oxidation is by far the most widely used of these reactions. It is admirably
suited to the synthesis of aldehydes containing both sensitive functionality and labile
stereochemistry, as is illustrated by Examples 18.54 and 18.55 of Swern oxidations used
in Evans’ total synthesis of rutamycin B.44 In this synthesis, the retention of labile stereo-
centers adjacent to aldehyde carbonyl groups was essential, and the Swern oxidation was
the reaction of choice for forming the required aldehydes. Ireland45 has used the Swern
oxidation as a method for the manipulation of highly reactive carbonyl compounds by
trapping the crude product of the Swern oxidation in situ with nucleophiles (Examples
18.56 and 18.57).
Ph Ph
Me2SO, (COCl)2
(18.54)
Et3N, CH2Cl2, –60°C
CHO
OH 96%
TBSO OPMB TBSO OPMB

Me2SO, (COCl)2 (18.55)
Et3N, CH2Cl2, –60°C CHO
OH
93%
I I
H Me2SO H H
O O O O O O
(COCl)2
O O MeMgBr O (18.56)
Et3N, THF Et2O OH
O H OH O H O O H
–35°C –78°C
85% (2 steps)
O Ph O Ph O Ph
Me2SO
(COCl)2 Ph3P=CHCO2Me
OH (18.57)
O Et3N, CH2Cl2 O CHO 99% (2 steps) O CO2Me
O –35°C O O
E:Z, 95:5
The involvement of the chlorodimethylsulfonium ion in the Swern oxidation led a

number of workers to experiment with other sulfonium ions carrying a leaving group at
sulfur. The most widely used of these new methods for oxidation is the Corey-Kim oxida-
tion,46 in which a mixture of dimethyl sulfide and N-chlorosuccinimide, which generates
the actual oxidant, N-(dimethylsulfonium)succinimide. This reaction is an excellent method
for the selective oxidation of primary alcohols to aldehydes, but the need to use dimethyl
sulfide has inhibited its widespread use. More recently, efforts have been focused on replac-
ing dimethyl sulfide with more benign, less volatile sulfides (e.g., decyl methyl sulfide, as in
Example 18.58).47 A fluorous analog of the reaction has also been developed.48
44. Evans, D.A.; Ng, H.P.; Rieger, D.L. J. Am. Chem. Soc. 1993, 115, 11446.
45. Ireland, R.E.; Norbeck, D.W. J. Org. Chem. 1985, 50, 2198.
46. (a) Corey, E.J.; Kim, C.U. J. Am. Chem. Soc. 1972, 94, 7586. (b) Corey, E.J.; Kim, C.U. Tetrahedron Lett.
1974, 15, 287. (c) Katayama, S.; Fukuda, K.; Watanabe, T.; Yamauchi, M. Synthesis 1988, 178. (d) Review: Tidwell,
T.T. Synthesis 1990, 857. (e) Pulkkinen, J.T.; Vepsäläinen, J.J. J. Org. Chem. 1996, 61, 8604.
47. (a) Ohsugia, S.-I.; Nishidea, K.; Oonob, K.; Okuyamab, K.; Fudesakaa, M.; Kodamaa, S.; Node, M. Tetra-
hedron 2003, 59, 8393. (b) Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865.
48. Crich, D.; Neelamkavil, S. Tetrahedron 2002, 58, 3865.

OH O
1) C10H21SMe, NCS
CH2Cl2, –40°C, 2 h
(18.58)
2) Et3N, CH2Cl2
–40°C, 14 h
O (91%) O
The Parikh-Doering oxidation can be carried out at room temperature, which makes
it especially convenient. This has led to a resurgence of its popularity in recent years, as
illustrated by Examples 18.5949 and 18.60.50
O O SO3•py, Me2SO O O
HO (18.59)
O O EtNPri2, CH2Cl2 O O
O r.t. O O
MeO Ph MeO Ph
N N
SO3•py (4 eq)
H Me2SO-CH2Cl2 (1:2) H (18.60)
H 23°C, 1 h. H
S S
(70%)
CHO
S HO S HO
OH
Oxidations with the Dess-Martin Periodinane51,52

Among the more useful reagents for the oxidation of alcohols under mild conditions are
the Dess-Martin periodinane (Example 18.61; DMP),53 a hypervalent iodine species readily
prepared from o-iodobenzoic acid,54 and the related o-iodoxybenzoic acid (Example 18.62;
IBX). Of the two, DMP is easier to use because of its greater solubility in organic solvents.
AcO OAc O
I OAc I OH
O O
O O
DMP IBX
(18.61) (18.62)
Treatment of an alcohol with DMP in dichloromethane gives the carbonyl compound

(Example 18.64) via an oxygen-linked periodinane (Example 18.63). The reaction rate is
markedly accelerated by the presence of small amounts of water (e.g., Example 18.66).55
The reaction is particularly suited to the oxidation of compounds bearing a wide range of
49. Veitch, G.E.; Beckmann, E.; Burke, B.J.; Boyer, A.; Maslen, S.L.; Ley, S.V. Angew. Chem. Int. Ed. 2007, 46, 7629.
50. Nicolaou, K.C.; Peng, X.-S.; Sun, Y.-P.; Polet, D.; Zou, B.; Lim, C.S.; Chen, D.Y.-K. J. Am. Chem. Soc. 2009,
131, 10587.
51. (a) Dess, D.B.; Martin, J.C. J. Am. Chem. Soc. 1991, 113, 7277. (b) Boeckmann, R.K., Jr.; Shao, P.; Mullins,
K. Org. Synth. 2000, 77 141.
52. Reviews: (a) Stang, P.J.; Zhdankin, V.V. Chem. Rev. 1996, 96, 1123. (b) Kitamura, T.; Fujiwara, Y. Org. Prep.
Proc. Int. 1997, 29, 409.
53. (a) Dess, D.B.; Martin, J.C. J. Org. Chem. 1983, 48, 4155.
54. The Dess-Martin periodinane has been reported to be shock-sensitive under some conditions, and to explode
above 200°C under confined conditions: Plumb, J.B.; Harper, D.J. Chem. Eng. News 1990 68 (No. 28, July 16), p. 3.
For an improved synthesis of this reagent, see: (c) Ireland, R.E.; Liu, L.J. J. Org. Chem. 1993, 58, 2899.
(d) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64, 4537.
James Cullen Martin (1928–1999) was educated at Vanderbilt University (MS, 1952) and Harvard Univer-
sity (PhD, 1956). He served on the faculty at Illinois (1956–1985) and Vanderbilt (1985–1992). For more detail,
see: Akiba, K.-Y. Phosphorus, Sulfur, Silicon Relat. Elem. 2006, 181, 1201.
55. Meyer, S.D.; Schreiber, S. J. Org. Chem. 1994, 59, 7549.

sensitive functionalities, as illustrated by Examples 18.67 and 18.68.56 Ionic liquids have
also been shown to be excellent solvents for both DMP and IBX oxidations of a wide vari-
ety of alcohols.57
R
R (18.64)
R R R
O O R OAc
OAc H AcO
AcO H
OAc HO I O I
I O
O O O
Me
O HOAc O HOAc O
(18.61) (18.63) (18.65)
Ph DMP (1.5 eq) Ph

(18.66)
CH2Cl2
OH O
no H2O: 14 h
1.1 eq H2O: 0.5 h
(97%)
OH
OHC O O
O O DMP (1.2 eq)
CH2Cl2
O (18.67)
O O
O 12 h, 58%
O
O
N3 N3
AcO AcO
Me O N3 OH Me O N3 O
DMP
N O N O
Ac CH2Cl2 Ac (18.68)
O HO O O HO O
Me (82%) Me
HO HO
N3 N3
Oxidation by Hydride Transfer to an Acceptor π Bond

Aluminum-Based Reagents
Aluminum alkoxides react with carbonyl compounds to give products involving hy-
drogen transfer from carbon, with the concomitant generation of carbonyl com-
pounds. The first observation of this type of reactivity in aluminum compounds was
by Russian chemist V. E. Tishchenko.58 He published a series of eight papers (four in
Russian, four in German) in 1906, where he described the conversion of aromatic al-
dehydes (Example 18.69) to benzyl benzoates (Example 18.71) catalyzed by aluminum
ethoxide.59 The reaction is now known as the Tishchenko reaction. It is formally a
disproportionation of the aldehyde with the first molecule of aldehyde transferring a
hydrogen atom to the second and probably involves a hemiacetal derivative of the type
shown as Example 18.70.
56. Hanessian, S.; Szychowski, J.; Pablo, J. Org. lett. 2009, 11, 429.
57. Yadav, J.S.; Reddy, B.V.S.; Basak, A.K.; Venkat Narsaiah, A. Tetrahedron 2004, 60, 2131, and refer-
ences therein.
58. Vyacheslav Yevgenievich Tishchenko (1861–1941) graduated from St. Petersburg in 1883 and was ap-
pointed lecturer at the university in 1891. Much of his research was in applied organic chemistry. For more
detail, see: Lewis, D.E. Early Russian Organic Chemists and Their Legacy (Springer: Heidelberg, 2012), p. 114.
59. (a) Tishchenko, V.E. Zh. Russ. Fiz.-Khim. Obshch. 1906, 38, 355, 482, 540, 547. (b) Tishchenko, V. Chem.
Zentr. 1906, II, 1309, 1552, 1555,1556.

Ar O H H
Al(OR)3
O
Ar O Ar
H
(18.69) (18.71)
H H
Ar
(RO)3Al Ar Ar
O Ar
O O O
(RO)3Al
H H
(18.70)
In 1937, Rupert Viktor Oppenauer published a method for the oxidation of alcohols
60
by heating their aluminum salts with acetone.61 The Oppenauer oxidation occurs by means
of hydride transfer from the aluminum alkoxide (Example 18.72) to the carbonyl com-
pound through a cyclic, six-membered transition state (Example 18.73). The reaction is
reversible, and the position of the equilibrium is determined by the reduction potentials of
the two carbonyl compounds.62 Carbonyl acceptors (i.e., the oxidizing participant in the
reaction) are most effective if the groups bonded to the carbonyl carbon are electron-
withdrawing. The reaction tolerates a wide range of functional groups. In oxidations of
homoallylic alcohols such as cholesterol, the migration of the alkene double bond into the
position of conjugation is usually observed.63 This isomerization is likely catalyzed by the
alkoxide anion bases present in the reaction mixture.
Me Me
O Me ‡
H Me H R1
R1
H 1) Al(OBut)3 R1 R1 O O
R1 2) Me2CO, ∆ R1 R1
O Al(OR')2 O Al R1
OH
(18.72) OR'
R'O
(18.73)
In 2002, Maruoka reported a modified aluminum catalyst (Example 18.74) for the reac-
tion.64 In 2006, Nguyen and his coworkers reported that using trimethylaluminum as the
source of the aluminum alkoxide and nitrated benzaldehydes as the hydride acceptor65 gives
generally high (> 95%) yields when two to three equivalents of the hydride acceptor are used
in toluene at room temperature. The same authors also noted that the reaction displays a
significant preference for the oxidation of a secondary alcohol over a primary alcohol. Like-
wise, 1,1,1-trifluoroacetone has been reported as a superior hydride acceptor.66
O
O
S C8F17
N (18.74)
Al Me
O
60. Rupert Viktor Oppenauer (1910–1969) was educated in Zürich at the ETH under two Nobel laureates:
Leopold Ružička (Chemistry, 1939), and Tadeus Reichstein (Physiology or Medicine, 1950). Oppenauer entered
industry, where he spent his entire career. Beginning in the late 1930’s Oppenauer’s work appears primarily in
the patent literature, with assignments to Ciba and Roche Pharmaceutical companies, with Oppenauer’s ad-
dress listed as Amsterdam. His final patent, which issued after his death, was a German patent assigned to
Merck. During the last five years of his life, he moved from Innsbruck to Buenos Aires.
61. Oppenauer, R.V. Rec. Trav. Chim. Pays-Bas 1937, 56, 137.
62. (a) Graves, C.R.; Campbell, E.J.; Nguyen, S.T. Tetrahedron:Asymmetry 2005, 16, 3460. (b) de Graauw,
C.F.; Peters, J.A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1007.
63. Eastham, J.F.; Teranishi, R. Org. Syn., Coll. Vol. 4, 1963, 192; Org. Syn. 1955, 39, 39.
64. Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002, 4, 2669.
65. Graves, C.R.; Zheng, B.-S.; Nguyen, S.T. J. Am. Chem. Soc. 2006, 128, 12596.
66. Mello, R.; Martinez-Ferrer, J.; Asensio, G.; González-Núñez, M.E. J. Org. Chem. 2007, 72, 9376.

Ruthenium-Catalyzed Reactions
Ruthenium has become an important element in a wide range of catalytic reactions
in organic chemistry.67 Among other applications of this element in synthesis,
low-valent ruthenium complexes (especially Shvo’s catalyst;68 Example 18.75) react
with alcohols by oxidative addition of the O—H bond, followed by β-elimination of
hydrogen to give carbonyl compounds. Although the oxidation of secondary alcohols
to ketones is without complication, the ruthenium-catalyzed formation of aldehydes
is usually followed by Tishchenko-type disproportionation of the aldehydes to esters
(e.g., Example 18.76).69 A variety of hydrogen acceptor molecules have been used in
this reaction, including acetone, benzylideneacetone, and diphenylacetylene (used in
Example 18.77).
Ph O H O Ph
Ph Ph
Ph Ph (18.75)
Ph OC Ru H Ru CO Ph
OC CO
O O
O (Ph3P)2RuH2 O
(18.76)
Me2CO, PhMe, 180°C
OH (95%) O O
OH
C7H15 O C7H15
Ru3(CO)12
HO Ph Ph, 145°C C7H15 O (18.77)
(97%)
As pointed out above, the Oppenauer oxidation of homoallylic alcohols such as choles-
terol is often accompanied by migration of the double bond into conjugation. This also
occurs using the ruthenium-catalyzed hydrogen transfer reaction, as illustrated by the
oxidation of the steroid in Example 18.78.70 In this case, the potassium carbonate used is
basic enough to catalyze the isomerization of the double bond.
OAc OAc
O O
OH OH
18.74
(18.78)
Me2CO, K2CO3, ∆
(67%)
HO O
Oxidations Catalyzed by Stable Nitroxyl Free Radicals

Relatively recently, N-oxonitronium ions, prepared in situ by oxidation of nitroxyl radi-
cals with a secondary oxidant, have found application in the oxidation of alcohols (e.g.,
Examples 18.79 and 18.80).71 In these reactions, the nitroxyl radical is an organocatalyst.
67. Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. Rev. 1998, 98, 2599.
68. Shvo, Y.; Czarkie, D.; Rahamim, Y. J. Am. Chem. Soc. 1986, 108, 7400.
69. (a) Blum, Y.; Reshef, D.; Shvo, Y. Tetrahedron Lett. 1981, 22, 1541. (b) Blum, Y.; Shvo, Y. J. Organomet.
Chem. 1984, 263, 93. (c) Blum, Y.; Shvo, Y. Isr. J. Chem. 1984, 24, 144. (d) Menashe, N.; Shvo, Y. Organometallics
1991, 10, 3885.
70. Almeida, M.L.S.; Kočovský, P.; Bäckvall, J.-E. J. Org. Chem. 1996, 61, 6587.
71. Review: Vogler, T.; Studer, A. Synthesis 2008, 13, 1979.

Me Me Me
N
OH O OH O
(H2C)8 (H2C)8 + (H2C)8 (18.79)
OH NaOCl (1.1 eq)
CH2Cl2/H2O CHO CHO
68% 10%
OH OH OH OH
OHC
TEMPO, CuCl2, O2 O
O O O (18.80)
DMF
(>69%)
O O O
One useful feature of this oxidation is that it permits the oxidation of a primary hydroxyl
group in preference to a secondary hydroxyl group,72 as illustrated by the oxidation of the
unprotected glycoside derivatives shown in Example 18.81.73 The identity of the co-oxidant
is not critical, with molecular oxygen serving as the oxidant when 2,2,6,6-tetramethylpiperi
dinyloxy (TEMPO) is used in dimethylformamide (DMF) solution with a catalytic amount
of copper (I) chloride.74 Because of its ease of use and the high yields that it can give, oxida-
tion with TEMPO as an organocatalyst using inexpensive terminal oxidants such as sodium
hypochlorite, trichloroisocyanuric acid, or oxygen is becoming an important industrial
method for the selective oxidation of alcohols.75 In these applications, the more expen-
sive TEMPO can often be replaced by the much less expensive 4-hydroxy-TEMPO and
4-acetamido-TEMPO. The TEMPO-catalyzed oxidation of 1,2-diols to give α-diketones
(e.g., Example 18.82)76 provides a mild method for the synthesis of these important pre-
cursors to medicinally important heterocycles. Fluorinated TEMPO derivatives with
multiple triazole ring systems have recently been proposed as improved catalysts with
catalytic sodium bromide and using sodium hypochlorite as the stoichiometric oxidant
(e.g., Example 18.83),77 conditions first used by Agnelli.72 In the same paper, the use of a
mixed manganese (II)-cobalt (II) catalyst with the same fluorinated TEMPO and molec-
ular oxygen as the oxidant has been found to be efficient for the oxidation of primary
alcohols to aldehydes, using conditions developed by Minisci (e.g., Example 18.84).78
H
HO TEMPO (2.5 mol %) O
HO O O
HO
HO O Cl HO
X OMe N X OMe
Cl N O (0.8 eq) (18.81)
N
O Cl X = α-OH (79%)
X = β-OH (84%)
NaHCO3 (30. eq.) X = α-NHAc (66%)
DMF, 0°C, 4-9 h
OH TEMPO (8 mol %) O
(18.82)
PhICl2 (3 eq.)
OH pyridine (6 eq) O
CHCl3, 50°C, 5 h (98%)
72. (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52, 2559. (b) Anelli, P.L.; Banfi, S.;
Montanari, F.; Quici, S. J. Org. Chem. 1989, 54, 2970.
73. Angelion, M.; Hermansson, M.; Dong, H.; Ramström, O. Eur. J. Org. Chem. 2006, 4323.
74. (a) Semmelhack, M.F.; Schmid, C.R.; Cortes, D.A.; Chou, C.S. J. Am. Chem. Soc. 1984, 106, 3374. (b) Li,
C.; Bardhan, S.; Pace, E.A.; Liang, M.-C.; Gilmore, T.D.; Porco, J.A., Jr. Org. Lett. 2002, 4, 3267.
75. Review: Ciriminna, R.; Pagliaro, M. Org. Proc. Res. Dev. 2010, 14, 245.
76. Zhao, X.-F.; Zhang, C. Synthesis 2007, 551.
77. Gheorghe, A.; Chinnusamy, T.; Cuevas-Yañez, E.; Hilgers, P.; Reiser, O. Org. Lett., 2008, 10, 4171.
78. (a) Cecchetto, A.; Fontana, F.; Minisci, F.; Recupero, F. Tetrahedron Lett. 2001, 42, 6651. (b) Minisci, F.;
Recupero, F.; Rodino, M.; Sala, M.; Schneider, A. Org. Proc. Res. Dev. 2003, 7, 794.

OH
CHO
catalyst, KBr (0.2 eq)
NaOCl (1.1 eq), NaHCO3 (18.83)
OH CHO
catalyst, O2
Mn(NO3)2•4H2O (2 mol %)
(18.84)
Co(NO3)2•6H2O (2 mol %)
AcOH
Me Me
(92-98%)
Oxidations with Molecular Oxygen

The direct oxidation of alcohols using oxygen as the terminal oxidant has received consid-
erable impetus from the movement toward “green” chemistry. The process of oxidizing
alcohols with oxygen is not trivial, however, and much of the work in this area is focused
on the development of catalysts for the reaction.
The first reaction in which a palladium catalyst was used for the oxidation of alcohols by
molecular oxygen was the 1996 report by Kaneda that palladium cluster complexes such as
Pd4Phen2(CO)(OAc)4 catalyzed the dehydrogenation of allylic and benzylic alcohols with
molecular oxygen as the stoichiometric oxidant (Example 18.85).79 Nevertheless, the Kaneda
oxidation did not result in what may be termed a breakthrough in the use of molecular
oxygen for the oxidation of alcohols. That breakthrough came with the reports by Uemura’s
group that oxidation of alcohols by palladium (II) acetate was catalyzed by pyridine deriva-
tives (e.g., Example 18.86).80 This stimulated a rapid exploration of asymmetric oxidation
using molecular oxygen as the terminal oxidant and chiral amines as promoters. This reac-
tion will be covered in much more detail when we discuss asymmetric oxidation reactions.
OH
CHO
O2, Pd4(phen)2CO(OAc)4
(18.85)
C6H6, 50°C, 48 h
(92%)
E:Z 98:2 E:Z 98:2
Pd(OAc)2, py, O2 CHO

OH (18.86)
3Å mol. sieves
O O PhMe, 80°C O O
(87%)
Drill Exercises
What is the major organic product obtained from the oxidation of the alcohol
below with each of the following reagents? Where appropriate, give your reasons.
(1) PCC, CH2Cl2, 25°C, 30 min
(2) MnO2, pentane, 25°C
(3) CrO3, H2SO4, H2O, acetone, 25°C
(4) BaMnO4, CH2Cl2
79. Kaneda, K.; Fujii, M.; Morioka, K. J. Org. Chem. 1996, 61, 4502.
80. (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. Tetrahedron Lett. 1998, 39, 6017. (b) Nishimura, T.;
Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750.

(5) TPAP, NMMO, CH2Cl2, 25°C

(6) (COCl)2, Et3N, CH2Cl2, −78°C, 25°C
(7) TEMPO, CH2Cl2, NaOCl, H2O
(8) Me2S, NCS, Et3N, CH2Cl2, −25°C
Substrates:
OH
HO
HO OH
OH
(a) (b) (c)
OH
OH HO
OH
OH
(d) (e) (f)
OH
H
OH
Problem
18-6 Which reagent(s) from the list in the Drill Exercises above can be used to effect
the changes below, and which cannot? Give reasons.
MeO OMe OH
MeO OMe
O O O O CHO
(a) (b)
OH
O
HO O
O O CHO H H
OH
(c) (d) H H
H CO2Et H CO2Et
O O OEt OEt
OEt OEt
HO H O H
H H
(e) (f)
OH OH
OH CHO O O
MeO2C MeO2C
OH OH O O
OCH
HO
Reaction Synopses
Oxidation of Alcohols to Aldehydes and Ketones
R [O] R
OH O
R R
Reagents:
Cr (VI): PCC, CH2Cl2; PDC, CH2Cl2; CrO3•2py, CH2Cl2; etc.
Mn (VI): BaMnO4, CH2Cl2
Mn (IV): MnO2, C6H6, ∆ (allylic and benzylic alcohols only)
Mn (VII): KMnO4, CuSO4•5H2O, Al2O3, r.t. (solvent-free)
(continues)

Ru (VII): TPAP, NMMO, CH2Cl2, r.t.

Ag (I): Ag2CO3, celite, C6H6, ∆
Al (III): Al(O-i-Pr)3, Me2CO, ∆ (Oppenauer);
Ru (II), R 2CO: (Ph3P)2RuH2, PhMe, Me2CO, 180°C; Shvo’s catalyst, K 2CO3,
Me2CO, ∆; etc.
Me2SX+: (COCl)2, Me2SO, CH2Cl2, Et3N, −60°C (Swern); DCC, Me2SO,
CH2Cl2 (Pfitzner-Moffatt); Me2S, NCS, Et3N, CH2Cl2, −25°C
(Corey-Kim); etc.
Dess-Martin: DMP, CH2Cl2(, H2O); selective for 2° ROH over 1°
TEMPO: TEMPO, CH2Cl2, NaOCl, H2O; TEMPO, CuCl, O2, DMF; etc.
O2: O2, Pd(OAc)2, pyridine, PhMe, 80°C
Oxidation of Primary Alcohols to Esters
O
R CHO R R
O
Reagents:
(R=aryl): Al(OR 3) (Tishchenko);
(R=akyl): Ru3(CO)12, PhC≡CPh, ∆; Shvo’s catalyst,
PhCH=CHCOMe, ∆; etc.
18.5 Oxidations to Carboxylic Acids
The reactivity of chromium and manganese agents can be significantly modified by the
solvent used. Thus, although pyridinium dichromate in non-polar solvents oxidizes pri-
mary alcohols to aldehydes, in DMF solution it can be used to oxidize a primary alcohol
to a carboxylic acid (Example 18.87).81 Similarly, although potassium permanganate often
reacts only sluggishly with primary alcohols, when solubilized in benzene as a quaternary
ammonium salt82 or by means of a crown ether83 (“purple benzene”), it is an excellent re-
agent for oxidizing primary alcohols to carboxylic acids. However, the reagent also rapidly
cleaves alkene π bonds (Example 18.88)84 and oxidizes aldehydes.
OH
CO2H
PDC, DMF
(18.87)
EtO2C 76% EtO2C
Ph Ph
KMnO4, (C8H17)3NMe Cl
(18.88)
C6H6, 40-45°C, 1 h
CO2H
(92%)
81. Gruefeld, N.; Stanton, J.L.; Yuan, A.M.; Ebetino, F.H.; Browne, L.J.; Gude, C.; Huebner, C.F. J. Med. Chem.
1983, 26, 1277.
82. Herriot, A.W.; Picker, D. Tetrahedron Lett. 1974, 1511.
83. Sam, D.J.; Simmons, H.E. J. Am. Chem. Soc. 1972, 94, 4024.
84. Starks, C.M. J. Am. Chem. Soc. 1971, 93, 195.

Of the many chromium (VI) reagents, the Jones reagent (e.g., Example 18.89) is the least
selective. On occasion, however, its very reactivity and lack of selectivity allows multiple
steps to be accomplished in one pot. For example, the strongly acidic conditions of the Jones
oxidation permit the simultaneous deprotection of silyl ethers and oxidation of the revealed
alcohols.85 In the oxidation in Example 18.90,86 the Jones reagent oxidized both silyl ethers
directly to the corresponding carboxylic acids. Interestingly, the adsorption of Jones reagent
on silica gel allows it to be used to oxidize primary benzyl alcohols to aldehydes.87
CO2Et CO2Et
N N
N K2Cr2O7, H2SO4 N
CO2H (18.89)88
NH Me2CO-H2O NH
OH (62%)
O Jones reagent (5 eq.) O

N N (18.90)
O 0°C, 20 min. CO2H
OTBDMS O
HO2C
OTBDMS
The oxidation of primary alcohols and aldehydes to carboxylic acids can also be ac-
complished using chromium (VI) reagents (CrO3 and PCC have both been used) as cata-
lysts and periodic acid as the stoichiometric oxidant (Example 18.91).89 In these reactions,
the Cr (VI) reagent is responsible for the oxidation, with the periodic acid functioning to
recycle the Cr (VI) catalyst.
OH H5IO6 (2.2 eq) CO2H
PCC (2 mol %)
(18.91)
MeCN, r.t., 3 h
(95%)
There is a reagent for oxidizing alcohols to carboxylic acids that is a stronger oxidizing
agent than any reagent we have discussed to this point: ruthenium tetroxide.90 This ex-
tremely powerful oxidant also attacks carbon-carbon π bonds (including aromatic rings,
as we shall discuss later). In addition, it attacks ethers and amines, but esters and amides
tend to be resistant (but not completely inert) to ruthenium tetroxide oxidation, and,
oddly enough, even epoxides are oxidized only slowly by this reagent in comparison to
alcohols (Example 18.92).91 It has been used for decades as a method for the oxidation of
carbohydrate derivatives, such as the glucose derivative in Example 18.93.92
85. (a) Evans, P.A.; Roseman, J.D.; Garber, L.T. Synth. Commun. 1996, 26, 4685. (b) Evans, P.A.; Murthy, V.S.;
Roseman, J.D.; Rheingold, A.L. Angew. Chem., Int. Ed. 1999, 38, 3175. (c) Liu, H.-J.; Han, I.-S. Synth. Commun.
1985, 15, 759.
86. Farwick, A.; Helmchen, G. Org. Lett. 2010, 12, 1108.
87. Ali, M.H.; Wiggins, C.J. Synth. Commun. 2001, 31, 1389, 3383.
88. Vrudhula, V.M.; Dasgupta, B.; Pin, S.S.; Burris, K.D.; Balanda, L.A.; Fung, L.K.; Fiedler, T.; Browman,
K.E.; Taber, M.T.; Zhang, J.; Macor, J.E.; Dubowchik, G.M. Bioorg. Med. Chem. Lett. 2010, 20, 1905.
89. (a) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D.M.; Grabowski, E.J.J.; Reider, P.J. Tetrahedron Lett.,
1998, 39, 5323. (b) Hunson, M. Synthesis 2005, 2487.
90. Review: Lee, D.G.; van den Engh, M. In Trahanovsky, W.S., Ed. Oxidation in Organic Chemistry, Part B
(Academic Press: New York, 1973), p. 177.
91. Carlsen, P.H.J.; Katsuki, T.; Martin, V.S.; Sharpless, K.B. J. Org. Chem. 1981, 46, 3936.
92. (a) Beynon, P.J.; Collins, P.M.; Overend, W.G. Proc. Chem. Soc. 1964, 342. (b) Parikh, V.M.; Jones, J.K.N.
Can. J. Chem. 1965, 43, 3452.

Ph OH RuCl3•H2O Ph CO2H
(18.92)
H H NaIO4, MeCN H H
O O
(75%)
O H O H
O RuO2 (cat.), NaIO4 O
O O O O (18.93)
H CCl4, H2O H
HO O (85-90%) O O
As with osmium tetroxide, ruthenium tetroxide is volatile and expensive, so consider-

able effort has gone into developing methods that are catalytic in ruthenium. These almost
always start with ruthenium trichloride or ruthenium dioxide. The reagent is black, which
allows the course of the reaction to be followed visually; when the yellow color of the ru-
thenium tetroxide persists, the reaction is complete. What is also interesting with the ru-
thenium reagent is that its reactivity can be quite muted under catalytic conditions; this
raises the possibility (as yet unaddressed) that the +8 oxidation state of ruthenium may
not be the active oxidant under these conditions.
In 1882, Bernard Tollens93 described a reaction between aldehydes and ammoniacal
silver (I) hydroxide that led to reduction of the metal, and oxidation of the aldehyde to the
corresponding carboxylic acid (e.g., Example 18.94).94 This became the basis of the Tollens
test for aldehydes. The reaction is very mild and almost specific for the aldehyde func-
tional group, but it suffers from low yields in many cases. In addition, the high cost of the
reagent, which is used stoichiometrically rather than catalytically, makes it prohibitively
expensive except on the small scale.
Ph Ph
CHO CO2H
S Ag2O, THF, H2O 95
S (18.94)
4 days
(45%)
Ph Ph
In 1973,96 Lindgren and Nilsson introduced sodium chlorite as a much more econom-
ical and predictable reagent for oxidizing aldehydes to carboxylic acids. The method was
adapted by Kraus and Taschner,97 who used 2-methyl-2-butene as a chlorine scavenger.
The Kraus procedure was thoroughly tested by Pinnick,95c and the reaction is now often
described as a Pinnick-type oxidation. This improvement in the chlorite oxidation of
aldehydes has now made the two-stage oxidation of primary alcohols to carboxylic acids
(as in Examples 18.95 to 18.97) the method of choice for carrying out this transforma-
tion. An alternative method for the oxidation of benzylic aldehydes to methyl esters in-
volves using vanadium pentoxide and hydrogen peroxide in methanol containing
perchloric acid.98 The oxidation of primary alcohols to acids by a composite catalyst of
vanadium pentoxide, copper (II) 2-ethylhexanoate, and 1,4-diazabicyclo[2.2.2]octane
93. Bernhard Christian Gottfried Tollens (1841–1918) studied under Wöhler and Fittig in Göttingen (PhD,
1864). He traveled to Heidelberg, Paris (1868), and Coimbra, Portugal (1869) before returning to Göttingen in
1870, where he was later appointed as Professor and Director of the agricultural chemistry laboratory. For more
detail, see: Wallach, O. Ber. dtsch. chem. Ges. 1918, 51, 1539.
94. Tollens, B. Ber. dtsch. chem. Ges. 1882, 15, 1635.
95. LaLonde, R.T.; Florence, R.A.; Horenstein, B.A.; Fritz, R.C.; Silveira, L.; Clardy, J.; Krishnan, B.S. J. Org.
Chem. 1985, 50, 85.
96. Lindgren, B.O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888.
97. (a) Kraus, G.A.; Taschner, M.J. J. Org. Chem. 1980, 45, 1175. (b) Kraus, G.A.; Roth, B. J. Org. Chem. 1980,
45, 4825. (c) Bal, B.S.; Childers, W.E., Jr.; Pinnick, H.W. Tetrahedron 1981, 37, 2091.
98. Gopinath, R.; Patel, B. Org. Lett. 2000, 2, 577.

(DABCO) in an ionic liquid, as well as using molecular oxygen as the stoichiometric re-
agent, has recently been reported.99
HO HO
O 1) PhI(OAc)2, cat. TEMPO O
O O
CH2Cl2
O (18.95)100
O
2) NaClO2, Me3COH-H2O
Me2C=CHMe
(77% over 2 steps) HO2C
OH
Boc Boc
H N H N
Boc Boc
N N
HO
1) Me2SO, SO3•py, Et3N HO2C
HN HN 101
2) NaClO2, Na2HPO4, Me3COH (18.96)
Me2C=CHMe, THF-H2O
BocHN BocHN
OH CO2H
OMEM OMEM
H H
CO2H
1) cat. TEMPO, PhI(OAc)2
O OH (70%) O
H H (18.97)102
2) NaClO2, Na2HPO4
Me2C=CHMe
OTBS (95%) OTBS
Manganese dioxide oxidation of primary allylic alcohols leads to the formation of

α,β-unsaturated aldehydes. The addition of a nucleophile to the aldehyde leads to a new
allylic alcohol that can be further oxidized by manganese dioxide. This has led to a number
of useful extensions to this oxidation, due in part to the relative lack of reactivity by man-
ganese dioxide toward a wide range of functional groups. The use of manganese dioxide in
tandem oxidation reactions has been reviewed.103
The first of these adaptations of the manganese dioxide oxidation of allylic alcohols is
provided by the oxidation of primary allyl alcohols to methyl esters by manganese dioxide
and sodium cyanide in methanol (Example 18.98).104 In this reaction, the primary alcohol
is first oxidized to the aldehyde, which then reacts with cyanide to give a cyanohydrin,
which is further oxidized to the acyl cyanide. This compound, which is a less reactive
analog of an acyl chloride or acid anhydride, then reacts with methanol to regenerate the
cyanide. A similar adaptation has been developed by replacing the toxic cyanide anion by
an N-heterocyclic carbene (NHC),105 which adds to the aldehyde to give a 2-(1-hydroxyal-
kyl)imidazolium ion that is oxidized to the 2-acylimidazolium ion, which can then react
with the alcohol to release the NHC, giving the ester (e.g., Example 18.99).
99. Jiang, N.; Ragauskas, A.J. J. Org. Chem. 2007, 72, 7030.
100. Katoh, N.; Nakahata, E.; Kuwahara, S. Tetrahedron 2008, 64, 9073.
101. Govek, S.P.; Overman, L.E. Tetrahedron 2007, 63, 8499.
102. Mueller Hendrix, A.J.; Jennings, M.P. Tetrahedron Lett. 2010, 51, 4260.
103. Taylor, R.J.K.; Reid, M.; Foot, J.; Raw, S.A. Acc. Chem. Res. 2005, 38, 851.
104. Corey, E.J.; Gilman, N.W.; Ganem, B.E. J. Am. Chem. Soc. 1968, 90, 5616.
105. (a) Maki, B.E.; Chan, A.; Phillips, E.M.; Scheidt, K.A. Org. Lett. 2007, 9, 371. (b) Maki, B.E.; Chan, A.;
Phillips, E.M.; Scheidt, K.A. Tetrahedron 2009, 65, 3102.

OH
CO2Me
MnO2, NaCN
(18.98)
HOAc, MeOH, 20-25°C
95%
Ar N N Ar Cl
Me DBU Me CO2Bu
OH
(18.99)
MnO2, BuOH
Ph Ph
(91%)
Worked Problem
18-2 What reagent or reagents could be used to carry out each of the oxidations specified?
(w)
(y)
(z) OH
OH
OH H
OH
(x)
(a) Oxidize hydroxyl group w to the aldehyde without any other oxidation.
(b) Oxidize the primary hydroxyl groups (w and y) to aldehydes and the second-
ary hydroxyl group (x) to a ketone.
(c) Oxidize the primary hydroxyl groups (w and y) to aldehydes without any
other oxidation.
(d) Oxidize the hydroxyl group w to a methyl ester group without affecting any
other functional group.
(e) Oxidize the primary hydroxyl groups (w and y) to aldehydes, the secondary
hydroxyl group (x) to a ketone, and the tertiary hydroxyl group to a ketone
with allylic rearrangement of the double bond.
(f) Oxidize the primary hydroxyl groups (w and y) to carboxylic acids and the
secondary hydroxyl group (x) to a ketone.
(g) Oxidize the secondary hydroxyl group (x) to a ketone without any other change.
(h) Oxidize the primary hydroxyl groups (w and y) to aldehydes and the second-
ary hydroxyl group (x) to a ketone, with rearrangement of the double bonds
into positions conjugated with the carbonyl groups.
§Answers below.

A: MnO2, CH2Cl 2; or BaMnO4, CH2Cl 2; or O2, Pd4Phen2(CO)(OAc)4, C6H6, 50°C; etc.
B: PCC, CH2Cl 2; or PDC, CH2Cl 2; or (COCl)2, Me2SO, Et 3N, CH2Cl 2, −60°C;
or R 2S, NCS, CH2Cl 2, NEt 3; or DMP, CH2Cl 2(, H2O); etc.
C: TEMPO, NaOCl, CH2Cl 2, H2O; or O2, TEMPO, CuCl, DMF; etc.
D: MnO2, NaCN, MeOH; or MnO2, NHC, MeOH; etc.
E: This is a Babler-type oxidation—PCC, CH2Cl 2, 24 h.
F: Jones’ reagent—CrO3, H2SO4, H2O, Me2CO; or 1) cat. TEMPO, PhI(OAc)2, CH2Cl 2; then NaClO2, NaH2PO4,
Me2C=CHMe, H2O; or cat. PCC, H5IO6, MeCN.
G: O2, V2O5 (3 mol %), K 2CO3 (0.5 eq), PhMe, 100°C.
H: Oppenauer oxidation—Al(OCMe3)3, Me2CO, ∆; or Me3Al, Me2CO, ∆.

Drill Exercises
What will be the major organic product formed when each of the compounds in
the list below is treated with each of the reagents specified?
H H
O OH
OH OH
(a) (b) (c)
O
H OH
OH OH
H H
O O
OH
(d) (e) (f)
OH
H
OH OH
Reagents:
A: MnO2, NHC, EtOH
B: PDC, DMF, r.t.
C: KMnO4, H2O
D: CrO3, H2SO4, H2O, acetone
E: (1) PhI(OAc)2, CH2Cl2, TEMPO; (2) NaClO2, NaHCO3, THF, H2O
F: (1) DMP, CH2Cl2; (2) Ag2O, NH3, H2O
Reaction Synopses
Oxidation of Alcohols to Carboxylic Acids
[O]
R CH2OH R CO2H
Reagents:
Cr (VI): K 2Cr2O7, H2SO4, H2O; K 2Cr2O7, H2SO4, acetone, H2O; CrO3,
H2SO4, H2O, acetone, 0°C (Jones reagent); PDC, DMF; PCC,
H5IO6MeCN; etc.
Mn (VII): KMnO4, H2O; KMnO4, H2O, Bu4NCl, C6H6; KMnO4,
18-C-6. PhH; etc
Ru (VIII): RuO4; RuCl3•H2O, NaIO4, MeCN; RuO2, NaIO4, CCl4, H2O; etc.
Oxidation of Aldehydes to Acids or Esters
[O]
R CHO R CO2H
Reagents: Ag(NH3)2OH, H2O; Ag2O, THF, H2O; etc.

or NaClO2, NaH2PO4, Me2C=CHMe, THF, H2O
or V2O5, H2O2, HClO4, MeOH; etc.
18.6 Oxidation of Ethers and Amines
The C—H σ bond α to the oxygen of an ether is amenable to oxidation under free radical
conditions (e.g., Example 18.100) because the radical formed is strongly stabilized by res-
onance, as we discussed in Chapter 13. In fact, this very susceptibility of primary or sec-
ondary alkyl ethers to free radical oxidation by atmospheric oxygen106 makes care in
106. Steere, N.V. In Patai, S., Ed. The Chemstry of the Ether Linkage (Interscience: London, 1967), ch. 16.

storing these solvents especially important, because the products of these atmospheric
oxidations are highly explosive and shock-sensitive peroxides that must be removed before
the ether can be used safely as a solvent.107
R R
O O O O O OH
OH O O O (18.100)
R R R R R R n
ether peroxide – shock-sensitive
The oxidation of ethers can be accomplished in a controlled manner, however, by
means of ruthenium tetroxide, which oxidizes simple ethers to esters and cyclic ethers to
lactones (e.g., Example 18.101).108 Under conditions of a two-phase reaction with water and
excess oxidant, γ-lactones may be further oxidized to γ-ketoacids.108d
RuO4, CCl4 (18.101)

O ( 100%) O O
Amination α to an ether by nitrene insertion has been used in the formation of highly
functionalized stereochemically complex amine derivatives (Example 18.102) that can be
elaborated to a wide range of target molecules.109
O H O
O H2N S O cat Rh2(O2CR)4 O N
S O (18.102)
O PhI(OAc)2, MgO O
O O
CH2Cl2
(92%)
There are two locations where oxidation of an amine can occur: at carbon or at ni-
trogen. The oxidation of amines at carbon ultimately leads to the conversion of the
amine to an amide or an imide, and the reaction is generally (but not exclusively) re-
stricted to methylene groups attached to nitrogen. Again, one reagent that is highly
effective for this oxidation is ruthenium tetroxide, which oxidizes open-chain amines
to amides and oxidizes cyclic amines to give cyclic imides (e.g., Example 18.103)110
or lactams.111
Me Me
NaIO4, RuO2•xH2O
CCl4, H2O (18.103)
N O N O
(70%)
Ph Ph
The oxidation of tertiary amines with mercuric acetate (e.g., Example 18.104)112 pro-
vides a convenient entry into both enamines and iminium ions. The oxidation has a ste-
reoelectronic requirement that makes the oxidation of amines where the β-hydrogen and
107. Vogel, A.I. Practical Organic Chemistry, 3rd. ed. (Longmans: London, 1956), p. 163.
108. (a) Berkowitz, L.M.; Rylander, P.N. J. Am. Chem. Soc. 1958, 80, 6682. (b) Wolff, M.E.; Kerwin, J.F.;
Owings, F.F.; Lewis, B.B.; Blank, B. J. Org. Chem. 1963, 28, 2729. (c) Gopal, H.; Adams, T.; Moriarty, R.M. Tet-
rahedron 1972, 28, 4259. (d) Smith, A.B., III; Scarborough, R.M., Jr. Synth. Commun. 1980, 10, 205.
109. Fleming, J.J.; Fiori, K.W.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 94305.
110. Bettoni, G.; Franchini, C.; Morlacchi, F.; Tangari, N.; Tortorella, V. J. Org. Chem. 1976, 41, 2780.
111. Lin, G.; Midha, K.K.; Hawes, E.M. J. Het. Chem. 1991, 28, 215.
112. (a) Leonard, N.J.; Hay, A.S.; Fulmer, R.W.; Gash, V.W. J. Am. Chem. Soc. 1955, 77, 439. (b) Leonard, N.J.;
Sauers, R.R. J. Am. Chem. Soc. 1957, 79, 6210. (c) Leonard, N.J.; Middleton, W.J.; Thomas, P.D.; Choughury, D.
J. Org. Chem. 1956, 21, 344.

the nitrogen lone pair can adopt an anti arrangement much more facile than the oxidation
of amines, where this cannot happen. For example, 11-methyl-11-azabicyclo[5.3.1]decane
(Example 18.105) cannot adopt this arrangement except at the methyl group, and the
oxidation occurs exclusively at the methyl group113.
Hg(OAc)2 NaOH, H2O N Me

(18.104)
N AcOH, H2O, ∆ N (68%) N
(59%) (18.105)
Tertiary amines react with peracids to form amine N-oxides. These compounds O
(e.g., N-methylmorpholine-N-oxide; NMO or NMMO) are often used as co-oxidants in
reactions such as hydroboration-oxidation, instead of hydrogen peroxide anion. In 1926,
N
the French chemists Max and Michel Polonovski reported that tertiary amine N-oxides Me O
reacted with acetic anhydride or acetyl chloride to give the acetamide of the secondary NMMO
amine; the reaction is now known as the Polonovski reaction.114 The reaction is consid-
ered to proceed through the mechanism shown in Figure 18.3. The procedure was modi-
fied by French chemist, Pierre Potier, who replaced the acetic anhydride by trifluoroacetic
anhydride, which a llowed the iminium ion intermediate to be isolated due to the lower
nucleophilicity of the carboxylate anion. This modification of the reaction is occasionally
referred to as the Polonovski-Potier reaction.115 Aqueous workup of the Polonovski-Potier
reaction gives the ketone as the product, as shown below; adding perchloric acid to the
reaction mixture permits the iminium perchlorate to be isolated. Figure 18.4 compares
the two variants of the reaction. The Polonovski reaction gives the acetamide (18.112) as
the major product, whereas the major product in the Polonovski-Potier reaction is the
ketone 18.113.
X Figure 18.3 The mechanism

X of the Polonovski reaction
R O R X O R R O
R R R R H R
R N O R N OH R N O
R R R
(18.106) (18.107) (18.108)
R
R H2O R
R
O R
H2O R
N R
H N R
R
N R R
R (18.110) (18.109)
113. Leonard, N.J.; Morrow, D.F. J. Am. Chem. Soc. 1958, 80, 371.
114. (a) Polonovski, M.; Polonovski, M. Bull. Soc. Chim. France 1926, 39, 147; 1927, 41, 1190. (b) Huisgen, R.;
Bayerlein, F.; Heydkamp, W. Chem. Ber. 1959, 92, 3223. (c) Oae, S.; Kitao, T.; Kitaoka, Y. J. Am. Chem. Soc. 1962,
84, 3366. (d) Metlesics, W.; Silverman, G.; Sternbach, L.H. J. Org. Chem. 1964, 29, 1621.
Reviews: (e) Katritzky, A.R.; Lagowski, J.N. Chemistry of Heterocyclic N-Oxides (Academic Press: New York,
1971) p 279, 362. (f) Grierson, D. Org. React. 1990, 39, 85. (g) Grierson, D.S.; Husson, H.-P. In Trost, B.M.;
Fleming, I., Eds. Comprehensive Organic Synthesis. (Pergamon: Oxford, 1991) vol 6, 909–924.
115. (a) Cave, A.; Kan-Fan, C.; Potier, P.; Le Men, J. Tetrahedron 1967, 23, 4681. (b) Tamminen, T.; Jokela, R.;
Tirkkonen, B.; Lounasmaa, M. Tetrahedron 1989, 45. 2683. (c) Sundberg, R.J.; Gadamasetti, K.G.; Hunt, P. J.
Tetrahedron 1992, 48, 277.

Figure 18.4 Comparison of O

O
the Polonovski and Potier- O H
O
Polonovski reactions H
Ac2O
+
H CHCl3
O ∆, 3h Me O
O N H
H H
Ac (18.112) (18.113)
(70%) (20%)
O
O O
N H
Me H
Me TFAA
+ (18.113)
(18.111) CH2Cl2 (60%)
Me
N
H H
(18.114)
(40%)
Reaction Synopses
Oxidation of Ethers and Amines to Esters and Amides
O O
R R R R
O R O R N R N R
H H
Reagents: RuO4; RuCl3•H2O, NaIO4, MeCN; RuO2, NaIO4, CCl4, H2O; etc.
or Hg(OAc)2, HOAc, H2O, ∆ (3° amines)
Polonovski Reaction
R O R R R R R
N R N O and/or O N
R R R R R R'CO R R
Reagents: Ac2O, CHCl3, ∆; AcCl, CHCl3; etc (Polonovski reaction);

(CF3CO)2O, CH2Cl2 (Polonovski-Potier); etc.
18.7 Oxidative Rearrangements116
The final type of oxidation in Figure 18.1 leads to the cleavage of a σ bond between a car-
bonyl carbon and the α carbon, and its replacement by two carbon-heteroatom σ bonds,
which is equivalent to the insertion of a heteroatom between two carbon atoms. The
process results in an increase in the number of bonds to electronegative atoms at each
end of the C—C σ bond and so corresponds formally to an oxidation. Many named reac-
tions fall within this overall category, and some of the more important ones are summa-
rized in Table 18.6.
Most of these reactions proceed through a variant of the mechanisms shown in
Figure 18.5. The most important feature of these mechanisms is that the rearrangement is
intramolecular, with synchronous migration and loss of the leaving group through tran-
sition states such as 18.115 for aldehydes and ketones and 18.116 for acid derivatives.
Because the migrating group never becomes completely detached from the rest of the
116. Review: Smith, P.A.S. In de Mayo, P, Ed. Molecular Rearrangements, Part 1 (Interscience Publishers: New
York, 1963), p. 457.

Table 18.6 Oxidative Rearrangements
Substrate Reagent Product Reaction Name
OH O
N Beckmann
H2SO4; H3PO3; etc. R1
N R2 rearrangement117
R1 R2 H
O O
HN3; etc. R1 Schmidt reaction118
R1 R2 N R2
H
O O
Baeyer-Villiger
RCO3H; etc. R1
R1 R2 O R2 oxidation119
O O Curtius
∆ or hν R1 C
R1 N3 N rearrangement120
O
OH
O Lossen
R1 N
H2SO4; TsCl; etc. R1 C
N rearrangement121
H
O O Hofmann
Br2, KOH R1 C
R1 NH2 N rearrangement122
molecule or ion, almost all these reactions occur with complete (or almost complete) re-
tention of configuration at the migrating center.123
117. (a) Beckmann, E. Ber. dtsch. chem. Ges. 1886, 19, 988. (b) Blatt, A.H. Chem. Rev. 1933, 12, 215. (c) Jones,
B. Chem. Rev. 1944, 35, 335. (d) Popp, F.D.; McEwen, W.E. Chem. Rev. 1958, 58, 370. (e) Heldt, W.Z.; Donaruma,
L.G., Org. React. 1960, 11, 1. (b) Gawley, R.E. Org. React. 1988, 35, 1. (c) McCarty, C.G. In Patai, S., Ed. Chemistry
of the Carbon-Nitrogen Double Bond (Wiley: New York, 1970), p. 408.
118. (a) Schmidt, K.F. Z. angew. Chem. 1923, 36, 511. (b) Schmidt, K.F. Chem. Ber. 1924, 57, 704. (c) Wolff, H.
Org. React. 1946, 3, 307. (d) Benson, F.R. Chem. Rev. 1947, 41, 48. (e) Popp, F.D.; McEwen, W.E. Chem. Rev.
1958, 58, 370.
119. (a) Baeyer, A.; Villiger, V. Ber Deut. chem. Ges. 1899, 32, 3625. (b) Baeyer, A.; Villiger, V. Ber Deut. chem.
Ges. 1900, 33, 858. (c) Hassall, C.H. Org. React. 1957, 9, 73. (d) Krow, G.R. Org. React. 1993, 43, 251. (e) Rentz, M.;
Meunier, B. Eur. J. Org. Chem. 1999, 737.
120. (a) Curtius, T. Ber. dtsch. chem. Ges. 1890, 23, 3023. (b) Curtius, T. J. Prakt. Chem. [2] 1894, 50, 275.
(b) Smith, P.A.S. Org. React. 1946, 3, 337. (c) Saunders, J.H.; Slocombe, R.J. Chem. Rev. 1948, 43, 205.
121. (a) Lossen, W. Ann. Chem. Pharm. 1872, 161, 347. (b) Lossen, W. Ann. Chem. Pharm. 1875, 175, 271, 343.
(c) Yale, H.l. Chem. Rev. 1943, 33, 209. (d) Popp, F.D.; McEwen, W.E. Chem. Rev. 1958, 58, 370.
122. (a) Hofmann, A.W. Ber. dtsch. chem. Ges. 1881, 14, 2725. (b) Hofmann, A.W. Ber. dtsch. chem. Ges. 1882,
15, 407, 762. (c) Hofmann, A.W. Ber. dtsch. chem. Ges. 1884, 17, 1406. (d) Hofmann, A.W. Ber. dtsch. chem. Ges.
1885, 18, 2734. (e) Hofmann, A.W. Ber. dtsch. chem. Ges. 1882, 15, 752. (f) Franklin, E.C. Chem. Rev. 1934, 14, 219.
(g) Wallis, E.S.; Lane, J.F. Org. React. 1946, 3, 267.
123. For stereochemical studies of these reactions, see:
Baeyer-Villiger reaction: (a) Turner, R.B. J. Am. Chem. Soc. 1950, 72, 879. (b) Gallagher, T.F.; Kristschevsky,
T.H. J. Am. Chem. Soc. 1950, 72, 882. (c) Mislow, K.; Brenner, J. J. Am. Chem. Soc. 1953, 75, 2319.
Beckmann rearrangement: (a) Kenyon, J.; Young, D.P. J. Chem. Soc. 1941, 263. (b) Campbell, A.; Kenyon, J.
J. Chem. Soc. 1946, 25. (c) For a contradictory result, see Hill, R.K.; Chortyk, O.T. J. Am. Chem. Soc.
1962, 84, 1064.
Curtius rearrangement: (a) Jones, L.W.; Wallis, E.S. J. Am. Chem. Soc. 1926, 48, 169. (b) Schrecker, A.W.
J. Org. Chem. 1957, 22, 33
Hofmann rearrangement: (a) Wallis, E.S.; Nagel, S.C. J. Am. Chem. Soc. 1931, 53, 2787. (b) Wallis, E.S.;
Moyer, W.W. J. Am. Chem. Soc. 1933, 55, 2598. (c) Kenyon, J.; Phillips, H.; Pittman, V.P. J. Chem. Soc. 1939, 1072.
(d) Arcus, C.L.; Kenyon, J. J. Chem. Soc. 1939, 916. (e) Archer, S. J. Am. Chem. Soc. 1940, 62, 1872.
Schmidt rearrangement: von Braun, J.; Friehmelt, E. Chem. Ber. 1933, 66, 684.
Lossen rearrangement: Wallis, E.S.; Dripps, R.D. J. Am. Chem. Soc. 1933, 55, 1701.

H
H H
O O O
O OH
R R R R R R
X H
H Y O R Z R Z
H X
X H Y
R R H
Y X O
X
Y Y
‡ H R X Y
H δ+ O H H
O O
R ‡
R R R O
X R X R X O
C δ
Y δ+ Y+
X R X
H R δ+ H
(18.115) (18.116)
Figure 18.5 General mechanisms of oxidative rearrangements
Insertion of Oxygen into a C—C σ Bond: The Baeyer-Villiger Oxidation

The Baeyer124-Villiger125 oxidation is the reaction between an aldehyde or ketone with a
peroxidic reagent to give an ester by the formal insertion of an oxygen atom into the σ
bond between the carbonyl carbon and the α carbon. The Baeyer-Villiger reaction has
been especially useful for the synthesis of lactones from cyclic ketones (e.g., the synthesis
of δ-lactones from cyclopentanones126).
The mechanism of the reaction, shown in Figure 18.6, involves two separate stages:
(1) the addition of the peroxidic nucleophile to the carbonyl group (18.117) and (2) the
rearrangement, with cleavage of the peroxide bond (18.118). Either of these stages may be
rate determining, although the rearrangement step is slower in most cases.127 It is import-
ant to note that there is a stereoelectronic requirement in the Baeyer-Villiger oxidation:
the alkyl group anti to the departing carboxylate is the one that migrates. As illustrated by
Figure 18.6 The mechanism O G

of the Baeyer-
Villiger oxidation O
HO O G O G
O R' O
O O H
R O
R' (18.117) H (18.118) R O
R O
R'
124. Johann Friedrich Wilhelm Adolf von Baeyer (1835–1917) studied under Bunsen and Kekulé (PhD,
Berlin, 1858). His academic career took him to Berlin, Strasbourg, and Munich. His work in organic chemistry
ranged from organic synthesis to physical organic chemistry. He was awarded the Nobel Prize in Chemistry in
1905. For more information, see: de Meijere, A. Angew. Chem. Int. Ed. 2005, 44, 7836, and the Nobel Founda-
tion web site.
125. Victor Villiger (1868–1934) obtained his PhD in 1893 under Baeyer. Until 1904 he was Baeyer’s personal
assistant, then 1904 he left to work for Badische Anilin- und Sodafabrik, now BASF, and ultimately became
a leader of the laboratories of the German chemical giant, I.G. Farben. For more detail, see: Hofmann, K.A. Ber.
dtsch. chem. Ges. 1934, 67, A111.
126. Sager, W.F.; Duckworth, A. J. Am. Chem. Soc. 1955, 77, 188.
127. Rearrangement rate determining: (a) Hawthorne, M. F.; Emmons, W. D. J. Am. Chem. Soc. 1958, 80,
6398. (b) Okuno, Y. Chem. Eur. J. 1997, 3, 212. Addition rate determining: Singleton, D. A.; Szymanski, M. J.
J. Am. Chem. Soc. 1999, 121, 9455.

the oxidation of optically active 2-exo-acetylnorbornane, the reaction occurs with reten-
tion of configuration (Example 18.119).128
O PhCO3H
(18.119)
OAc
CHCl3, 25°C
81%
As one might expect from the fact that addition to the carbonyl group is involved and
that addition to a carbonyl group is catalyzed by acids, the Baeyer-Villiger oxidation is fa-
cilitated by acids. By far the most common reagents for Baeyer-Villiger oxidation of ketones
are organic peracids, and the ability of these acids, R—CO2OH, to promote the reaction
decreases as the electron deficiency of the α-carbon (i.e., the acid strength) decreases:129
CF3 > c-CH=CHCO2H > o-C6H4CO2H > p-C6H4NO2 > H ≈

m-C6H4Cl > C6H5 > Me >> Bu
However, the move toward “green” chemistry and “green” oxidants has led to a resur-
gence of the examination of hydrogen peroxide as an oxidant for this reaction.130 The first
successes using hydrogen peroxide for the Baeyer-Villiger oxidation of cyclic ketones were
with strained cycloalkanones such as cyclobutanones.131 Arsonic acids have also been
found to catalyze the reaction with unstrained cycloalkanones,132 and certain platinum
complexes also catalyze the reaction.133 More recently, the use of fluorinated alcohols
with134 or without135 Brønsted acids in the Baeyer-Villiger reaction of cycloalkanones has
allowed the use of hydrogen peroxide as the terminal oxidant. The use of Oxone® in ionic
liquids as solvents136 has also proved to be a useful “green” modification of the reaction.
The use of heterogeneous catalysts in the Baeyer-Villiger reaction has been reviewed.137
When a ketone is unsymmetrical and has the conformational flexibility to obtain
more than one conformation suitable for rearrangement, the question of which group ac-
tually migrates becomes important. The migratory aptitudes, or propensity of alkyl
groups to migrate in the Baeyer-Villiger oxidation, is:138
3°R > cyclohexyl ≈ 2°R ≥ PhCH2 ≈ Ph ≈ vinyl > 1°R > cyclopropyl > Me
In general, the migratory aptitude of a saturated alkyl group, R parallels the ease with
which the corresponding alkyl bromide R-Br undergoes SN1 substitution reactions. Thus, the
methyl group almost never migrates when a methyl ketone is treated with a peracid, and sec-
ondary alkyl groups usually migrate in preference to primary alkyl groups. However, this gen-
eral rule of thumb applies only to saturated alkyl groups. In general, unsaturated groups (vinyl
groups and aryl groups) migrate approximately as readily as a secondary alkyl group and more
readily than hydrogen, which, in turn, migrates more readily than a primary alkyl group.
128. (a) Berson, J. A.; Suzuki, S. J. Am. Chem. Soc. 1969, 81, 4088. (b) Gallagher, T.F.; Kritchevsky, T.H. J. Am.
Chem. Soc. 1960, 72, 882. (c) Turner, R.B. J. Am. Chem. Soc. 1960, 72, 878. (d) Mislow, K.; Brenner, J. J. Am.
Chem. Soc. 1963, 75, 2318.
129. Krow, G.C. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; (Pergamon: Oxford,
1991), vol. 7, pp 671–688.
130. Review: ten Brink, G.-J.; Arends, I.W.C.E.; Sheldon, R.A. Chem. Rev. 2004, 104, 4105.
131. Bogdanowicz, M.J.; Ambelang, T.; Trost, B.M. Tetrahedron Lett. 1973, 14, 923.
132. Jacobson, S.E.; Mares, F.; Zambri, P.M. J. Am. Chem. Soc. 1979, 101, 6938.
133. Strukul, G. Angew. Chem., Int. Ed. Engl. 1998, 37, 1198.
134. Berkessel, A.; Andreae, M.R.M. Tetrahedron Lett. 2001, 42, 2293.
135. Neimann, K.; Neumann, R. Org. Lett. 2000, 2, 2861.
136. Chrobok, A. Tetrahedron 2010, 66, 6216.
137. Jiménez-Sanchidrián, C.; Ruiz, J.R. Tetrahedron 2008, 64, 2011.
138. (a) Doering, W.v.E.; Speers, L. J. Am. Chem. Soc. 1950, 72, 5515. (b) Friess, S.L.; Soloway, A.H. J. Am.
Chem. Soc. 1951, 73, 3968. (c) Sauers, R.R.; Ubersax, R.W. J. Org. Chem. 1965, 30, 3939.

Insertion of Nitrogen into a C—C σ Bond of an Aldehyde or Ketone:

The Beckmann and Schmidt Rearrangements
The accepted mechanism of the Beckmann139 rearrangement (Figure 18.7) proceeds from
a protonated oxime (18.120) to a nitrilium ion (18.122) that is trapped by water to give the
amide (18.125). Oximes can exist as geometric isomers, and when the Beckmann rear-
rangement is carried out under conditions where the two geometric isomers are not inter-
converted, the group anti to the oxime hydroxyl group migrates (18.120). By contrast,
when the Beckmann reaction is carried out under strongly ionizing conditions, the two
isomers of the oxime are rapidly interconverted,140 and a mixture of the possible products
is formed. In certain cases, the isomerization occurs more rapidly than the rearrange-
ment, making the product independent of the reactant stereochemistry.141 Aliphatic ketox-
imes isomerize so rapidly that practically all the mechanistic (and stereochemical) studies
on the Beckmann rearrangement have been carried out on aromatic systems. The solvent
also has a role to play in the Beckmann rearrangement, as confirmed by computational
studies.142 Isomerization of the oxime is less pronounced in low dielectric solvents with
Lewis acids and is facilitated by proton acids in protic solvents.143 In an ironic twist,144 the
Beckmann rearrangement of cyclohexanone oxime to caprolactam (Example 18.126, an
important intermediate in the synthesis of Nylon®) is catalyzed by the ionic liquid formed
between caprolactam itself and tetrafluoroboric acid! More recently, the soft Lewis acid,
mercuric chloride, has been found to promote the Beckmann rearrangement in aprotic
solvents (e.g., Example 18.127).145
Figure 18.7 Mechanism
H
of the Beckmann
rearrangement ‡
δ+
HO H2O H2O
N N
N δ+
Rs Ra Rs Ra Ra
Rs
(18.120) (18.121)
Ra Ra
Ra H Ra N
HN N N
Rs OH2 :OH2
Rs O Rs OH
Rs
(18.125) (18.124) (18.123) (18.122)
139. Ernst Otto Beckmann (1853–1923) was educated at Leipzig, (PhD; 1878). A journeyman in many ways,
his career took him from Strasbourg (1878) to Brunswick (1879), to Leipzig (1884), to Giessen (1891), and to
Erlangen (1892). He then returned to Leipzig (1897) and ended his career in Berlin (1902). His research covered
areas of organic synthesis and natural products chemistry. For more biographical information, see: Oesper,
R.E. J. Chem. Educ 1944, 21, 470.
140. It has long been known that the isomerization of oximes is promoted by acids: Hantzsch, A.; Lucas, A.
Ber. dtsch. chem. Ges. 1895, 28, 744.
141. Smith, P.A.S.; Antoniades, E.P. Tetrahedron 1960, 9, 210.
142. (a) Nguyen, M.T.; Raspoet, G.; Vanquickenborne, L.G. J. Am. Chem. Soc. 1997, 119, 2552. (b) Yamabe, S.;
Tsuchida, N.; Yamazaki, S. J. Org. Chem. 2005, 70, 10638.
143. Brown, R.F.; van Gulick, N.M.; Schmidt, G.H. J. Am. Chem. Soc. 1955, 77, 1094.
144. Guo, S.; Du, Z.; Zhang, S.; Li, D.; Li, Z.; Deng, Y. Green Chem. 2006, 8, 296.
145. Ramalingan, C.; Park, Y.-T. J. Org. Chem. 2007, 72, 4536.

HO
N O
H2SO4, ∆ NH 146
(18.126)
(56-65%)
Ph Ph H
HgCl2, MeCN Ph N
Ph (18.127)145
NOH 80°C, 8 h
O
(96%)
In mechanistic terms (Figure 18.8), the Schmidt147 reaction of azides is formally the
nitrogen analog of the Baeyer-Villiger oxidation, with molecular nitrogen functioning as
the leaving group. In the Schmidt reaction, the carbonyl compound is treated with hydra-
zoic acid and a strong acid catalyst to give an adduct (18.128) that then loses nitrogen to
give the amide. The reaction occurs by one of two mechanisms: (1) by concerted rearrange-
ment of 18.128 with concomitant loss of nitrogen and formation of the conjugate acid of
the amide (18.124) and (2) by dehydration of 18.128, with rearrangement of the cationic
intermediate (18.129) to a nitrilium ion (18.122). The exact mechanism followed depends
on the carbonyl compound, but—regardless of mechanism—at no time does the migrat-
ing group dissociate completely from the rest of the molecule: it rearranges with retention
of configuration.
The possibility of replacing the hydrazoic acid with an alkyl azide has been explored
off and on for many years with little or no success. Recently, however, an intramolecular
analog of the Schmidt reaction has been developed. In this reaction, an ω-azidoketone
(Example 18.130) is treated with a strong acid or Lewis acid, and an intramolecular rear-
rangement through the cyclic N-diazonium ion 18.132 ensues. Loss of the Lewis acid then
provides the final amide (Example 18.133). The rearrangement proceeds with retention of
configuration at the migrating carbon.148
Figure 18.8 Mechanisms
OH OH O
of the Schmidt reaction
R1 N2
N R1 NH R1 NH
R2 H R2
R2
O OH
(18.128) (18.124) (18.125)
R1 R2 R1 R2
H
OH R2
R1
N R1 N2
H N2 N R1 N N
R2 R2
H N2
(18.129) (18.122)
(18.128)
N R
O Cl4Ti O R N
R O
TiCl4 R O N N
N N N N N N Cl4Ti
(18.130) (18.131) (18.132) (18.133)
146. Marvel, C.S.; Eck, J.C. Org. Synth., Coll. Vol. 2 1943, 371.
147. Karl Friedrich Schmidt (1887–1971) was educated at Heidelberg (PhD; 1912, under Curtius). From 1912
to 1921, he was Assistant to Theodor Curtius, except for World War I. His career then took him to the Swedish
University of Åbo in Turku, Finland (1921) and then Heidelberg (1925). From 1926 to 1936 Schmidt was a direc-
tor of Knoll AG, and in 1936 he opened his own research laboratory (but remained associated with Knoll).
Schmidt’s work consisted of adapting earlier reactions to industrial use and production.
148. Milligan, G.L.; Mossman, C.J.; Aube, J. J. Am. Chem. Soc. 1995, 117, 10449.

Oxidative Rearrangements in Carboxylic Acids: The Hofmann,

Curtius, and Lossen Rearrangements
The most widely used oxidative rearrangements of carboxylic acid derivatives all give rise
to amine derivatives by migration of carbon to nitrogen to form an intermediate isocya-
nate. As we saw in Figure 18.6, all three reactions share a common mechanism, with only
the identity of the leaving group changing.
In the Hofmann rearrangement,149 the participating reactant is the anion of an
N-haloamide. This is formed by treatment of the amide with halogen and base, which
first gives an N-haloamide (Example 18.134) that is then rapidly deprotonated by the
base. The conjugate base then rearranges with loss of the halide anion to give the isocya-
nate (Example 18.135). The isocyanate then reacts further to give a carbamate anion
(Example 18.137), whose spontaneous decarboxylation yields the product amine. Since
its discovery, the Hofmann rearrangement has been the subject of continuous study, es-
pecially with respect to the oxidant used. Thus, over the second half of the 20th century,
a wide range of oxidizing reagents was studied, including lead tetraacetate,150 benzyl-
trimethylammonium perbromide and sodium hydroxide,151 and N-bromosuccinimide in
the presence of mercury or silver salts in DMF.152 In the last two decades or so of the
century, the use of iodine (III) reagents was extended to the Hofmann rearrangement,
permitting this reaction to be carried out under mildly acidic conditions.153 Iodine (III)
reagents permit the reaction to be carried out without using highly toxic reagents or
heavy metals, making the reaction much “greener.”
O OH
O O
Br C
R N Br N
R N
H R
(18.134) OH (18.135)
CO2
O OH
NH2 C C
O NH O N
R
H2O R R
HO
(18.137) (18.136)
149. Review: Wallis, E.S.; Lane, J.F. Org. React. 1946, 3, 267.
August Wilhelm von Hofmann (1818–1892) was educated at Giessen under Liebig. His career took him
from Bonn (1841) to the Royal College of Chemistry in London (1845). He returned to Bonn in 1864 and in 1865
he moved to Berlin, where he remained until his death in 1892. He was ennobled (made von Hofmann) in 1888.
For more biographical details, see: Beer, J.J. J. Chem. Educ. 1960, 37, 248; Meinel, C. Angew. Chem. Int. Ed. Engl.
1992, 31, 1265; Travis, A.S. Endeavour 1992, 16, 59.
150. (a) Baumgartan, H.E.; Smith, H.L.; Staklis, A. J. Org. Chem. 1975, 40, 3554. (b) Acott, B.; Beckwith, A.L.J.;
Hassanali, A. Aust.J.Chem 1968, 21, 197. (c) Acott, B.; Beckwith, A.L.J.; Hassanali, A. Aust. J. Chem. 1968, 21, 185.
(d) Acott, B.; Beckwith, A.L.J. J. Chem. Soc., Chem. Commun. 1965, 161.
151. Kajigaeshi, S.; Asano, K.; Fujasaki, S.; Kakinami, T.; Okamoto, T. Chem. Lett. 1989, 463.
152. Jew, S.A.; Park, H.G.; Park, H.-J.; Park, M.A. ; Cho, Y.-S. Tetrahedron Lett. 1990 ,31, 1559.
153. (a) Radhakrishna, A.S.; Parham, M. E.; Riggs, R.M.; Loudon, G.M. J. Org. Chem. 1979, 44, 1746.
(b) Loudon, G.M.; Radhakrishna, A.S.; Almond, M.R.; Blodgett, J.K.; Boutin, R.H. J. Org. Chem. 1984, 49, 4272.
(c) Loudon, G.M.; Boutin, R.H. J. Org. Chem. 1984, 49, 4277. (d) Almond, M.R.; Stimmel, J.B.; Thompson, A.E.;
Loudon, G.M. Org. Synth. 1988, 67, 132. (e) Tamura, M.; Jacyno, J.; Stammer, C.H. Tetrahedron Lett. 1986, 27,
5435. (f) Radhakrishna, A.S.; Rao, C.D.; Varma, R.K.; Sing, B.B.; Bhatnagar, S.P. Synthesis 1983, 538.
(g) Wasielewki, C.; Topolski, M.; Dembkowski, M. J. Prakt. Chem. 1989, 331, 507. (h) Lazbin, I. M.; Koser, G.F.
J. Org. Chem. 1986, 51, 2669. (k) Vasudervan, A.; Koser, G.F. J. Org. Chem. 1988, 53, 5158. (l) Moriarty, R.M.;
Khoshrowshahi, J.S.; Awaathi, A.K.; Penmaata, R. Synth. Commun. 1988,18, 1179. (m) Moriarty, R.M.; Chany,
C.J., II; Vaid, R.K.; Prakash, O.; Tuladhar, S.M. J. Org. Chem. 1993, 58, 2478.

In the Curtius154 rearrangement, an acyl azide (Example 18.138) is the participating

reactant. The azide is formed by the reaction of an acid chloride or mixed anhydride with
azide ion or by the reaction of an acyl hydrazide with nitrous acid. On heating, or on irra-
diation with ultraviolet light, it loses molecular nitrogen to give the isocyanate. One major
advantage of the Curtius rearrangement is that it permits the isocyanate (Example 18.135)
to be generated under anhydrous conditions, where it may be isolated.
O O O
N2 C
R N N2 N
R N
R
(18.138) (18.135)
In the Lossen155 rearrangement, the conjugate base of an O-acylhydroxamic acid or

an O-sulfonyl-hydroxamic acid (Example 18.139) is the participating reactant. To obtain
this reactant, the carboxylic acid is first converted to a hydroxamic acid, which is then
acylated or sulfonated on oxygen to give the O-acyl or O-sulfonylhydroxamate. The treat-
ment of this hydroxamate derivative with base gives the conjugate base that then loses
either a carboxylate or sulfonate anion to give the isocyanate. The Lossen rearrangement
can also be carried out directly on the hydroxamic acid itself by heating with strong acid.
The general move toward “green” chemistry has also had a major impact on the Lossen
rearrangement. Although this reaction had not been developed as rapidly as the Curtius,
Schmidt, and Hofmann rearrangements, carbonyl-diimidazole has been found to be an
effective reagent for the Lossen rearrangement of hydroxamic acids (as in Example
18.140),156 as has cyanuric chloride.157 In an intriguing twist on this reaction, it has re-
cently been reported that certain arylhydroxamic acids actually rearrange with potas-
sium carbonate in dimethyl sulfoxide.158 In this reaction, the hydroxamic acid also
furnishes the leaving group.
O O O
X C
R N X N
R N
R
(18.139) (18.135)
X = OCOR, OSO2R
O
N N O
O N N
60°C
O N C O (18.140)
MeCN O MeCN
R NHOH R
R N
Like the analogous reactions in aldehydes and ketones, these reactions proceed with
retention of configuration at the migrating carbon. Their utility in synthesis is illustrated
154. Julius Wilhelm Theodor Curtius (1857–1928) was educated at Heidelberg and Leipzig (PhD; 1882).
Curtius immediately moved to Munich to study under Baeyer. His career then took him to Erlangen (1886), Kiel
(1889), Bonn (1897), and Heidelberg (1898), where he remained for the rest of his career. For more biographical
information, see: Freudenberg, K. Chem. Ber. 1963, 96, I.
155. Wilhelm Lossen (1838–1906) studied under Albert Niemann, the first chemist to isolate cocaine, at
Göttingen. His career took him to Karlsruhe (1862), Halle (1863), Heidelberg (1866), and the Albertus Univer-
sity in Königsburg, Prussia (1877), where he taught until 1904. Lossen’s work included the discovery of hydrox-
ylamine and deducing the first correct structure for cocaine. For additional detail, see: Priesner, C. Neue
Deutsche Biographie, vol. 15, p. 202.
156. Dubé, P.; Fine, N.F.; Vitelino, M.; Couturier, M.; Abbousafy, C.L.; Pichette, S.; Jorgensen, M.L.; Hardinck,
M. Org. Lett. 2009, 11, 5622.
157. Hamon, F.; Prié, G.; Lecornué, F.; Papot, S. Tetrahedron Lett. 2009, 50, 6800.
158. Hoshino, Y.; Okuno, M.; Kawamura, E.; Honda, K.; Inoue, S. Chem. Commun. 2009, 2281.

by the historical examples below, where the absolute configurations of (+)-hydratropic

acid (Example 18.141) and (−)-α-phenylethylamine (Example 18.144) were correlated.159
1) PCl3
CONH2 CONHBr NaOH
2) NH3 Br2
H H
Me NaOH Me
Ph Ph
(18.142) (18.143)
CO2H 1) PCl3 CON3 NH2

2) NaN3 1) ∆ or hν
H H H
Me Me 2) H2O Me
Ph Ph Ph
(18.141) (18.145) (18.144)
1) PCl3 CONHOH 1) PhCOCl

2) NH2OH 2) MeOK, ∆
H
Me 3) KOH, H2O
Ph
(18.146)
Problem
18-7 Draw the structure of the major product of each of the following reactions. Give
reasons for your answer.
O O
NaN3, HCl 1) NH2OH
(a) (b)
2) H3PO4
O
H
m-CPBA COCl 1) NaN3
(c) (d)
CH2Cl2 2) hν, H2O
H
Br2, KOH COCl 1) NH2OH

(e) CONH2
(f)
H2O 2) TsCl
3) KOMe, MeOH
Ph
m-CPBA O hν, C6H6
(g) Br COMe (h)
Me3C Br CH2Cl2
N CON3
Reaction Synopses
Baeyer-Villiger Oxidation
O RCO3H O
R'
R R' CH2Cl2 R O
Reagents: HCO3H; MeCO3H; m-CPBA; etc.

or H2O2, R FOH, PhAsO3H; H2O2, R FOH, TsOH; etc.
or H2O2, zeolites; etc.
159. This correlation has been accomplished by all five methods (Hofmann, Curtius, Lossen, Schmidt, and
Beckmann rearrangements): (a) Arcus, C.L.; Kenyon, J. J. Chem. Soc. 1939, 916. (b) Kenyon, J.; Young, D.P. J.
Chem. Soc. 1941, 263. (c) Campbell, A.; Kenyon, J. J. Chem. Soc. 1946, 25.

Beckmann Rearrangement
HO
N O
R'
R R' R N
H
Reagents: H2SO4, H3PO4 or POCl3, PCl5, P2O5, SOCl2, (COCl)2, cyanuric

chloride, Ac2O, RN=C=NR, RN=C=O; etc.
Schmidt Reaction
O O
R'
R R' R N
H
Reagents: HN3; NaN3, HCl; Me3SiN3, ZnI2; etc.

Hofmann Rearrangement
R NH2
H2O
O
N C O
R NH2 R O
R'OH R R'
N O
H
Reagents: Br2, KOH, H2O; NaOCl, H2O; etc. or Br2, ROH, RONa
Curtius Rearrangement
O O hν
N C O
R OH R N3 or ∆ R
Reagents: (1) PCl3; (2) NaN3; (3) ∆

or (1) ClCO2Et, Et3N, THF; (2) NaN3, H2O; (3) hν, PhH
or NaN3, H2SO4, H2O, ∆
or (1) PCl3; (2) H2NNH2; (3) HONO
Lossen Rearrangement
O O (base)
OH OR' N C O
R N R N R
H H
Reagents: H2SO4; H3PO4; etc.

or (1) PhCOCl; (2) KOMe, MeOH, ∆; Ac2O, NaOAc, ∆;
or (1) TsCl, py; (2) KOCMe3; etc.
or K 2CO3, Me2SO, ∆; etc.
18.8 Oxidation of Unsaturated Hydrocarbons
Up to now, we have discussed the oxidation of organic compounds at functional groups

with a heteroatom: alcohols, ethers, aldehydes, ketones and amines. Now, we will change
focus and concentrate on the oxidation of hydrocarbons, instead. Hydrocarbon oxida-
tions generally fall into two major classes (Table 18.7). The first of these is oxidative substi-
tution, which may involve replacement of the C—H σ bond by a σ bond to a more
electronegative element, or replacement of a C—C σ bond by bonds to an electronegative

Table 18.7 Forms of Oxidation Reactions
Oxidative Substitution Dehydrogenation
HX HH
R H R X R R R R' R R'
HX R R
O R O R R R
H H
R R R R
R H R X
R R R R R R R R
HO OH OO X Y
R R R R R R R R
R R R R
OO
R R R R
element. The second is dehydrogenation, where a pair of hydrogen atoms is removed from
adjacent or non-adjacent carbon atoms to give a new carbon-carbon bond.
The presence of a π bond in a molecule renders the adjacent groups unusually reactive
because the intermediates generated by cleavage of the σ bond adjacent to the π bond are
resonance-stabilized. Allyl and benzyl halides are much more susceptible to displacement
by both SN1 and SN2 mechanisms. Allyl and benzyl alcohols are oxidized by reagents that
do not oxidize similar saturated alcohols, and these reactions may proceed through allyl
and benzyl free radicals. Allylic hydrogens can be replaced by other groups under rela-
tively mild conditions. The hydrogen atoms α to a carbonyl, cyano, or similar group are
unusually acidic because the conjugate base formed (an enolate-type anion) is stabilized
by resonance.
Oxidation of Alkenes by Addition

Epoxidation
The most important reaction that oxidizes an alkene π bond may well be epoxidation if one
is to judge by the frequency with which it is used as a critical step in a synthesis. The most
common method for forming epoxides is by oxidation of alkenes with organic peroxyacids
(or peracids),160 a reaction occasionally known as the Prilezhaev reaction after the Russian
chemist who first reported it.161 One important peroxyacid is m‑chloroperbenzoic acid
(m-CPBA), whose thermal stability and commercial availability made it a reagent of
choice for the preparation of epoxides. Recent difficulties in obtaining this reagent due
to regulations for its transportation have led to its frequent replacement by magnesium
160. Reviews: (a) Plesnicar, B. In Trahanovsky, W.S., Ed. Oxidation in Organic Chemistry. Part C. (Academic
Press: New York, 1978), 211. (b) Hudlicky, M. Oxidations in Organic Chemistry. Am. Chem. Soc. Monogr. 186
(American Chemical Society: Washington, D.C., 1990).
161. Prileschajew, N. Ber. dtsch. chem. Ges. 1909, 42, 4811.
Nikolai Aleksandrovich Prilezhaev (1872–1944) was destined for the priesthood by his father, but studied
in chemistry under Wagner at Warsaw (M Chem, 1912). His career took him from Warsaw (1912); to Kiev
Polytechnic Institute (1915), where he was Rector after the Russian Revolution; and to Minsk (1924), where he
helped to organize the chemistry faculties at Belarus State University and Belarus Polytechnic Institute. He was
elected a Corresponding Member of the USSR Academy of Sciences in 1933 and of the Belarus Academy of
Sciences in 1940. For more biographical detail, see: Akhrem, A.A.; Prilezhaeva, E.N.; Meshcheriakov, A.P. Zh.
Obshch. Khim. 1951, 21 (11).

R Figure 18.9 Transition state

H R for concerted transfer of
O oxygen in epoxidation
O
R O R
R
monoperphthalate (MMPP),162 which is much less shock sensitive and whose transporta-
tion is less heavily regulated.
The reaction in non-hydroxylic solvents is concerted and is generally considered to
involve the transfer of the hydroxyl oxygen to the alkene from the intramolecularly
hydrogen-bonded form of the peroxyacid (Figure 18.9).163 It gives the epoxide where the
oxygen atom is added to the less hindered face of the π bond in a suprafacial manner,
thus preserving the stereochemistry of the original alkene in the epoxide product. In the
reaction 18.147, for example, the epoxidation occurs on the less hindered exo face of
the molecule. In dienes and polyenes, the oxygen is added to the most substituted, most
electron-rich π bond first.
Epoxidation of alkenes by peracids is facilitated by electron-withdrawing groups on the

peracid164 and by electron-releasing groups on the alkene.165 Epoxidation by peracids is also
facilitated by non-polar solvents and retarded by solvents that can form hydrogen bonds to
the peracid.166 One of the limitations of epoxidation reactions with organic peracids is the
potential for further reactions of the epoxide catalyzed by the carboxylic acid by-product.
For this reason, sodium bicarbonate is often used as a buffering agent in epoxidations.
The epoxidation of alkenes can be carried out using organic peroxides (e.g., tert-butyl
hydroperoxide, t-BuOOH) and transition metal compounds as catalysts. tert-Alkyl hy-
droperoxides have three properties that make them attractive oxidants: they are stable,
they are commercially available, and they do not form acidic reduction products. Thus, the
treatment of an alkene with molybdenum hexacarbonyl and tert-butyl or amyl hydroper-
oxide (Example 18.148) gives the epoxide; if the alkene contains two π bonds (e.g.,
S-limonene), the more substituted double bond is oxidized first. Predicting the stereo-
chemistry of epoxidation is not always straightforward, but it is usually safe to predict that
oxygen will be delivered to the less hindered face of the π bond, as illustrated by the epox-
idation of β-pinene (Example 18.149). Here, access to the top face of the double bond is
hindered by the methyl group on the bridge.
162. Review: Heaney, H.H. Aldrichimica Acta 1993, 26, 35.

163. Bartlett, P.D. Rec. Chem. Progr. 1957, 18, 111.
164. (a) Vilkas, M. Bull. Soc. Chim. France 1959, 1401. (b) Ogata, Y.; Tabushi, I. J. Am. Chem. Soc. 1961, 83,
3440. (c) Ogata, Y.; Tabushi, I. J. Am. Chem. Soc. 1961, 83, 3444.
165. (a) Lee, J.B.; Uff, B.C. Quart. Rev. Chem. Soc. 1967, 21, 431. (b) Medvedev, S.; Blokh, O. J. Phys. Chem.
(Moscow) 1933, 4, 721. (c) Boeksen, J.; Stuurman, J. Rec. Trav. Chim. Pays-Bas 1937, 56, 1034. (d) Boeksen, J.;
Nonegraaff, C.J.A. Rec. Trav. Chim. Pays-Bas 1942, 61, 69. (e) Swern, D. J. Am. Chem. Soc. 1947, 69, 1692.
(f) Frostick, F.C., Jr.; Phillips, B.; Starcher, P.S. J. Am. Chem. Soc. 1959, 81, 3350.
166. (a) Renolen, P.; Ugelstad, J. J. Chim. Phys. 1960, 57, 1976. (b) Itier, J.I.; Tournaire, M.; Casadevall, A. Compt.
rend. Hebd. Seances Acad. Sci. , Ser. C 1970, 271, 878. (c) Kavčič, R.; Plesničar, B. J. Org. Chem. 1970, 35, 2033.

O O
EtCMe2O—OH
+ (18.148)
Mo(CO)6
21% 50%
S-Limonene
t-BuOOH
Mo(CO)6 (18.149)
O
β-Pinene
Epoxidation of Allyl Alcohols

The functional group of an allylic alcohol affects both the regiochemistry and the stereo-
chemistry of the epoxidation reaction due to its ability to form hydrogen bonds to the re-
agent. The hydroxyl group affects regiochemistry by directing the epoxidizing agent to the
double bond nearest to itself whether the oxidizing agent is a peracid or a metal-based reagent.
The effect of the allylic hydroxyl group on the stereochemistry of epoxidation is nicely
illustrated by cyclic allylic alcohols. Peracids oxidize cyclic allylic alcohols to the epoxide
where the epoxide oxygen is cis to the hydroxyl group. When the hydroxyl group is ester-
ified, the stereochemistry of the epoxidation is determined by steric factors and the re-
agent approaches the less hindered face of the molecule. For instance, 2-cyclohexenol
reacts with perbenzoic acid to give predominantly (90:10) the epoxide where the epoxide
oxygen is cis to the hydroxyl group (Example 18.150).167 Its acetate ester, on the other hand,
gives a 57:43 mixture of products in which the major isomer is the one with the epoxide
oxygen trans to the ester group (Example 18.151).
OH OH OH
PhCO3H, C6H6
O + O (18.150)
(8%) (78%)
OAc OAc OAc
PhCO3H, C6H6
O + O (18.151)
(38%) (30%)
These observations have been rationalized on the basis of a transition state (Example
18.152) in which the peracid is hydrogen bonded to the alcohol hydroxyl group.168 Accord-
ing to this model, the peracid forms a hydrogen bond with one of the peroxy oxygens of
the peracid, resulting in the peracid being directed to the same face of the double bond.
‡
R O
H
O O O
H
(18.152)
167. Chamberlain, P.; Roberts, N.L.; Whitham, G.H. J. Chem. Soc. B 1970, 1374.
168. (a) Henbest, H.B. Proc. Chem. Soc., London 1963, 159. (b) Cerefice, S.A.; Fields, E.K. J. Org. Chem. 1976, 41, 355.

Transition metal catalyzed epoxidation is especially useful when the double bond is
part of an allyl alcohol. In these reactions, a vanadium complex, VO(acac)2, has proved to
be particularly useful, normally giving the desired product in yields of 80% or more. By
using this reagent, it is possible to epoxidize an allyl alcohol to the exclusion of other
double bonds (e.g., Example 18.153).169
OH OH OH
[O]
O + (18.153)
CH2Cl2
O
m-CPBA 33% 67%

t-BuOOH, VO(acac)2 99% 1%
Epoxidation of Conjugated Carbonyl Compounds

The alkene π bond conjugated to a carbonyl group is electron deficient, so epoxidation
with electrophilic oxidizing agents is often slow. However, epoxidation of α,β-unsaturated
carbonyl compounds can be readily effected using a nucleophilic oxidizing agent. By far
the most widely used such reagents are the conjugate bases of hydrogen peroxide and alkyl
hydroperoxides (e.g., Examples 18.154 and 18.155).170 These reactions proceed by a two-
step mechanism171 involving Michael addition of the peroxide nucleophile, followed by
intramolecular displacement of the leaving group from oxygen. As a consequence, they
are not stereospecific like the reactions discussed earlier but are stereoselective, as illus-
trated by epoxidation of the geometric isomers of 3-methyl-3-penten-2-one (Examples
18.156 and 18.157), which give the same major product (Example 18.158).174
O O
H2O2, NaOH
O (18.154)172
MeOH
70%
Ph Ph
t-BuOOH, NaOH 173
O (18.155)
MeOH, pH 8.5
CHO 35-40°C CHO
73%
O
Me H2O2
Me
NaOH
Me O
Me
(18.156) Me
O (18.158)174
O Me
Me
Me H2O2
NaOH
Me
(18.157)
169. Sharpless, K.B.; Verhoeven, T.R. Aldrichimica Acta 1979, 12, 63.
170. (a) Hassall, C.H. Org. React. 1957, 9, 73. (b) Yang, N.C.; Finnegan, R.A. J. Am. Chem. Soc. 1958, 80, 5845.
171. Bunton, C.A.; Minkoff, G.O. J. Chem. Soc. 1949, 665.
172. Wasson, R.L.; House, H.O. Org. Syn. Coll. Vol. 4. 1963, 552.
173. Payne, G.B. J. Org. Chem. 1960, 25, 275.
174. House, H.O.; Ro, R.S. J. Am. Chem. Soc. 1958, 80, 2428.

A reagent that has become gradually more popular for epoxidizing alkenes, includ-
ing conjugated enones, is dimethydioxirane.175 Dioxiranes in general are readily pre-
pared from ketones and a persulfate salt. The most popular oxidant is Oxone®,
2KHSO5•KHSO4•K 2SO4, which oxidizes a wide range of ketones to the corresponding
dioxiranes. In the presence of an alkene, the dioxirane effectively transfers an oxygen
atom to give the epoxide in a high-yield, stereospecific reaction (e.g., Examples 18.160
and 18.161). The reaction is stereospecific, involving syn, or suprafacial, addition of
oxygen to the alkene π bond,176 although there is evidence that the mechanism may in-
volve homolysis of the three-membered ring instead of an oxygen atom insertion
mechanism.177
Me Me
CO2Me O O O CO2Me 178
H (18.159)
H
Me Me2CO, CH2Cl2 Me
Ph –20°C, 24 h Ph
(99%)
MeO2C MeO2C
Me O O O Me 173
H (18.160)
Me2CO, CH2Cl2 H
Me –20°C, 24 h Me
Ph (98%) Ph
Ph Ph
O O O
H H (18.161)
179
H Me2CO, CH2Cl2 H
Ph –20°C, 24 h Ph
(quant.)
Hydroxylation
The synthesis of 1,2-diols from alkenes (formally, the addition of hydrogen peroxide across
the π bond) is known as hydroxylation. The reaction can be carried out with either anti,
(antarafacial, 18.162) or syn (suprafacial, 18.163) stereochemistry, depending on the re-
agent. See Table 18.8.
Table 18.8 Stereochemistry of Hydroxylation
OH
1) HCO2—OH, CH2Cl2
(18.162) anti (antarafacial)
2) NaOH, H2O Hydroxylation
OH
(±)
OH
OsO4, t-BuOOH syn (suprafacial)
(18.163)
t-BuOH, 25°C Hydroxylation
OH
175. Reviews: (a) Murray, R. W. Chem. Rev. 1989, 89, 1187. (b) Adam, W.; Curci, R.; Edwards, J.O. Acc. Chem.
Res. 1989, 22, 205. (c) Adam, W.; Hadjiarapoglou, L.P. Top. Curr. Chem. 1993,164, 45.
176. Baumstark, A.L.; McCloskey, C.J. Tetrahedron Lett. 1987, 28, 3311.
177. Bravo, A.; Fontana, F.; Fronza, G.; Minisci, F.; Zhao, L. J. Org. Chem. 1998, 63, 254.
178. Adam, W.; Hadjiarapoglou, L.; Nestler, B. Tetrahedron Lett. 1990, 31, 331.
179. Murray, R.M.; Singh, M. Org. Syn. 1996, 74, 91.

Note that in six-membered rings, anti hydroxylation occurs preferentially to give the
product of diaxial addition (Example 18.165). However, the diequatorial isomer (Example
18.166) can still be observed as a minor pathway due to the greater conformational flexi-
bility of the cyclohexene oxide, which allows anti ring opening through the other half-
chair conformation.
OH
1) HCO3H, CH2Cl2 OH
OH
2) NaOH, H2O
major OH minor
(18.164) (18.165) (18.166)
syn Hydroxylation
Several reagents accomplish the suprafacial addition of the elements of hydrogen peroxide
to an alkene. High-valent compounds of manganese and osmium are the most common.
The controlled oxidation of alkenes with alkaline potassium permanganate was first
developed as a useful reaction in a series of papers by the Russian chemist Wagner180 (of
Wagner-Meerwein rearrangement fame), following preliminary reports of the oxidation
of oleic acid (Example 18.167).181 Wagner also suggested182 that a cyclic manganate ester
was probably involved in the reaction. Thus, the reaction of an alkene with alkaline per-
manganate at low temperature under carefully controlled conditions gives the dihydroxy
compound (diol) in which the two hydroxy groups have both been added to the less hin-
dered face of the double bond. The yields in potassium permanganate hydroxylations can
often be improved by using a phase-transfer catalyst (e.g., the yield of cyclooctanediol
from cyclooctene is increased from 7% to 50% by the addition of benzyltriethylammo-
nium chloride and the use of a two-phase reaction system183). It is important that the reac-
tion be carried out with dilute, alkaline permanganate and that it be carried out at low
temperature184 because the diol is itself susceptible to oxidation by potassium permanga-
nate under neutral or acidic conditions. Over-oxidation is a frequent side reaction with
this reagent.
HO
KMnO4, KOH HO
184
(18.167)
H2O, 0-10°C
CO2H 100% (±) CO2H
One of the most useful alternatives to permanganate oxidation for the preparation of
syn diols is the reaction between an alkene and osmium tetroxide, first reported in 1852.185
Osmium tetroxide adds to the less hindered face of the π bond to form an intermediate
osmate (VI) ester186 that is subsequently cleaved with a reducing agent such as sodium bi-
sulfite or hydrogen sulfide.
180. Wagner, G. Ber. dtsch. chem. Ges. 1888, 21, 1230, 3343, 3347, 3356. Review: Fatiadi, A.J. Synthesis 1987, 85.
181. (a) Gröger, M. Ber. dtsch. chem. Ges. 1885, 18, 1268. (b) Saytzeff, A. J. Prakt. Chem. 1885, 31, 541. (c) Saytzeff,
A. J. Prakt. Chem. 1886, 33, 300. (d) Zaitsev, A.M. Zh. Russ. Fiz.-Khim. Obshch. 1885, 17, 417.
182. (a) Vagner, E.E. Zh. Russ. Fiz.-Khim. Obshch. 1895, 27, 219. (b) Boesken, J. Rec. Trav. chim. 1922, 41, 199.
(c) Boesken, J. Rec. Trav. chim. 1928, 47, 683.
183. Weber, W.P.; Shepherd, J.P. Tetrahedron Lett. 1972, 4907.
184. (a) Robinson, G.M.; Robinson, R. J. Chem. Soc., Trans. 1925, 127, 175. (b) Lapworth, A.; Mottram, E.N.
J. Chem. Soc., Trans. 1925, 127, 1628.
185. (a) Butlerov, A. Bull. Phys. Math. Acad. St. Petersburg 1852, 177. (b) Butlerow, A. Ann. Chem. Pharm.
1853, 84, 278.
186. (a) DelMonte, A.J.; Haller, J.; Houk, K.N.; Sharpless, K.B.; Singleton, D.A.; Strassner, T.; Thomas, A.A.
J. Am. Chem. Soc. 1997, 119, 9907. (b) Pidun, U.; Boehne, C.; Frenking, G. Angew Chem. Int. Ed. Engl. 1997, 35, 2817.

Figure 18.10 Cyclic ester O

intermediates in Mn
O O O O OH
hydroxylation O OH
Mn
O O H2O
OH
(18.168)
manganate ester
O
Os
O O O O OH
O HSO3
Os
O O H2O
OH
(18.169)
osmate ester
Potassium permanganate and osmium tetroxide oxidations are both thought to occur
by suprafacial addition of the oxidant to the double bond (either concerted or stepwise) to
give a cyclic manganate [Mn(V), 18.168] or osmate [Os(VI), 18.169] ester (Figure 18.10). In
the permanganate oxidation, the function of the aqueous base is to free the diol from the
manganate ester by hydrolysis before the ester reacts further to give products of over-
oxidation. In the osmium tetroxide oxidation, the product can be released from the osmate
ester by reduction. Unlike the cyclic manganate ester, the osmate ester does not react
f urther if not cleaved immediately.
Osmium tetroxide reacts with alkenes to the exclusion of virtually all other functional
groups, and it gives only syn addition.187 There are two disadvantages to using osmium
tetroxide as a stoichiometric reagent on all but the smallest scales or with the most valuable
alkenes. One, it is extremely costly—on a gram-for-gram basis, osmium (VIII) oxide and
gold (III) oxide were almost the same price between 2010 and 2013, for example. Two, it
combines high volatility with reputed high toxicity,188 so it may constitute a serious
personal exposure hazard. Thus, much effort has gone into developing catalytic reactions
that release the diol by oxidizing the osmate ester back to osmium tetroxide rather than
reducing it. Most reactions of this type use peroxides (e.g., Example 18.170),189 amine-
N-oxides,190 or aqueous sodium191 or barium chlorate192 as the co-oxidant. The problems
inherent in the volatility of the active oxidant have been obviated, in part, by the use of
osmium tetroxide encapsulated in a poly(phenoxyethoxy-methylstyrene-co−styrene)
carrier, using aqueous acetone as solvent and K 3Fe(CN)6 as the co-oxidant.193
187. Schröder, M. Chem. Rev. 1980, 80, 187.

188. However, the chronic toxicity of osmium compounds may not be as serious as commonly portrayed:
(a) McLaughlin, A.I.G.; Milton, R.; Perry, M.K.A. Br. J. Ind. Med. 1946, 3, 183; Chem. Abstr. 1946, 40, 5841.
(b) Hinckley, C.C.; Bemiller, J.N.; Strack, L.E.; Russell, L.D. In Lippard, S.J., Ed. Platinum, Gold and Other
Metal Chemotherapeutic Agents. ACS Symp. Ser. 1983, 209, 421.
189. Hydrogen peroxide: (a) Milas, N.A.; Sussman, S. J. Am. Chem. Soc. 1936, 58, 1302. (b) Milas, N.A.;
Sussman, S. J. Am. Chem. Soc. 1937, 59, 2345.
tert-Butyl hydroperoxide: (c) Sharpless, K.B.; Akashi, K. J. Am. Chem. Soc. 1976, 98, 1986. (d) Akashi, K.;
Palermo, R.E.; Sharpless, K.B. J. Org. Chem. 1978, 43, 2063.
190. N-Methylmorpholine-N-oxide (NMMO): VanRheenen, V.; Kelly, R.C.; Cha, D.Y. Tetrahedron Lett.
1976, 1973. Trimethylamine-N-oxide (TMO): Ray, R.; Matteson, D.S. Tetrahedron Lett. 1980, 449.
191. (a) Hofmann, K.A.; Ehrhart, O.; Schneider, O. Ber. dtsch. chem. Ges. 1913, 46, 1657. (b) Milas, N.A.; Terry,
E.M. J. Am. Chem. Soc. 1925, 47, 1415. (c) Braun, G. J. Am. Chem. Soc. 1929, 51, 228. (d) Braun, G. J. Am. Chem.
Soc. 1930, 52, 3176, 3188. (e) Criegee, R. Justus Liebigs Ann. Chem. 1936, 522, 75
192. (a) Plaha, L.; Weichert, J.; Zvacek, J.; Smolik, S.; Kakac, B. Coll. Czech. Chem. Commun. 1960, 25, 237.
(b) Kende, A.S.; Bentley, T.V.; Mader, R.A.; Ridge, D. J. Am. Chem. Soc. 1974, 96, 4332. (c) Danishesfky, S.;
Schuda, P.F.; Kitahara, T.; Etheredge, S.J. J. Am. Chem. Soc. 1977, 99, 6066.
193. Ishida, T.; Akiyama, R.; Kobayashi, S. Adv. Synth. Catal. 2003, 345, 576 and references therein.

H HO Table 18.9 Oxidizing Electrophiles That Add to Alkenes

OsO4, t-BuOOH
H H (18.170) to Give anti Adducts
H t-BuOH, H2O
OH
(73%) Electrophile
(E—Nu) Typical Reagents Ref.
anti Hydroxylation X—X' Br2, CH2Cl2; BrCl, CH2Cl2
The hydroxylation of an alkene with antarafacial (anti)
X—OH Br2, H2O; NBS, Me2SO, H2O; Br2, MeOH; 196
stereochemistry cannot be accomplished in a single step. It
(X—OR)
almost always involves the ring opening of an epoxide, a
reaction that occurs with inversion of configuration at the Br—OH, NaBrO3 (or NaIO4), NaHSO3, H2O, MeCN; 197
reacting carbon.194 This leads to overall antarafacial ste- I—OH
reochemistry of addition, although the reaction does not X—OCOR Br2, HOAc; Br2, NaOAc, MeCN
always lead to a single stereoisomer in the product, as
RS—X PhSCl, CH2Cl2; PhSCl, NaOAc, THF 198
shown by the ring opening of epoxides 18.171 and 18.174.195
The epoxide exists in a half-chair conformation, so the RSe—X PhSeCl, CH2Cl2; PhSeCl, NaOAc, THF 199
products both arise from antarafacial addition; the di- I—N3 IN3, CH2Cl2 200
equatorial diol is formed in the twist boat conformation
through a higher energy activated complex than that lead- Br—N3 HN3, Br2 201
ing to the diaxial product. In the twist-boat, the two hy- I—NCO AgNCO, I2 202
droxyl groups are anti to each other, and the ring then
X—SCN I2, (NCS)2; Cl2, Pb(SCN)2 203
reverts to the more stable chair conformation with the two
hydroxyl groups equatorial.
H OH H
H, H2O
+ OH
H HH OH
O OH H
90 10
(18.171) (18.172) : (18.173)
Me OH Me
H, H2O Me +
Me OH
Me OH
O OH Me
71 : 29
(18.174) (18.175) : (18.176)
Other Oxidative anti Additions to Alkenes

A wide array of reagents adds to alkenes with anti stereochemistry. The prototypical re-
agents for this are the halogens and hypohalic acids. However, there are many reagents
194. (a) Böeseken, J. Rec. trav. chim. 1928, 47, 683. (b) Criegee, R.; Stanger, H. Ber. dtsch. chem. Ges. 1936,
69B, 2753.
Review: (c) Parker, R.E.; Isaacs, N.S. Chem. Rev. 1959, 59, 737.
195. Henbest, H.B.; Smith, M.; Thomas, A. J. Chem. Soc. 1958, 3293.
196. (a) Guss, C.O.; Rosenthal, R. J. Am. Chem. Soc. 1955, 77, 2549. (b) Dalton, D.R.; Dutta, V.P.; Jones, D.C.
J. Am. Chem. Soc. 1968, 90, 5498. (c) Sisti, A.J.; Meyers, M. J. Org. Chem. 1973, 38, 4431. (d) Langman, A.W.;
Dalton, D.R. Org. Syn. 1979, 59, 16.
197. Masuda, H.; Takase, K.; Nishio, M.; Hasegawa, A.; Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1994, 59, 5550.
198. (a) Tuladhar, S.M.; Fallis, A.G. Tetrahedron Lett. 1987, 28, 523. (b) Muehlstaedt, M.; Schubert, C.; Klein-
peter, E. J. Prakt. Chem. 1985, 327, 270. (c) Muehlstaedt, M.; Widera, R.; Olk, B. J. Prakt. Chem. 1982, 324, 362.
199. (a) Bennett, F.; Knight, D.W. Tetrahedron Lett. 1988, 29, 4625. (b) Danishefsky, S.; DeNinno, S.; Lartey,
P. J. Am. Chem. Soc. 1987, 109, 2082. (c) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org. Chem. 1986, 51, 1724.
(d) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org. Chem. 1987, 52, 2018.
200. Fowler, F.W.; Hassner, A.; Levy, L.A. J. Am. Chem. Soc. 1967, 89, 540.
201. Hassner, A.; Boerwinkle, F.P.; Levy, A.B. J. Am. Chem. Soc. 1970, 92, 4879.
202. (a) Hassner, A.; Lorber, M.; Heathcock, C. J. Org. Chem. 1967, 32, 540. (b) Hassner, A.; Hoblitt, R.P.;
Heathcock, C.; Kropp, J.E.; Lorber, M. J. Am. Chem. Soc. 1970, 92, 1326
203. (a) Maxwell, R.J.; Silbert, L.S. Tetrahedron Lett. 1978, 4991. (b) Guy, R.G.; Pearson, I. J. Chem. Soc.,
Perkin Trans. 1 1973, 281. (c) Guy, R.G.; Pearson, I. J. Chem. Soc., Perkin Trans. 2 1973, 1359.

that will give products with anti stereochemistry. These reagents are all electrophiles that
share a general structure with a lone pair on the electrophilic atom and react through a
three-membered onium ion intermediate (Example 18.177). Table 18.9 contains a number
of reagents that are variations on this theme.
Nu
Nu
(18.177)
E Nu E
E
Among the most valuable of these reactions are cyclizations such as the halolactoniza-
tion (especially iodolactonization of unsaturated carboxylic acids, esters, and amides,
which have been widely used for the stereocontrolled formation of chiral centers in a mol-
ecule (e.g., Examples 18.178 and 18.179).204 Ring size in lactones is governed by stereoelec-
tronic factors: five-membered lactones are favored k inetically, and six-membered lactones
are favored thermodynamically (Example 18.180).205
O
HO2C OH
I2, MeCN O OH 206
H (18.178)
NaHCO3
(88%)
I
1) I2, MeCN O 207

O 2) NaHCO3 (18.179)
t (68%) O O
O OBu
I
I O
I2, NHCO3
O
CHCl3
Ph
Ph (18.180)
CO2H O
I2, MeCN I
O
Ph
The change from kinetic to thermodynamic control in the addition reaction can also
manifest itself in changed stereochemistry for the reaction, as shown in Example 18.180.208
Reagents other than halogens, such as sulfenyl and selenenyl halides, can be used to initi-
ate the cyclization, as is illustrated by Examples 18.181 to 18.184.
O
O
H
NMe2 I
I2, H2O (18.181)
209
H
O THF
O O
(64%)
204. Review: Bartlett, P.A. In Morrison, J.D., Ed. Asymmetric Synthesis (Academic Press: New York, 1984),
vol. 3, p. 411.
205. (a) Bartlett, P.A.; Myerson, J. J. Am. Chem. Soc. 1978, 100, 3950. (b) Gonzàlez, F.B.; Bartlett, P.A. Org.
Syn. 1985, 64, 175.
206. Neukom, C.; Richardson, D.P.; Myerson, J.H.; Bartlett, P.A. J. Am. Chem. Soc. 1986, 108, 5559.
207. Bartlett, P.A.; Meadows, J.D.; Brown, E.G.; Morimoto, A.; Jernstedt, K.K. J. Org. Chem. 1982, 47, 4013.
208. Gonzàlez, F.B.; Bartlett, P.A. Org. Syn. 1985, 64, 175; 1990, Coll. Vol. 7, 164.
209. Fleet, G.W.J.; Gough, M.J. Tetrahedron Lett. 1982, 23, 4509.

I
H H
O O O I2, NaHCO3
Me (18.182)210
H2O O O O
NH2 Ph O
Ph (75%) O Ph
Ph
SePh
H
PhSeCl O
O (18.183)211
CO2H (93%)
H
PhSCl PhS 212

(18.184)
HO EtN(i-Pr)2 O
(85%)
The use of molecular bromine for addition reactions is complicated by its volatility, its
reactivity, and its toxicity. In recent years, molecular bromine has been replaced by
N-bromosuccinimide (NBS) with species capable of opening the three-membered bro-
monium ion such as amides,213 sulfonamides,214 and lithium bromide.215
Addition of Metal-Based Reagents

The addition of metals as part of the converting alkenes to other products is well estab-
lished. For example, in the first step of the oxymercuration-demercuration sequence for
Markovnikov hydration of an alkene π bond (Example 18.185), the mercury acts as an
electrophile to give a cyclic mercurinium ion that is then attacked by water, giving over-
all anti addition. The replacement of mercury by hydrogen gives a product where neither
overall oxidation nor overall reduction has taken place. However, its replacement by
another electronegative element permits the net oxidation of the molecule.216 This same
reactivity motif, slightly modified, is also exhibited by palladium (II), which adds to
alkenes to give β-hydroxyalkylpalladium compounds by overall anti addition through
a π complex of the alkene with the palladium. Unlike the organomercury compounds,
however, the palladium group is subject to β-elimination, with concomitant reduction
to palladium (0). This has the net effect of replacing a carbon-hydrogen bond with a
carbon-heteroatom bond (if the nucleophile in the addition is a heteroatom nucleophile.
This reaction provides the basis of the Wacker reaction, which we will discuss later in
this chapter.
Me Me
Me OH
Hg(OAc)2, H2O NaBH4, NaOH OH
(18.185)217
Et2O H2O
HgOAc
(70-75% overall)
210. Hirama, M.; Uei, M. Tetrahedron Lett. 1982, 23, 5307.

211. Nicolaou, K.C.; Seitz, S.P.; Sipio, W.J.; Blount, J.F. J. Am. Chem. Soc. 1979, 101, 3884.
212. Tuladhar, S.M.; Fallis, A.G. Tetrahedron Lett. 1987, 28, 523.
213. Wang, Z.; Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Synlett 2008, 2667.
214. (a) Thakur, V.V.; Talluri, S.K.; Sudalai, A. Org. Lett. 2003, 5, 861. (b) Huang, X.; Fu, W.-J. Synthesis
2006, 1016.
215. Shao, L.-X.; Shi, M. Synlett 2006, 1269.
216. For a review of the uses of organomercury compounds in synthesis, see: Larock, R.C. Angew. Chem. Int.
Ed. Engl. 1978, 17, 27.
217. Jerkumica, J.M.; Taylor, T.G. Org. Synth. 1988, Coll. Vol. 6, 766; 1973, 53, 94.

Reaction Synopses
Addition of Halogens and Halogen-like Reagents
Y
Y
E Nu
E
Reagents: Br2, CH2Cl2; Cl2, CH2Cl2; IN3; Br2, H2O; etc.

or (Y=CO2H): Br2, NaHCO3, H2O; I2, NaHCO3, H2O; I2, MeCN; etc.
Stereochemistry: anti addition predominates
Oxymetallation
R R MLn R R
Nu ML(n-1)
R R H Nu R R
Reagents: Hg(OAc)2, H2O, THF; Hg(OCOR)2, ROH; Hg(OCOR)2,

RNHCOR'; Pd(OAc)2, H2O, MeCN; etc.
Replacement of metal by heteroatom: leads to net oxidation
Epoxidation of Alkenes (Prilezhaev Reaction)
R R R R
R R R O R
m-CPBA, CH2Cl2; HCO3H, CH2Cl2; CF3CO3H, CH2Cl2;

Reagents:
MMPP, CH2Cl2; 1) Br2, H2O, 2) K 2CO3, acetone; etc.
Stereochemistry: overall suprafacial addition to the π bond
Epoxidation of Conjugated Carbonyl Compounds
R E R E
R R R O R
E=COR, CO2R, CN, etc.

Reagents: H2O2, KOH; Me3COOH, KOH; Me2CO2, Me2CO; Me2CO2,
Me2CO; Me2CO, Oxone®; etc.
Hydroxylation of Alkenes
HO OH
Stereochemistry: may be either syn (suprafacial) or anti (antarafacial)

syn: KMnO4, KOH, H2O; KMnO4, R4N+, H2O, CH2Cl2;
Reagents:
(1) OsO4, (2) KOH;
or NaHSO3, H2O; OsO4, NaClO3, H2O, CH2Cl2; etc.
anti: (1) HCO3H, CH2Cl2, (2) KOH, H2O; etc.
Worked Problem
18-3 Give the structure of the starting material in the reaction below. Be sure to
include stereochemistry.
OH
OsO4, NaClO3
C10H20
H2O, CCl4
OH
§Answer on the next page.

Drill Exercises
Draw the structure of the major product expected when carvone is treated with
one equivalent of each of the following reagents:
A. Br2 (1 eq.), CH2Cl2

B. OsO4, NMMO, CH2Cl2.
C. (1) m-CPBA, CH2Cl2; (2) NaOAc, DMF
D. H2O2, Me3COH, KOH
E. Me3COOH, Mo(CO)6
F. IN3, CH2Cl2, 0°C
G. PhSeBr, NaOAc
H. Me3COOH, VO(acac)2
I. PhCO3H, PhH
Problems
18-8 Which reagent or sequence of reagents should be used to accomplish the follow-
ing transformations?
OH
OH
(a) (b)
OH OH
(±) (±)
OH OH
(c) (d)
OH HO
CO2H
O H H
O
OH OH
(e) O (f)
(±)
I
(continues)

It is important to consider the stereochemistry in this reaction before answering. The product here is a meso
diol, drawn with the two hydroxy groups anti to each other. It is very tempting to simply write the E-alkene as the
starting material but this is wrong, since that alkene would require a reagent that adds the two hydroxyl groups
anti. Osmium tetroxide, however, results in syn addition of the two hydroxy groups to the alkene. This means that
the stereochemistry of the alkene must not be E, but Z, and that the product has simply been drawn in a confor-
mation different from that in which it is initially produced; one may change the stereochemistry of the product by
changing the stereochemistry of the starting alkene or by changing the stereochemistry of the reaction:
OH
a
a.OsO4 (syn)
b OH
b OH
b. 1) RCO3H; 2) H or HO , H2O
a
OH

OH OH
O
O O
(g) (h)
O
18-9 An alternative syn-hydroxylation of alkenes, known as the Woodward hydroxyl-

ation, consists of treating the alkene with iodine and silver (I) or copper (II) ace-
tate in wet acetic acid. The key feature of this reaction is that the hydroxyl groups
end up on the more hindered face of the π bond (in contrast to osmium tetroxide,
which adds to the less hindered face). When the reaction is carried out under an-
hydrous conditions, the diesters of the anti diol are formed. Suggest a mechanism
for this reaction that accounts for the formation of products under both anhy-
drous and hydrated conditions.
OH OH
OsO4, Me3COOH AgOAc, I2
Me3COH H2O, HOAc
OH OH
H H H
18-10 Draw a mechanism that accounts for the differences in the two reactions below.
I
I I2, MeCN I2, MeCN
O O NaHCO3 CO2H
O O
18-11 The following reactions were used in the total synthesis of several natural
products. Give the structure of the major organic product formed in each
reaction.
H
H2O2, NaOH m-CPBA
(a) (b)
MeOH CH2Cl2
TBSO H O O
O
O SiMe2Ph OsO4, NMO OsO4, NMO

(c) O Me2CO
(d) MeCN-H2O
OH N
Ph CHO
Ph
MeO2C
+
OH
HO pyH Br3– (1 eq) O O OsO4, py
(e) pyridine, 0°C
(f)
NC OTBS O Br
I2, MeCN I2, MeCN

(g) HO (h) HO
OH O
PhH2C
O OH pyH+ Br3– Me3COOH, NaOH

(i) H2O-dioxane
(j) O
MeOH
O
O O
References: (a), (b) [J. Am. Chem. Soc. 2010, 132, 1488]. (c) [Org. Lett. 2003, 5, 1697]. (d) [Org. Lett.
2002, 4, 2469]. (e), (f) [J. Am. Chem. Soc. 1996, 118, 233]. (g), (h) [J. Am. Chem. Soc. 1981, 103, 3963];
which reaction gives which isomer, and why? (i) [Tetrahedron Lett. 1989, 30, 907]. (j) [J. Am. Chem.
Soc. 1982, 104, 872].

18.9 Oxidative Cleavage of Carbon-Carbon Bonds
Reactions where carbon-carbon σ bonds are cleaved under mild conditions are relatively
rare, with two notable exceptions: the cleavage of vicinal diols, and the oxidative cleavage
of alkenes.
The oxidative cleavage of 1,2-diols is often a side reaction during oxidations with chro-
mium (VI) reagents, although the reaction is seldom useful in a preparative sense. The one
place where oxidative cleavage with a chromic acid oxidant is actually useful is as part of
the Barbier-Wieland degradation218 of carboxylic acids (Example 18.186). In this two-
reaction sequence to convert a carboxylic acid to its next lowest homolog, the ester is
treated with phenylmagnesium bromide to give the diphenylcarbinol, which is then oxi-
dized with chromic acid to the carboxylic acid with one less carbon than the starting
compound. Given the extremely vigorous conditions of the oxidation, this is obviously
limited to very robust substrates, and relatively difficult to control.
K2Cr2O7
O OH O
PhMgBr H2SO4/∆
Ph OH (18.186)
R OR' Et2O
R Ph R
Ph
O
Ph
Oxidative Cleavage of Vicinal Diols

In contrast to their monohydric counterparts, the vicinal diols (the 1,2-diols) are suscepti-
ble to oxidative cleavage by reagents such as sodium periodate (e.g., Example 18.187)219 and
lead tetraacetate (e.g., Example 18.188).220 The periodate cleavage of vicinal diols has been
quite extensively studied, and there is good evidence to support a mechanism involving a
five-membered cyclic periodate ester. The lead tetraacetate cleavage of vicinal diols is
sometimes called the Criegee oxidation.
HO OH OH
NaIO4, Me2CO OHC 221
(18.187)
HO OHC
OCOPh H2O, 0°C OCOPh
OH
Pb(OAc)4 CHO
CH2Cl2 (18.188)
222
O O
O O OH 90%
Ph Ph
Ph Ph
Evidence supporting a mechanism involving a cyclic intermediate comes from kinetic
studies of periodate cleavage of related diols. Although cis‑1,2-cyclohexanediol (which can
readily from a cyclic periodate ester; Example 18.189) undergoes rapid cleavage with periodate,
the trans isomer (which does not readily from a cyclic periodate ester; Example 18.190) cleaves
218. (a) Wieland, H. Chem. Ber. 1912, 45, 484. (b) Barbier, P.; Locquin, R. Compt. Rend. 1913, 156, 1443.
(c) Wieland, H.; Schlichting, O.; Jacobi, R. Z. Physiol. Chem. 1926, 161, 80. (d) Shoppee, C.W. Ann. Rep. Chem. Soc.,
(London) 1947, 44, 184. (e) Baker, W.; Curtis, R.F.; McOmie, J.F.W.; Oliol, L.W.; Rogers, V. J. Chem. Soc. 1958, 1007.
219. (a) Malaprade, L. Bull. Soc. chim. France 1928 [iv], 43, 683. (b) Malaprade. L. Bull. Soc. chim. France 1934
[v], 1, 833. Reviews: (c) Jackson, E.L. Org. React. 1942, 2, 341. (d) Bunton, C.A. In Wiberg, K.B., Ed. Oxidation in
Organic Chemistry, Part B (Academic Press: NewYork, 1965), p. 367. (e) Perlin, A.S. In Augustine, R.L., Ed.
Oxidation (Marcel Dekker: New York, 1969), vol. 1, p. 189.
220. Reviews: (a) Rubottom, G.M. In Trahanovsky, W.S., Ed. Oxidation in Organic Chemistry, Part D. (Aca-
demic Press: New York, 1982), p. 1. (b) Aylward, J.B. Quart. Rev. Chem. Soc. 1971, 25, 407.
221. Chida, N.; Yoshinaga, M.; Tobe, T.; Ogawa, S. Chem. Commun. 1997, 1043.
222. Mulzer, J.; Scharp, M. Synthesis 1993, 615.

30 times more slowly.223 Periodate cleavage has been especially widely applied in the carbohy-
drate field, where the water solubility of the organic substrate is an advantage, and it has been
used in aqueous acetone for systems that do not have appreciable water solubility. Like the
periodate cleavage, the lead tetraacetate cleavage of diols appears to require a cyclic intermedi-
ate in most cases, and there is substantial evidence that the formation of the cyclic intermediate
is rate determining. However, there is also evidence that the cleavage may occur by an acyclic
mechanism where a cyclic intermediate cannot form, such as glycols 18.191 and 18.192, both of
which are cleaved by lead tetraacetate and neither of which is cleaved by periodic acid.224 For
this reason, the Criegee oxidation is sometimes preferred over the periodate method.
OH
OH O
O I OH (18.189)
OH O OH
OH O
OH OO I (18.190)
OH
HO OH
OH OH
OH OH
(18.191) (18.192)
Ozonolysis225 and Its Alternatives

Ozonolysis is one of the few reactions of alkenes that leads to the cleavage of both bonds of
the double bond—the π bond and the σ bond—without any rearrangements, so that one
can use it to locate double bonds within a molecule. This was one of its most important
applications historically. More recently, however, ozonolysis has been used as a means to
permit alkenes to be used as masked aldehydes.
In almost all of its reactions, ozone reacts as an electrophile. The currently accepted
mechanism for ozonolysis (Figure 18.11) was first proposed by Criegee.226 In the Criegee
Figure 18.11 The Criegee

mechanism of ozonolysis O
O O O retro- O O O
[3+2] O O [3+2] O O O [3+2] O
O O
primary carbonyl "normal"

ozonide oxide ozonide
223. (a) Price, C.C.; Kroll, T.J. J. Am. Chem. Soc. 1942, 60, 2727. For other papers on the effects of stereochem-
istry on the reaction rate, see also; (b) Criegee, R.; Büchner, E.; Walther, W. Ber. dtsch. chem. Ges. 1940, 73, 571.
(c) Bulgrin, V.C. J. Phys. Chem. 1957, 61, 702. (d) Bulgrin, V.C.; Dahlgren, G. J. Am. Chem. Soc. 1958, 80, 3883.
(e) Bunton, C.A.; Carr, M.D. J. Chem. Soc. 1963, 770.
224. Criegee, R.; Büchner, E.; Walther, W. Ber. dtsch. chem. Ges. 1940, 73, 571.
225. (a) Bailey, P.S. Ozonization in Organic Chemistry, (Academic Press: New York, 1981), vol. 1. (b) Belew, J.S.
In Augustine, R.L. Ed. Oxidation, (Marcel Dekker: New York, 1969), vol. 1, p. 262.
226. (a) Criegee, R. Rec. Chem. Progr, 1957, 18, 111. (b) Criegee, R. Angew. Chem. Int. Ed. Engl. 1975, 14, 745.
(c) Kuczkowski, R.L. Acc. Chem. Res. 1983, 16, 42. (d) Pryor, W.A.; Giamalva, D.; Church, D.F. J. Am. Chem. Soc.
1985, 107, 2793.
Rudolf Criegee (1902–1975) was educated at Würzburg (PhD, 1926). His independent work, which he
started at Marburg and continued after his move to Karlsruhe in 1930, concerned the oxidation of organic
compounds. For much more detail, see: Maier, G. Chem. Ber. 1977, 110, XXVII, Huisgen, R. (Gilde, H.G., transl.)
J. Chem. Educ. 1979, 56, 369.

mechanism, ozone, a 1,3-dipolarophile, first adds to the alkene in a 1,3-dipolar cycloaddi-

tion (also termed a [3 + 2]-cycloaddition) to give the primary ozonide, a 1,2,3-trioxolane.
This highly unstable intermediate undergoes a retro-[3 + 2]-cycloaddition, or [3 + 2]-
cycloreversion, to generate a carbonyl compound and a new 1,3-dipolarophile known as a
carbonyl oxide. The final step of the reaction is a second 1,3-dipolar cycloaddition to give
the 1,2,4-trioxolane, or “normal” ozonide. Note how all three reactions in this sequence
are pericyclic reactions.
Ozonides are stable compounds, but most decompose explosively when heated or sub-
jected to shock. Although there are some known ozonide natural products, one seldom
isolates the ozonide itself, but oxidizes or reduces it prior to isolation of the products.
Depending on the isolation procedure, one may use ozonolysis of alkenes to prepare
carboxylic acids, aldehydes, or alcohols. By far the most common isolation procedure in-
volves the addition of dimethyl sulfide, which reduces the ozonide to a pair of carbonyl
compounds (Example 18.194). Reduction with sodium borohydride gives a pair of alco-
hols instead (Example 18.193). Alternatively, the ozonide may be oxidized with hydrogen
peroxide or a peracid to give the carboxylic acid (Example 18.195). Oxidative workup also
leads to oxidation of aldehyde products to the carboxylic acid. Despite its reactivity, many
common functional groups are resistant to oxidation by ozone. Among these are ethers,
ketones, nitriles, amides, esters, and carboxylic acids.
NaBH4
OH + HO (18.193)
MeOH
R OR
O R R
Me2S
CHO + (18.194)
O
O O R R
R R
relative rate of ozonolysis

H2O2
CO2H + (18.195) R
O
HCO2H
R R
Electron-rich alkenes react most rapidly, and the more substituted usually react more
R
rapidly. Trans-disubstituted alkenes tend to react more rapidly than their cis-disubstituted R
isomers. The approximate order of reactivity is shown for a series of alkenes. As shown by
R R
Examples 18.196 and 18.197, it is possible to achieve selective cleavage of one π bond in a
diene by limiting the amount of ozone. R
OMe
R
1) O3, MeOH, –78°C CO2Me 227 O
(18.196)
2) Me2S CHO
1) O3, CH2Cl2
py, –78°C O 228
(18.197)
2) Et3N CHO
Ozone is a powerful oxidant that can attack aromatic rings, giving the α-dicarbonyl
products that would be expected from the Kekulé structures following the reduction of
227. Corey, E.J.; Katzenellenbogen, J.A.; Gilman, N.W.; Roman, S.A.; Erickson, B.W. J. Am. Chem. Soc.
1968, 90, 5618.
228. (a) Knöll, W.; Tamm, C. Helv. Chim. Acta 1975, 58, 1162. (b) Heath, R.R.; Doolittle, R.E.; Sonnet, P.E.;
Tumlinson, J.H. J. Org. Chem. 1979, 45, 2910. (c) Griesbaum, K.; Hilß, M.; Bosch, J. Tetrahedron 1996, 52, 14813.

the ozonide. An effective alternative reaction for the cleavage of alkenes that does not
affect aromatic rings is the Lemieux-Johnson oxidation.229
In this reaction, the alkene is treated with a catalytic amount of osmium tetroxide in
the presence of sodium metaperiodate. The periodate functions in much the same way as
the co-oxidants in the catalytic osmium tetroxide hydroxylations discussed earlier—it
cleaves the osmate ester and regenerates the osmium tetroxide. However, rather than al-
lowing the diol to be isolated, as do such co-oxidants as sodium chlorate, the sodium
periodate cleaves the diol to give aldehydes and ketones. Thus, the Lemieux-Johnson oxi-
dation is the equivalent of ozonolysis followed by reduction of the ozonide with dimethyl
sulfide. In certain cases (e.g., Example 18.198230), the Lemieux-Johnson oxidation is supe-
rior to selective ozonolysis.
Using periodate as the oxidant to cleave the osmate ester (e.g., Example 18.198) gives al-
dehydes when one end of the alkene is monosubstituted (e.g., cyclohexene gives hexanedial as
the oxidation product under Lemieux-Johnson conditions). The alkene can be converted to
the carboxylic acids by replacing the periodate oxidant with Oxone®; trans-stilbene, for ex-
ample, is oxidized by this reagent to benzoic acid.231 The reagent is selective for electron-rich
alkenes, so nootkatone can be oxidized to the diketone shown in Example 18.199.
O
O O
O O
OsO4, NaIO4
O O (18.198)
dioxane-H2O
78%
OH O O OH O O
OsO4 (0.01 eq) O

Oxone® (4 eq) (18.199)
DMF
O (60%) O
Earlier, we discussed ruthenium tetroxide,232 a much more powerful oxidant, and its use
in oxidizing alcohols to acids. This reagent is reactive enough to cleave both bonds (σ and π)
of an alkene to give carboxylic acids and ketones instead of aldehydes and ketones as prod-
ucts. In contrast to sodium periodate, ruthenium tetroxide also rapidly oxidizes α-dicarbonyl
compounds with cleavage of the carbon-carbon bond to give carboxylic acid derivatives.
OAc OAc
RuO4 (cat.)
NaIO4
(18.200)
H2O, Me2CO
80% HO2C
O O
229. Pappo, R.; Allen, D.S., Jr.; Lemieux, R.U.; Johnson, W.S. J. Org. Chem. 1956, 21, 478.
William Sumner Johnson (1913–1995) was educated at Amherst College (AB, 1936) and Harvard (AM,
1938; PhD, 1940). His academic career started at Amherst (1936) and continued at Wisconsin (1940) and Stan-
ford (1960). For more biographical detail, see: Stork, G. Biogr. Mem. 2001, 80, 1.
Raymond Urgel Lemieux (1920–2000) took his PhD in 1946 (McGill). After a year at Ohio State, he re-
turned to Canada. His career took him from Saskatchewan (1947) to the National Research Council (1949)
to the University of Ottawa (Dean, 1954), to Alberta, where he retired in 1985. In 1967 he was made a Fellow
of the Royal Society. For more biographical information, see: Biogr. Mem. Fell. Roy. Soc. London 2002, 48, 251.
230. (a) Krohn, K.; Böker, N.; Flörke, U.; Freund, C. J. Org. Chem. 1997, 62, 2350. (b) Krohn, K. Eur. J. Org.
Chem. 2002, 1351.
231. Travis, B.R.; Narayan, R.S.; Borhan, B. J. Am. Chem. Soc., 2002, 124, 3824.
232. Review: Lee, D.G.; van den Engh, M. In Trahanovsky, W.S., Ed. Oxidation in Organic Chemistry, Part B
(Academic Press: New York, 1973), p. 177.

O O
RuO2, NaIO4 (18.201)

Me2CO, H2O HO2C
(68%) HO2C
HO
Example 18.200, the oxidation of testosterone acetate,233 is testament to the power of
this reagent: the double bond in this compound is unaffected under Lemieux-Johnson
conditions. This reagent can also attack aromatic rings, which are oxidized to carboxylic
acids, as illustrated by the oxidation of estrone (Example 18.201).234 Ethers are oxidized by
this reagent to esters, and amines are oxidized to amides. Its reactivity limits its use to
solvents such as carbon tetrachloride, water, and aqueous acetone. The substitution in the
aromatic ring does affect the outcome of the oxidation, as shown by the series of reactions
in Example 18.202. When the para substituent is strongly electron withdrawing (e.g., NO2,
CO2Me, or 2-pyridyl), the starting ester is recovered unchanged.235
X
RuO4, NaIO4 CO2H

(18.202)
CCl4, MeCN, H2O Me OAc
Me OAc
Reaction Synopses
Oxidative Cleavage of 1,2-Diols
R R' R R'
[O]
HO OH O + O
R R' R R'
Reagents: HIO4; Pb(OAc)4, CH3CO2H; CrO3; etc.

In cyclic systems, cis-diols react faster than their
trans isomers.
Ozonolysis
R R' R R'
O + O
R R' R R'
Reagents: (1) O3, CH2Cl2, −78°C; (2) Zn, H2O;

or (1) O3, CH2Cl2, −78°C; (2) Me2S; etc.
or (1) O3, CH2Cl2, −78°C; (2) CH3CO2OH; etc.
Lemieux-Johnson Oxidation Reactions
R R' R R'
O + O
R R' R R'
Reagents: OsO4, NaIO4, CCl4, H2O; etc. to give aldehydes;

or OsO4, Oxone®, DMF; etc. to give acids
(continues)
233. Patiak, D.M.; Bhat, H.B.; Caspi, E. J. Org. Chem. 1969, 34, 112.
234. Piatak, D.M.; Herbst, G.; Wicha, J.; Caspi, E. J. Org. Chem. 1969, 34, 116.
235. Kasai, M.; Ziffer, H. J. Org. Chem. 1983, 48, 2346.

Ruthenium Tetroxide Oxidation

R R' R R'
O + O
R H R OH
Reagents: RuO4, CCl4; RuO4, Me2CO, H2O;

or (RuO2 or RuCl3), NaIO4, CCl4, H2O
Worked Problem
18-4 What are the major products of the following reactions?
H
1) O3, CH2Cl2, –78°C MeO OsO4, NaIO4
(a) 2) Zn, H2O, AcOH
(b) MeO
H
RuO2, Me2CO 1) O3, CH2Cl2, –78°C

(c) NaIO4, H2O
(d) 2) NaBH4, MeOH
O N
H H
OsO4, CCl4 RuO2, Me2CO

(e) NaIO4, H2O
(f) NaIO4, H2O
O
§Answers below.
Problems
18-12 The oxidative cleavage of meso-2,3-butanediol by lead tetraacetate and periodic

acid occurs much more slowly than the oxidative cleavage of the (±)-isomer under
the same reaction conditions. Suggest a reason why this should be so (it will help
to use models here).
18-13 What reagent or reagents should be used to complete each of the following
transformations? Where more than one reagent can be used to complete the
CO2H
(a) CHO + (b) MeO CHO (c)
O O N CO2H
H
CHO
HO HO2C CO2H
(d) (e) (f)
CO2H
CHO
(a) The reduction of the ozonide by zinc in acetic acid gives the aldehyde and/or ketone. (b) This is a straight-
forward Lemieux-Johnson cleavage of the alkene π bond. (c) The ruthenium tetroxide generated by oxidation
of the ruthenium dioxide will cleave the double bonds to generate carboxylic acids. (d) Reduction of the ozonide
with sodium borohydride gives the primary alcohol rather than the aldehyde. (e) This Lemieux-Johnson oxida-
tion is straightforward. (f) The α-dicarbonyl compounds formed by the initial oxidation of the alkene π bonds
are further oxidized with C—C cleavage to carboxylic acids.

transformation, give all options and suggest which reagent may be best
(with reasons).
OH O
O O O O
(a) (b)
OH O
OH OHC OH
O
(c) OMe MeO2C
OMe
MeO2C CO2Me
18.10 Oxidative Substitution of Carbon-Hydrogen s Bonds
Oxidative substitution of a carbon-hydrogen bond is one of the “holy grails” of organic

synthesis, especially when the position is unactivated. Although progress has been made
in that arena, by far the greatest number of oxidative substitution reactions currently
known involve unsaturated substrates, so that is where we will start.
The Wacker Oxidation and Related Reactions

The oxidation of an alkene to an enol derivative by replacement of the vinyl hydrogen with
oxygen is known as the Wacker oxidation. In the classical Wacker oxidation, the enol or
enol acetate is formed by oxopalladation of the alkene, followed by β-hydride elimination.
The reaction was first used for the industrial oxidation of ethylene to acetaldehyde236 but is
generally applicable to the conversion of terminal alkenes to methyl ketones (e.g., Example
18.203) by way of the corresponding enol. The most common reagent for carrying out the
Wacker oxidation is a mixture of palladium (II), with copper (I) or copper (II) as a catalyst
for reoxidation of the palladium to the active +2 oxidation state, with molecular oxygen
as the stoichiometric oxidant.237 The mechanism has been studied extensively, and the
catalytic cycle currently accepted for the Wacker process is shown in Figure 18.12. Al-
though it had originally been proposed that the hydroxylation of the double bond was
accomplished by intramolecular migration of OH from palladium to carbon,238 it is now
generally accepted that the hydroxypalladation occurs by addition of water to the η2 alkene
complex (18.204) with trans stereochemistry.239
H PdCl2, CuCl, O2 O
DMF, H2O (18.203)
C8H17 C8H17
(65-73%)
Oxidation Adjacent to π Bonds

Allylic Halogenation
Historically the most common allylic oxidation reaction of alkenes has been halogenation.
This can be carried out using the halogen itself, but it is more often achieved by using
a halogen surrogate such as N-bromosuccinimide. As we have already seen (in the
236. (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Ruttinger, R.; Kojer, H. Angew. Chem. 1959, 71, 176.
(b) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, J.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80.
237. Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth., Coll. Vol. VII 1990, 137.
238. Henry, P.M. Acc. Chem. Res. 1973, 6, 16.
239. Bäckvall, J.-E.; Åckermark, B.; Ljunggren, S.O. J. Chem. Soc., Chem. Commun. 1977, 264.


O2, H R
cycle of the Wacker oxidation
PdIIL2
of 1-alkenes R
H2O L2PdII (18.204)
Cu+
Cu2+ H2O:
L2Pd0
R
H (18.205)
R R HO PdIL2
O HO
orey-Kim oxidation of alcohols), N-halosuccinimides are just such a convenient replace-

C
ment for the halogen itself.240 The favored reagent for allylic bromination is NBS,241 which
is a crystalline solid that reacts with alkenes in a non-polar solvent in the presence of a free
radical initiator to give the allylic bromide (e.g., Example 18.206). The advantages of
avoiding the toxicity and corrosiveness of the free halogen are improved by the fact that
the by-product of the NBS oxidation is succinimide, which is neutral, rather than hydro-
gen bromide. Thus, side reactions caused by excess acid are also avoided.
NC AcO NC AcO
NBS, CCl4 242

(18.206)
∆ Br
MeO2C MeO2C
The brominating agent under these conditions is actually still elemental bromine,243
which is formed by the rapid ionic reaction between the NBS and hydrogen bromide
(Example 18.207; the HBr probably comes from hydrolysis of the NBS by a trace of water).
The reaction proceeds only as long as there is a trace of hydrogen bromide present. More
recently, lithium bromide has been used as a reagent to convert NBS to molecular bromine.
O O
N Br + HBr N H + Br2 (18.207)
O O
N-bromosuccinimide succinimide
Allylic Oxidation of Alkenes to Give Alcohols, Esters, and Enones

Allylic bromination has been by far the most commonly used method for the allylic oxi-
dation of alkenes. However, the very reactivity of the allyl bromides produced often results
in side reactions, leading to unsatisfactory yields of the desired product. For example,
most NBS oxidations give yields below 80%, and many give yields below 40%. It is partly
240. Corey, E.J.; Kim, C.U. J. Am. Chem. Soc. 1972, 94, 7586.
241. Djerassi, C. Chem. Rev. 1948,43, 271.
242. Trost, B.M.; Shuey, C.D.; DiNinno, F., Jr.; McElvain, S.S. J. Am. Chem. Soc. 1979, 101, 1284.
243. (a) Adam, J.; Gosselain, P.A.; Goldfinger, P. Nature 1953, 171, 704. (b) Adam, J.; Gosselain, P.A.; Goldfin-
ger, P. Bull. soc. chim. Belges 1956, 65, 533. (c) Skell, P.S.; Tuleen, D.L.; Readio, P.D. J. Am. Chem. Soc. 1963, 85,
2850. (d) Walling, C.; Rieger, A.L.; Tanner, D.D. J. Am. Chem. Soc. 1963, 85, 3129. (f) Russell, G.A.; Desmond,
K.M. J. Am. Chem. Soc. 1963, 85, 3139. (g) Pearson, R.E.; Martin, J.C. J. Am. Chem. Soc. 1963, 85, 3142.

for this reason that there has been considerable effort expended to develop alternative
methods for the oxidation of alkenes at the allyl position. Oxidation at allylic positions
can be arranged to give a wide range of substitution products by taking advantage of
π-allylpalladium (II) complexes (η3-allylpalladium complexes). In the presence of an ex-
ternal base, such as pyridine, the η2 palladium (II) complex initially formed in the Wacker
process can be deprotonated to give the η3-allylpalladium (II) complex. This complex can
then be intercepted by a wide range of nucleophiles, including oxygen and nitrogen nuc-
leophiles, (oxidative heterocyclization244), as well as electron-rich π bonds such as those
in the heterocyclic ring of furans and indoles (see Examples 18.208 to 18.210). The attack
of the nucleophile gives a new η3-allylpalladium (II) complex that provides the product
where the allylic hydrogen has been substituted by a nucleophile, in what is a formal oxi-
dation process with oxygen as the stoichiometric oxidant.
HO O O
Pd(OAc)2 (0.1 eq)
air 245
(18.208)
MeOH–H2O (6:1)
25°C OMe OMe
OMe
3 : 1
Ts Ts
HN Pd(OAc)2 (0.05 eq)
N 246
py (0.1 eq) (18.209)
PhMe, 80°C
Pd(OAc)2 (0.01 eq), O2
CO2Et (0.4 eq)

N 247
(18.210)
EtCMe2OH-HOAc (4:1)
N N
Me (82%) Me
Another successful method for the oxidation of allylic C—H bonds involves treating
the alkene with a tert-butyl perester and a cuprous salt; the product of this reaction is the
corresponding allyl ester (e.g., Example 18.211).248 The reaction is believed to involve a
copper (III) species such as the one in Example 18.212, formed by the addition of an allyl
radical to copper (II) benzoate.249 This then undergoes an intramolecular rearrangement
to give the observed product. This has the consequence that where two regioisomeric
esters are possible, the product with the less substituted double bond tends to predominate
(but not always; see Example 18.213).250 By the use of a chiral ligand for copper, this reac-
tion can be used to prepare chiral esters from alcohols.251
OCOPh
PhCO3But
(18.211)
CuBr, ∆
71-80%
244. Reviews: (a) Zeni, G.; Larock, R.C. Chem. Rev. 2006, 106, 4644. (b) Stoltz, B.M. Chem. Lett. 2004, 33,
362. (c) Stahl, S. S. Angew.Chem., Int. Ed. 2004, 43, 3400. (d) Sigman, M.S.; Schultz, M.J. Org. Biomol. Chem.
2004, 2, 2551.
245. Hosokawa, T.; Miyagi, S.; Murahashi, S.-I.; Sonoda, A. J. Org. Chem. 1978, 43, 2752.
246. Fix, S.R.; Brice, J.L.; Stahl, S.S. Angew. Chem. Int. Ed. 2002, 41, 164.
247. Ferreira, E.M.; Zhang, H.; Stoltz, B.M. Tetrahedron 2008, 6, 5987.
248. Pedersen, K.; Jakobson, P.; Lawesson, S.-O. Org. Syn., Coll. Vol. 5 1973, 70.
249. Kochi, J.K.; Bemis, A. Tetrahedron 1968, 24, 5099.
250. Rawlinson, D.J.; Sosnovsky, G. Synthesis 1972, 1.
251. (a) Andrus, M.B.; Chen, X. Tetrahedron 1997, 53, 16229. (b) Sekar, G.; DattaGupta, A.; Singh, V.K. J.Org.
Chem. 1998, 63, 2961. (c) Malkov, A.V.; Bella, M.; Langer, V.; Kocovsky, P. Org. Lett. 2000, 2, 3047.

R H R
Cu(I) O
O Cu(II)
Ph O
O
Ph O HO
(18.212)
R R
O O O Cu(III) Ln
O
Ph
Ph
AcO
CH3CO3Me
+ (18.213)
CuCl, PhCl OAc
70°C
83% 13%
A variation of this approach involves the oxidation of alkenes with palladium (II) ac-
etate in acetic acid and dimethyl sulfoxide (DMSO), with benzoquinone as the terminal
oxidant. In the traditional Wacker process, DMSO is absent, and the reaction gives ke-
tones or enol acetates. The addition of DMSO as cosolvent, however, or the use of a
bis-sulfoxide ligand for the metal, leads to the formation of allylic acetates. The ratio of
allylic isomers may be controlled by adjusting the reaction conditions, as shown in Exam-
ple 18.214.252 Sanford has reported regioselective palladium-catalyzed oxidation at the
benzylic hydrogen of heterocyclic aromatics by using the directing influence of a nitrogen
atom in the heterocycle (e.g., Example 18.215).253
OS SO
Ph Pd Ph OAc
AcO OAc OAc
(cat) + (18.214)
benzoquinone
solvent
Me2SO:AcOH, 1:1 40% 2%
CH2Cl2:AcOH (1:1) 8% 66%
Pd(OAc)2
PhI(OAc)2
(18.215)
AcOH, 100°C
N N
(88%)
AcO
Manganese (III) acetate has proved to be a particularly mild oxidant for the synthesis
of conjugated enones from alkenes, as shown in the oxidation of α-pinene to verbenone
(Example 18.216).254 The same oxidation can be accomplished by oxidation with molecular
oxygen in the presence of a cobalt (II) catalyst.255 An interesting dichotomy of reactivity
has been observed, depending on the exact nature of the cobalt (II) catalyst.256 The same
252. Chen, M.S.; White, M.C. J. Am. Chem. Soc. 2004, 126, 1346.
253. Dick, A.R.; Hull, K.L.; Sanford, M.S. J. Am. Chem. Soc. 2004, 126, 2300.
254. Shing, T.K.L.; Yeung, Y.-Y.; Su, P.L. Org. Lett. 2006, 8, 3149. (b)
255. Lajunen, M.; Koskinen, A.M.P. Tetrahedron Lett. 1994, 35, 4461.
256. Reddy, M.M.; Punniyamurthy, I.; Iqbal, J. Tetrahedron Lett. 1995, 36, 159.

reagent can be used for the regioselective oxidation of conjugated enones to give
α'-hydroxyketones.257 The oxidation of aromatic compounds by this reagent generally
proceeds by a free radical mechanism.258
Mn3O(OAc)9
(18.216)
t-BuOH
O2 O
Similar oxidations at allylic positions are accomplished by using tert-butyl hydroper-

oxide and a metal catalyst. Doyle and his coworkers have reported259 that, in the presence
of a rhodium (II) catalyst, this oxidant oxidizes the allylic position of alkenes by a free
radical mechanism to give conjugated carbonyl compounds. This has been especially
useful in the synthesis of conjugated dicarbonyl compounds (e.g., Example 18.217).260 The
regiochemistry of oxidation of ∆5-steroid derivatives with the catalytic reagents above
almost always gives the C-7 ketone. Crich has shown that this regiochemistry can be re-
versed when a fluorous seleninic acid and iodoxybenzene are used to effect the oxidation
(Example 18.218).261
OAc OAc
t-BuOOH,
Rh2(cap)4
(18.217)
H2O, 40°C
(68%)
O O
(cap = caprolactamate)
O
O O
C8F17SeO2H
(18.218)
PhIO2, PhCF3, ∆
(65%)
PhCO2 PhCO2
O
Selenium Dioxide Oxidations and Photosensitized Singlet Oxygen Oxidations

Oxidation at allylic and benzylic positions can also be accomplished using selenium di-
oxide (Example 18.219) or by the photosensitized ene reaction with singlet oxygen
(Example 18.220). In the selenium dioxide reaction, the products are allylic alcohols or
α,β-unsaturated carbonyl compounds, where the allylic hydrogen is replaced without
rearrangement of the double bond. The reaction with singlet oxygen gives the rearranged
hydroperoxide, which is usually reduced in situ. The mechanism of the reaction re-
mains elusive.262
SeO2 (0.1 eq)

Me3COOH OAc (18.219)
OAc OAc
OH
CHO
50% 5%
257. Tanyeli, C.; Iyigün, Ç. Tetrahedron 2003, 59, 7135.

258. Bryant, J.R.; Taves, J.E.; Maer, J.M. Inorg. Chem. 2002, 41, 2769.
259. (a) Choi, H.; Doyle, M.P. Org. Lett. 2007, 9, 5349. (b) McLaughlin, E.C.; Choi, H.; Wang, K.; Chiou, G.;
Doyle, M.P. J. Org. Chem. 2009, 74, 730.
260. Salvador has reported a similar oxidation using bismuth (III) as the catalyst in the presence of the clay,
montmorillonite K10, which facilitates the isolation of the product: Salvador, J.A.R.; Silvestre, S.M. Tetrahedron
Lett. 2005, 46, 2581
261. Crich, D.; Zou, Y. Org. Lett. 2004, 6, 775.
262. (a) Frimer, A,H. Chem. Rev. 1979, 79, 359. (b) Singleton, D.A.; Hang, C.; Szymanski, M.J.; Meyer, M.P.;
Leach, A.G.; Kuwata, K.T.; Chen, J.S.; Greer, A.; Foote, C.S.; Houk, K.N. J. Am. Chem. Soc. 2003, 125, 1319.

1) O2, hν, sens OH

MeOH
(18.220)
2) NaBH4, MeOH
The mechanism of the selenium dioxide oxidation (Figure 18.13) involves an initial
ene reaction of the alkene with selenium dioxide (18.221), followed by [2,3]-sigmatropic
rearrangement (18.222) of the seleninic acid and hydrolysis of the selenium-oxygen
bond of the product (18.223) to give the alcohol.263 This reaction may be made cata-
lytic in selenium dioxide by using tert-butyl hydroperoxide as a co-oxidant.264 The
oxidation of 2-methyl-2-alkenes exhibits a useful selectivity for the formation of the E
product.265
O Dehydrogenation of Alkenes and Dienes

Cl CN The dehydrogenation of alkenes and dienes (especially 1,3- or 1,4-cyclohexadienes) can be
DDQ readily accomplished by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
Cl CN (DDQ). This quinone is a powerful oxidant that can lead to insertion of a double bond in
O
conjugation with an aromatic ring.
The substrate must, however, have a benzylic or allylic hydrogen, or a carbonyl group
with an available α-hydrogen. An example of this reactivity is provided by the synthesis of
the chromene (Example 18.224).266 The same reagent can be used to introduce a double
bond in conjugation with a carbonyl group267 and the oxidative deprotection of benzyl268
and electron-rich silyl269 ethers.
OMe OMe
DDQ (18.224)
MeO O MeO O
Figure 18.13 Mechanism of R1

selenium dioxide oxidation H (18.221) R1
of alkenes O
R2 R3 Se OH
O R2 Se
R3
O
R1
O
(18.222) R2 Se
R3
R1 R1 OH
OH H2O O
Se
R2 R3 R2 R3 OH
(18.223)
263. Sharpless, K.B.; Lauer, R.F. J. Am. Chem. Soc. 1972, 94, 7154.
264. Umbreit, M.A.; Sharpless, K.B. J. Am. Chem. Soc. 1977, 99, 5526.
265. (a) Bhalerao, U.T.; Rapoport, H. J. Am. Chem. Soc. 1971, 93, 4835. (b) Büchi, G.; Wüerst, H.W. Helv.
Chim. Acta 1967, 50, 2440.
266. Ahluwalia, V.K. ; Jolly, R.S. Synlett, 1982, 74.
267. Walker, D.; Hiebert, J.D. Chem. Rev., 1966, 66, 153.
268. Wang, W.; Li, T.; Attardo, G. J. Org. Chem., 1997, 62 , 6598.
269. Paterson, I.; Cowden, C.J.; Rahn, V.S.; Woodrow, M.D. Synlett, 1998, 915.

Worked Problem
18-5 What is (are) the major organic product(s) formed when indane is treated with
each of the reagents in the list? Assume that one equivalent of the reagent is used.
Reagents:
(a) Br2, hν
(b) NBS, ROOR, CCl4, ∆ or hν
(c) PhCO3CMe3, CuBr, ∆
(d) SeO2, Me3COOH
(e) DDQ, CH2Cl2
§
Answers below.
18-6 What is the major organic product when indene is treated with each of the re-
agents in the list below?
Reagents:
(a) PdCl2, CuCl, O2, DMF, H2O
(b) Mn(OAc)3, Me3COH, O2
(c) (PhSOCH2)2Pd(OAc)2, benzoquinone, AcOH:Me2SO (1:1)
¶
Answers below.
Drill Exercises
What is (are) the major organic product(s) formed when each of the alkenes in
the first list below is treated with each of the reagents in the second list? Assume
that one mole equivalent of the oxidant is consumed unless otherwise noted.
Alkenes:
(a) (b) (c) (d)
(continues)
§ Answers to Worked Problem 8-5:

Br Br OCOPh OH
(a) (b) (c) (d)
(e)
¶ Answers to Worked Problem 8-6:

O O OAc
(a) (b) (c)

(Drill Exercises continued)
H OH
(e) (f) (g) (h)
H
Reagents:
(a) Br2, hν
(b) NBS, ROOR, CCl4, ∆ or hν
(c) PhCO3CMe3, CuBr, ∆
(d) SeO2, Me3COOH
(e) PdCl2, CuCl, O2, DMF, H2O
(f) Mn(OAc)3, Me3COH, O2
(g) PhSOCH2)2Pd(OAc)2, benzoquinone, AcOH:CH2Cl2 (1:1)
Oxidation at the α Carbon of Carbonyl Compounds and Nitriles

The α carbon of carbonyl compounds shares much of the reactivity of the allyl position of
alkenes, and this extends to the oxidation at this position. Replacement of one of these hy-
drogens by a heteroatom is often the first step in introducing a π bond in conjugation with
the carbonyl group. The most useful oxidative substitutions at the α carbon involve replace-
ment of hydrogen by halogen, sulfur, or selenium. All three of these reactions occur through
the enol or enolate anion of the carbonyl compound, as illustrated in Example 18.225.
H O
O OH
(18.225)
X O
X = Cl, Br, I, SR, SeR
Halogenation is usually carried out in acid solution, through the enol as the reactive spe-
cies (formation of the enol is usually the rate-limiting step). Treatment of a ketone with the
halogen, or with the halogen in acetic acid, gives controlled monohalogenation to give the
α-haloketone.270 The halogen may also be generated in situ from the N-halosuccinimide or by
oxidation of the halide anion with a secondary oxidant (such as bromate; Example 18.226271).
O O
Br
NaBrO3, HBr
HOAc
(18.226)
(95%)
N N
Cl Cl
270. (a) Levene, P.A. Org. Syn., Coll. Vol. 3 1943, 88. (b) Cowper, R.M.; Davidson, L.H. Org. Syn., Coll. Vol. 3
1943, 480. (c) Newman, M.S.; Farbman, M.B.; Hipsher, H. Org. Syn. 1945, 22, 22.
271. Winstein, S.; Jacobs, T.L.; Linden, G.B.; Seymour, D.; Levy, E.F.; Day, B.F.; Robson, J.H.; Henderson,
R.B.; Florsheim, W.H. J. Am. Chem. Soc. 1946, 68, 1831.

The α-bromination of carboxylic acids carried out using bromine in the presence of a
catalytic amount of red phosphorus is known as the Hell-Volhard-Zelinskii reaction.272
The reaction actually proceeds through an acid bromide or anhydride formed by the reac-
tion of the carboxylic acid with phosphorus tribromide formed in situ by the reaction be-
tween bromine and phosphorus (Example 18.227). The acid derivative plays an important
role for two reasons. One, it is much more readily enolized than the carboxylic acid or the
anhydride. Two, the bromination itself occurs by addition of bromine to the enol
double bond.
PBr3 Br2 Br
(18.227)
O OH Br O Br OH O OH
The halogenation of carbonyl compounds under basic conditions proceeds through

the enolate anion, which leads to polyhalogenation, because the initial monohalogenated
product compound is more acidic than the starting carbonyl compound. In methyl ke-
tones, this results in the formation of α,α,α-trihalomethyl ketones that react with the
base to give the carboxylic acid with one less carbon and the haloform.273 Controlled
hydroxylation of an enolate anion, on the other hand, can be accomplished using the
MoO5•py•HMPA complex (MoOPH, HMPA = hexamethylphosphoramide; Exam-
ple 18.228).274
1) LDA, THF
OH
–23°C
(18.228)
2) MoOPH
O O
(77%)
5:1 endo:exo
A more controlled oxidation at the α carbon of carbonyl compounds is provided by

selenylation and sulfenylation. The treatment of a carbonyl compound with two equiva-
lents of a strong base (typically a hindered lithium amide) and phenylselenyl chloride gives
the conjugate base of the α-phenylseleno derivative. The reagents used to introduce the
selenium into the molecule depend on the nature of the carbonyl group itself. With esters,
diselenides (RSeSeR) can be used (e.g., Example 18.229), but with ketones, whose enolate
anion is less basic, selenyl halides (RSeX) must be used to avoid an unfavorable equilib-
rium (e.g., Example 18.230).275
HO H HO H
PhSeSePh, KH
(18.229)276
OH THF-DMF (9:1) PhSe OH
MeO2C O MeO2C O
O O
MeO MeO
1) LDA, THF
–78°C
O O (18.230)277
2) PhSeCl
SePh
O H O H
O O
272. (a) Hell, C. Ber. dtsch. chem. Ges. 1881, 14, 891. (b) Volhard, J. Ann. Chem. Pharm. 1887, 242, 141.
(c) Zelinsky, N. Ber. dtsch. chem. Ges. 1887, 20, 2026. (d) Watson, H.B. Chem. Rev. 1930, 7, 180.
273. (a) Lieben, A. Ann. Chem. Pharm. (Suppl.) 1870, 7, 218. (b) Fuson, R.C.; Bull, B.A. Chem. Rev.
1934, 15, 275.
274. (a) Vedejs, E.; Engler, D.A.; Telschow, J.E. J. Org. Chem. 1978, 43, 188. (b) Vedejs, E.; Telschow, J.E. J. Org.
Chem. 1976, 41, 740. (c) Vedejs, E.; Larsen, S. Org. Syn. 1990, Coll. Vol. 7, 277.
275. Reich, H.J.; Renga, J.M.; Reich, I.L. J. Am. Chem. Soc. 1975, 97, 5434.
276. Lombardo, L.; Mander, L.N.; Turner, J.V. J. Am. Chem. Soc. 1980, 102, 6626.
277. (a) Grieco, P.A.; Nishizawa, M.; Burke, S.D.; Marinovic, N. J. Am. Chem. Soc. 1976, 98, 1612. (b) Grieco,
P.A.; Nishizawa, M.; Oguri, T.; Burke, S.D.; Marinovic, N. J. Am. Chem. Soc. 1977, 99, 5773.

The analogous reaction with a sulfur electrophile (Example 18.231) is sulfenylation.278

The sulfides produced can participate in several reactions similar to the selenides, al-
though the reactions usually require more vigorous conditions than the analogous sele-
nium reactions. For this reason, the selenium compounds are usually preferred unless cost
is a factor.
SMe
1) LICA, THF
–78°C
O O (18.231)278 (a)
2)MeSSMe
One situation where sulfenylation is particularly useful is the bis-sulfenylation reac-

tion (Example 18.232), where the reaction is used to introduce a carbonyl group α to an
existing carbonyl or cyano group by making a dithioketal. Liberation of the new carbonyl
group from the dithioketal is effected by hydrolysis accompanied by alkylation, oxidation,
or mercury desulfurization.279 The reaction typically involves activating the α carbon by
preparing the hydroxymethylene compound, which then reacts with propylene dithioto-
sylate with concomitant loss of the formyl group to give the α-acyl-1,3-dithiane.
H 1) NaH, HCO2Et, PhH S H
r.t., 8 h
S (18.232)
O 2) TsSCH2CH2CH2STs O
KOAc, EtOH, ∆, 7 h
(85%)
Dehydrogenation of Saturated Carbonyl Compounds

Although the most obvious method for introducing a double bond into a position of con-
jugation with a carbonyl group is the β-elimination from an α-halocarbonyl compound,
itself prepared by halogenation as discussed above, the reaction is seldom easy to carry out
cleanly. The dehydrohalogenation of α-haloaldehydes and α-haloketones, especially, has
the potential for competing Favorskii rearrangement.280 A wide variety of bases have been
used to carry out this reaction, including magnesium oxide in DMF,281 calcium carbonate
in dimethylacetamide,282 lithium bromide and lithium carbonate in DMSO283 or DMF,284
lithium chloride in DMF,285 HMPA,286 and collidine (2,4,6-trimethylpyridine).287 Never-
theless, alternative methods for the dehydrogenation of carbonyl compounds have long
been the subject of research because of the unsatisfactory nature of the dehydrohalogena-
tion reaction and its potential for side reactions.
Until recently, the same dehydrogenation was almost invariably carried out by means of
the thermal syn elimination from sulfoxides and selenoxides obtained by oxidation of the
corresponding sulfides or selenides with peroxide-based oxidants (e.g., Example 18.233),288
278. (a) Trost, B.M.; Salzmann, T.N. J. Am. Chem. Soc. 1973, 95, 6840. (b) Seebach, D.; Teschner, M. Tetrahe-
dron Lett. 1973, 5113. (c) Zoretic, P.A.; Soja, P. J. Org. Chem. 1976, 41, 3587. (d) Gassman, P.G.; Balchunis, R.J.
J. Org. Chem. 1977, 42, 3236.
Reviews: (e) Trost, B.M. Pure Appl. Chem. 1975, 43, 563. (f) Caine, D. In Augustine, R.L. Carbon-Carbon
Bond Formation (Marcel Dekker: New York, 1979), vol. 1, p. 278.
279. (a) Woodward, R.B.; Patchett, A.A.; Barton, D.H.R.; Ives, D.A.J.; Kelly, R.B. J. Chem. Soc. 1957 , 1131.
(b) Woodward, R.B.; Pachter, I.J.; Scheinbaum, M.L. J. Org. Chem. 1971 , 36, 1137. (c) Marshall, J.A.; Roebke, H.
J. Org. Chem. 1969, 34, 4188.
280. (a) Favorskii, A. Zh. Russ. Fiz.-Khim. Obshch. 1905, 37, 643. (b) Wallach, O. Justus Liebigs Annn. Chem.
1918, 414, 296. (c) Kende, A.S. Org. React. 1960, 11, 261.
281. Miyano, M.; Dorn, C.R. J. Org. Chem. 1972, 37, 268.
282. Green, G.F.H.; Long, A.G. J. Chem. Soc. 1961, 2532.
283. Grimshaw, J.; Grimshaw, J.T.; Juneja, H.R. J. Chem. Soc., Perkin Trans. 1 1972, 50.
284. Payne, T.G.; Jefferies, P.R. Tetrahedron 1973, 29, 2575.
285. Taylor, K.G.; Hobbs, W.E.; Clark, M.S.; Chaney, J. J. Org. Chem. 1972, 37, 2436.
286. Hanna, R. Tetrahedron Lett. 1968, 2105.
287. Shoppee, C.W.; Roy, S.K.; Goodrich, B.S. J. Chem. Soc. 1961, 1583.
288. Hove, T.H.; Kurth, M.J. J. Org. Chem. 1978, 43, 3693.

or in steroidal systems especially, by dehydrogenation with DDQ. However, the last decade
has seen a strong move toward catalytic reactions using more benign terminal oxidants. This
has extended to the dehydrogenation of saturated carbonyl compounds to their conju-
gated analogs.
H 1) LDA, THF, –78°C H
O 2) PhSeBr O
O O (18.233)
3) H2O2, THF, 0°C
(60%)
In 1978, Saegusa reported a method, now known as the Saegusa oxidation, for dehy-
drogenating a ketone to give the conjugated enone by treating the trimethylsilyl enol ether
with palladium (II) chloride in the presence of a hydrogen atom acceptor—typically a
benzoquinone derivative.289 On the small scale, it has been found to be more convenient to
carry the reaction out using palladium (II) acetate as the stoichiometric oxidant. Its mild
conditions have made the reaction a popular method for introducing unsaturation into a
ketone in complex systems, as illustrated by Examples 18.234 to 18.237.
OSiMe3 O
Ph(OAc)2 (0.1 eq) 294
(18.234)
O2, Me2SO, 75 h
O O
(85%)
O O
O O
O 1) NaHDMS, Et3SiCl O 290

(18.235)
TBSO TBSO
2) Pd(OAc)2
(61%)
O O
O O
O O
1) LHDMS, Me3SiCl 291

CO2Me CO2Me (18.236)
2) Pd(OAc)2, MeCN
Boc Boc
O N O N
O O
O 1) LTMP, Me3SiCl O
THF, –78°C 292
(18.237)
H 2) Pd2(dba)3•CHCl3 H
H2C=CHCH2O)2CO
PMBO MeCN PMBO
H OTIPS (90%) H OTIPS
The reaction pathway (Figure 18.14) is similar to that of the Wacker oxidation of
alkenes. It involves electrophilic addition of the palladium to the electron-rich enol ether
π bond to give the oxonium ion 18.238, which is then desilylated to give the ketone 18.239.
β-Hydride elimination from this σ complex leads to the π complex 18.240, from which
the unsaturated ketone and acetic acid are liberated, to produce a palladium (0) species.293
289. (a) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011. (b) Review: Muzart, J. Eur. J. Org. Chem. 2010, 3779.
290. Wilson, E.M.; Trauner, D. Org. Lett. 2007, 9, 1327.
291. (a) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K. Science 2004, 305, 495. (b) Miyashita, M.
Pure Appl. Chem. 2007, 79, 651.
292. Oshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546.
293. Bäckvall, J.E.; Akermark, B.; Ljunggren, S.O. J. Am. Chem. Soc. 1979, 101, 2411.

Figure 18.14 Reaction OAc

pathway proposed for the Me3Si
Saegusa oxidation O H O
Me3Si
O
PdII
AcO PdII OAc OAc
PdII
OAc (18.239)
(18.238)
O O
Pd0 O
O
H PdII OAc
HOAc
(18.240)
Larock has reported that the palladium (0) product may be reoxidized to palladium (II)
using molecular oxygen if dimethylsulfoxide is used as the reaction solvent without added
acetate anion.294
Work by Tsuji has allowed the use of tris(dibenzylideneacetone)dipalladium (0), as in
Example 18.241, abbreviated Pd2(dba)3, as a catalyst for the reaction, with diallyl carbonate
as the oxidant. The reaction proceeds in acetonitrile solvent to give the conjugated prod-
uct. In other solvents, α-allylation is the major pathway.295 The procedure has been ex-
tended to the use of enol acetates and alkyl allyl carbonates. 296
Pd Ph
Pd (18.241)
Ph
O 3
Drill Exercises
Suggest two or more methods for carrying out each of the following
transformations.
O O
CO2Me CO2Me H H
O O
(a) (b)
O O
H H
O O
(c) (d)
O O
294. Larock, R.C.; Hightower, T.R.; Kraus, G.A.; Hahn, P.; Zheng, D. Tetrahedron Lett. 1995, 36, 2423.
295. (a) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 5635. (b) Minami, I.; Takahashi, K.;
Shimizu, I.; Kimura, T.; Tsuji, J. Tetrahedron 1986, 42, 2971.
296. Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 5639.

Me Me
(e) O O (f) O O
N N
Me Me
O O
O CO2Et O CO2Et
(g) (h)
O Ph O Ph
O O
(i)
MeO MeO
Reaction Synopses
Allylic Halogenation
R R
R R "X2" R R
R R
R H R X
Reagents: Br2, hν, Cl2, hν; etc.

or NBS, CCl4, ∆; NCS, CCl4, ∆; etc.
Allylic Oxidation
R R R
[O]
R R R R and/or R R
H H
R H R X R O
Reagents: RCO2OBut, Cu+, ∆ (R'=OCOR; with allylic rearrangement)

SeO2 (R' = H; without allylic rearrangement); SeO2,
Me3COOH; SeO2, NaOCl; etc.
R FSeO2H, PhIO2, PhCF3, ∆; But OOH, BiCl3, MeCN;
(similar reactions with Cu, Co, Mo, V, etc. as metal);
O2, hν, rose bengal (R'=OOH; with allylic rearrangement)
DDQ, CH2Cl2;
Mn3O(OAc)9, But OH, O2;
(PhSOCH2)2Pd(OAC)2, benzoquinone, solvent
(solvent = AcOH, Me2SO 1:1 allylic rearrangement)
(solvent = AcOH, Ch2Cl2 1:1 no allylic rearrangement);
O2, Co(py)2Br2, MeCN; or O2, CoL2, Me2CHCHO, MeCN
α-Halogenation
R R
R "X2" R
O O
R R
H X
Reagents: Br2, HOAc; Cl2, HOAc; etc. (halogenation)

(continues)

α-Selenylation and Sulfenylation

R R
R 1) Base R
O O
R 2) X-Y R
H X
Base: LDA, THF, −78°C; NaH, THF; KH, THF; etc.

X—Y: PhSeCl; PhSeBr; PhSeSePh; PhSCl;
PhSBr; RSSR
α-Hydroxylation
O R O R
OH
R R R R
Reagents: (1) LDA, THF, −23°C, (2) MoOPH

Dehydrogenation of Carbonyl Compounds
R R
R O [O] R O
R R R R
Reagents: (1) LDA, THF, −78°C, (2) RSeBr, (3) H2O2

or (1) LDA, THF, −78°C, (2) RSSR, (3) H2O2, (4) ∆
or (1) Br2, HOAc, (2) base, ∆
or DDQ, CH2Cl2; etc.
Dehydrosilylation of Enol Ethers (Saegusa Oxidation)
OSiR3 O
R R R R
Reagents: Pd(OAc)2, MeCN, p-benzoquinone; Pd(OAc)2, Me2SO, O2

or Pd(OAc)2, MeCN
or Pd2(dba)3•CHCl3, MeCN, (H2C=CH-CH2O)2CO
18.11 Oxidation of Alkanes
And now we return to the “holy grail.” One of the functions of cytochrome P450 in living
cells is the oxidation of hydrocarbons by direct insertion of an oxygen atom from molec-
ular oxygen into a C—H σ bond, while the flavin enzymes carry out dehydrogenation of
saturated alkyl chains. Finding catalytic methods to mimic these activities has been a
subject of intense research in the last decade or so.297 Significant research into catalytic
dehydrogenation has also been carried out in the first decade of the 21st century.298
The direct functionalization of alkanes presents a unique problem for organic chem-
ists because these hydrocarbons are unique in having neither an accessible HOMO nor an
accessible LUMO—they are neither nucleophilic nor electrophilic. All other organic
297. Reviews: (a) Ishihara, Y.; Baran, P.S. Synlett 2010, 1733. (b) Newhouse, T.; Baran, P.S. Angew. Chem. Int.
Ed. 2011, 50, 3362.
298. (a) Crabtree, R.H.; Mihelcic, J.M.; Quirk, J.M. J. Am. Chem. Soc. 1979, 101, 7738.

compounds have at least one accessible frontier orbital that renders them reactive toward
a complementary species.
The lack of an accessible HOMO or LUMO makes the C—H σ bond in alkanes one of the
least reactive bonds in a molecule. The effect is to make many (most) of the reactions involv-
ing its cleavage and replacement inherently endothermic. Oxidations of C—H σ bonds in
alkanes must therefore be coupled with a strongly exothermic reduction reaction, or they
must be carried out under conditions where energy is provided, often in the form of photons.
It is for these reasons that the number of reactions that allow selective oxidation of al-
kanes is actually quite small and that the earliest direct oxidation methods for alkanes were
based on free radicals. Following the formation of the initiating free radical (often effected by
photochemical cleavage of a suitable precursor), a free radical chain reaction will proceed to
completion, provided that the net reaction (the sum of the propagation steps) is exothermic.
The radical oxidation of alkanes by halogens was the first of these reactions to be studied in
depth. It was an essential part of the early work that led to the reactivity-selectivity princi-
ple.299 To date, the most successful functionalizations of unactivated C—H bonds have in-
volved intramolecular transfer of a hydrogen atom, and we will focus on these reactions here.
The transfer of a hydrogen atom from a remote site to a reactive center in the same
molecule has been known for more than a century. Intramolecular hydrogen atom trans-
fer300 to reactive free radicals provided the first reliable methods for the regioselective ox-
idation of alkane hydrocarbons. One of the first such reactions was the Norrish type II
photochemical reaction of ketones (Figure 18.15)301 In this reaction, the excited state of the
carbonyl group (18.243) abstracts a hydrogen from the γ carbon to generate the diradical
(18.244) that then collapses by radical recombination to give cyclobutanols (18.245) or by
fragmentation to generate an enol and an alkene (18.246).
It was established fairly early on that the most facile hydrogen atom transfer would
occur through a six-membered transition state.302 Work by Houk has shown that the trans-
fer occurs through a transition state where the angle O—H—C is large (> 150°).303 As we
saw in Chapter 14, this was put to use in spectacular fashion by Barton, whose synthesis of
aldosterone304 relied on a key intramolecular hydrogen atom transfer from an unactivated
methyl group to an alkoxy radical (Example 18.248) generated by photolysis of a nitrite
ester (Example 18.247).305 Trapping of the resultant alkyl radical (Example 18.249) by nitric
oxide gave a nitroso compound that tautomerized to the oxime (Example 18.250). When
Barton carried out this reaction, the product that crystallized in his reaction flask had a
market value of more than a million dollars. Of course, the price immediately plummeted.
H R H R R OH R Figure 18.15 The Norrish

O hν O OH type II photochemical
R
R R R reaction of a ketone
(18.242) (18.243) (18.244) (18.245)
OH R
+
R
(18.246)
299. Review: Pross, A. Adv. Phys. Org. Chem. 1977, 14, 69.
300. Review: Feray, L.; Kuznetsov, N.; Renaud, P. In Renaud, P.; Sibi, M.P., Eds. Radicals in Organic Synthesis
(Wiley-VCH: Weinheim, 2001), Part II, ch. 3.6, p.246.
301. (a) Norrish, R.G.W. Trans. Faraday Soc. 1937, 33, 1521. (b) Yang, N.C.; Yang, D.-H. J. Am. Chem. Soc.
1958, 80, 2913. (c) Wagner, P.J. Acc. Chem. Res. 1971, 4, 168. (d) Wagner, P.; Park, B-S. In Padwa, A., Ed. Organic
Photochemistry (Marcel Dekker: New York, 1991) Volume 11; Chapter 4.
302. Barton, D.H.R.; Hesse, R.H.; Pechet, M.M.; Smith, L.C. J. Chem. Soc., Perkin Trans. 1 1979, 1159.
303. (a) Dorigo, A.E.; Houk, K.N. J. Am. Chem. Soc. 1987, 109, 2195. (b) Dorigo, A.E.; McCarrick, M.A.; Lon-
charich, R.J.; Houk, K.N. J. Am. Chem. Soc. 1990, 112, 7508. (c) Ihmels, H.; Scheffer, J.H. Tetrahedron 1999, 55, 885.
304. Barton, D.H.R.; Beaton, J.M. J. Am. Chem. Soc. 1961, 83, 4083.
305. Barton, D.H.R.; Beaton, J.M.; Geller, L.E.; Pechet, M.M. J. Am. Chem. Soc. 1961, 83, 4076.

OAc OAc
HO
NO O N O
O HO
H
H H
hν
H H (34%) H H
O O
(18.247) (18.250)
•NO
OAc OAc
ON•
H O O
O
HO
H H
H H
H H H H
O O
(18.248) (18.249)
An alternative source of oxygen-centered free radicals that can abstract the remote
hydrogen is an alkyl hypoiodite, generated by oxidation of the alcohol with lead tetraace-
tate and iodine or, more recently, with diacetoxyiodobenzene and iodine (Example
18.251).306 These compounds undergo facile homolysis on irradiation to give the corre-
sponding alkoxy radicals that abstract the hydrogen atom from the γ position. The final
product of the hypoiodite reaction is usually a tetrahydrofuran derivative.
O O O
PhI(OAc)2, I2 HN HN
HN OH C6H12, hν (A) O O
TBSO N TBSO N
or O O (18.251)307
N
O
O Pb(OAc)4, CaCO3, I2 O O
O C6H12, hν (B)
O O O O O
TBSO method A: (25%) (43%)

method B: (19%) (24%)
Another reaction that involves the intramolecular transfer of a hydrogen atom from
an unactivated alkyl group to a reactive free radical is the Hofmann-Löffler-Freytag
reaction.308 The reaction involves the homolysis of an N-haloammonium ion, with hydro-
gen atom transfer to the nitrogen, followed by trapping of the radical by the halogen.
Treatment of the product with base provides a convenient entry into pyrrolidine rings.
The one limitation of the Hofmann-Löffler-Freytag reaction is that it requires strongly
acidic conditions; for example, the conversion of l-leucine to a 1:1 mixture of cis- and
trans-4-methyl-l-proline involves a Hofmann-Löffler-Freytag reaction carried out in 80%
sulfuric acid (Example 18.252).309
CO2Et 1) t-BuOCl, C6H6, 0-5°C

2) hν, H2SO4 (80%) CO2H (18.252)
NH2 N
3) NaOH, pH 7.0-7.4 H
306. (a) Concepción, J.I.; Francisco, C.G.; Hernández, R.; Salazar, J.A.; Suárez, E. Tetrahedron Lett. 1984, 25, 1953.
(b) Baker, R.; Brimble, M.A. J. Chem. Soc., Chem. Commun. 1985, 78. (c) Martin, A.; Salazar, J. A.; Suárez, E. J. Org.
Chem. 1996, 61, 3999. (d) Dorta, R.L.; Martin, A.; Salazar, J. A.; Suárez, E.; Prangé, T. Tetrahedron Lett. 1996, 37, 6021.
307. Kittaka, A.; Kato, H.; Tanaka, H.; Nonaka, Y.; Amano, M.; Nakamura, K.T.; Miyasaka, T. Tetrahedron
1999, 55, 5319.
308. (a) Hofmann, A.W. Ber. dtsch. chem. Ges. 1883, 16, 558. (b) Löffler, K.; Freytag, C. Ber. dtsch. chem. Ges.
1909, 42, 3427.
Reviews: (c) Wolff, M.E. Chem. Rev. 1963, 63, 55. (d) Neale, R.S. Synthesis 1971, 1. (e) Minisci, F. Synthesis
1973, 1. (f) Mackiewicz, P.; Furstoss, R. Tetrahedron 1978, 34, 3241. (g) Majetich, G. Tetrahedron 1995, 51, 7095.
309. Titouani, S.L.; Lavergne, J.-P.; Viallefont, P.; Jacquier R. Tetrahedron 1980, 36, 2961

The reaction can also be carried out under neutral conditions by the reaction of an
amide with iodine and lead tetraacetate. This reaction gives the N-iodoamide, which un-
dergoes homolysis on irradiation to give the reactive radical that then abstracts the hydro-
gen from the remote site. The use of phosphoramidates (e.g., Example 18.253) facilitates
this version of the reaction.
I2, Pb(OAc)4, hν
c-C6H12 (18.253)310
AcO AcO
N
HN O
P RO P
OR
OR RO O
Converting an amine to the N-bromo-trifluoroacetamide (Example 18.254) also provides

a much more reactive intermediate on photolysis; this has permitted the synthesis of selectively
brominated l-isoleucine derivatives in good yields by the Hofmann-Löffler-Freytag route.
Nitrogen-centered free radicals in which nitrogen is bonded to a third-row or higher element
such as tin tend to be much more reactive in hydrogen atom transfer reactions. These radicals
can be formed by reduction of azides with stannanes (e.g., Example 18.255).
NHCOCF3 NHCOCF3
1) MeCO2Br, CCl4, 23°C
(18.254)311
CO2Et 2) hν CO2Et
(90%) Br
O O
N3 1) Bu3SnH, AIBN TsHN 312
(18.255)
Bu3Sn 2) TsCl. Et3N
(53%)
Problems
18-14 The Barton synthesis of aldosterone gave the compound below as a second major
product from the nitrite ester irradiation. Write a mechanism to account for the
formation of this product.
OAc
AcO H O
H
HON H
18-15 The two oximes below are the major organic products of irradiation of the nitrite
ester shown. Provide a reasonable mechanism that accounts for the formation of
both products. [See Tetrahedron 1995, 51, 7095]
OH O
N
OH
(39%)
O
ON
O hν
OH O
N
OH
(38%)
(continues)
310. Betancor, C.; Conceptión, J.I.; Hernandez, R.; Salazar, J.A.; Suárez. E. J. Org. Chem. 1983, 48, 4430.
311. Rajender Reddy, L.; Subba Reddy, B.V.; Corey, E.J. Org. Lett. 2006, 8, 2819.
312. Kim, S.; Yeon, K.M.; Yoon, K.S. Tetrahedron Lett. 1997, 38, 3919.

18-16 Supply the structure of the expected organic product in each of the following
reactions:
O OEt
hν P hν
(a) (b) O O O
OEt
(20%) (28%)
O NO
NO O
H Cl
hν N hν
(c) N H2SO4
(d) CF3CO2H
Cl
(25%) (39%)
Me
References: (a) J. Am. Chem. Soc. 1975, 97, 430. (b) Tetrahedron Lett. 1989, 30, 3023. (c) J. Heterocycl.
Chem. 1975, 12, 289. (d) Chem. Pharm. Bull. 1985, 33, 3187.
Reaction Synopses
Intramolecular Hydrogen Atom Transfer
R R
OH OH
H X
R R
Reagents: (1) NOCl, pyridine; (2) hν (Barton reaction);

or (1) I2, Pb(OAc)4; (2) hν (hypoiodite reaction);
or I2, PhI(OAc)2, cyclohexane, hν; etc.
Products may react with base to give tetrahydrofuran derivatives.
Norrish Type II
R R
R
O hν OH O
or +
H
R
R R
Hofmann-Löffler-Freytag Reaction
Y X H H X Z
N R N R
R' R'
Reagents: (1) t-BuOCl; (2) hν (X=H2, Y=alkyl, Z=halogen);

or (1) MeCO2Br; (2) hν (X=O, Y=H, Z=halogen);
or Pb(OAc)4, I2, cyclohexane, hν (X=O, Y=H, Z=halogen)
Products may react with base to give pyrrolidine derivatives.
18.12 A Catalogue of Oxidation Reactions: Oxidation at a Glance
In this chapter, we have been concerned with oxidation reactions, and it is now time to put
all these reactions together in a way that will allow us to see the available choices. This is
done in Table 18.10, where oxidation methods and the functional groups that are incom-
patible with them are listed.

Table 18.10 Catalogue of Oxidation Reactions
Incompatible Other Limitations

Transformation Reagents Functional Groups or Features
PCC, PDC; CrO3, py; Thiol, sulfide, 1,2-diols

CrO3, py, CH2Cl2; etc. can be a problem; 1,3-
diols can be a problem
Swern reagent, Primary and
Moffatt-Pfitzner secondary amines can
reagent, Corey-Kim interfere by reacting
reagent, etc. with the
dehydrating agent
OH O
R R Al(O-t-Bu)3, Me2CO, ∆ Reaction is reversible
H
OH O TPP (Ley reagent) Often gives higher
R
R'
R yields than Swern
R'
oxidations
DMP, IBX, etc. Can be used in ionic
liquids; tolerates most
functional groups
TEMPO, NaOCl; etc.
Ag2CO3, celite Expensive—usually
reserved for small-
scale reactions
OH O Pd(OAc)2, py, O2 Reaction is catalytic in
R R
H
Pd; py is essential
OH O
R R
R' R'
Jones reagent 1,2- and 1,3-

Diols; aldehydes
KMnO4; Alkenes; aldehydes;
OH O Bu4NMnO4, PhH; etc. “purple benzene” is an
R R
OH extremely
OH O powerful oxidant
R R
R' R' CrO3 (cat), H5IO6 Same as Jones reagent
RuO4; RuCl3, Alkenes; ethers
NaIO4; etc. and amines
PDC, DMF
NaClO2, t-BuOH, Two-stage oxidation of
H2O, Me2C=CHMe primary alcohols is
O O preferred way to make
R R
H OH a carboxylic acid
Ag2O, NH3, H2O Highly selective,
but expensive
(continued)


MnO2 Reagent can be

difficult to make with
reproducible activity
H BaMnO4 Reagent is easier to

OH O make and needs
less than MnO2
PDC, EtOAc Reagent can be used to
oxidize 1,2-diols where
one OH is allylic
PCC, CH2Cl2, ≥ 24 h Primary and
H OH O secondary alcohols
Cr (VI) reagents Usually an unwanted

side reaction in
alcohol oxidations
HO OH O O
HIO4 Does not cleave diols
that cannot form a
cyclic periodate ester
Pb(OAc)4 Cleaves all 1,2-diols
KMnO4, KOH, H2O Aldehydes, sulfides
OsO4 (catalytic or Can be carried out
stoichiometric) enantioselectively
using
X Y
AD-mix reagents
Br2, ROH; I2, TOH; Reaction conditions
IN3; RSX, RSeX; etc. may change product
m-CPBA, Sulfides, selenides
MgMPP, etc.;
Mn(salen), NaOCl Works best with cis
alkenes; chiral
O
complexes give
chiral epoxides
Oxone®, Me2CO; Works best with
Oxone®, fructose trisubstituted alkenes;
derivative epoxneide is chiral
with fructose derivative
OsO4, NaIO4; etc.
(1) O3 then Aromatic rings
(2) Me2S; etc. are cleaved
O O
RuO4; RuCl3, Alcohols, aldehydes Aromatic rings
HIO4; etc. are cleaved
Bu4NMnO4, Alcohols, aldehydes
C6H6; etc.


NBS, CCl4; Thiols, sulfides Electron-rich

NBS, hν; etc. aromatics undergo
substitution
RCO2OR', CuI; etc.

H X
SeO2, t-BuOOH; etc.
O2, hν, sensitizer

Pd(OAc)2, py,
MeOH-H2O; etc.
t-BuOOH, RhII or Sulfides
BiIII, etc.
H O Mn(OAc)3, O2 Sulfides
CF3SeO2H, PhIO2; Sulfides
etc.
DDQ, CH2Cl2 X must be C=O or Ar
(1) LDA, (2) PhSeCl, X must be C=O or
X X (3) m-CPBA (X=CO) similar anion-
H H
stabilizing group
(1) Me3SiCl, i-PrNEt 2;
(2) Pd(OAc)2,
benzoquinone
t-BuOOH, M M=VO(acac)2,
Mo(CO)6; etc. reaction
O
is enantioselective
OH OH when Ti(O-i-Pr)4 and
a dialkyl tartate are
used as the catalyst
(1) LDA, then X=O; Y=RS, RSe; etc.;
(2) Y2 or YBr cannot be used to
halogenate
X X
carbonyl compounds
Y
X 2, HOAc X=Cl, Br
(1) LDA, then Y=OH; product is
(2) oxaziridine chiral if a chiral
oxaziridine is used
m-CPBA (X=O); Alkenes Reactions proceed

O O
(1) NH2OH, then with retention of
X (2) H2SO4 or TsCl, py; configuration at
HN3 migrating center
KOH, Br2 (X=NH2) Reactions proceed with

(1) NH2OH, (2) TsCl, retention of
O N
C
O (3) base (X=Cl, OR) configuration at
X
(1) (COCl)2, (2) NaN3, migrating center
(3) ∆ or hν (X=OH)

Chapter Summary
This chapter has introduced oxidation in organic chemistry, beginning with the concepts
of oxidation and reduction and the use and limitations of oxidation numbers in organic
chemistry. The oxidations of alcohols with metal-based reagents (e.g., PCC, KMnO4,
MnO2, Ag2O, TPAP.) has been discussed, and alcohol oxidation by non−metal-based ox-
idants (e.g., DMP, Me2SO, TEMPO) has been introduced. Dehydrogenation of carbonyl
compounds has been considered, and rearrangements involving insertion of an electro-
negative atom (e.g., N, O) into C—C bonds have been introduced. The oxidation of
hydrocarbons—hydroxylation, epoxidation, allylic oxidation, and oxidative cleavage of
alkenes—has been introduced. Free radical intramolecular hydrogen atom transfers as
methods for the oxidation of an unactivated C—H bond have also been introduced.
Key Terms
allylic oxidation Hell-Volhard- oxymetallation

Babler oxidation Zelinskii reaction ozonolysis
Baeyer-Villiger Hofmann-Löffler- Prilezhaev reaction
rearrangement Freytag reaction reduction
Barton reaction Hofmann rearrangement Sarett reagent
Beckmann rearrangement hydroxylation Saegusa oxidation
Collins reagent Jones reagent Schmidt rearrangement
Corey-Kim oxidation Lemieux-Johnson cleavage Swern oxidation
Criegee oxidation Lossen rearrangement Tishchenko reaction
Curtius rearrangement Meerwein-Ponndorf- Tollens reagent
dehydrogenation Verley reduction TPAP
Dess-Martin perio- Moffatt-Pfitzner oxidation Uemura oxidation
dinane (DMP) Norrish type II reaction Wacker oxidation
Fétizon reagent Oppenauer oxidation
halolactonization oxidation
Additional Problems

O
Me CHO
1) RuCl3, NaIO4, 30°C
(a) N 2) CH2N2, Et2O
[Org. Lett. 2005, 7, 3045]
OMe
O S
CO2Me
N
[J. Am. Chem. Soc. 2009,
(b) NaIO4, THF
O Br
131, 16045]
PhSe
OMe
N N
OsO4, NMMO [J. Org. Chem.
(c) H
2009, 74, 7577]
Me OsO4, NMMO [J. Am. Chem. Soc. 2009,

(d) H
OH Me2CO-H2O (3:1)
131, 17066]
Me

O
H
O m-CPBA [Angew. Chem. Int. Ed.
(e) CH2Cl2, 0-25°C
(55%)
2009, 48, 9105]
H
O
O
RuCl3.NaIO4
(f) H2O-MeCN-CCl4
[Org. Lett. 2007, 9, 1231]
O
R NHBoc
PdCl2, CuCl, O2
(g) CHO DMF-H2O [Org. Synth. 1988, 67, 121]
O
O
1) Me3SiCl (6 eq.), LDA, –50°C
N O [Angew. Chem. Int. Ed.
(h) 2) Pd(OAc)2 (1.5 eq.), CaCO3,
O
O MeCN/55°C 2009, 48, 8905]
H
m-CPBA
(i) O CH2Cl2, 0°C
HO O 2009, 48, 9105]

TBSO
O
H IBX, Me2SO
MOMO
(j) PhMe [Org. Lett. 2005, 7, 4181]
H
NaIO4, RuCl3 (cat) [Bioorg. Med. Chem. Lett.

(k) AcO OAc CCl4-H2O-MeCN 2007, 17, 5894]
OH NHBoc
O O3, MeOH
(l) O
H
O
[Synthesis 2006, 2155]
CO2H
I2, NaHCO3 [Angew. Chem. Int. Ed.
(m) O
N
OTBS
2007, 46, 2883]
MeO2C CO2Me [Chem. Comm. 2004, 2404]

H H 1) O3, Me2CO, MeCHO, –78°C
(n) 2) Ph3P
[Org. Biomol. Chem.
2005, 3, 1557]
OH
[Org. Lett. 2006, 8, 2905]
1) O3, MeOH, CH2Cl2
(o) Ph
2) Me2S, CSA
[Hint: RCOSO2R + MeOH →
O S OTBS
O (MeO)3CH RCO2Me]
BnO H
H
H OsO4 (cat), Me3COH [J. Org. Chem.
(p)
N CO2Me NMO, Me2CO, H2O 2005, 70, 2325]
Boc
O
MeO
N O
H 1) O3, CH2Cl2, –78°C
(q) OTMS 2) Ph3P [Tetrahedron 2006, 62, 5756]
MeO
O
MeO
N O
H CAN, MeCN-H2O
OH
MeO

1) Me2SiOTf, , CH2Cl2, 0°C

O
Me N Me
(r) 2) Pd(OAc)2, MeCN, 12 h
[Org. Lett. 2007, 9, 2677]
CO2CMe3
Pd(OAc)2, MeCN
(s) (70%)
[Org. Lett. 2005, 7, 3425]
OSiMe3
OAc
SeO2, dioxane [J. Chem. Soc., Chem.
(t) OAc
∆
Comm. 1981, 507]
F
OH [Org. Biomol. Chem.
(u) OsO4, Me3NO
OH
CH2Cl2, H2O 2007, 5, 2267]
RuO4, NaIO4
(v) Me3C
O N EtOAc-H2O [Org. Lett. 2005, 7, 585]
O
AcO RuCl3, NaIO4 [J. Am. Chem. Soc. 1983,

(w) Me2CO-H2O
105, 5688]
O
DDQ, dioxane
(x) O
∆
[Tetrahedron Lett. 1975, 743]
O
O
H
RuCl3, NaIO4
(y) O
MeCN-CCl4-H2O [Org. Lett. 2000, 2, 3683]
N3 O
Me
O Ph
O OsO4, NaIO4, NaHCO3 [J. Am. Chem. Soc. 2003,
(z) Ph O OO Me3COH-H2O-Et2O
125, 7822]
O
HO
VO(acac)2, Me3COOH
(aa) O O CH2Cl2, decanes [Org. Lett. 2003, 5, 1805]
O
O
O OCMe3 IBr, PhMe [Tetrahedron Lett.

(bb) –78°C
1997, 38, 8667]
PhH2CO
Et3SiO CO2CH2Ph O O
(cc) Me2CO, CH2Cl2
–78°C 128, 13095]
O [J. Am. Chem. Soc. 2005,

(dd) OSiMe3
Pd(OAc)2
O MeCN 127, 5342]
18-18 In Corey’s classic synthesis of prostaglandin F2α, the oxidation of the ketoalkene
with m-chloroperbenzoic acid occurs to give the lactone shown instead of the
epoxide. Rationalize both the chemoselectivity (i.e., functional group selectivity)
of this reaction, and its regioselectivity [J. Am. Chem. Soc. 1969, 91, 5675].
MeO MeO
m-CPBA O
O O

18-19 The allylic oxidation of ∆5-steroids by most allylic oxidants results in oxidation at
C-7, whereas the fluorinated seleninic acid discussed above leads to oxidation at
C-4. Suggest a plausible reason why this should occur. (Hint: compare this seleni-
um-based reagent with SeO2.)
RCO2 O RCO2 RCO2

O
18-20 The steps shown below occur in a synthesis of pinitol [Tetrahedron 1989, 45,
3463]. The molecule has six chiral centers, all introduced in a stereocontrolled
manner from the starting meso diol.
OH OH
1) PhCOCl O CSA (cat.) OsO4 (cat)
OH OBz MeO OBz MeO OBz
DMAP MeOH NMO
2) m-CPBA Me3COH
OH ClCH2CH2Cl OBz OBz THF-H2O HO OBz
OH
(a) What would be the product of the epoxidation reaction if the diol were not
converted to the dibenzoate ester first?
(b) The acid-catalyzed ring opening of the epoxide proceeds with the regiochem-
istry and stereochemistry shown. Rationalize both.
(c) Suggest a reason why the diol formed in the osmium tetroxide hydroxylation
has the stereochemistry shown.
18-21 Suggest intermediates in the following transformation [Org. Lett. 2000, 2, 3217].
MOMO MOMO
OH Pd(OAc)2 OH
HO K2CO3, MeCN O
22°C H H
N O N O
Me Me
18-22 Supply the missing reagent from each of the following transformations.

(a)
OH O 2008, 47, 131]
OH
O
CONMe2 O
H
I
(b) [Tetrahedron 2010, 66, 6340]
OTBS OTBS
OTES O
(c)
130, 13765]
O O

(d) OCOPh OCOPh
OTMS O
2008, 47, 131]
HO OH
CHO
O OCHO
(e) [Tetrahedron 2010, 66, 6321]
H H

Br
OMe OMe
MeO MeO [Tetrahedron Lett.
(f) O O
MeO MeO 2006, 47, 2535]
OMe OMe
SEMO SEMO
H [Angew. Chem. Int. Ed.
(g) H SiMe3 SiMe3
OBn O OBn 2010, 49, 4264]
H H
HO CO2Me HO CO2Me
H H
O O
O O [Angew. Chem. Int. Ed.

(h) SEMO SEMO
2008, 45, 8605]
CHO
OTIPS OTIPS
CF3 H H CF3 H H
O O [J. Am. Chem. Soc. 2003,
(i) N H H H N H H
O O 125, 2400]
H OMOM H OMOM
O H O H
(j) N N
OH
[Org. Lett. 2004, 6, 1445]
O O OTES O O OTES
OH
OH
OH O
O OH O [J. Am. Chem. Soc. 2011,
(k) H H
133, 8014]
H H H H
O O
O O
O O O O
H O H
H H H H
O O
I
Me Ph Ph
[Synlett 2004, 901;
H
(l) O N Ph O
N
Tetrahedron: Asymmetry
CO2But
O
CO2But O 2009, 20, 758]
18-23 The taxane skeleton has been a popular target for synthesis due to the highly useful
anticancer properties of Taxol®, especially against solid tumor, and the limited sup-
plies of the natural material. Each of the following oxidations has been carried out
on the taxane ring system. Suggest the reagent for each transformation. Where
more than one option is available, suggest which would be best and tell why.
H H [J. Org. Chem.

(a) OH
2000, 65, 7865]
H OH H OH
AcO O OTES AcO O OTES
H H
(b) TESO TESO Br [Chem. Eur. J. 1999, 5, 121]
O O O O
O O

AcO O OTES AcO O OTES
H H
(c) O O O [Nature 1994, 367, 630]
HO O OAc HO O OAc
O O
Ph Ph
O O OMe HO O O OMe
(d) H H
TBSO Cl TBSO Cl 122, 3811]

O O O O
AcO OAc OAc AcO OAc OAc
[Tetrahedron Lett.
(e) H H
AcO OTES AcO OTES 2000, 41, 3907]

H OH O
18-24 When certain secondary allylic alcohols are treated with an excess of the Swern
reagent, the major product isolated is the corresponding halogenated enone. It is
believed that the halogenation reaction involves the conjugated enone as the reac-
tant. Suggest a mechanism for this transformation. [J. Org. Chem. 2007, 72, 7054].
OH O
(COCl)2, Me2SO Cl
Et3N, CH2Cl2
Cl Cl
–60°C

PCC, SiO2, CH2Cl2 [J. Org. Chem.
(a) (quantitative)
HO 2010, 75, 2333]
OR
PCC, CH2Cl2 [Angew. Chem. Int. Ed.
(b) O
2009, 48, 9549]
OH
OH
Me TEMPO, NaOCl, NaHCO3 [J. Am. Chem Soc. 2009,
(c) H OH
OH CH2Cl2-H2O (5:2) 131, 17066]
Me
OH
MnO2, CH2Cl2 [J. Am. Chem Soc. 2009,

(d)
HO Me (79%) 131, 14630]
H
O O
OH
IBX, Me2SO
(e)
H O 2009, 48, 9105]
O
OTBS
cat. TEMPO [Tetrahedron Lett.
(f) NaOCl, CH2Cl2
HO (87%)
1998, 39, 8405]
OH
OH
(g) 4-MeO-TEMPO, NaOCl [Org. Lett. 2010, 11, 4767]
CH2Cl2/H2O

OTBS [Tetrahedron Lett. 1998, 39,

CF3CO3H, CH2Cl2
(h) –15°C 8405] Which isomer
O (83%; mixture of isomers)
predominates, and why?
F OH
TEMPO (0.1 eq.)

KBr (0.05 eq.)
N N [Org. Process Res. Dev.
(i) NaOCl (1.12 eq)
N N EtOAc-H2O 2010, 14, 441]
Me (93%)
N N 83 mole scale!!
Me
Cl O
O N
TEMPO/ O N Cl
O N [J. Org. Chem.
(j) H H Cl O
(MeO)2C=O, EtOAc (5:1) 2009, 74, 8298]
OH (96%)
PhCO2
OH
PCC, CH2Cl2
(k) 4Å mol. sieve [Tetrahedron 2010, 66, 6445]
(85%)
TBPSO O IBX, Me2SO

(l) CH2Cl2, 0°C
[Synthesis 2010, 1171]
HO
(78%)
(COCl)2, Me2SO, CH2Cl2

(m) OH Et3N, –78°C, 2 h [Synthesis 2010, 1217]
OH
PhI(OAc)2, cat. TEMPO
TBSO
(n) CH2Cl2, 0°C to r.t., 16 h
[Tetrahedron 2010, 66, 6534]
OH
OH
OTBS
CF3CO3H/CH2Cl2
(o) –15°C [Synthesis 2010, 2533]
O (83%; mixture of isomers)
HO O O DMP, CH2Cl2
0°C, 1 h
(p) TBDMSO O [Synthesis 2010, 2643]
O
Ph
TPAP, NMMO, CH2Cl2

TESO
(q) OH 10°C, 30 min [Tetrahedron 2010, 66, 6462]
(61%)
OPMB OPMB
DMP, CH2Cl2
CHO
(r) OH r.t., 1 h
(95%)
18-26 The reaction below proceeds with the stereochemistry shown, with ee’s between
66 and 89%. Write a reasonable mechanism for the reaction. What is the function
of the SnCl4?
O O
O O SnCl4 (2-5 eq) O
H3O O O [Tetrahedron
O O +
m-CPBA, CH2Cl2 Lett. 1997,
Ph
(quantitative) Ph Ph 38, 6019]
Ph
83-94% 6-17%

18-27 The Beckmann rearrangement of cyclohexanone oxime under “green” conditions

involves the use of the ionic liquid formed between caprolactam and tetrafluorob-
oric acid. In the paper [Green Chem. 2006, 8, 296], the structure of the ionic
liquid is written as shown. Is this a likely structure for the ionic liquid? Why
or why not?
O
NH2
BF4
18-28 The following synthesis of fluostatins [J. Am. Chem. Soc. 2008, 130, 2783] illus-
trates the application of a wide range of oxidation reactions. Supply the missing
reagents a-f in the synthesis below.
O Me O Me O Me O Me
O H O H O
H H H
H a H b HO c O
H OTIPS H OTIPS HO H OTIPS HO H OTIPS
MOMO MOMO MOMO MOMO
TsOH
O Me O Me O Me O Me
O H O
H H
HO f O H e O H d O
OTIPS H OTIPS H OTIPS H OTIPS
HO HO HO MOMO
O O
18-29 Each of the following oxidations occurs in the synthesis of the C(1)-C(25)
southern hemisphere of the spirastrellolides A and B, reported by Smith et al.
[Tetrahedron 2010, 66, 6597]. Provide reasonable alternative reagents to accom-
plish each of the transformations shown. Where more than one reagent may be
used to effect the transformation, provide all reasonable alternatives. Suggest why
the authors may have chosen the reagent they did.
Ph Ph
O O
OBPS DMP OBPS
(a) O H O O H NaHCO3 O H O O H
Ph OBPS CH2Cl2 Ph OBPS
HO O
Ph Ph
O H SO3•py O H
OH CHO
(b) O H O O
Me2SO
O H O O
i-Pr2NEt Ph OMe
Ph OMe
CH2Cl2
Ph S Ph S
O S O S
DMP
(c) OH
py
O
O H O O H H O O H
CH2Cl2
Ph OMe Ph OMe
O H O H
DMP
O OH O CHO
NaHCO3
(d) H O O
CH2Cl2
H O O
H OMe H OMe
PivO O PivO O
18-30 The Baeyer-Villiger oxidation of the two isomeric ketones shown proceeds with
differing regiochemistry, depending only on the stereochemistry of the ketone.

Suggest a reason why this should happen. What can be learned from this experi-
ment? [Angew. Chem., Int. Ed. 2000, 39, 2852].
O O O
R O R O R
R'
R' + R'
R=H, R'=F: 29 : 71
R=F, R'=H: 91 : 9
18-31 The oxidations below were used by Cooksey, et al. in their synthesis of (−)-ebe-
lactones A and B [Tetrahedron 2010, 66, 6462]. Provide reagents to accomplish
each of the transformations shown. Provide reasonable alternatives to the reagent
chosen, and suggest why the authors may have chosen the reagent they did.
PMBO OSEM OH OH PMBO OSEM OH
DMP
(a) CH2Cl2
CO2H
1) PhI(OAc)2
PMBO OSEM OH OH TEMPO PMBO OSEM OH
CO2H
(b) 2) NaClO2
NaH2PO4
Me2C=CHMe
18-32 The 2009 Tetrahedron Prize for Creativity in Organic Chemistry was awarded to
Steven V. Ley of Cambridge University. In his award article [Tetrahedron 2010 66,
6270], the following alcohol oxidation reactions were highlighted. Give the prod-
uct of each.
OH
O CrO3, H2SO4
O
(a) N
acetone
SEM O
TBSO OH HO TEMPO, NaOCl

(b) KBr, aliquot 336
OTBS
HO OTBPS
H
O
O
(c) O (COCl)2, Me2SO, CH2Cl2
O O –78°C, then Et3N
H H H
TIPSO
O
O TPAP, NMMO
O
(d) Ph CH2Cl2, 4 Å MS
OH
Cl Cl K2Cr2O7, H2SO4
[Tetrahedron 2009,
(a) Me2CO, 8 h
HO O (>81%)
65, 10323]
Ph CrO3, H2SO4
CHO
[J. Med. Chem.
(b) Me2CO-H2O, 0°C
OMe
2008, 51, 6839]
OH CrO3, H2SO4
C6H13 [J. Org. Chem.
(c) F Me2CO-H2O, 0°C
(61%)
2006, 71, 3518]

OBn OBn
H
CrO3, H2SO4
[J. Org. Chem.
(d) H
BocN
O
Me2CO-H2O, 0°C
BnO OBn
(90%)
2005, 70, 5508]
OBn
HO O CrO3 (1.1 mol%)

H5IO6 (2.5 eq) [Tetrahedron Lett.
(e) N
Ph
O
MeNO2-H2O
(0.75% H2O)
1998, 39, 5323]
OH IBX (1.2 eq)

(f) [bmim]BF4
[Tetrahedron 2004, 60, 2131]
OH
PCC (2 mol%)
CHO H5IO6 (2.2 eq)
(g) [Synthesis 2005, 2487]
MeCN, r.t.
DMP (1.4 eq)

(h) H
H2O (1.1 eq)
[J. Org. Chem. 1994, 59, 754]
H H CH2Cl2
HO
Ph TBPS PCC (3 eq)

Al2O3
(i) [Synthesis 2000, 1223]
OH hexane-CH2Cl2
V2O5 (4 mol %)
HClO4 (0.6 eq)
(j) CHO
H2O2 (30%, 4.4 eq)
[Org. Lett. 2000, 2, 577]
O
MeOH/5°C
PhIO (1.3 eq)

TEMPO (5 mol %)
OH
(k) Yb(OTf)3 (2 mol %)
[Synlett 2006, 2055]
OH CH2Cl2, r.t.
cyanuric chloride
(TCT) [J. Org. Chem.
(l) NOH
DMF, r.t. 2002, 67, 6272]
CO2H (Boc)2O (1.1 eq)
NaN3 (3.5 eq)
(m) Bu4NBr (0.15 eq) [Org. Lett. 2005, 7, 4107]
Zn(OTf)2 (3.3 mol %)
O
THF
1) PhSO2Cl, Na2CO3, H2O

(n) CONHOH 2) NaOH, H2O [J. Org. Chem. 1959, 24, 1293]
CO2H
O
1) N N N , MeCN, ∆
(o) N [Org. Lett. 2009, 11, 5622]
NHOH
2) PhCH2OH
O
Al-clays, PhCl or neat

[Green Chem. 2007, 9, 1109]
(p) N microwaves, 180°C Note: the Al-based
OH 5 min
reagent is acidic
OH
DMP or IBX
(q) O NBoc [Tetrahedron 2004, 60, 2131]
n-Bu N N Me BF4

CN
N DMP, CH2Cl2, py
H
(r) (83%)
[Tetrahedron 2006, 62, 8655]
NH
OH
N CO2Et
O
O DMP, CH2Cl2, py
(s) O (75%) [Tetrahedron 2003, 59, 6967]
HO
O OMe
O PCC, CH2Cl2
(t) Ph O OMe
3 Å mol. sieve [Tetrahedron 2009, 65, 9378]
OH
OH
DMP, CH2Cl2
(u) H (>98%) [Tetrahedron 2009, 65, 7001]
O H
OH
O (COCl)2, Me2SO
(v) MeO Et3N, CH2Cl2, –50°C
[Tetrahedron 1994, 50, 1435]
O
(76%)
OMe
OTBS (COCl)2, Me2SO

(w) Et3N, CH2Cl2, –50°C [Tetrahedron 2006, 62, 8933]
OH (98%)
O Oxone®
(x) BmimBF4 [Tetrahedron 2010, 66, 6212]
(95%)
18-34 Rationalize the formation of the product shown in the oxidation of the allylic al-
cohol by manganese dioxide [Tetrahedron Lett 2009, 50, 6597].
OH H
O
MnO2, CH2Cl2
O
OH (99%) O
Ph
OH Ph
18-35 The benzyl group is frequently used as a protecting group for alcohols, amines,
and amides. It has been reported [Synthesis 2007, 3129] that the N-benzyl group
can be removed from a carboxamide by treatment with NBS. Suggest a mecha-
nism for this.
Me NBS (2.5 eq), MeNHAc (10 mol %) H
N Ph CHCl3, 25°C, 18 h N
Me
Cl O Cl O
(COCl)2, Me2SO, Et3N [J. Am. Chem. Soc. 2010,

(a) TBSO
OH CH2Cl2, –78°C 132, 1488]
H CHO
Me2C=CHMe, Me3COH
(b) AcO O H O H OAc [Org. Lett. 2003, 5, 5035]
NaClO2, NaH2PO4, H2O
H
OMe

HO
O
N (COCl)2, Me2SO, Et3N [J. Org. Chem.
(c) CH2Cl2, –60°C
2007, 72, 4246]
Me2C=CHMe, Me3COH
(d) TBSO CHO
NaClO2, NaH2PO4, H2O
[Org. Lett. 2005, 7, 3371]
O NCS, Me2S, NEt3

(e) HO CH2Cl2, –40°C
O 101, 1609]
CHO Me2C=CHMe, Me3COH
MeN
(f) OH
NaClO2, NaH2PO4, H2O [Org. Lett. 2004, 6, 3305]
O OH OTES
OPMB
OTES Me2C=CHMe, Me3COH

(g) [Synthesis 2005, 1183]
TBSO NaClO2, NaH2PO4, H2O
CHO
MeO
OTBS
HO py•SO3, Et3N
(h) Me2SO, 23°C
[Org. Lett. 2007, 9, 4619]
TBDPSO
18-37 Each of the following transformations may be accomplished by at least two re-
agents. Suggest reagents to accomplish the transformation, and rank them in
order of probable effectiveness. One lead reference to a reagent that could be used
to effect this transformation is given.
O O
[Tetrahedron Lett.
(a)
OHC
O
HO2C
O 1996, 37, 4191]
(b) S S [J. Org. Chem. 1988, 53, 1441]

S OH S CHO
MeO MeO

(c) O O
128, 14042]
MeO OH MeO H O
OH O

(d) TBSO TBSO
OH
CHO
132, 1488]
OH
CO2Me [J. Am. Chem. Soc. 2006,
(e) PhMe2Si PhMe2Si 127, 16038]
OMOM OMOM
OHC N3 N3
O
O O
OTBDPS
O [J. Org. Chem.
(f) O
OTBDPS
O
O
OMOM
O
2008, 73, 1234]
O O

Chapter nineteen
Redox Reactions II
Reduction with Molecular Hydrogen or Its Equivalent
19.1 Overview of Reduction
In Figure 19.1, four common, fundamental types of reduction used in organic chemistry
are represented schematically. The reactions in Example 19.1 are reductions of carbon-
carbon π bonds in alkenes and alkynes. These reactions lead to products containing at
least two more carbon-hydrogen σ bonds and at least one less carbon-carbon π bond. The
reactions in Example 19.2 are the reduction of carbonyl compounds to alcohols. These
reactions are reductions of polar π bond in the molecule without the cleavage of any
groups. In Example 19.3 are the reductive elimination reactions: reductions that lead to
the cleavage of polar σ bonds and their replacement by a non-polar π bond. The fourth
type of reductions, shown in Example 19.4, involves reductions of carbon-heteroatom σ
bonds adjacent to carbon-carbon or carbon-oxygen π bonds.
A closer examination of the reactions in Figure 19.1 reveals that they can be subdivided
into three major classes: (1) the reduction of a non-polar π bond and its replacement by
two σ bonds to hydrogen (19.1), (2) the reduction of a polar π bond and its replacement by
two σ bonds to hydrogen (19.2), and (3) the reduction of one or more polar σ bonds and
their replacement by σ bonds to hydrogen or a non-polar π bond (19.3, 19.4). What reagent
is best used is determined by which of these classes of reduction is required.
Since 1980, the chemistry of reductions has focused intensely on the development and
use of methods for carrying out the reaction in an enantioselective manner. However, it is
important that we first discuss these basic reactions without considering stereochemical
control, because they provide the basis for understanding much of the asymmetric redox
chemistry that will then be discussed in Chapter 21.
19.2 Catalytic Hydrogenation
The reduction of non-polar π bonds is most frequently carried out by catalytic hydroge-
nation,1 a reaction that was first studied in depth by the French chemists Paul Sabatier2
1. Monographs and reviews: (a) Augustine, R.L. Catalytic Hydrogenation (Marcel Dekker: New York, 1965).
(b) Rylander, P.N. Catalytic Hydrogenation over Platinum Metals (Academic Press: NewYork, 1967). (c) Freifelder,
M. Practical Catalytic Hydrogenation (Wiley-Interscience: New York, 1971). (d) House, H.O. Modern Synthetic
Reactions, 2nd ed (Benjamin: New York, 1972), ch. 1. (e) Thomas, C.L. Catalytic Processes and Proven Catalysts
(Academic Press: New York, 1970), p. 125. (f) Rideal, E.K. Concepts in Catalysis (Academic Press: London, 1968),
p.109. (g) Burwell, R.L. Chem. Rev. 1957, 57, 895. (h) Brieger, G.; Nestrick, T.J. Chem. Rev. 1974, 74, 567.
(h) Rylander, P.N. Aldrichimica Acta 1997, 12, 53. (i) Siegel, S. In Trost, B.M.; Fleming, I., Eds. Comprehensive
Organic Synthesis (Pergamon: Oxford, 1991), vol. 8, p. 417.
2. Paul Sabatier (1854–1941) was educated at the Collège de France (Dr ès Sc, 1880). In 1882, he joined the
Université de Toulouse, where he remained for his entire career. He received the Nobel Prize in 1913 for his work
in hydrogenation. For more biographical details, see: the web site of the Nobel Foundation and Rideal, E.K.
Biogr. Mem. Fell. Roy. Soc. 1942, 4, 63.
855

856 Advanced Organic Chemistry | Chapter nineteen
Figure 19.1 Major classes of

reduction reactions in H H
organic chemistry
(19.1)
H H H H
H H
R OH
(19.2)
R CHO R CO2H
O
R R
R R
(19.3)
HO OH R R
R R O + O
R R R R
O O
R R R R
X (19.4)
X
and Jean-Baptiste Senderens,3 who demonstrated its generality.4 The addition of hydrogen
to a carbon-carbon π bond (e.g., Examples 19.5 to 19.7) is an exothermic process, but the
activation energy for the uncatalyzed process is very high. So high, in fact, that the reac-
tion occurs only extremely slowly—more on the geological time scale than the laboratory
time scale. In the presence of a catalyst, however, the addition of hydrogen occurs quite
readily, and the reaction has therefore become a major method of reduction. Most func-
tional groups are susceptible to reduction by hydrogen in the presence of a catalyst, al-
though their relative reactivity varies widely.
H2
H H
cat.
(19.5)
H H H2 H2 H H
H H
cat. cat.
(19.6) (19.7)
3. Jean-Baptiste Senderens (1856–1937), chemist and priest, took his Dr ès Sc in 1892 at Toulouse. From
1883–1913 he was director of the «École superieure des Sciences» and Professor of Chemistry at the «Institut
catholique» at Toulouse, as well as a collaborator with Sabatier (who later refused to acknowledge Senderens’
contribution to the Nobel-winning work). In 1913 he began work with the Poulenc chemical company, and in
1922 Poulenc built in a personal laboratory in his home village. In 1905 he won the Prix Jecker, and in 1923
he was made a chevalier of the Légion d’Honneur. For more biographical information, see: Couderc, F. Jean-
Baptiste Senderens (Institut catholique: Toulouse, 2009).
4. Sabatier, P.; Senderens, J.B. Compt. rend. 1899, 128, 1173; 1900, 130, 1761; 1901, 132, 210, 566, 1254; 1902, 134,
1127; 1902, 135, 87.

Redox Reactions II 857
Practically all known active hydrogenation catalysts are based on transition

Fe Co Ni
metals. The most common catalysts used are based on the Group VIIIB metals: nickel,
catalyst
palladium, and platinum are most widely used However, other noble metals (espe- Ru Rh Pd activity
cially rhodium, ruthenium, and iridium) can be used to effect catalytic hydrogena- Os Ir Pt
tions under specific circumstances. The catalysts can be either the finely divided
metal or metal oxide, in which case the reaction is known as heterogeneous catalytic catalyst
activity
hydrogenation, or soluble metal complexes, in which case the reaction is known as
homogeneous catalytic hydrogenation. Heterogeneous hydrogenation is much more
widely used, but more is known about the course of the hydrogenation under homo-
geneous catalysis.
Factors Affecting Reactivity in Catalytic Hydrogenation

The ease of hydrogenation of a π bond tends to increase with increasing electron density
of the π bond and decrease with increasing polarity of the π bond. Thus, the non-polar
C–C π bonds of alkynes hydrogenate rapidly, followed by the C–C π bonds of alkenes,
the C–N π bonds of nitriles and imines, and the C–O π bonds of carbonyl compounds.
The alkene π bonds of conjugated enones can be reduced selectively over more electron-
rich alkenes by using rhodium as the catalyst.5 The most difficult π bonds to hydrogenate
are those of aromatic rings. The hydrogenation of alkynes can be arrested at the alkene
stage by using an appropriate “poisoned” palladium catalyst. The hydrogenation of C–N
and C–O π bonds leads to amines or alcohols, regardless of the starting compound.
Among carbonyl compounds, the aldehydes are the most readily hydrogenated, and
carboxylate anions do not hydrogenate under any circumstances at all. This order of
reactivity permits the chemist a degree of control over the reaction. For example, hydro-
genation of α,β-unsaturated ketones over palladium on carbon leads to the saturated
ketone, especially in the presence of a small amount of diphenyl sulfide as a catalyst
poison (e.g., Example 19.8).6
C N
O
N
substrate
activity
H2, 10% Pd-C

O Ph2S (0.01 eq) O
(19.8)
Ph Ph MeOH Ph Ph
(quant.)
The activity of the catalyst is an important determining factor in the rate of a hydro-
genation reaction. Platinum catalysts are the most reactive, and they are usually prepared
as the finely divided metal by in situ reduction of a platinum compound, most commonly
platinum dioxide, PtO2, known as Adams catalyst7 after American chemist Roger
5. Roy, S.K.; Wheeler, D.M.S. J. Chem. Soc. 1963, 2155.

6. Mori, A.; Miyakawa, Y.; Ohashi, E.; Haga, T.; Maegawa, T.; Sajiki, H. Org. Lett. 2006, 8, 3279.
7. (a) Adams, R.; Voorhees, V. Org. Syn., Coll. Vol. 1 1932, 61. (b) Adams, R.; Voorhees, V.; Shriner, R.L. Org.
Syn., Coll. Vol. 2 1941, 463.

Adams,8 and chloroplatinic acid, H2PtCl4. Rather less reactive, and therefore more selec-
tive, are the palladium catalysts, prepared by precipitating the finely divided metal on an
inert support. Palladium on charcoal and palladium on alumina are particularly popular
catalysts for hydrogenating alkenes under mild conditions (1 to 3 atmospheres pressure
and temperatures below 100°C). Nickel is usually used as Raney nickel,9 discovered by
Murray Raney10 and developed by Homer Adkins11 and his students.12 Raney nickel is
prepared by dissolving the aluminum from an aluminum-nickel alloy (Raney alloy) in
sodium hydroxide; when prepared in this way, it has a large amount of chemisorbed
hydrogen.
Nickel is the least active of the common metal catalysts, and it must be used under
pressure and often at high temperatures. It does, however, have the advantage of being
particularly resistant to deactivation by catalyst “poisons.” The most common catalyst
“poisons” are sulfur compounds, amines, and lead compounds. Platinum and palladium
catalysts are especially vulnerable to poisoning; poisoning by amines can be reduced by
carrying out the reduction in acidic solution. Occasionally, catalyst poisoning can be
useful. Poisoning of Raney nickel by sulfur compounds has been exploited in the reduc-
tive desulfurization of dithioketals. Catalytic hydrogenation of alkynes over a palladium
catalyst poisoned with quinoline and lead (Lindlar’s catalyst, named for British-Swiss
chemist, Herbert Lindlar13) gives Z alkenes.
Industrially, copper chromite14 is used for the hydrogenation of fatty esters. The five
most common hydrogenation catalysts and their uses in hydrogenation reactions are
summarized in Table 19.1.
The outcome of a heterogeneous catalytic hydrogenation can be highly dependent on
the catalyst chosen, the method of catalyst preparation, the solvent, the catalyst loading,
the reaction temperature, and the pressure. Indeed, most reviews of the reaction empha-
size the difficulty of predicting the performance of a particular catalyst in a specific appli-
cation and the importance of trial-and-error in optimizing the reaction conditions.
8. Roger Adams (1889–1971) was educated at Harvard (PhD, 1912), and then worked with Diels and Willstät-
ter in Germany. He joined the University of Illinois in 1916 and spent his entire career there. For more biograph-
ical information, see: Tarbell, D.S.; Tarbell, A.T. Biogr. Mem. (National Academy of Sciences: Washington,
D.C., 1982), p. 1.
9. Raney, M. U.S. Patent No. 1,628,190 [May, 1927].
10. Murray Raney (1885–1966) was a mechanical engineer. He worked as a teacher (and heating and
lighting supervisor) at Eastern Kentucky State Normal College until 1910. His research career began in
1915, when he joined the Lookout Oil & Refining Company; here he began work on nickel alloys that would
later yield “Raney catalysts.” In 1925, he took a sales manager position with Gilman Paint and Varnish Co.,
rising to president of the company. In 1950, he left Gilman to found the Raney Catalyst Company and
devote full-time effort to the production of his catalysts. The company was acquired by W.R. Grace &
Company in 1963.
11. Homer Burton Adkins (1892–1949) received his education at Denison University (BS, 1915) and the Ohio
State University (MS, 1916; PhD, 1918). After temporary appointments during 1918–1919 in the War Department,
Du Pont, and Ohio State, he joined the University of Wisconsin, where he spent the rest of his life. For more
biographical information, see: Daniels, F. Biogr. Mem., Natl. Acad. Sci. 1952, 291.
12. Adkins, H. Reactions of Hydrogen with Organic Compounds over Copper Chromium Oxide and Nickel
(University of Wisconsin Press: Madison, WI, 1937).
Among later papers by Adkins and his students, the following are illustrative: (b) Durland, J.R.; Adkins, H.
J. Am. Chem. Soc. 1932, 60, 1501. (c) Wojcik, B.; Adkins, H. J. Am. Chem. Soc. 1934, 56, 2424. (d) Adkins, H.;
Krsek, G. J. Am. Chem. Soc. 1948, 70, 412. (e) Pavlic, A.A.; Adkins, H. J. Am. Chem. Soc. 1946, 68, 1471.
(f) Adkins, H.; Billica, H.R. J. Am. Chem. Soc. 1948, 70, 695. (g) Billica, H.R.; Adkins, H. Org. Syn., Coll. Vol. 3
1955, 176.
13. Herbert Wilson Lindlar (1909–2009) was a British-Swiss chemist (PhD, Bern 1939). He spent his entire
career at Hofmann-La Roche, in Basel. He retired in 1974, and then worked as British Vice-Consul in Zurich.
He died three months after his 100th birthday.
14. Connor, R.; Folkers, K.; Adkins, H. J. Am. Chem. Soc. 1931, 53, 2012; 1932, 54, 1138.

Table 19.1 Heterogeneous Catalysts for Hydrogenation
Catalyst Reaction Comments
Can cause π bond migration

during reaction. To prevent this,
use Ni or Ru.
R R
R R
To avoid this reaction, Rh catalysts
O should be used.
NO2
R R NH2
N3
Pd This may be halted at alkene stage

by limited catalyst and hydrogen.
This uses a Lindlar catalyst, or Pd/

H H polyethyleneimine.
Cl H
R
Pd catalyst is poisoned with S and/
R
O O or quinoline.
Cl
R Br R H
I
N NH
Reduction of aldehydes usually

O OH
requires Fe2+ as an accelerator.
Pt
N NH
OH
N NH2
1 atmosphere; ambient temperature
Ni 100–200 atmosphere; 100–200°C
O OH 50–100°C; high pressure
(continued)

Catalyst Reaction Comments
R R
1–4 atmosphere; 50–100°C
NR2
50–100°C; high pressure; NH3

C N H NH2 added to minimize yield of
H secondary amine
1 atmosphere; ambient temperature
5–10 atmospheres; 50–100°C; does

Rh not usually lead to loss of benzyl
substituents
50–100°C; high pressure; NH3
C N H NH2 added to minimize yield of
H secondary amine
Only heterogeneous catalyst for

Ru O OH this transformation; 300–600
atmospheres; H2 required in H2O
O
R R
OH OH
Despite the obvious complexity of the reaction, certain general facts about the reaction
mechanism have emerged. It is generally accepted that the first event of the reaction is
adsorption of the reactants onto the metal surface. This occurs by a process known as
chemisorption, which is adsorption accompanied by covalent bond formation. The
chemisorption of the alkene on the catalyst surface is susceptible to steric hindrance, and
evidence for this comes from the hydrogenation of alkenes in which the two faces of the
double bond are not equivalent. In these reactions, the hydrogen is selectively added to the
less hindered face of the π bond.
The stereochemistry of reduction of such compounds results in the major product of hy-
drogenation invariably being the alkane formed by syn addition of the hydrogen atoms to the
less hindered surface of the π bond. This is shown in Examples 19.9 and 19.10 and Figure 19.2.
Figure 19.2 The initial step of

catalytic hydrogenation is
the chemisorption of the
alkene on the catalyst
surface. If one face of the
double bond is blocked from
close approach to the metal
surface so efficient orbital
overlap between the π bond
and the metal atoms cannot
occur, hydrogenation will
occur from the other side.

OH
H H
H H
O
H H2, PtO2 (19.9)15
OH
EtOH H
H
Me Me Me Me Me Me
H2/Pt 16
+ (19.10)
Me H
Me
H Me
90 : 10
Even today, a century after the development of the reaction, neither the exact bonding
involved in the chemisorption of the reactants to the catalyst surface nor the mechanistic
details of heterogeneous catalytic hydrogenation are well understood. In large part, this is
because of the heterogeneity of the reacting system. Thus, many questions critical to
understanding what actually occurs remain unanswered.
Nevertheless, some general conclusions about the mechanism have been drawn. It is
generally accepted that the process involves the sequence of steps in Figure 19.3, which are
a slight modification of the original proposal by Horiuti and Polanyi17:
1. Chemisorption of hydrogen on the metal surface to give metal-hydrogen bonds (19.11)

2. Chemisorption of the alkene on the surface to give metal-carbon bonds by syn addition
to the π bond (this also anchors the alkene to the metal so that the two faces of the
alkene are differentiated) (19.12)
3. Stereospecific replacement of the metal in one metal-carbon bond by hydrogen to give
a carbon-hydrogen bond with retention of configuration at carbon (19.13)
4. Stereospecific replacement of the metal in the other metal-carbon bond by hydrogen
with retention of configuration at carbon (19.14)
One of the important features of this model is that all steps of this mechanism are re-
versible. This provides a means for isomerizing the π bond during hydrogenation and a
method for the net anti addition of hydrogen by desorption (19.17) and resorption of the
isomerized alkene (19.18) on the other face of the π bond (Figure 19.4). Alternatively, it
allows for shifting of the π bond during hydrogenation, leading to other unexpected
hydrogenation products.18
It is important to remember that, despite almost a century of study, the actual nature of
the bonding of the hydrogen and the alkene to the metal remains unknown.19 The
15. Linstead, R.P.; Doering, W.v.E.; Davis, S.B.; Levine, P.; Whetstone, R.R. J. Am. Chem. Soc. 1942, 64, 1985,
1991, 2003, 2007, 2009, 2014, 2022.
16. (a) Bell, H.M. PhD Thesis, Purdue University, 1964. Cited in: (b) Brown, H.C.; Kawakami, J.H. J. Am.
Chem. Soc. 1970, 92, 201. (c) Brown, H.C.; Kawakami, J.H.; Liu, K.-T. J. Am. Chem. Soc. 1973, 95, 2009.
17. Horiuti, I.; Polanyi, M. Trans. Faraday Soc. 1934, 30, 1164.
18. Siegel, S.; Smith, G.V. J. Am. Chem. Soc. 1960, 81, 6082, 6087.
19. (a) Burwell, R.L., Jr.; Schrage, K. J. Am. Chem. Soc. 1965, 87, 5234. (b) McKee, D.W. J. Am. Chem. Soc.
1962, 84, 1109. (c) Siegel, S. Adv. Catal. 1966, 16, 123. (d) Ledoux, M.J. Nouv. J. Chim. 1978, 2, 9. (e) Clarke, J.K.A.;
Rooney, J.J. Adv. Catal. 1976, 25, 125. (f) Bautista, F.M.; Campelo, J.M.; Garcia, A.; Guardeño, R.; Luna, D.;
Marinas, J.M. J. Chem. Soc., Perkin Trans. 2 1989, 493.

Figure 19.3 Accepted
mechanism of heterogeneous H H
catalytic hydrogenation
* * * * * *
H H
(19.11) (19.12)
H H
* * * * * * * * * * * *
(19.14)
(19.13)
H
H
H H * * * * * *
* = reactive site on metal
Figure 19.4 Mechanism b c
whereby isomerization of the
a
π bond regiochemistry or b c
stereochemistry may occur H
H H a
* * * * * * (19.15) H
a b c (19.16)
H H
H
(19.17)
* * * * * *
c
b
a b c
H H
H H (19.18) a
* * * * * *
Horiuti-Polanyi model in Figure 19.3 does, however, predict that the overall stereochemis-
try of the addition to the chemisorbed face of the π bond should be s uprafacial. Experimen-
tal observations confirm this. Hydrogenation of the isomeric 2,3-diphenyl-2-butenes over
palladium in acetic acid gives exclusively the (±) isomer from the E alkene (Example 19.19)
and almost exclusively the meso isomer from the Z alkene (Example 19.20).20
Ph Me H2, Pd black Ph Me
H H (±) (19.19)
HOAc, 1 atm.
Me Ph Me Ph
(98%)
Ph Ph H2, Pd black Ph Ph (contains

H H 2% dl (19.20)
HOAc, 1 atm.
Me Me Me Me isomer)
(99%)
However, there is significant work that has identified several different types of sites on the metal surface:
(g) Augustine, R.L.; Yaghmaie, F.; Van Peppen, J.F. J. Org. Chem. 1984, 49, 1865. (h) Brower, W.E.; Matyjaszczyk,
M.S.; Pettit, T.L.; Smith, G.V. Nature (London), 1983, 301, 497. (i) Somorjai, G. Acc. Chem.Res. 1976, 9, 248.
(j) Smith, G.V.; Zahraa, O.; Molnar, A.; Khan, M.M.; Richter, B.; Brower, W.E. J. Catal. 1983, 83, 238.
20. von Wessely, F.; Welleba, H. Chem.Ber 1941, 74, 777.

Table 19.2 Relative Ease of Hydrogenation of Functional Groups*
Approximate Functional Reduction Approximate Functional Reduction

Rank Group Product Rank Group Product
O O
1 7 Ar OR Ar H
Cl H
O OH
2 NO2 NH2 8
H H
3† 9
O OH
4 H H 10 H
O H HO
O OH O H
H
5‡ H 11
H H HN HN
H
6 C N NH2 12
H
*The order is catalyst-dependent. Functional groups not listed (e.g., carboxylate anions) are considered resis-
tant to hydrogenation.
†
The high level of reactivity of alkynes is due to the much stronger chemisorption of the alkyne on the catalyst surface.
‡
Fe2+ or Fe3+ is required as an accelerator with Pt. Pd often leads to decarbonylation competing with
hydrogenation.
The ease of reduction of functional groups depends in large part on the catalyst used.
Thus, palladium catalysts are excellent for use in hydrogenation of non-polar π bonds and in
hydrogenolysis of benzyl substituents but are seldom the catalyst of choice for the hydroge-
nation of carbonyl groups. To avoid hydrogenolysis, rhodium catalysts are preferred. In fact,
rhodium allows the hydrogenation of aromatic rings to cyclohexanes without hydrogenolysis
of the benzyl substituent. Table 19.2 contains a composite picture of the general order of
reactivity of functional groups toward hydrogen in the presence of palladium, platinum, or
nickel. Of course, this is only an approximate order, and as the preceding discussion implies,
it may be significantly modified by the actual choice of catalyst.
Homogeneous Catalytic Hydrogenation of Alkenes

Few advances have had as profound an impact on the development of a synthetic method
as the introduction of soluble transition metal catalysts (which allow the reaction to be
carried out under homogeneous, rather than heterogeneous conditions) have had on
hydrogenation. Homogeneous catalytic hydrogenation is now a major method for the
reduction of alkenes.21 The prototypical catalyst for homogeneous catalytic hydrogenation
21. (a) James, B.R. Homogeneous Hydrogenation (Wiley: New York, 1973). (b) Strohmeier, W. Fortschr. Chem.
Forsch. 1972, 25, 71. (c) Harmon, R.E.; Gupta, S.K.; Brown, D.J.; Chem. Rev. 1973, 73, 21. (d) Birch, A.J.;
Williamson, D.H. Org. React. 1976, 24, 1. (e) Collman, J.P.; Hegedus, L.S.; Norton, J.R.; Finke, R.G. Principles
and Applications of Organotransition Metal Chemistry (University Science Books: Mill Valley, CA, 1987), p. 523.
(f) Takaya, H.; Noyori, R. In Trost, B.M.; Fleming, I., Eds. Comprehensive Organic Synthesis (Pergamon:
Oxford, 1991), vol. 8, p. 443.

Figure 19.5 The proposed PPh3 H

PPh3 H2
catalytic cycle for PPh3 PPh3
(19.21) Cl Rh PPh3 Cl Rh H Rh
homogeneous hydrogenation PPh3
Ph3P PPh3
over Wilkinson’s catalyst 16 e Cl
16 e (19.22) 14 e
(19.23)
H
16 e 18 e
H
H H
PPh3
PPh3
Rh H Rh PPh3
PPh3 Cl
H Cl
(19.25)
(19.24)
was the rhodium (I) catalyst, [(C6H5)3P]3RhCl, called Wilkinson’s catalyst22 after its devel-
oper, Sir Geoffrey Wilkinson. Subsequently, it was found that ruthenium (II) catalysts also
worked very well.23
Wilkinson’s catalyst is a 16-electron rhodium complex (19.21) that loses one triphenyl-
phosphine ligand under the reaction conditions to give a 14-electron complex, 19.22,
which is the active form of the catalyst during the reaction. The accepted mechanism for
the reaction24,25 is shown in Figure 19.5. It is worth noting that as the reaction proceeds, the
geometry around the central rhodium atom becomes more sterically crowded (19.22 [14
electrons] is trigonal planar, 19.23 and 19.25 [16 electrons] are trigonal bipyramidal, and
19.24 [18 electrons] is octahedral). This means that steric hindrance in the alkene should
have a noticeable effect on the rate of the reaction. It does, and homogeneous catalysis is
an excellent method for reducing the less hindered of two double bonds. Like heteroge-
neous catalytic hydrogenation, hydrogenation of alkenes over Wilkinson’s catalyst in-
volves suprafacial addition of the two hydrogen atoms to the less hindered face of the
alkene.
Because the intermediates in a homogeneous catalytic hydrogenation are discrete mol-
ecules or ions, rather than regions of a surface, the geometry of the intermediates in the
reaction can be much more easily understood and controlled. It is often found, for exam-
ple, that both the regioselectivity and the stereoselectivity of hydrogenation of alkenes is
much higher when a homogeneous catalyst is used in the reaction.
22. (a) Jardine, F.H.; Osborn, J.A.; Wilkinson, G.; Young, J.F. Chem. Ind. (London) 1965, 560. (b) Osborn,
J.A.; Jardine, F.H.; Young, J.F.; Wilkinson, G. J. Chem. Soc., A 1966, 1711. (c) Bennett, M.A.; Longstaff, P.A.
Chem. Ind. (London) 1965, 846. (d) Osborn, J.A.; Wilkinson, G. Inorg. Synth. 1967, 10, 67. (e) Biellmann, J.F.
Bull. Soc. Chim. France 1968, 3055. (f) van Bekkum, H.; van Rantwijk, F.; van de Putte, T. Tetrahedron Lett.
1969, 1.
Sir Geoffrey Wilkinson (1921–1996) took his PhD from Imperial College in 1946 after service in World
War II. After postdoctoral work at Berkeley and the Massachusetts Institute of Technology, he joined Harvard
(1951) and Imperial College (1955). Wilkinson shared the 1973 Nobel Prize in Chemistry. For more biographical
detail, see: Green, M.L.H.; Griffith, W.P. Biogr. Mem. Fell. Roy. Soc. 2000, 46, 593, and the web site of the Nobel
Foundation.
23. (a) Hallman, P.S.; McGarvey, B.R.; Wilkinson, G. J. Chem. Soc., A, 1968, 3143. (b) Jardine, F.H.; McQuillin,
F.J. Tetrahedron Lett. 1968, 5189.
24. Reviews: (a) Crabtree, R.H. Organometallic Chemistry of the Transition Metals (Wiley: New York, 1988),
p. 190. (b) Jardine, F.H. In Hartley, F.R. The Chemistry of the Metal-Carbon Bond (Wiley: New York, 1987),
vol. 4, p. 1049.
25. (a) Collman, J.P. Acc. Chem. Res. 1968, 1, 136. (b) Vaska, L. Acc. Chem. Res. 1968, 1, 335. (c) Halpern, J.
Quart. Rev. 1956, 10, 463. (d) Halpern, J. J. Phys. Chem. 1959, 63, 398. (e) Halpern, J. Ann. Rev. Phys. Chem. 1965,
16, 103. (e) Tolman, C.A.; Meakin, P.Z.; Lindner, D.L.; Jesson, J.P. J. Am. Chem. Soc. 1976, 96, 2762.

In 1976, Crabtree published the first in a series of papers describing iridium catalysts for
the homogeneous catalytic hydrogenation of unactivated alkenes.26 Crabtree’s catalyst,
(cod)Ir(PCy3)py•PF6, has proved to be an extremely efficient catalyst for the h ydrogenation
of tetrasubstituted alkenes, compounds which are otherwise difficult to hydrogenate. The
catalyst has also been highly useful in directed hydrogenations (e.g., Example 19.26,27 where
an allylic hydroxyl group directs the reaction to the same face of the adjacent π bond, sim-
ilar to the way in which an allylic hydroxyl group directs a peracid to the adjacent π bond).
This has been taken advantage of in the synthesis of taxanes (e.g., Example 19.27).28
OH OH
(cod)Ir(PCy)3py•PF6
27
(19.26)
H2, CH2Cl2, r.t.
Me Me
O O
H O H O
(cod)Ir(PCy)3py•PF6 28
(19.27)
TIPSO H2, CH2Cl2, r.t. TIPSO
OH (98%) OH
HO HO
OH OH
Reaction Synopses
Catalytic Hydrogenation
R R [H] R R [H] R
R R
catalyst catalyst
R R R R R
[H]: H2; NH4OCHO, HCO2H; cyclohexene; R 2CHOH; etc.

Catalyst: Ni; PtO2; Pd; Os; Ru; etc; heterogeneous catalysts may be pow-
ders or supported metals (on C, BaSO4, CaCO3, etc.)
(Ph3P)3RhCl; etc.
Stereochemistry: syn (suprafacial)
Worked Problem
19-1 What will the major organic product of the following reaction be? [J. Am. Chem.
Soc. 1980, 102, 889]
MeO
O
OMe H2, (Ph3P)3RhCl
OMe
H
26. (a) Crabtree, R.H.; Felkin, H.; Morris, G.E.; King, T.J.; Richards, J.A. J. Organometal. Chem. 1976, 113, C7.
(b) Crabtree, R.H.; Morris, G.E. J. Organometal. Chem. 1977, 135, 395. (c) Crabtree, R.H.; Felkin, H.; Morris,
G.E. J. Organometal. Chem. 1977, 141, 205. (d) Crabtree, R.H. Acc. Chem. Res. 1979, 12, 331. (d) Crabtree, R.H.;
Davis, M.W. J. Org. Chem. 1986, 51, 2655.
27. Evans, D.A.; Morrissey, M.M. Tetrahedron Lett. 1984, 25, 4637.
28. Wender, P.A.; Badham, N.F.; Conway, S.P.; Floreancig, P.E.; Glass, T.E.; Gränicher, C.; Houze, J.B.; Jänichen, J.;
Lee, D.; Marquess, D.G.; McGrane, P.L.; Meng, W.; Mucciaro, T.P.; Mühlebach, M.; Natchus, M.G.; Paulsen, H.;
Rawlins, D.B.; Satkofsky, J.; Shuker, A.J.; Sutton, J.C.; Taylor, R.E.; Tomooka, K. J. Am. Chem. Soc. 1997, 119, 2755.

Problem
O
H2, PtO2 H2, Pd-C
(a) (b) O
O (1 eq. H2)
O
H
CO2H CO2Me
OH H2, Ir black CO2Me H2, Pd-C
(c) (d)
200 atm, HOAc H
HClO4 O
[3 eq. H2 reacts; product
contains a lactone ring]
BnO
H2, Rh-C H H2, Pt-C
(e) O O
THF
(f) O EtOAc
OMe
(1 eq. H2) MeO2C OMOM
OTHP
OTBDMS CO2Me
HO
H2, PtO2 O H2, PtO2
(g) EtOAc
(h) H pentane
HO
References for problems: (a) J. Am. Chem. Soc. 1980, 102, 6351. (b) Tetrahedron Lett. 1976, 2041.
(c) J. Am. Chem. Soc. 1979, 101, 1608. (d) J. Am. Chem. Soc. 1979, 101, 4398. (e) J. Am. Chem. Soc. 1978,
100, 8031. (f) J. Am. Chem. Soc. 1983, 105, 1988. (g) J. Am. Chem. Soc. 1979, 101, 4749. (h) J. Org. Chem.
1981, 46, 479.
Hydrogenation of Alkynes
One of the most important catalytic hydrogenations of functional groups other than
alkenes is the hydrogenation of alkynes to alkenes over a palladium catalyst poisoned with
lead and quinoline (“Lindlar” catalysts).29 This reaction owes its importance to the fact
that the alkene produced is almost entirely the Z isomer. This becomes even more import-
ant when one considers that the asymmetric epoxidation by either the Jacobsen-Katsuki30
29. (a) Lindlar, H. Helv. Chim. Acta 1952, 35, 446. (b) Lindlar, H.; Dubuis, R. Org. Syn. 1966, 46, 89.
30. Review: Matsumoto, K.; Katsuki, T. In Ojima, I., Ed. Catalytic Asymmetric Synthesis, 3rd ed. (John
Wiley & Sons: New York, 2010), ch. 11, p. 839.

The homogeneous rhodium catalyst will reduce the least hindered double bond first, from the most accessi-
ble face. The perspective representation of this molecule, based on an examination of molecular models, reveals
that the exocyclic methylene group is the least hindered and that the exo face of the bicyclo[3.3.0]octane ring
system will be the less hindered in terms of being able to bind the metal. Thus, we predict that the major product
will be as shown below:
MeO MeO
O O
OMe H2, (Ph3P)3RhCl OMe
OMe OMe
H Me H


or Shi31 catalytic methods, which we will discuss in the next chapter, works best with cis
alkenes.
The classical Lindlar catalyst is made by adding a lead salt (the acetate, sulfate, oxide,
and carbonate have all been used) to palladium supported on calcium carbonate or
barium sulfate. Palladium precipitated on a support in the presence of quinoline has been
reported to be superior to the original Lindlar catalyst in terms of preparation, stereose-
lectivity, and reproducibility (e.g., Example 19.28). Pre-prepared Lindlar catalysts are
now commercially available (e.g., Example 19.29). In cases where the Lindlar catalyst is
ineffective, P2-nickel, prepared by reduction of nickel (II) acetate by sodium borohydride
in ethanol under an atmosphere of hydrogen, in the presence of ethylenediamine as a
catalyst poison has provided a useful alternative.32 Recently, a “green” alternative to the
lead-based Lindlar catalyst for the same hydrogenation of alkynes to Z-alkenes has been
reported.33 In this procedure, the catalyst is a palladium-polyethyleneimine (PEI)
complex (Example 19.30).
(CH2)3CO2Me H2,Pd-BaSO4 H (CH2)3CO2Me

MeOH 34
(19.28)
quinoline
H (CH2)3CO2Me
(CH2)3CO2Me (97%)
CO2H O
H2, Pd-Pb-CaCO3 35
O (19.29)
quinoline, EtOAc
C8H17 OH (80%)
C8H17
R'
5% Pd0–PEI (10%), H2 H R'
(19.30)
MeOH, dioxane, r.t.
H R
R
Problem
19-2 Give the major organic product of each of the reactions below.
TBSO OPMB H2, Pd-BaSO4
(a) TBSO quinoline
O O H2, Pd-BaSO4
(b)
PbSO4, quinoline
H
H2, Pd-BaSO4
(c) N
OHC PbSO4, quinoline
O
H H H2, Pd-C
O
(d)
Et3N, EtOAc
(±)
(continues)
31. Review: Shi, Y. Acc. Chem. Res. 2004, 37, 488.

32. Ganame, D.; Quach, T.; Poole, C.; Rizzacasa, M.A. Tetrahedron Lett. 2007, 48, 5481.
33. Sajiki, H.; Mori, S.; Ohkubo, T.; Ikawa, T.; Kume, A.; Maegawa, T.; Monguchi, Y. Chem. Eur. J. 2010, 14, 5109.
34. Cram, D.J.; Allinger, N.L. J. Am. Chem. Soc. 1956, 78, 2518.
35. Jakubowski, A.A.; Guziec, F.S., Jr.; Sugiura, M.; Tam, C.C.; Tishler, M.; Omura, S. J. Org. Chem. 1982, 47, 1221.

(Problem continued)
OTBS
H2, Pd-C
(e) EtOAc
O
References: (a) J. Org. Chem. 2002, 67, 2751. (b) Org. Lett. 2002, 4, 119. (c) Org. Lett. 2002, 4, 2469.
(d) Biosci. Biotechnol Biochem. 2011, 75, 976. (e) Org. Lett. 2004, 6, 1493.
Hydrogenation of Carbonyl Compounds

In 1969, McAlees and McCrindle established that the ease of hydrogenation of carboxylic
acid derivatives followed the order: anhydrides > esters > carboxylic acids > amides.36
The reduction of amides by hydrogen is especially difficult. It almost always requires high
temperatures and high pressures,37 and it seldom gives good yields of the desired products.
Therefore, the reduction of amides is still carried out predominantly by means of hydride-
reducing agents (LiAlH4 or B2H6), despite the replacement of such reagents being one of
the priorities for “greening” of pharmaceutical manufacture.38 Some of the problems
associated with direct hydrogenation of amides have been overcome by using silanes as
hydrogen donors in metal-catalyzed reductions.39 In general, however, the catalytic hydro-
genation of carbonyl groups is usually more conveniently carried out using complex metal
hydride reducing agents. Thus, the hydrogenation of carbonyl compounds is not often a
useful synthetic method.
The one exception to this generalization is the Rosenmund reduction of acid chlorides
to aldehydes over a modified supported palladium catalyst (e.g., Example 19.31).40 In the
presence of a number of modifiers containing sulfur (thiourea, tetramethylthiourea, and
sulfur-quinoline), acid chloride groups can be reduced selectively in the presence of alkene
π bonds.41 A more modern version of this reaction (Example 19.32) involves the hydroge-
nation of esters of hydroxytriazine. The reagent used in this reaction reacts with the car-
boxylic acid by an addition-elimination mechanism (can you write a mechanism for this
reaction?) to give the nucleophilic aryl substitution product. Aromatic acids in this mod-
ification of the reaction tend to give over-reduction to the alcohol, but the reaction can be
used to reduce Boc-protected α-amino acids to the corresponding aldehydes without
epimerization.42
36. McAlees, A.J.; McCrindle, R. J. Chem. Soc. C 1969, 2425.

37. (a) Wojcik, B.; Adkins, H. J. Am. Chem. Soc. 1934, 56, 247. (b) Paden, J. H.; Adkins, H. J. Am. Chem. Soc.
1936, 58, 2487. (c) Sauer, J. C.; Adkins, H. .I. Am. Chem. Soc. 1938, 60, 402. (d) D’Ianni, J. D.; Adkins, H. J. Am.
Chem. Soc. 1939, 61, 1675. (e) Broadbent, H.S.; Bartley, W J. J. Org. Chem. 1963, 28, 2345. (f) Guyer, A.; Bieler, A.;
Gerliczy, G. Helv. Chim. Acta 1955, 38, 1649. (g) Galinovsky, F.; Stem, E. Chem. Ber. 1943, 76, 1034.
Even modern bimetallic catalysts that give good yields of the desired amine products require temperatures
above 150°C and pressures of 100 atm: Hirosawa, C.; Wakasa, N.; Fuchikami, T. Tetrahedron Lett. 1996, 37,
6749.
38. Constable, D.J.C.; Dunn, P.J.; Hayler, J.D.; Humphrey, G.R.; Leazer, J.L., Jr.; Linderman, R.J.; Lorenz, K.;
Manley, J.; Pearlman, B.A.; Wells, A.; Zaks, A.; Zhang, T.Y. Green Chem. 2007, 9, 411.
39. Igarashi, M.; Fuchikami , T. Tetrahedron Lett. 2001, 42, 1945.
40. (a) Rosenmund, K.W. Ber. dtsch. chem. Ges. 1918, 51, 585. (b) Rosenmund, K.W.; Zetzsche, F. Chem. Ber.
1921, 54, 425. (c) Mosettig, E.; Mozingo, R. Org. React. 1948, 4, 362.
Karl Wilhelm Rosenmund (1884–1965) took his PhD under Otto Diels at Berlin in 1906. He was then ap-
pointed as Assistant in the Pharmacy Institute at Berlin. In 1925, he joined the University of Kiel as Professor of
Chemistry and Director of the Pharmacy Institute. Following his retirement, he returned to Berlin as an unof-
ficial Extraordinary Professor of Chemistry.
41. (a) Weygand, C.; Meusel, W. Chem. Ber. 1943, 76, 503. (b) Affrossman, S.; Thomson, S.J. J. Chem. Soc.
1962, 2024.
42. Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. J. Org. Chem. 1999, 64, 8962.

O O
COCl H2, Pd-BaSO4 CHO
(19.31)
HN HN
PhMe, ∆
O (65%) O
OMe
N N
O N N OMe
1) CHO
CO2H Me (19.32)
NHBoc 2) H2, Pd-C NHBoc
DME-EtOH
(85%)
The major problem with the Rosenmund reduction is that the results tend to be highly
variable, with the catalyst and the catalyst “poison” both having major effects on the reac-
tion outcome. One rationalization for this irreproducibility was the fact that hydrogen
chloride is produced in the reaction. In the 1970s, Burgstahler43 and Van Bekkum44
reported that tertiary amines could be used as modifiers in the Rosenmund reduction
(e.g., Example 19.33), thus eliminating the need for the quinoline-sulfur “poison.” Van
Bekkum found, also, that this would permit hydrogenation of acid chlorides in the pres-
ence of aromatic nitro groups (e.g., Example 19.34). More recently, the deactivation of
palladium on carbon by prolonged heating in xylene at 140°C under an atmosphere of
hydrogen has been shown to be sufficient to produce a good catalyst for the Rosenmund
reduction (e.g., Example 19.35).45 The one caveat with using the deactivated palladium on
carbon catalyst is that the pressure of hydrogen must be kept high enough to prevent
decarbonylation of the aldehyde product.
COCl CHO
H H2, 5% Pd-BaSO4 H 66
2,6-Me2py, THF (19.33)
(96%) H
H
COCl CHO
H2, 10% Pd-C
(19.34)67
i-Pr2NEt, EtOAc
(>90%)
NO2 NO2
O O
O O 1) (COCl)2 O O 68
(19.35)
2) H2, Pd-C*,
MeO2C CO2H xylene, 100°C MeO2C CHO
*deactivated at 140°C prior to use
43. Burgstahler, A.W.; Weigel, L.O.; Schaefer, C.G. Synthesis 1976, 767.
44. Peters, J.A.; Van Bekkum, H. Rec. Trav. Chim. Pays-Bas 1971, 90, 1323.
45. Ancliff, R.A.; Russell, A.T.; Sanderson, A.J. Chem. Commun. 2006, 3243.

Hydrogenation of Nitrogen-Containing Functional Groups

Amines are almost universally biologically active and occupy by far a dominant position
among pharmaceuticals. This means that methods for the formation of amines assume a
high level of economic importance, and techniques for doing so have thus been the subject of
intensive research. The synthesis of amines by catalytic hydrogenation can be effected start-
ing from five different functional groups: oximes (Examples 19.36 and 19.37), nitro groups
(Example 19.38), azides (Example 19.39), nitriles (Example 19.40), and imines (usually
formed in situ in reductive aminations of carbonyl compounds). In all five cases, poisoning
of the catalyst by the amine product is a potential problem that is usually suppressed by
carrying out the reduction in acidic solvents or by the use of Raney nickel as the catalyst.
NOH NH2
O O O O
H2, Ra-Ni 46
Br Br (19.36)
N (87%) N
N Boc N Boc
Me Me
HN HN
HON H2N
O O
H2, Ra-Ni
Br Br (19.37)
N N
N Boc N Boc
Me Me
O O
H2 (80 atm) 47
O Ra-Ni O (19.38)
CO2Me 55°C, 24 h
NO2 HN
(95%)
O
O O
O OMOM O OMOM
O H2, 10% Pd-C O 48
N3 NH2 (19.39)
OH EtOH OH
O O
O (quantitative) O
CN O CN O
49
H2, 10% Pd-C (19.40)
O O
NC H2N
The hydrogenation of nitriles is complicated by the propensity of the primary amine to

react with the nitrile to give products that are then reduced to secondary or tertiary amines.
This type of activity can be modulated by appropriately choosing the catalyst. Ru and Ni cata-
lysts tend to favor the formation of primary amines, Cu and Rh catalysts tend to favor second-
ary amine formation, and Pd and Pt catalysts tend to favor tertiary amines.50 Hydrogenation of
46. Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794.
47. Dong, L.; Xu, Y.-J.; Cun, L.-F.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2005, 7, 4285.
48. Sato, K.; Akai, S.; Shoji, H.; Sugita, N.; Yoshida, S.; Nagai, Y.; Suzuki, K.; Nakamura, Y.; Kajihara, Y.;
Funabashi, M.; Yoshimura, J. J. Org. Chem. 2008, 73, 1234.
49. Minato, H.; Nagasaki, T. Chem. Comm. 1965, 377.
50. (a) Volf, J.; Pašek, J. In Červený, L., Ed. Catalytic Hydrogenation; (Elsevier: Amsterdam, 1986) p. 105.
(b) Barrault, J.; Pouilloux, Y. Catal. Today 1997, 37, 137. (c) Huang, Y.; Sachtler, W.M.H. Appl. Catal. A 1999, 182, 365.

acetonitrile over heterogeneous Mo/P catalysts has shown that the Mo/P ratio can dramati-
cally affect the outcome of the reduction: high Mo/P surface ratios favor ethylamine, and low
Mo/P surface ratios favor secondary and tertiary amines.51 Homogeneous catalysis of the
hydrogenation of nitriles usually leads to secondary amines as the major products.52 This can
be changed by carrying out the hydrogenation in CO2-expanded solvents.53
Worked Problem
19-2 What will the major organic product of the following reaction be? [Tetrahedron
Lett. 2009, 50, 3654]
CN H2,
0.5 mol % Ru(cod)(methallyl)2
SIMesBF4 (0.5-1.0 mol %)
MeO
KOBut (10 mol %)
Ru(cod)(methallyl)2 : Ru SIMesBF4 : N N BF4
§Answer below.
Reaction Synopses
Catalytic Hydrogenation of Alkynes
(a) To saturated systems
[H]
R R R
catalyst R
Reagents: see hydrogenation of alkenes

(b) To Z-alkenes
H2 R R R
R R
catalyst
H H R
Catalyst: Pd-CaCO3, PbCO3; Pd-CaCO3, PbSO4; Pd-Al2O3, PbSO4; etc.

H2, Pd-BaSO4, PbSO4, quinoline (Lindlar Pd); H2, Pd-CaCO3, PbSO4,
quinoline (Lindlar Pd); Pd-PEI, MeOH, dioxane: a “green” alternative
(continues)
51. Yang, P.; Jiang, Z.; Ying, P.; Li, C. J. Catal. 2008, 253, 66.
52. De Bellefon, C.; Fouilloux, P. Catal. Rev.–Sci. Eng. 1994, 36, 459.
53. Xie, X.; Liotta, C.L.; Eckert, C.A. Ind. Eng. Chem. Res. 2004, 43, 7907.

The homogeneous catalyst is based on ruthenium, so we predict that the reaction will lead to formation of
the primary amine. Thus, we predict that the major product will be as shown below:
NH2
CN H2,
0.5 mol % Ru(cod)(methallyl)2
SIMesBF4 (0.5-1.0 mol %)
MeO MeO
KOBut (10 mol %)

Rosenmund Reduction
O O
R R
X H
Reagent: X=Cl, H2, Pd-BaSO4, S, quinoline; H2, Pd-C, R 3N; H2, Pd-C*; etc.
X=triazine ester, H2, Pd-BaSO4; etc.
Problem
19-3 Give the major organic product of each of the following reactions or reaction se-
quences. Specify stereochemistry where appropriate.
CO2H 1) (COCl)2, PhMe
(a)
2) H2, Pd-C, 2,6-lutidine
CO2Me
THF
1) SOCl2, CHCl3
(b)
2) H2, Pd-BaSO4, PhMe
O O O CO2H
HO2C O
1) (COCl)2, PhMe
(c) O 2) H2, Pd-C, 2,6-lutidine
THF
References: (a) Tetrahedron Lett. 1993, 34, 2593. (b) Tetrahedron Lett. 2006, 47, 2405. (c) J. Am. Chem.
Soc. 2003, 125, 1458.
Transfer Hydrogenation, Ionic Hydrogenation, and Organocatalysis

Hydrogenation catalyzed by transition metals is a cornerstone of organic synthesis. How-
ever, there are problems, such as the cost of the catalysts involved, their occasional toxicity
and air sensitivity, and the dangers inherent in handling hydrogen at high pressures. These
have prompted efforts to develop methods for the reduction of carbon-carbon and carbon-
heteroatom π bonds that do not require a transition metal catalyst and/or molecular hy-
drogen. Reactions that do not involve a transition metal catalyst are now often described
using the term organocatalytic, meaning that the catalysis of the reaction is provided by
a non–metal-containing molecule or ion. Most organocatalytic reactions involve proton
transfer as one of the steps.
Transfer Hydrogenation54
The first technique that we will discuss as a replacement for traditional catalytic hydroge-
nation is transfer hydrogenation. In this technique, a molecule such as an ammonium salt
of formic acid, cyclohexene, 1,4-cyclohexadiene, or isopropyl alcohol serves as the source of
hydrogen for the reduction. It is itself oxidized during the reaction (formic acid derivatives
54. Reviews: (a) Brieger, G.; Nestrick, T.J. Chem. Rev. 1974, 74, 567. (b) Ram, S.; Ehrenkaufer, R.E. Synthesis
1988, 91.

to carbon dioxide, isopropyl alcohol to acetone, and cyclohexene and cyclohexadiene to

benzene). The elimination of molecular hydrogen from the system has made this a popular
reaction in process chemistry, where reactions are often carried out on the ton scale. The
reaction has been widely used for the reduction of nitro compounds, which are reduced
with ammonium formate over a number of supported metals (Examples 19.41 to 19.44).
OH OH
55
NH4OCHO (19.41)
Ph OTHP Pd-C, THF-MeOH Ph OTHP
NO2 (80%) NH2
O2 N CHO CoHMA H2N CHO 56

(19.42)
Me2CHOH, ∆
Cl Cl
(88%)
NH4OCHO 57
(19.43)
NO2 Pd-C, THF-MeOH NOH
Br Br
(34%)
B10H14 (30 mol %)

Me2SO (3 eq) 58
(19.44)
NO2 10% Pd-C (30 wt. %) NOH
Cl Cl
MeOH
(93%)
The reduction occurs with retention of configuration,59 which suggests that the sub-
strate is not released from the catalyst until the reduction is complete. Conjugated
nitroalkenes are reduced using the same method to oximes (presumably formed from the
corresponding saturated nitroso compounds).60 The effects of the support for certain
metals can be quite striking. Using mesoporous aluminosilicate molecular sieves, for ex-
ample, leads to selectivity that allows the chemoselective transfer hydrogenation of nitro
groups, aldehydes, and halides.61 The activity of the ruthenium catalyst in Example 19.45
shows a fairly strong dependence on pH, with an optimum pH of 4.62
O HCO2Na, H2O, pH 4 OH
70°C, 13 h
(97%)
(19.45)
N N
Ru
OH2
55. (a) Ram, S.; Ehrenkaufer, R.E, Tetrahedron Lett. 1984, 25, 3415. (b) Ram, S.; Ehrenkaufer, R.E. Synthesis
1986, 133. (c) Barrett, A.G.M.; Spilling, C.D. Tetrahedron Lett. 1988, 29, 5733.
56. Mohapatra, S.K.; Sonavane, S.U.; Jayaram, R.V.; Selvam, P. Tetrahedron Lett. 2002, 43, 8527; Tetrahedron
Lett. 2003, 44, 1107.
57. Kabalka, G.W.; Goudgaon, N.M. Synth. Commun. 1988, 18, 693.
58. Lee, S.H.; Park , Y.J.; Yoon, C.M. Org. Biomol. Chem. 2003, 1, 1099.
59. Barrett, A.G.M.; Spilling, C.D. Tetrahedron Lett. 1988, 29, 5733.
60. (a) Varma, R.S.; Varma, M.; Kabalka, G.W. Synth. Commun. 1986, 16, 91. (b) Varma, R.S.; Varma, M.;
Kabalka, G.W. Synth. Commun. 1985, 15, 1325.
61. (a) Mohapatra, S.K.; Sonavane, S.U.; Jayaram, R.V.; Selvam, P. Tetrahedron Lett. 2002, 43, 8527; Tetrahe-
dron Lett. 2003, 44, 1107 (Co). (b) Selvam, P.; Mohapatra, S.K.; Sonavane, S.U.; Jayaram, R.V. Tetrahedron Lett.
2004, 45, 2003 (Ni). (c) Selvam, P.; Sonavane, S.U.; Mohapatra, S.K.; Jayaram, R.V. Tetrahedron Lett. 2004, 45,
3071 (Pd).
62. Ogo, S.; Abura, T.; Watanabe, Y. Organometallics 2002, 21, 2964.

Reductive Amination of Aldehydes and Ketones

The synthesis of amines from aldehydes and ketones by treatment with a nitrogen nucleo-
phile and a reducing agent is known as reductive amination.63 The condensation between
the aldehyde or ketone and ammonia or a primary amine gives an imine (Example 19.47)
as the major product, and the condensation with a secondary amine gives an enamine
(Example 19.48). Like the polar π bond of the carbonyl compounds, the polar C=N π
bond of an imine or its conjugate acid, an iminium ion, is susceptible to reduction by com-
plex metal hydrides. However, being less polar than the π bond of the carbonyl group, it is
also susceptible to hydrogenation. Both reduction pathways lead to the same final product.
In modern variants of the reductive amination, the carbonyl compound is either con-
verted to the iminium ion, which is then reduced in situ with a hydride-reducing agent (we
will discuss this reaction in more detail later in this chapter), or the neutral imine or
enamine is reduced by hydrogenation (e.g., Example 19.5064).
R1
N
R4 R2 R3
R1 R1 R4=H [H] R1
HN (19.47)
R4 R4
R3
O N N
R1
R2 R4=H, alkyl R2 R3 R2 R3
R4 [H]
R4=alkyl N (19.49)
(19.46) R2 R3
(19.48)
H2N O O PhCHO H
Ph N O O (19.50)
H2, 10% Pd-C
EtOH
(56%)
Ionic Hydrogenation65
Ionic hydrogenation is defined broadly as the reduction of a π bond by means of a
complementary pair of reagents comprising a proton donor and a hydride ion donor
(Example 19.51). The two parts of the reagent may be two separate molecules, or
they may be part of the same molecule. In general, the key task in an ionic hydroge-
nation is to identify the hydride donor; the proton donor is almost always a strong
Brønsted acid.
R H R R
X XH H XH (19.51)
R R R
H M M
X = CR2, NR, O M = Si, transition metals
63. Reviews: (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069. (b) Shimizu, H.; Nagasaki, I.; Matsumura,
K.; Sayo, N.; Saito, T, Acc. Chem. Res. 2007, 40, 1385. (c) Tararov, V.I.; Kadyrov, R.; Riermeier, T.H.; Dingerdissen,
U.; Boerner, A. Org. Prep. Proced. Int. 2004, 36, 99. (b) Tararov, V.I.; Boerner, A. Synlett 2005, 203.
64. Ziegler, F.E.; Kloek, J.A.; Zoretic, P.A. J. Am. Chem. Soc. 1969, 91, 2342.
65. Review: Kursanov, D.N.; Parnes, Z.N.; Loim, N.M. Synthesis 1974, 633.

Figure 19.6 Ionic
hydrogenation of
representative alkenes shows
that only those alkenes that
can give relatively unreactive
carbocations will give
Et3SiH Et3SiH hydrogenation products.
CF3CO2H CF3CO2H
Silanes were the first hydride donors used in ionic hydrogenations, and this early work
has since been expanded to involve hydride complexes of a wide range of transition metals.
The common feature of these reactions is that there is an initial protonation of the π bond
followed by hydride transfer from the metal hydride. The treatment of an alkene with a
silane in trifluoroacetic acid leads to reduction of the alkene if the double bond can be
protonated to give a relatively stable carbocation. Alkenes that give tertiary or benzyl
cations on protonation are reduced with triethylsilane and trifluoroacetic acid, but alkenes
that give secondary carbocations are not (Figure 19.6)66 The reaction can be used to reduce
carbonyl groups and the alkene π bond of conjugated carbonyl compounds, but it is also a
useful method for the reduction of (1) hemiacetals to ethers and (2) aminals and
α-aminoethers to amines (e.g., Example 19.52).67
OMe Me
N N
O O
O Et3SiH O (19.52)
CF3CO2H HO
HO CH2Cl2
N O N O
Me (63%) Me
O O Ph
Ph
More recently, ionic hydrogenations have been carried out using Hantzsch esters as
the hydride donor, in a reaction that is strongly reminiscent of the biological reduction of
carbonyl compounds by NADH (e.g., Example 19.53). Activation of the π bond, either by
means of a strong Brønsted acid or by conjugation with a strongly electron-withdrawing
group, is necessary for this reaction to proceed. When a Brønsted acid is used, it is im-
portant that the conjugate base of the acid be a poor nucleophile, so that it does not com-
pete successfully with the Hantzsch ester for the cation. One of the most useful approaches
to the reduction of enones and enals has been to convert them into iminium ions by
means of a catalytic amount of a secondary amine; the carbonyl group is regenerated
during the reaction.
66. Kursanov, D.N.; Parnes, Z.N.; Bassova, G.I.; Loim, N.M.; Zdanovich, D.I. Tetrahedron 1967, 23, 2235.
67. Ataraschi, S.; Choi, J-K.; Ha, D-C.; Hart, D.J.; Kuzmich, D.; Lee, C-S.; Ramesh, S.; Wu, S.C. J. Am. Chem.
Soc. 1997, 119, 6226.

R
EtO2C CO2Et
R3 R3
X Me N Me X
H
(19.53)
R1 R1
R2 R2
Reaction Synopses
Transfer Hydrogenation
X XH
H-donor
R R catalyst R R
X=CR 2, O, NR
Reagents:
H-donor: cyclohexene, cyclohexadiene, phellandrene, etc.; i-PrOH, etc.;
HCO2H, HCO2NH4, etc.
Catalyst: heterogeneous: Pd-C preferred; cozeolites; etc.
homogeneous: Ru, Rh, Pd complexes; etc.
Ionic Hydrogenation
X XH
H-donor
R R catalyst R R
X=CR 2, O, NR
Reagents:
H-donor: R 3SiH; Hantzsch ester; etc.
Catalyst: CF3CO2H; BF3•Et2O; (RO)2PO2H; etc.
Problems
19-4 Give the major organic product of each of the following reactions or reaction se-
quences. Specify stereochemistry where appropriate.
H2C=O, H2O, H2
(a) NH
Pd-C, EtOAc-MeOH
N H
H
Ph
Et3SiH (2 eq.)
(b) S
CF3CO2H (7 eq)
50°C, 20 h
O
Me NH4OCHO, NH3
(c) MeOH-H2O, [(R)-tol-binap]RuCl2
[product has R configuration]
References: (a) J. Am. Chem. Soc. 2010, 132, 8282. (b) Tetrahedron 1975, 31, 311. (c) Angew. Chem. Int.
Ed. 2003, 42, 5472.

19.3 Hydrogenolysis
Carbon-heteroatom bonds located adjacent to a π bond tend to be much more reactive than
their saturated counterparts. This extraordinary reactivity applies to most allyl and benzyl
functional groups, as well as to α-substituted carbonyl compounds. All these compounds are
susceptible to reactions in which the allylic carbon-heteroatom σ bond is replaced by a car-
bon-hydrogen σ bond (Examples 19.54 to 19.56). This reaction, which can be effected either
with hydrogen and a catalyst or a dissolving metal (which will be discussed in more detail in
the next chapter) is called hydrogenolysis (“cleavage by hydrogen”). However, the name is
often restricted to the reactions with hydrogen using a palladium or nickel catalyst.68
X [H] H (19.54)
[H]
X H (19.55)
X H
[H] (19.56)
O O
X = Cl, Br, I, OH, OR, NR2, OCOR, NHCOR,

OTs, OP(O)(OR)2, etc.
[H] = H2, Pd-C; H2, Ni; etc.

The preferred catalyst for hydrogenolysis of benzyl groups is palladium on carbon
because competing ring hydrogenation occurs only very slowly with this catalyst.
When hydrogenolysis of benzyl and allyl substituents is to be minimized, rhodium
and ruthenium catalysts are preferred.69 Although the hydrogenolysis of benzyl alco-
hols, ethers, and amines is synthetically useful, the corresponding hydrogenolysis of
allyl compounds is often less satisfactory due to competing hydrogenation of the
double bond.
In general, the rate of hydrogenolysis of a benzyl carbon-heteroatom bond increases
with the ability the heteroatom to carry an additional unit of negative charge.70 For exam-
ple, the ease of hydrogenolysis of benzyl carbon-oxygen bonds parallels the approximate
base strength of the leaving groups. The relative order for hydrogenolysis of benzyl
carbon-oxygen bonds in a series of benzyl compounds over palladium is:
∙ ∙
HO–CH2Ph < RO–CH2Ph < ArO–CH2Ph < RO–CH2Ph < H2O–CH2Ph < AcO–CH2Ph < F3CCO2–CH2Ph
–
In similar fashion, the relative rates of hydrogenolysis of other carbon-heteroatom

bonds follow the order: NR 3+ > OR > NR 2. This is illustrated by the hydrogenolysis of the
68. (a) Hartung, W.H.; Simonoff, R. Org. React. 1953, 7, 263. (b) Entwhistle, I.D.; Wood, W.W. In Trost, B.M.;
Fleming, I., Eds. Comprehensive Organic Synthesis (Pergamon: Oxford, 1991), vol. 8, p. 955.
69. (a) Burgstahler, A.W.; Bithos, Z.J. Org. Syn. 1962, 42, 62. (b) Stocker, J.H. J. Org. Chem. 1962, 27, 2288.
(c) Barkdoll, A.E.; England, D.C.; Gray, H.W.; Kirk, W., Jr.; Whitman, G.M. J. Am. Chem. Soc. 1953, 75, 1156.
(d) Ham, G.E.; Coker, W.P. J. Org. Chem. 1964, 29, 194. (e) Meyers, A.I.; Beverung, W.; Garcia-Muñoz, G. J. Org.
Chem. 1964, 29, 3427. (f) Kaye, I.A.; Matthews, R.S. J. Org. Chem. 1963, 28, 325.
70. (a) Khan, A.M.; McQuillin, F.J.; Jardine, I. J. Chem. Soc. 1967, 136. (b) Kieboom, A.P.G.; deKreuk, J.J.; van
Bekkum, H. J. Catal. 1971, 20, 58.

ammonium (Example 19.57). In this compound, the quaternary salt is selectively deben-
zylated in the presence of the benzyl ether.71
OTs O Ph H2 (1 atm) OTs O Ph

10% Pd-C
(19.57)
N EtOH, 25°C Me N
Ph
Me (62%) H
The hydrogenolysis of benzyl and allyl groups proceeds with either retention or inver-
sion of configuration, depending on the catalyst used. Early work with atrolactic acid (e.g.,
Example 19.58)72 and 2-phenyl-2-butanol73 showed that hydrogenolysis over nickel pro-
ceeds largely with retention of configuration; the typical ratios of retention to inversion in
these studies vary from 95:5 to 82:18. In contrast to hydrogenolysis over nickel, hydrogeno-
lysis over palladium occurs with inversion of configuration,74,75 as illustrated by the hy-
drogenolysis of the 9-oxabicyclo[3.3.1]nonane derivative in Example 19.59. This is not
always the case, however. The results of a series of experiments using derivatives of the
conformationally locked 4-tert-butyl-1-phenylcyclohexyl system75a are shown in Table 19.3.
Table 19.3 Stereochemical Outcome of Hydrogenolysis Experiments
X X H H
Catalyst
X=OH Pt 76 24
X=OH Pt 74 26
X=OH 10% Pd-C 80 20
X=OH 10% Pd-C 90 10
X=OH Ra-Ni 100 0
X=OH Ra-Ni 0 100
X=OAc Pt 0 100
X=OAc Pt 100 0
X=OAc 10% Pd-C 0 100
X=OAc 10% Pd-C 100 0
X=OAc Ra-Ni 0 100
X=OAc Ra-Ni 100 0
X=OMe Ra-Ni 100 0
X=OMe Ra-Ni 0 100
71. House, H.O.; Wickham, P.P.; Müller, H.C. J. Am. Chem. Soc. 1962, 84, 3139.
72. Bonner, W.A.; Zderic, J.A.; Casaletto, G.A. J. Am. Chem. Soc. 1952, 74, 5086.
73. Cram, D.J.; Allinger, N.L. J. Am. Chem. Soc. 1954, 76, 4516.
74. (a) Cope, A.C.; McKervey, M.A.; Weinshenker, N.M. J. Am. Chem. Soc. 1967, 89, 2932. (b) Cope, A.C.;
McKervey, M.A.; Weinshenker, N.M.; Kinnel, R.B. J. Org. Chem. 1970, 35, 2918. (c) Ojima, I.; Shimizu, N. J. Am.
Chem. Soc. 1986, 108, 3100.
75. (a) Bonner, W.A.; Zderic, J.A. J. Am. Chem. Soc. 1956, 78, 3218. (b) Garbisch, E.W., Jr. J. Org. Chem. 1962,
27, 3363. (c) Garbisch, E.W., Jr. Chem. Commun. 1967, 806. (d) Garbisch, E.W., Jr.; Schreader, L.; Frankel, J.J.
J. Am. Chem. Soc. 1967, 89, 4233. (e) Zderic, J.A.; Rivera, M.E.C.; Limon, D.C. J. Am. Chem. Soc. 1960, 82, 6373.

These experiments reveal that the course of the hydrogenolysis depends on both the
catalyst and the benzyl substituent.
HO H
CO2H CO2H
H2, Ni
(19.58)
Ph Ph Ph
HO [H]
(19.59)
O O O
H2, Ra-Ni, EtOH 100 0

H2, Pd-C, HClO4, EtOH 11 : 89
In general, reactions over Raney nickel are stereospecific. The alcohols and ethers react
with retention of configuration, and the acetates react with inversion of configuration.
Over palladium and platinum, the acetates react with inversion of configuration, but the
alcohols react to give the same mixture of stereoisomers regardless of the stereochemistry
of the starting material. The reduction of 4-tert-butyl-1-phenylcyclohexene gives 40% to
50% of cis-1-tert-butyl-4-phenylcyclohexane, regardless of the catalyst.
Hydrogenolysis of benzyl ethers and benzyl esters proceeds readily, so the benzyl
group is a useful protecting group. An example of how this reaction can be applied in
synthesis is provided by the synthesis of the pyrrolizidine derivative shown in Exam-
ple 19.60. The reductive amination of the ketone occurs once the free amine is revealed by
the hydrogenolysis of the benzyl urethane.
OEt OEt
CO2Me
O O
H H2, 10% Pd-C H O 76
(19.60)
MeOH
N O (93%) N CO2Me
Ph
O
Hydrogenolysis often competes with reduction of alkenes and alkynes, and it is often
an undesired side reaction under those circumstances. For this reason, considerable effort
has been expended in developing methods for the selective reduction of alkenes and
alkynes in the presence of benzylic ethers, esters, and halides. One recent approach, men-
tioned earlier in this chapter uses diphenyl sulfide as a catalyst “poison” to prevent hydrog-
enolysis (Example 19.61).77
H2, 10%Pd-C
CO2Bn CO2Bn (19.61)
Ph2S (0.01 eq), MeOH
( 100%)
Recall that the C–C σ bonds in cyclopropane differ from the C–C σ bonds in other
cycloalkanes by having a substantial part of the electron density in the bond outside the in-
ternuclear region (i.e., outside the perimeter of the ring). These σ bonds therefore exhibit
some of the reactivity of C–C π bonds. They will, for example, react with halogens and other
76. Snider, B. B.; Gao, X. Org. Lett. 2005, 7, 4419.

77. Mori, A.; Miyakawa, Y.; Ohashi, E.; Haga, T.; Maegawa, T.; Sajiki H. Org. Lett., 2006, 8, 3279.

electrophiles to give 1,3-disubstituted propane derivatives. This reactivity extends to react-

ing with hydrogen in the presence of a catalyst, but because it is a σ bond rather than a π
bond that is broken, these reactions are formally hydrogenolysis reactions.
As with hydrogenation of alkenes, the course of the hydrogenation of cyclopropanes is
controlled by which of the three sides of the ring can best complex (chemisorb) to the
Figure 19.7 Chemisorption of metal surface (Figure 19.7). This is decided, in turn, by steric and electronic considerations.
a cyclopropane onto a metal Sterically congested sides of a cyclopropane cannot chemisorb well onto the metal surface,
surface so they often do not hydrogenate as effectively. In contrast, an atom that can form a com-
plex with metal atoms (e.g., oxygen or nitrogen) can often facilitate the hydrogenolysis of
the adjacent ring bond.
Which bond of the three-membered ring is cleaved is determined by a number of fac-
tors, including steric hindrance and the conjugating or non-conjugating nature of the ring
substituents.78 The mechanism of the hydrogenolysis is not known with certainty. How-
ever, in studies of the hydrogenolysis of 1,1-difluorocyclopropanes (e.g., Example 19.62)
over p alladium, B essard and Schlosser postulated79 a metallocyclobutane intermediate
(e.g., Example 19.63) in the reaction to account for dehalogenation that occurred at the
same time. A similar palladium insertion into the ring bond was proposed by Jackson and
his coworkers in the late 1970s, based on their studies of the stereochemistry of the
hydrogenolysis of propellenes containing three-membered rings.80 These same workers
found that the hydrogenolysis over platinum and palladium is not stereoselective
(Example 19.65).
O O
H2, Pd-C
F
(69%)
F F F
(19.62) (19.64)
O
LnPd
F
F
(19.63)
H2, cat
+ (19.65)
H H
50:50 ± 12%
The inclusion of a conjugating group (e.g., aryl, carbonyl) on the ring activates the
adjacent ring bonds toward hydrogenolysis, Thus, one finds that hydrogenolysis of cyclo-
propyl ketone and cyclopropanecarboxylic acid derivatives leads to the cleavage of the
α,β-bond of the carbonyl compound,81 as illustrated by the hydrogenolysis in Example
19.66. Like several other hydrogenation methods, the hydrogenolysis of cyclopropanes has
been shown to be amenable to asymmetric reduction.82
78. Roth, J.A. J. Catal. 1971, 26, 97.

79. Bessard, Y.; Schlosser, M. Tetrahedron 1991, 47, 1231.
80. (a) Akhtar, M.N.; Jackson, W.R.; Rooney, J.J. J. Chem. Soc., Perkin Trans. 2, 1976, 12, 141. (b) Akhtar, M.N.;
Rooney, J.J.; Summan, N.G.; Hügel, H.M.; Jackson, W.R.; Nicholson, D.M.; Rash, D. Aust. J. Chem. 1977, 30,
1509. (c) Gooding, K.R.; W Jackson, W.R.; Pincombe, C.F.; Rash, D. Aust. J. Chem. 1977, 30, 1517.
81. Schultz, A.L. J. Org. Chem. 1971, 36, 383.
82. Barluenga, J.; Suárez-Sobrino, A.L.; Tomás, M.; García-Granda, S.; Santiago-García, R. J. Am. Chem. Soc.
2001, 123, 10494.

O H O
H2, Pd(OH)2 O
O (19.66)
83
HO HO
EtOH
H H
(99%)
CO2Me CO2Me
Reductive Desulfurization of Dithioketals and Dithioacetals

Both sulfur atoms of a dithioketal or dithioacetal can be replaced by hydrogen when an ap-
propriate reducing agent is used, and this sequence of dithioacetal formation and desulfur-
ization is often used as a simple two-step alternative to the Wolff-Kishner reduction (discussed
in Chapter 20) and its variants. The most widely used methods for desulfurization of the
dithioketals are hydrogenation over Raney nickel (Examples 19.67 and 19.68), and Birch re-
duction (discussed in Chapter 20). The most effective catalyst is W-2 Raney nickel, although
nickel boride catalysts are also highly effective for effecting desulfurization.
1) (CH2SH)2, BF3 84
(19.67)
2) Ra-Ni
O
(81%)
85
H2, Ra-Ni, EtOH (19.68)
S S
∆, 3 h
S S (90%)
Worked Problem
19-3 What is the major organic product of the following reaction? [J. Am. Chem. Soc.
2002, 124, 14546]
N OPMB
NiCl2, NaBH4
EtS N Ac MeOH-EtOH
OSEM

§ Answer below.
83. Rigby, J.H.; Laxmisha, M.S.; Hudson, A.R.; Heap, C.H.; Heeg, M.J. J. Org. Chem. 2004, 69, 6751.
84. Sondheimer, F.; Wolfe, S. Can. J. Chem. 1959, 37, 1870.
85. Eaton, P.E.; Mueller, R.H.; Carlson, G.R.; Cullison, D.A.; Cooper, G.F.; Chou, T.C.; Krebs, E.-P. J. Am.
Chem. Soc. 1977, 99, 2751.

N OPMB N OPMB
NiCl2, NaBH4
EtS N Ac N Ac
MeOH-EtOH
OSEM OSEM
The sodium borohydride reduces the nickel chloride to an especially active form of the metal that then cat-
alyzes the reaction of sodium borohydride with solvent to generate to hydrogen. The substrate is then added to
the metal, and hydrogenolysis of the C–S bonds occurs to generate the product. Note how this reaction shows
that all C–S bonds (not just those in dithioacetals and dithioketals) are susceptible to hydrogenolysis.

Problems
19-5 What is the structure of the final product of each of the following reactions or
reaction sequences?
S H
S H2, Ra-Ni
(a) N EtOH
O N
H H2, Ra-Ni, H3BO3

(b) MeOH-H2O
OH
References: (a) Org. Lett. 2004, 6, 1493. (b) Org. Lett. 2001, 3, 2611.
19-6 Give the major organic product that will be formed when each of the compounds
in the list below is hydrogenated over Raney nickel.
O Ph
O H
S O
(a) (b) (c) O (d) O OMe
S O
H O
NMe2
Ph
H Br
O
(e)
O
(f) O
O
H
Ph
H H2, Pt-C O H2, Pd-C
O
(a) O EtOAc
(b) O EtOAc
MeO2C OMOM O
OMOM
MsO OBn
H2, Pd-C
(c)
O O
References: (a), (b) J. Am. Chem. Soc. 1983, 105, 1988. (c) J. Am. Chem. Soc. 1979, 101, 1038.
Reaction Synopses
Hydrogenolysis
X H2/cat. H H2/cat.
H H
X: NR 3+, CF3CO2 > OH2+ > OAc > OR > OH ≈ NR 2

Catalyst: Pd preferred; Ni, Pt may be used.

To suppress hydrogenolysis: use Rh, Ru.

Regiochemistry of hydrogenolysis of cyclopropane controlled by substituent
groups on ring
Stereochemistry: inversion with Pd, retention Ni; Pt varies
Chapter Summary
This chapter has introduced reduction in organic chemistry—by means of with heterogeneous
and homogeneous catalytic hydrogenation, which are most useful for the reduction of C–C π
bonds by the suprafacial addition of H–H across the π bond. Hydrogenation of polar bonds
includes the Rosenmund reduction, transfer and ionic hydrogenation of carbonyl compounds,
and reductive amination. Hydrogenolysis of allyl and benzyl substituents can be carried out
with either retention (Ni) or inversion (Pd) of configuration. Hydrogenolysis of cyclopropanes
occurs on the most electron-rich ring bond, or the sterically most accessible bond.
Key Terms
catalytic hydrogenation hydrogenolysis transfer hydrogenation

Hantzsch esters ionic hydrogenation Wilkinson’s catalyst
heterogeneous catalytic Lindlar hydrogenation
hydrogenation reductive amination
homogeneous catalytic reductive desulfurization
hydrogenation Rosenmund reduction
Additional Problems
Comprehensive Reduction Review Problem Set. What is the major organic

product formed when each of the reactants in the first list is treated with each of
the reducing agents in the second list? If a reagent can react more than once with
the particular reducing agent, show the product of each step in the reduction
when an excess of the reducing agent is used (e.g., when ethyl acetate reacts with
lithium aluminum hydride, the first product is acetaldehyde, and this is further
reduced to ethanol).
Note that not all the reactants will react with every reducing agent.
Compounds:
H
O O O N CO2H
(a) (b) (c) (d)
O
OMe
CO2H O
(e) (f) (g) (h)
O
CN OMe
S O
(i) (j) (k) (l) O
S
O Ph
O O H
H O
(m) (n) (o) O OMe
H H O
MeO CO2Me H
MeO O
Ph

O
O H Br
O
(p) (q) (r) O (s)
O H O O
O
CO2H
O
(t) NH (u) (v)

CONMe2 NO2
Reagents:
(i) H2, PtO2. (ii) H2, Pd-BaSO4, PbSO4, quinoline.
(iii) H2, Pd-C. (iv) BuSiH3, CF3CO2H, CH2Cl2.
(v) H2, Rh-C. (vi) NH4OCHO, Pd-C, MeOH, THF.
19-8 What is wrong with the proposed reaction below?
S NO2 H2, Ra-Ni NO2
(a) EtOH
S OH OH
COCl H2, Pt CHO

(b)
OMe H2, Pd-CaCO3 OMe

(c) H
H2, Pd-C
(d)
[molecular models will be useful here]
19-9 What is the major organic product expected from each of the following reac-
tions? Where appropriate, specify stereochemistry.
H
OMe [J. Am. Chem. Soc.
H2, (Ph3P)3RhCl
1980, 102, 889; Bull.
(a) OMe (1 eq. H2 absorbed)
Soc. Chim. Fr. 1980,
MeO
O 327]
O [J. Am. Chem. Soc.

H2, Pd-C
(b) HO2C 1980, 102, 4262; 1981,
HO 103, 4136]
C5H11
H2, Pd-BaSO4 [Tetrahedron Lett.

(c) quinoline, PbSO4 1980, 1129]
hexane
OH
Ph O OH
Et3SiH, BF3•Et2O [Tetrahedron Lett.
(d) HO H
Ph
2011, 52, 4720]
O

Note that stereochemistry may be important in many of these reactions.
O Ph H2, Pd-BaSO4 [Tetrahedron Lett.

(a) O O PbSO4, quinoline 2010, 51, 6018]
O 1) (COCl)2
O
O
2) H2, Pd-C*, xylene, 100°C [Chem. Commun.
(b)
CO2Me
2006, 3243]
HO2C *modified by prior heat treatment
CO2Me H2, Pd-BaSO4

(c) THPO PbSO4, quinoline
[Synlett 2008, 1500]
O H2 (1 atm), PtO2 [Org. Lett. 2004, 6,

(d) EtOAc 3345]
H
O OH Me
H2, Pd-BaSO4 [Org. Lett. 2009, 11,
(e) PbSO4, quinoline
OH
4556]
O N Boc
H
H2, Pd-BaSO4 [Tetrahedron Lett.
(f) O PbSO4, quinoline 2009, 50, 1236]
HO N(i-Pr)2
O
OH
OH
O H2, Pd-BaSO4 [ARKIVOC 2008,
(g) HO H
O OH
PbSO4, quinoline xiv, 314]
O NH
OH
O
P OEt H2, Pd-CaCO3 [Tetrahedron Lett.
(h) Ts N OEt
EtOAc 2010, 51, 60]
Ph
R=CH2OMe
HO
OR
CO2Me [C. R. Chimie 2008,
(i) OR H2, Pd-BaSO4, quinoline
11, 1318]
MeO OR EtOAc, 30 min
OR
MeO2C CO2H 1) (COCl)2, hexane, DMF (cat.) [Tetrahedron Lett.

(j) 2) H2, Pd-C, 2,6-pyMe2, THF 1984, 25, 5881]

CO2Et
[Bull. Chem. Soc.
(k) H2, Rh-Pt
HOAc Japan 1960, 33, 566]
Me CO2H
OH H2, Rh-Pt (200 atm)
C15H24O2 [J. Org. Chem. 2004,
(l) AcOH-HClO4
Me 69, 5219]
[3 eq, H2 absorbed]
Ph O
TIPS
O H2 (1 atm), Pt-C [J. Am. Chem. Soc.
(m) EtOAc
N 2009, 131, 5635]
H O
O
H2, Pd-BaSO4
[Tetrahedron 2011,
(n) quinoline
67, 6659]
O H O
N O
H2, Pd-CaCO3, "Pb" [Org. Lett. 2001, 3,
(o) EtOAc
N N
HO
3927]
Me O H [2 eq. H2 absorbed; unusual]
MeO
N H2 (20 atm), Pd-C [Org. Lett. 2001, 3,
(p) MeO MeOH
2555]
[2 eq. H2 absorbed]
O
OH
H2, PtO2 [Tetrahedron Lett.

(q) HOAc 2011, 52, 4619]
OH
HN
[Tetrahedron 2011,
(r) H2, Pd-C
67, 6547]
MeOH
Ph
O
O CO2Me H2, Pd-C [Tetrahedron Lett.
(s) N HN C9H12N2O4
CO2Me
MeOH 2011, 52, 4570]
H O
H2, Pd-C
MeO [Tetrahedron 2011,
(t) Ph O MeOH
O [3 eq H2 absorbed] 67, 6697]
Ph TBSO
OH OTBS
Me O Cl
OMe H2, Pd-C [Tetrahedron 2011,
(u) MeO
O HO
OTBS
EtOAc 67, 6206]
MeO O
OTBS
Me
Me
Me IrCl2
Me [J. Org. Chem. 2010,
(v) N
Me 2 75, 933]
N H2NCH2CH2NHTs, HCO2Na
AcONa, AcOH, pH 5.5

H
H2 (1 atm), PtO2 [J. Org. Chem. 2010,
(w) N
O EtOAc 75, 933]
O
Me
O O
N
O O
O
O
H2, Pd-CaCO3 (Pb) [Angew. Chem. Int.
(x) MeO2C
H
O O
HN quinoline, EtOAc Ed. 2003, 42, 343]
OH
N
O H2 (1 atm), PtO2 [Tetrahedron 2009,

(y) O
HCl, MeOH 65, 10623]
OMe
H2 (1 atm), PtO2 [J. Org. Chem. 1983,

(z)
HOAc 48, 1135]
CO2Me
O
H [(R)-(BINAP)RuCl2]2
O CO2Me [Tetrahedron 2011,
(0.5 mol %)
(aa)
O n-C9H9 H2 (0.6 atm), MeOH, 70°C 67, 6281]
H
Ph O
N O 1) 10% Pd-C, H2 [Tetrahedron 2011,

(bb) 2) Boc2O
Ph O
N Ph
67, 6281]
Ph
MeO OMe H2, Pd-C

[Tetrahedron 2011,
(cc) O THF-MeOH 67, 6073]
O2N OMe
MeO [p-cymene)RuCl2]2 (0.5 mol %)

(R,R)-TsDPEN (1 mol %) [Org. Lett. 2003, 5,
(dd) N HCO2H-Et3N, MeCN
MeO 4227]
S S
Ra-Ni*, THF, 25 h [J. Am. Chem. Soc.
(ee)
*deactivated by 2006, 128, 740]
O stirring in acetone
H 30 min
CO2C7H15
1) HCl•Et2O [Org. Lett. 2003, 5,
(ff) 2) H2, Pd-C, EtOH
N
O 3811]

19-11 The interesting reaction shown has been described as being carried out under
typical conditions for the hydrogenolysis of a cyclopropane [Org. Lett. 2008, 10,
3381]. However, there is no net gain of hydrogen during the reaction. Suggest a
mechanism.
OH
O O O
H2, Pd-C, THF-EtOH
O O
H
19-12 Suggest reasonable reagents that could be used to carry out the following
transformations:
O O
N N [J. Org. Chem.
(a)
2006, 71, 4170]
TBSO TBSO
O O
O H O H
[J. Org. Chem.
(b) H S H
N N 2005, 70, 5197]
H H
S S
TIPS TIPS
Me Me
TBSO TBSO [J. Am. Chem. Soc.

(c)
2002, 124, 773]
OMe OMe
Me OTBS Me OTBS
O O O OH
Ph [Tetrahedron
(d) HO H O HO H OH
N N 2010, 66, 9340]
Ph
NH2
CN
[Org. Lett.
(e) N N
2008, 10, 1437]
O O
Br Br
[J. Nat. Prod
(f)
O O 2003, 66, 520]
O H O
SS
O O [J. Org. Chem.
(g) H H H 2003, 68, 854]
HO HO
CO2Me CO2Me
N N
[Org. Lett.
(h) O O
HN HN 2011, 13, 1778]
H
O O

19-13 (a) Rationalize the outcome in Problem 19-12 (c). Only one equivalent of hydro-
gen is absorbed, so why does it add where it does?
(b) Why is the heterocyclic double bond in Problem 19-12 (e) resistant to
hydrogenation?
19-14 Suggest a mechanism for the transformation shown.
OMe OMe
CHO
N Et3SiH, CF3CO2H N O
OH
Me3Si I Me3Si I
[Angew. Chem. Int. Ed. Engl. 1996, 34, 2683]

19-15 The hydrogenation of alkene π bonds in the presence of C–S σ bonds is not a
simple process due to the easy hydrogenolysis of the C–S bond and the tendency
of sulfur compounds to act as catalyst “poisons.” How might the reaction at right
be carried out without extensive loss of sulfur?
S S S S
S S
[Tetrahedron 1975, 31, 311]

Chapter twenty
Redox III
Reduction with Complex Metal Hydrides
and Active Metals
20.1 Reductions with Metal Hydrides
As we saw in the previous chapter, catalytic hydrogenation is often poorly suited to the
reduction of polar π bonds (despite the inroads of transfer hydrogenation in this area). For
the reduction of carbonyl groups, imines, and nitriles, the use of complex metal hydrides,
especially hydrides based on Group IIIA metals, is the method of choice. This reaction has
been the subject of intense study over several decades, and therefore there is a huge litera-
ture covering the topic.1 Metal hydride reduction complements catalytic hydrogenation,
which tends to proceed most rapidly with electron-rich, non-polar π bonds. Alkenes,
whose π bonds are non-polar, are readily reduced by hydrogen in the presence of a palla-
dium catalyst. In general, ketones and, to a lesser extent, aldehydes, whose π bonds are
very polar, are not. Conversely, carbonyl compounds are typically reduced very rapidly by
complex metal hydrides, whereas alkenes are usually inert. The CN π bonds of nitriles and
imines, being of intermediate polarity, tend to be readily reducible by both methods.
D
LiAlD4 OH
Et2O
O
(20.1)
D O
D2, Pd-C
Nucleophilic Complex Metal Hydrides

In a formal sense, hydride anion, H–, is a nucleophile, but in a practical sense it seldom (if
ever) functions in this way because it reacts so rapidly as a base. The basicity of the hydride
anion can be reduced by complexing it with a suitable Lewis acid to give a less basic nuc-
leophile. Two of the most widely used reducing agents, sodium borohydride (NaBH4) and
lithium aluminum hydride (LiAlH4), both contain complex anions of this type. The AlH4–
anion, also known as tetrahydridoaluminate or aluminum hydride anion, is the complex
1. Monographs and reviews: (a) Gaylord, N.G. Reduction with Complex Metal Hydrides (Interscience: New
York, 1956). (b) Málek, J. Org. React. 1985, 34, 1. (c) Málek, J. Org. React. 1988, 36, 249. (c) Brown, H.C.; Krish-
namurthy, S. Tetrahedron 1979, 35, 567. (d) Brown, H.C. Boranes in Organic Chemistry (Cornell University
Press: Ithaca, NY, 1972). (e) Hajos, A. Complex Hydrides and Related Reducing Agents in Organic Synthesis
(Elsevier: Amsterdam, 1979). (f) Pelter, A.; Smith, K.; Brown, H.C. Borane Reagents (Academic Press: London,
1988). (g) Hudlicky, M. Reductions in Organic Chemistry, 2nd. ed., ACS Monograph 188 (American Chemical
Society: Washington, DC, 1996). (h) Brown, H.C.; Ramachandran, P.V. In Abdel-Magid, A.F., Ed. Reductions in
Organic Synthesis, ACS Symp. Ser. 641 (American Chemical Society: Washington, DC, 1996).
891

892 Advanced Organic Chemistry | Chapter twenty
of hydride anion with aluminum hydride (Example 20.2), and the BH4– anion, also known
as the tetrahydridoborate or borohydride anion, is its complex with borane (Example 20.3).
Both anions react as nucleophilic donors of hydride anion with the polar π bonds (carbonyl
groups and cyano groups). Generally speaking, neither anion reacts with an isolated
alkene π bond.
H H H H: H
H:
Al H H Al H B H H B H
H H H H
(20.2) (20.3)
The steric and nucleophilic properties of the complex metal hydrides are affected
by several factors: solvent, counterion, and the substitution of hydrogen atoms with
alkoxy or cyano groups. The reactivity of several common hydride reducing agents is
summarized in Table 20.1. The data in Table 20.1 show that (1) aluminum-based
reagents are usually stronger reducing agents than borohydrides and that (2) the more
effective the cation in forming a complex with the carbonyl oxygen, the stronger the
reducing agent.
Aluminum-Based Reagents
Lithium aluminum hydride is the strongest and least selective reducing agent for routine
reductions of carbonyl compounds and nitriles. Because it reacts explosively with water, it
must be used in anhydrous ether solvents. Its power as a reducing agent has made it a
popular reducing agent for reductions where chemoselectivity is not an issue. Its reactions
are characterized by the reduction of the substrate to the lowest oxidation level. C
arboxylic
acid derivatives are reduced to primary alcohols, amides are reduced to primary amines
by effective deoxygenation of the amide carbonyl group, and aldehydes and ketones are
reduced to alcohols. Even carboxylic acids and carboxylate anions are reduced to primary
alcohols by this reagent.
Sodium borohydride, on the other hand, reacts only very slowly with water or alco-
hols, so it can be easily used in these solvents. It reacts with only aldehydes, ketones, and
the more reactive derivatives of carboxylic acids—it will not react with nitriles. Lithium
borohydride exhibits reactivity intermediate between these two extremes. Solvent plays an
important role in borohydride reductions, in particular. Reactions of borohydrides tend to
be more stereoselective in alcohol solvents.
The substitution of hydrogen by alkoxy reduces the reactivity of the aluminum hy-
drides.2 With primary and secondary alkoxyaluminum hydrides, there is a rapid dispro-
portionation to LiAlH4 and LiAl(OR)4, a reaction that is suppressed in lithium
tri-tert-alkoxyaluminum hydrides, presumably due to the difficulty of forming the highly
hindered Al(OR)4− species with four tert-alkoxy groups.3 The modification of lithium alu-
minum hydride with tert-butyl alcohol to give lithium tri-tert-butoxyaluminum hydride
leads to a substantial reduction in reactivity and reducing power.4 This reagent will
reduce the more reactive acid derivatives, such as acid chlorides and anhydrides, but it
reduces esters only slowly. It can be used can be used, for example, to reduce an acid
chloride in the presence of other reducible groups, as shown in Example 20.4.5 Sodium
bis-(2-methoxyethoxy)aluminum hydride, available under the trade names Red-Al and ®
®
Vitride , is a nucleophilic aluminum hydride that is soluble in organic solvents and less
2. (a) Brown, H.C.; McFarlin, R.F. J. Am. Chem. Soc. 1958, 80, 5372. (b) Shoaf, C.J. PhD Dissertation, Purdue
University, 1957; Diss. Abstr. 1957, 17, 1904. (c) Hesse, G.; Schrödel, R. Ann. Chem. 1957, 607, 24.
3. Haubenstock, H.; Eliel, E.L. J. Am. Chem. Soc. 1962, 84, 2363.
4. Reviews: (a) Málek, J. Org. React. 1985, 34, 1. (b) Málek, J. Org. React. 1988, 36, 249.
5. Roush, W.R. J. Am. Chem. Soc. 1978, 100, 3599.

Redox III 893
Table 20.1 Common Hydride Reducing Agents and Products of Their Reactions
O O O OR' NR'2 OH N NR" O

Reducing Acronym or R
C
Agent Trade Name
R Cl R H R R' R O R O R O R R R' R
OH OH OH OH NR'2 OH NH2 HNR" OH

LiAlH4 LAH
R R R R' R R R R R R' R
R
OH OH OH OH NR'2 OH HNR" OH
NaAl(OR)2H2* Red-Al or
VitrideTM
® R
R R R R' R R R R R' R
O OH OH
LiAl(OBut)3H
R H R R R'
OH OH OH
NaBH4
R R R R'
OH OH OH OH HNR" OH
LiBH4
R R R R' R R R' R
R
OH OH OH OH OH OH
Zn(BH4)2†
R R R R' R R R
R
OH OH OH HNR"
NaBH3CN‡
R R R R' R R'
OH OH OH OH OH
Super-
LiEt 3BH
HydrideTM R
R R R R' R R
OH OH OH O OH
LiBu 3H s
L-Selectride TM
R R R R' R H R
R
*R=CH2CH2OMe.
†
Not commercially available.
‡
Acidic conditions usually required for reduction.
prone to disproportionation than other alkoxyaluminum hydride reagents. Its reactivity

is slightly less than that of lithium aluminum hydride, although it still reduces esters
under mild conditions, which allows its use for the reduction of esters in the presence of
amides, for example. It has also been used for the regioselective reduction of chiral epoxy
alcohols (e.g., Example 20.5).6 The source of the regioselectivity may be the ability of the
6. Gao, Y.; Sharpless, K.B. J. Org. Chem. 1988, 53, 4081.

alcohol hydroxyl group to displace one of the alkoxy groups on the reducing agent, thus
rendering the reaction intramolecular instead of intermolecular.
ClOC HO
LiAl(OCM3)3H
H H (20.4)
THF, 0°C
CO2Me (90%) CO2Me
O
O OH
Red-Al® Ph OH
Ph Ph Ph (20.5)
DME-PhMe H O
OH 0°C, 3 h Al
HO HO
H OR
93.5% 4.5%
Borohydrides
In contrast to lithium aluminum hydride, sodium borohydride is one of the least reactive
and most selective reducing agents available for the reduction of carbonyl compounds. It
reacts rapidly with aldehydes in aqueous or ethanol solution and with acid chlorides in
aprotic solvents to give primary alcohols. It also reacts with saturated ketones (but not aryl
ketones) to give secondary alcohols. It does not reduce acids, amides, or esters. The mech-
anism of reduction by borohydride anion appears to require prior complexation of the
carbonyl oxygen by the metal cation or a hydrogen bond to a protic solvent (e.g., Example
20.6). When the metal cation is completely complexed by a cryptand, no reduction of the
carbonyl compound occurred until a protic solvent such as water was added.7
H R" H
O O R"
O O (20.6)
BH3 R H BH3
R R' H R'
One useful property of sodium borohydride as a reducing agent is its ability to distin-
guish between saturated ketones and α,β-unsaturated ketones or aryl ketones. In the re-
duction of the ketones in Examples 20.7 and 20.8, for example, the saturated ketone
carbonyl group is reduced much faster than the conjugated carbonyl group in the same
molecule, even though the saturated carbonyl group in Example 20.7 is in a more hin-
dered position.
O OH
NaBH4
(20.7)8
O EtOH O
NaBH4 9
Ph Ph (20.8)
O i-PrOH OH
O O
Substitution of hydrogen by alkoxy increases the reactivity of the borohydrides.10 The

array of complex metal hydride reducing agents now commercially available includes the
7. (a) Pierre, J.-L.; Handel, H. Tetrahedron Lett. 1974, 2317. (b) Handel, H.; Pierre, J.-L, Tetrahedron Lett. 1976,
741. (c) Handel, H.; Pierre, J.-L, Tetrahedron Lett. 1976, 2029. (d) Costes, E.; Bénard, C.; Lattes, A. Tetrahedron
Lett. 1976, 1185.
8. Cocker, J.D.; Halsall, T.G. J. Chem. Soc. 1957, 3441.
9. Lansbury, P.T.; Peterson, J.D. J. Am. Chem. Soc. 1962, 84, 1756, 1963; 1963, 85, 2236.
10. (a) Brown, H.C.; Mead, B.J.; Subba Rao, B.C. J. Am. Chem. Soc. 1955, 77, 6209. (b) Brown, H.C.; Mead, B.J.;
Shoaf, C.J. J. Am. Chem. Soc. 1956, 78, 3616. (c) Garrett, E.R.; Lyttle, D.A. J. Am. Chem. Soc. 1953, 75, 6051.

Redox III 895
trialkylborohydrides,11 which are derived from the metal hydride and a trialkylborane.
The presence of the three alkyl groups on boron increases the reactivity of these reagents
beyond that of lithium borohydride itself, making these reagents air-sensitive compounds
that must be handled in ether solvents. The three most popular variants (lithium tri-sec-
®
butylborohydride, or L-Selectride , potassium tri-sec-butylborohydride, or K-Selectride , ®
and lithium triethylborohydride, or Super-HydrideTM) are available commercially as solu-
tions in tetrahydrofuran (THF). Their steric bulk has made them very popular reagents for
the stereoselective reduction of carbonyl groups.
Lithium triethylborohydride is a particularly effective nucleophilic reagent for reduction
at sp3-hybridized carbon, especially the reduction of primary alkyl halides and tosylates to
methyl groups, even in relatively hindered locations.12 The reduction of 1-adamantylmethyl
tosylate (Example 20.9)13 provides an interesting comparison of the reactivity of lithium
triethylborohydride and lithium aluminum hydride toward sp3-hybridized carbon atoms.
The borohydride reagent gives 1-methyladamantane in 91% isolated yield, whereas lithium
aluminum hydride gives only 25% of the methyladamantane.14 Final oxidative workup is
required due to the formation of triethylborane as a by-product of the reaction.
CH2OTs CH3
1) LiEt3BH, THF, ∆ (20.9)
2) NaOH, H2O, H2O2
(91%)
Lithium triethylborohydride and the Selectride reagents can also be used to reduce
conjugated carbonyl compounds by 1,4-addition of the nucleophile provided that the β
position of the conjugated system carries a hydrogen atom. Lithium triethylborohydride
in tert-butyl alcohol-THF can be used effectively to carry out the reduction of α,β-unsat-
urated esters to the saturated esters without competing condensation of the intermediate
enolate anion to give the Claisen condensation product.15
Sodium borohydride and the SelectrideTM reagents provide an interesting comparison
in terms of the stereochemistry of the reduction. With sodium borohydride in alcohol
solvents, the approach of the nucleophile to the carbonyl carbon in cyclohexanones is
from the axial direction, leading to the equatorial alcohol as the major product. With the
Selectride reagent, however, the large alkyl groups on boron lead to much more severe
1,3-diaxial interactions in the activated complex, leading to mainly equatorial attack and
to the axial alcohol as the major product. This is nicely illustrated by the reactions in
Figure 20.1.16 Both carbonyl groups in this molecule are hindered, but the carbonyl group
in the bicyclo[3.2.1]-octane ring system is the more hindered. Reduction of the less hin-
dered ketone with sodium borohydride gives the expected equatorial alcohol as the major
product of the reaction; with L-SelectrideTM, on the other hand, a 1:1 mixture of the axial
and equatorial diastereoisomers is obtained. An examination of models shows that the
nucleophile can approach the bicyclo[3.2.1]octanone only from the exo face, so reduction
of this functional group gives the axial alcohol.
The reactivity of sodium borohydride can be modified by the use of transition metal
cations. In the presence of 0.2 mole equivalents of cobalt (II) chloride in methanol solu-
tion, for example, sodium borohydride becomes an excellent reagent for the reduction of
11. Reviews: (a) Lane, C.F. Aldrichimica Acta 1974, 7, 32. (b) Krishnamurthy, S. Aldrichimica Acta 1974, 7, 55.
12. (a) Brown, H.C.; Krishnamurthy, S. J. Am. Chem. Soc. 1973, 95, 1669. (b) Brown, H.C.; Kim, S.C.;
K rishnamurthy, S. J. Org. Chem. 1980, 45, 1. (c) Krishnamurthy, S.; Schubert, R.M.; Brown, H.C. J. Am. Chem.
Soc. 1973, 95, 8486.
13. Krishnamurthy, S. J. Organomet. Chem. 1978, 156, 171.
14. Stetter, H.; Schwartz, M.; Hirschhorn, A. Chem. Ber. 1959, 92, 1629.
15. (a) Ganem, B.; Fortunato, J.M. J. Org. Chem. 1975, 40, 2846. (b) Ganem, B. J. Org. Chem. 1975, 40, 146.
(c) Fortunato, J.M.; Ganem, B. J. Org. Chem. 1976, 41, 2194.
16. Zou, Y.; Chen, C.-H.; Taylor, C.D.; Foxman, B.M.; Snider, B.B. Org. Lett. 2007, 9, 1825.

Figure 20.1 Reduction of an

intermediate in the total O O
NaBH4, EtOH
synthesis of
–78°C to 0°C
(±)-platensimycin O 20 min H OH
(20.10) (20.11)
(87%)
L-Selectride (4 eq.) L-Selectride (4 eq.)

THF, -78°C to r.t THF, -78°C to r.t
2 h (90%) 2 h (83%)
OH OH
H H
1 : 1
HO H H OH
(20.12) (20.13)
nitriles to primary amines.17 This reaction is especially applicable to the reduction of cy-
anohydrins to β-aminoalcohols (e.g., Example 20.14). Because acrylonitrile is reduced to
allylamine under these conditions, it is unlikely that the reaction involves hydrogenation
over a cobalt catalyst. Other metals that have been used to modify the reactivity of the
borohydride anion are aluminum,18 copper,19 nickel,20 tin,21 titanium,22 and zinc.23 Zinc
borohydride gives a mild reagent that is still more reactive than sodium borohydride and
soluble in solvents such as THF.24
OH OH
NaBH4, CoCl2 (20.14)
Ph Ph
CN MeOH, 20°C NH2
(80%)
Tetraalkylammonium triacetoxyborohydrides (also known as Gribble reagents)25

are a particularly useful addition to the arsenal of reducing agents, especially for the
chemoselective reduction of aldehydes and the stereoselective reduction of α- and
β-hydroxyketones to anti 1,2- and 1,3-diols (e.g., Example 20.19). The reduction pre-
sumably occurs through a five- or six-membered complex of the substrate and the
boron hydride so the hydrogen is delivered to the face of the carbonyl group syn to the
hydroxyl group (Figure 20.2). Similar chelation of the reducing agent by α-a lkoxyketones
has been invoked to rationalize the tendency of open-chain compounds to give high
levels of anti 1,2-diols (e.g., Example 20.21) with zinc borohydride and Red-Al , with ®
Figure 20.2 Putative R R
R R
mechanism for the reduction O (AcO)3BH OH O OH
of β-hydroxyketones by H O B
R O B OAc
triacetoxyborohydrides OH OAc OH
R
R AcOH (20.16) (20.17) R
(20.15) (20.18)
17. (a) Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron Lett 1969, 4555. (b) Satoh, T.; Suzuki,
S.; Kikuchi, T.; Okada, T. Chem. Ind. (London), 1970, 1626.
18. Brown, H.C.; Subba Rao, B.C. J. Am. Chem. Soc. 1956, 78, 2582.
19. (a) Fleet, G.W.J.; Fuller, C.J.; Harding, P.J.C. Tetrahedron Lett. 1978, 1437. (b) Sorrell, T.N.; Pearlman, T.S.
J. Org. Chem. 1980, 45, 3449.
20. Lin, S.T.; Roth, J.A. J. Org. Chem. 1979, 44, 309.
21. Kano, S.; Yuasa, Y.; Shibuya, S. Chem. Commun. 1979, 796.
22. Tanaka, Y.; Hibino, S. Chem. Commun. 1980, 415.
23. Review: Narasimhan, S.; Balakumar, R. Aldrichimica Acta 1998, 31, 19.
24. Review of zinc borohydride reactivity: Narasimhan, S.; Balakumar, R. Aldrichimica Acta 1998, 31, 19.
25. Nutaitis, C. F.; Gribble, G. W. Tetrahedron Lett. 1983, 24, 4287.

Redox III 897
the opposite selectivity (e.g., Example 20.22) when K-SelectrideTM (which does not che-
late) is used.
Ph Ph
O O
Me4N(AcO)3BH
O MeCN-AcOH, –35°C OH 26
(92%, >97% d.e.) (20.19)
PMBO OH PMBO OH
O Ph L-SelectrideTM, THF O Ph Zn(BH4)2, Et2O O Ph

-78°C -30°C;
HO O HO
or or
K-SelectrideTM, THF Red-Al®, PhMe 27

-95°C -78°C
OTHP OTHP OTHP
(20.22) (20.20) (20.21)
Worked Problem
20-1 What will be the major organic product of the following reactions?
O
Me4N(AcO)3BH
OH Me2CO-AcOH Zn(BH4)2
(a) (b) CO2H
THF, ∆
N
§Answers below.
Problem
MeO
TBSO LiAlH4, THF LiAlH4, THF

(a) (b) O ∆
0°C to r.t., 2 h
Me CO2Me N N
Me H Me
(continues)
26. Paterson, I.; Lombart, H. -G.; Allerton, C. Org. Lett. 1999, 1, 19.
27. Takahashi, T.; Miyazawa, M.; Tsuji, J. Tetrahedron Lett. 1985, 26, 5139.

(a) The reduction proceeds through a five-membered cyclic transition state to give the trans-cyclohexanediol
derivative. [Org. Lett. 2001, 3, 469]
O OH
Me4N(AcO)3BH
OH Me2CO-AcOH OH
(95%)
N N
(b) Unlike other borohydride reagents, zinc borohydride will reduce carboxylic acids in THF under reflux.
The product is the primary alcohol. [J. Org. Chem. 1995, 60, 5314]
Zn(BH4)2
CO2H
THF, ∆ OH

(Problem continued)
HO2C OPMB O
OH
O LiAlH4 OMe Red-Al, THF
(c) (d)
Et2O, 0°C 0°C
MeO
Me
OH O OH O H
NaBH4 OTES Li(t-BuO)3AlH
(e) MeOH, 0°C
(f) THF, 23°C
CO2Me O
References for Problems: (a) J. Am. Chem. Soc. 2010, 132, 1488. (b) Org. Lett. 2007, 9, 1219. (c) Org. Lett. 2006,
8, 1117. (d) Org. Let. 2005, 7, 4297. (e) Tetrahedron 2011, 67, 6300. (f) Tetrahedron Lett. 2011, 52, 4512.
Regiochemistry of Reduction of α,β-Unsaturated Carbonyl Systems

The α,β-unsaturated carbonyl group allows two possible regiochemical modes of reac-
tion: 1,2-addition, where the product is an allylic alcohol, and 1,4-addition, where the
product is the saturated carbonyl compound. The results of systematic studies of the re-
duction of conjugated systems by sodium borohydride and lithium aluminum hydride
(Figure 20.3) show that lithium aluminum hydride favors 1,2-reduction except in fairly
hindered systems, whereas sodium borohydride often gives substantial amounts of the
1,4-reduction product. The work of Anh and coworkers28 correlates the tendency of the re-
ducing agent to promote 1,4-reduction of conjugated ketones with the softness of the hy-
dride reagent: the softer the reagent, the higher the proportion of 1,4-reduction. Thus,
sodium borohydride gives more 1,4-reduction than lithium borohydride (sodium is a
softer Lewis acid than lithium), whereas lithium trimethoxyaluminum hydride gives more
1,2-reduction than lithium aluminum hydride (the alkoxy groups render the aluminum
hydride anion a harder base). In a systematic study of carbonyl compounds with sodium
Figure 20.3 Regiochemistry O OH OH
of reduction of representative [H]
+
conjugated aldehydes and
ketones NaBH4, EtOH-H2O 57 43
LiAlH4, Et2O 83 7
O OH OH
[H]
+
NaBH4, EtOH-H2O 92 8
LiAlH4, Et2O 100 0
[H]
CHO +
OH OH
LiAlH4, Et2O 96 2
[H]
CHO
OH + OH
LiAlH4, Et2O 100 0
28. Bottin, J.; Eisenstein, O.; Minot, C.; Anh, N.T. Tetrahedron Lett. 1972, 3015.

Redox III 899
borohydride, Johnson and Rickborn found that α,β-unsaturated ketones are much more
prone to 1,4-reduction with sodium borohydride.29 The effects of other additives (e.g., pyr-
idine) on the regiochemistry and stereochemistry of reduction of a number of 3-alkyliden-
ecamphor derivatives by sodium borohydride have been quantified.30
Neither lithium aluminum hydride nor sodium borohydride is universally reliable
for carrying out 1,2-reduction, so modifications of these reagents with metal ions have
been studied in an effort to obtain a reagent with exclusive, or almost exclusive,
1,2-reduction regiochemistry. This has been accomplished by the use of Ce 3+ ions as
additives with sodium borohydride. In the presence of cerium (III) chloride, sodium
borohydride becomes an effective reagent for the reduction of α,β-unsaturated alde-
hydes and ketones (e.g., E xample 20.23) to the corresponding allylic alcohols (e.g.,
Examples 20.24 and 20.25). In the presence of 0.25 mole equivalents of Ce 3+ ions per
mole of sodium borohydride, a reagent is obtained that cleanly reduces the carbonyl
group of the conjugated system.31
O OH OH
NaBH4
CO2Me CO2Me CO2Me
CeCl3
MeOH
HO HO HO
(20.23) (20.24) (20.25)
(38%) (32%)
Reductive Amination
In the previous chapter, we discussed reductive amination by means of catalytic hydroge-
nation. However, this reaction is more widely carried out using complex metal hydrides.
Among these, sodium cyanoborohydride, NaBH3CN,32 is probably most widely used—
despite its high toxicity—because it reduces iminium ions rapidly in alcohol or mildly
acidic solvents (e.g., Example 20.26) but reacts only sluggishly with carbonyl compounds.
Interestingly, this reagent will also reduce α,β-unsaturated iminium ions derived from
conjugated aldehydes to the saturated systems (e.g., Example 20.27). More recently,
sodium triacetoxyborohydride33 has gained popularity as a nontoxic replacement for this
toxic reagent, which can leave residual cyanide in the product.
O H2N
NH4OAc, NaBH3CN
(20.26)34
MeOH
("quantitative")
O O
NHEt
CHO
EtNH2, NaBH3CN 35
(20.27)
MeOH-AcOH
(91%)
29. Johnson, M.R.; Rickborn, B. J. Org. Chem. 1970, 35, 1041.

30. Richer, J.-C.; Rossi, A. Can. J. Chem., 1975, 50, 1376.
31. (a) Gemal, A.L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454. (b) Luche, J.-L. J. Am. Chem. Soc. 1978, 100,
2226. (c) Luche, J.-L.; Rodriguez-Hahn, L.; Crabbé, P. Chem. Commun. 1978, 601. (d) Gemal, A.L.; Luche, J.-L.
J. Org. Chem. 1979, 44, 4187.
32. (a) Borch, R.F.; Bernstein, M.D.; Durst, H.D. J. Am. Chem. Soc. 1971, 93, 2897. (b) Mattson, R.J.; Pham,
K.M.; Leuck, D.J.; Cowan, K.A. J. Org. Chem. 1990, 55, 2552. (c) Barney, C.L.; Huber, E.W.; McCarthy, J.R. Tet-
rahedron Lett. 1990, 31, 5547. (d) Hutchins, R.O.; Natale, N.R. Org. Prep. Proc. Int. 1979, 11, 201. (e) Lane, C.F.
Synthesis, 1975, 135. (f) Lane, C.F. Aldrichimica Acta 1975, 8, 3.
33. (a) Abdel-Magid, A.F.; Maryanoff, C.A.; Carson, K.G. Tetrahedron Lett. 1990, 31, 5545. (b) Abdel-Magid,
A.F.; Carson, K.G.; Harris, B.D.; Maryanoff, C.A.; Shah, R.D. J. Org. Chem. 1996, 61, 3849.
34. Boutique, M.-H.; Jacquesy, R. Bull. Soc. Chim. France 1973, 750.
35. Borch, R.F.; Bernstein, M.D.; Durst, H.D. J. Am. Chem. Soc. 1971, 93, 2897.

Before the advent of complex metal hydrides, the reducing agent of choice was formic
acid, and under these conditions the reductive amination occurs by a mechanism similar
to that of the crossed Cannizzaro reaction.36 Depending on the exact conditions used, this
reaction has several names. If ammonium formate is the reagent, the product is the pri-
mary amine and the reaction is called the Leuckart reaction.37 Extension of the Leuckart
reaction to using primary or secondary amines with the formic acid is known as the
Wallach reaction.38 In its most widely used form today, the carbonyl compound in the
Leuckart reaction is formaldehyde, and the product is usually the tertiary amine where all
the amine hydrogens have been replaced by methyl groups; this reaction is known as the
Eschweiler-Clarke reaction (e.g., Example 20.28).39 These reactions will be discussed in
greater detail later in this chapter.
H2N OH Me2N OH
H2C(OH2), HCO2H, ∆ 40
(20.28)
(63%)
Electrophilic Hydride Reducing Agents

Borohydrides and hydroaluminates are nucleophilic reducing agents whose reactivity is
promoted by Lewis acids. However, reduction of carbonyl compounds and nitriles can
also be effected by electrophilic reducing agents. Two of the most widely used electrophilic
reducing agents are diisobutylaluminum hydride (DIBAL-H)41 and borane (BH3) in the
form of its complex with a suitable Lewis base (e.g., THF or dimethyl sulfide). The key
difference between electrophilic and nucleophilic hydride reducing agents, mechanisti-
cally, is the ability of the metal atom in the hydride to form a Lewis acid–Lewis base com-
plex (20.29) with the carbonyl oxygen atom of the carbonyl group (Figure 20.4). This
36. For a discussion of the reductive amination with ammonium formate, see: (a) Lukasiewicz, A. Tetrahe-
dron 1963, 19, 1789. (b) Awachie, P.I.; Agwada, V.C. Tetrahedron 1990, 46, 1899.
37. (a) Leuckart, R. Ber. Dtsch. chem. Ges. 1885, 18, 2341. (b) Moore, M.L. Org. React. 1949, 5, 301.
Carl Louis Rudolf Alexander Leuckart (1854–1889) was educated at Leipzig (PhD, 1879) and stayed until
1880 as assistant to Kolbe before moving to Munich as an assistant to Baeyer. In 1883 he moved to Göttingen
and was promoted to professor in 1889. He died at Göttingen of an apparent stroke a scant month after his
thirty-fifth birthday. For more detail, see: Ber. dtsch. chem. Ges. 1889, 22, (Referate, Patente, Nekrologe), 885.
38. Wallach, O. Ann. Chem. Pharm. 1892, 272, 100.
Otto Wallach (1847–1931) was educated at Göttingen (PhD, 1869). His career took him to Bonn (1870), where
he became Professor of Pharmacy in 1876, and then back to Göttingen (1889). While at Bonn, Wallach became
interested in essential oils and formulated the isoprene rule for terpenes. He received the Nobel Prize in Chem-
istry in 1910. For more biographical detail, see; (a) Ruzicka, L. J. Chem. Soc. 1932, 1582; (b) Christmann, M.
Angew. Chem. Int. Ed. 2010, 49, 9580. Wallach’s autobiography is available on the Nobel Foundation web site.
39. (a) Eschweiler, V. Ber. Dtsch. chem. Ges. 1905, 38, 880. (b) Clarke, H.T.; Gillespie, H.B.; Weisshaus, S.Z.
J. Am. Chem. Soc. 1933, 55, 4571. For mechanistic and competitive reactions, see: (c) Baltzly, R. J. Am. Chem.
Soc. 1953, 75, 6083. (d) Cope, A.C.; Burrows, W.D. J. Org. Chem. 1965, 30, 2163.
Wilhelm Eschweiler (1860–1936) began his studies at the Technische Hochschule in Hannover in 1887, as
Assistant in the chemistry laboratory. This work led his PhD from Rostock in 1889 under Kraut. In 1892 he was
promoted to privat-dozent and rose through the ranks to become Professor of Analytical Chemistry at the
Technische Hochschule.
Hans Thacher Clarke (1887–1972) was educated at University College, London (BSc, 1908; DSc, 1914). His
career began at Eastman Kodak in Rochester, New York (1914), and he became Professor of Biological Chemis-
try at the College of Physicians and Surgeons at Columbia University in 1928. For more detail, see: Vickery, H.B.
Biogr. Mem. 1975, 1.
40. Tichy, M.; Vasickova, S. Coll. Czech. Chem. Commun. 1974, 39, 555.
41. For an overview of DIBAL-H reductions of functional groups, see: (a) Yoon, N.M.; Gyoung, Y.S. J. Org.
Chem. 1985, 50, 2443. (b) Winterfeldt, E. Synthesis 1975, 617.

Redox III 901
R R R R Figure 20.4 Reduction of

M R R R carbonyl compounds with
M M M
O H O H O H O R electrophilic reducing agents
R R R R (20.29) R R R H
R
process both renders the metal-hydrogen bond more strongly nucleophilic and the car-
bonyl carbon more electrophilic.
DIBAL-H has achieved considerable popularity for the reduction of conjugated car-
bonyl compounds to allylic alcohols (e.g., Examples 20.30 and 20.31) and nitriles to imines
(and hence to aldehydes; e.g., Example 20.32). With two equivalents of the reducing agent,
the reduction of esters gives the primary alcohol (e.g., Examples 20.30 and 20.31; exam-
ple 20.31 also shows that the reduction of the carbonyl group is faster than the hydroalu-
mination of the alkyne). With one equivalent of the reducing agent at low temperature
(usually −70°C or lower), the hemiacetal formed in the initial addition of hydrogen to the
ester carbonyl group is stable, and the aldehyde is the major product isolated. This reduc-
tion to an aldehyde has been especially useful for the reduction of lactones to cyclic hemi-
acetals (e.g., Example 20.33).
OMEM OMEM
DIBAL-H 42
(20.30)
O CH2Cl2, –78°C O
Ph (98%)
Ph OH
CO2Me
Me3Si Me3Si
CO2Et
DIBAL-H OH
(20.31)43
H PhMe H
Me3Si (82%) Me3Si
1) DIBAL-H, PhMe
2) HCl, H2O, 0°C (20.32)44
CN CHO
O OH
O DIBAL-H, CH2Cl2 O
H H
(20.33)45
–78°C, 2 h
H H
Diborane is another electrophilic reducing agent that is highly selective for carbox-
ylic acids (e.g., Example 20.34)46 and amides47—two functional groups that usually
resist reduction. The borane-THF and borane–dimethyl sulfide complexes, both of
42. Williams, D.R.; Brown, D.L.; Benbow, J.W. J. Am. Chem. Soc. 1989, 111, 1923.
43. Meyers, A.G.; Harrington, P.M.; Kuo, E.Y. J. Am. Chem. Soc. 1991, 113, 694.
44. Lewis, D.E.; Rigby, H.L. Tetrahedron Lett. 1985, 26, 3437.
45. Corey, E.J.; Carpino, P. J. Am. Chem. Soc. 1989, 111, 5472.
46. (a) Brown, H.C.; Subba Rao, B.C. J. Am. Chem. Soc. 1960, 82, 681. (b) Brown, H.C.; Korytnik, W. J. Am.
Chem. Soc. 1960, 82, 3866. (c) Brown, H.C.; Heim, P.; Yoon, N.M. J. Am. Chem. Soc. 1970, 92, 1637. (d) Yoon,
N.M.; Pak, C.S.; Brown, H.C.; Krishnamurthy, S.; Stocky, T.P. J. Org. Chem. 1973, 38, 2786.
47. Brown, H.C.; Heim, P. J. Org. Chem. 1973, 38, 912.

which function as sources of borane, BH3, react with the carboxylic acid much faster
than with all other carbonyl compounds. Thus, this reagent can be used to reduce a
carboxylic acid to a primary alcohol in the presence of most other carbonyl groups, in-
cluding esters (e.g., Example 20.35), amides, and ketones. Amides are reduced faster
than ketones by borane. The one problem encountered in borane reduction of amides is
the formation of very stable borane-amine complexes with the product of the reduction.
Fortunately, it has been found that these complexes can be decomposed using supported
palladium or Raney nickel in methanol. An interesting side effect of this cleavage reac-
tion is the simultaneous hydrogenolysis of benzyl groups in the molecule, as shown by
Example 20.36.48
OH
CO2H
1) BH3•THF (20.34)
2) H2O
(95%)
AcO CO2Et AcO CO2Et

BH3•THF, THF
(20.35)
0°C, 17 h OH
CO2H
(99%)
O
O Ph 1) BH3•THF O
N NH (20.36)
O 2) Pd-C, MeOH O
O (78%)
Hydroalumination of Alkynes
In contrast to the π bonds of unactivated alkenes, the triple bond of alkynes can be re-
duced by aluminum hydride reagents, which add to the triple bond to give organoalumi-
num intermediates that may be protonated or trapped with electrophiles to give alkenes
with defined stereochemistry. When the aluminum hydride is a neutral aluminum species
such as DIBAL-H, the reaction is known as hydroalumination (by analogy with hydrob-
oration), and the addition occurs with the anti-Markovnikov regiochemistry and syn ste-
reochemistry (e.g., Example 20.37). When the aluminum species is negatively charged,
however, the stereochemistry of the hydroalumination reaction is reversed (e.g., Example
20.38). Thus, with lithium aluminum hydride and lithium alkylaluminum hydrides the
overall addition of hydrogen becomes anti.49
H
1) DIBAL-H
(20.37)
2) MeLi
H
H
1) LiAlMe(i-Bu)2H
(20.38)
2) 100-130°C
H
48. Couturier, M.; Tucker, J.L.; Andresen, B.M.; Dubé, P.; Negri, J.T. Org. Lett., 2001, 3, 465.
49. (a) Zwiefel, G.; Steele, R.B. Tetrahedron Lett. 1966, 6021. (b) Zwiefel, G.; Steele, R.B. J. Am. Chem.
Soc. 1967, 89, 2754. (c) Zwiefel, G.; Steele, R.B. J. Am. Chem. Soc. 1967, 89, 5085. (d) Magoon, E.F.; Slaugh,
L.H. Tetrahedron 1967, 23, 4509. (e) Molloy, B.B.; Hauser, K.L. J. Chem. Soc., Chem. Commun. 1968, 1017.

Redox III 903
The hydroalumination of alkynes with anionic aluminum hydride species has been
used as a method for the formation of stereochemically pure trisubstituted alkenes
from propargyl alcohols. In this case, the aluminum adds to the end of the triple bond
furthest from the carbinol carbon. As expected for an anionic aluminum nucleophile,
the stereochemistry of the addition is anti. A typical example of this useful reaction
is the synthesis of the iodoallyl alcohol in Example 20.39; the product of the reaction is
the Z isomer.50
1) LiAlH4, THF, NaOMe, ∆ (20.39)

2) I2
HO
3) H2O HO
(60-75%) I
Worked Problem
20-2 What is the major product expected from the following reaction? What major
advantage does the reagent used possess?
MeS ButS CHO

TESO Na(AcO)3BH, CH2Cl2
N
N PMB
H
§Answer below.
Problems
20-2 Suggest a reasonable mechanism for the following transformation:
1) DIBAL-H, CH2Cl2 H
N Boc –78°C
OH N
2) 2N HCl-H2O Ts N Boc
O O
Ts NH O OH
[J. Am. Chem. Soc. 2007, 129, 11987]

(continues)
50. Corey, E.J.; Katzenellenbogen, J.A.; Posner, G.H. J. Am. Chem. Soc. 1967, 89, 4245.
§Answer to Worked Problem:

This is a reductive amination of the aldehyde by the secondary amine group of the starting material. The
reducing agent used will reduce only the imine, which makes it ideally suited to this reaction, where there are
so many sensitive functional groups involved [J. Am. Chem. Soc. 2009, 131, 13606].
MeS
MeS
ButS CHO TESO N
TESO N Na(AcO)3BH, CH2Cl2 N PMB
N PMB
H
ButS

(Problem continued)
20-3 What is the structure of major organic product of each of the following reactions?
CO2Me O O
O DIBAL-H (1 eq.)
DIBAL-H (3 eq.)
(a) CH2Cl2-hexane
(b) O
CN PhMe, –78°C
–78°C MOMO
OPMB N3
OMOM
TBDPSO
OTBDMS
Ph
H
CO2Et
H DIBAL-H (3 eq.) O DIBAL-H (1.5 eq.)
(c) OMe
CH2Cl2, –78°C
(d) PhMe, –78°C
O
O
OMe
OH
CHO
Cl
NaBH3CN H NaBH3CN
(e) N
MeOH, r.t.
(f) O O C16H25NO2
MeNH2•HCl
MeOH, pH 5
OMe
References: (a) J. Org. Chem. 2009, 74, 7220. (b) J. Org. Chem. 2008, 73, 1234. (c) Org. Lett. 2007, 9, 1461.
(d) Tetrahedron 2011, 67, 4036. (e) Tetrahedron 2011, 61, 6015. (f) J. Am. Chem. Soc. 1974, 96, 4332.
Reaction Synopses
Hydride Reduction of Aldehydes and Ketones
R R
O H OH
R R
Reagents: LiAlH4, Et2O (or THF); Red-Al ; etc. ®

or NaBH4, CH3OH; LiR 3BH, THF; etc.
or DIBAL-H, hexane
or BH3•THF; BH3, oxazaborolidine, THF; etc.
Hydride Reduction of Conjugated Carbonyl Compounds
To Allylic Alcohols
R R
R O R H OH
R R R R
Reagents: LiAlH4, Et2O, low temp., short time;

or DIBAL-H, hexane; etc.
or NaBH4, CeCl3, CH3OH; etc.
To Saturated Alcohols
R R
R O R OH
R R R R
Reagents: NaBH4, EtOH, extended time

Hydride Reductions of Acyl Compounds and Nitriles
To Alcohols
O OH
R R
X
X = Cl, OCOR, OR, OH, O–

Redox III 905
®
Reagents: LiAlH4, Red-Al ; BH3•THF (X=OH);
or DIBAL-H (X=Cl, OCOR, OR)
To Amines
O
R R R C N R
NR2 NR2 NH2
Reagents: LiAlH4; Red-Al ; etc. ®

or BH3•THF
To Aldehydes
R C N R CHO
Reagents: DIBAL-H, PhMe, 0°C, etc.

Reductive Amination
O NR"2
R R
R' R'
Reagents: R"2NH, HOAc, MeOH, NaBH3CN

or NH3, HCO2H, ∆ (Leuckart)
or R"2NH, HCO2H, ∆ (Wallach if R, R' = alkyl; Eschweiler-Clarke
if R, R' = H)
20.2 Reduction by Hydrogen Transfer from Carbon
The complex metal hydrides based on aluminum or boron are the most popular reagents
for reducing carbonyl groups. However, carbonyl compounds can also be reduced by a
process where the hydrogen atom transferred to the carbonyl group is originally bound to
carbon rather than boron or aluminum. Reduction by chiral boranes, in particular, has
become a popular method for asymmetric reduction of ketones.
The common feature of all these reductions is that they involve a six-membered cyclic tran-
sition state (Example 20.40)51 in which the hydrogen atom β to the electropositive e lement in a
metal alkyl or a metal alkoxide is transferred to the carbonyl carbon,52 formally as a hydride
ion. The mechanism may involve single electron transfer and free radical intermediates.53
When the electropositive element is bonded to carbon in the reducing agent, the most common
reducing agents used are Grignard reagents, in which case that element is magnesium, and
trialkylboranes, in which case that element is boron. When an alkoxide is the reducing agent,
the electropositive elements most commonly used are aluminum and magnesium.
‡
O O O M G
M G R M G O M
R H R H G
H R H
R R R R
(20.40)
M = B, Al, Mg, Zn
G = O, CR 2
During the reaction, the organometallic reducing agents (e.g., G = CR 2, M = Mg, Zn)
and boranes (G = CR 2, M = BR 2) eliminate an alkene as the hydrogen is transferred to the
51. Woodward, R.B.; Wendler, N.L.; Brutschy, F.K. J. Am. Chem. Soc. 1945, 67, 1425.
52. For example, aluminum alkoxides: (a) Doering, W.v.E.; Ashner, T.C. J. Am. Chem. Soc. 1953, 75, 393.
(b) Williams, E.D.; Krieger, K.A.; Day, A.R. J. Am. Chem. Soc. 1953, 75, 2404. (c) Lutz, R.E.; Gillespie, J.S., Jr.
J. Am. Chem. Soc. 1950, 72, 344.
53. For example, Grignard reagents: Ashby, E.C.; Goel, A.B. J. Am.Chem. Soc. 1981, 103, 4983.

carbonyl carbon. In reductions with metal alkoxides (e.g., G = O, M = Al, Mg, Zn, ), the
reagent is converted into a carbonyl compound, which makes these reactions reversible.
Reduction by Grignard Reagents (G = CR2, M = Mg)54

Normally, a Grignard reagent adds to a carbonyl compound to give the product of nucleophilic
addition to the carbonyl group. However, if the Grignard reagent is bulky (e.g., isopropylmag-
nesium halides or tert-butyl-magnesium halides) or if the carbonyl compound is sterically hin-
dered, the major product of the reaction is often due to reduction of the ketone by transfer of a
β hydrogen from the Grignard reagent to the carbonyl carbon. The mechanism of the reaction
has been the subject of numerous studies,55 which reveal that this reaction may be suppressed
by using hydrocarbon solvents for the addition of Grignard reagents to carbonyl compounds.
The reaction is most often observed when the carbonyl compound is a ketone, but this is not an
absolute restriction. Two typical examples are shown as 20.41 and 20.42.
Me Me Me Me Me Me
1) Me2CHMgBr
Et2O (20.41)56
OH H
Me 2) H2O Me Me
O H OH
(55%) (29%)
1) Me3CMgCl
Et2O 57
(20.42)
CHO
2) H2O
(>90%) OH
The Meerwein-Ponndorf-Verley Reduction (G = O, M = Al)58

In the mid-1920s, German chemists Hans Meerwein59 and Wolfgang Ponndorf,60 along
with French chemist Albert Verley,61 all independently reported that aldehydes and
54. (a) Whitmore, F.C.; George, R.S. J. Am. Chem. Soc. 1942, 64, 1239. (b) Conant, J.B.; Blatt, A.H. J. Am. Chem.
Soc. 1929, 51, 1227. (c) Conant, J.B.; Webb, C.N.; Mendum, W.C. J. Am. Chem. Soc. 1929, 51, 1246. (d) Blatt, A.H.;
Stone, J.F., Jr. J. Am. Chem. Soc. 1932, 54, 1495. (d) Kharasch, M.S.; Weinhouse, S. J. Org. Chem. 1936, 1, 209. (e)
Greenwood, F.L.; Whitmore, F.C.; Crooks, H.M. J. Am. Chem. Soc. 1938, 60, 2028. (f) Copwan, D.O.; Mosher,
H.S. J. Org. Chem. 1962, 27, 1. (g) Lajis, N.Hj.; Khan, M.N.; Hassan, H.A. Tetrahedron 1993, 49, 3405.
55. (a) Singer, M.S.; Salinger, R.M.; Mosher, H.S. J. Org. Chem. 1967, 32, 3821. (b) Denise, B.; Fauvarque, J.-F.;
Ducom, J. Tetrahedron Lett. 1970, 335. (c) Cabaret, D.; Welvart, Z. J. Organomet. Chem. 1974, 80, 199. (d) Morrison,
J.D.; Tomaszewski, J.E.; Mosher, H.S.; Dale, J.; Miller, D.; Elsenbaumer, R.L. J. Am. Chem. Soc. 1977, 99, 3167.
56. (a) Whitmore, F.C.; Whitaker, J.S.; Mosher, W.A.; Breivik, O.N.; Wheeler, W.R.; Miner, C.S., Jr.; Suther-
land, L.H.; Wagner, R.B.; Clapper, T.W.; Lewis, C.E.; Lux, A.R.; Popkin, A.H. J. Am. Chem. Soc. 1941, 63, 643.
(b) Hamelin, A. Bull. Soc. Chim. France 1961, 926.
57. Malkonen, P.J. Suomen. Kem. 1965, 38B, 89 [Chem. Abstr. 1965, 63, 8411b].
58. Wilds, A.I. Org. React. 1944, 2, 174.
59. Meerwein, H.; Schmidt, R. Liebigs Ann. Chem. 1925, 444, 221.
60. Ponndorf, W. Angew. Chem. 1926, 39, 138.
Wolfgang Ponndorf (1894–1948) obtained his PhD from the University of Berlin in 1918. He was working at
Anton Deppe & Sons when he reported his reduction. He later took his Dr Med (1931) from the Medical Uni-
versity Clinic of Hamburg-Eppendorf Hospital.
61. (a) Verley, A. Bull. Soc. Chim. France [4] 1925, 37, 537. (b) Verley, A. Bull. Soc. Chim. France [4] 1925, 37, 871.
Albert Verley (ca. 1896–1959?) spent his entire career in industry, founding his own company and establish-
ing himself as a perfumer in Paris. Albert Verley, Inc., was incorporated in 1932 in Chicago, and became Albert
Verley and Co. during the later 1930s (possibly when Verley’s son, Guy, became active in the running of the
company). He appears to have returned to France after 1944. In his youth, Verley was the only composition
student of French composer, Erik Satie. His career in music was cut short by a laboratory accident that perma-
nently injured his right hand.

Redox III 907
ketones could be reduced to alcohols by aluminum alkoxides. The reaction is now known
by their names: the Meerwein-Ponndorf-Verley (MPV) reduction. Unlike reductions
with complex metal hydrides, Grignard reagents or boranes, this reaction is reversible, so
that the final product is the more stable stereoisomer of the alcohol. It is worth noting that
if the MPV reduction is stopped after a short time—before the equilibrium mixture of
products is formed—it gives a higher proportion of the endo isomer. In similar fashion,
the reduction of the ketone gives only the β alcohol (Example 20.44; derived by attack of
the reagent from the less hindered exo direction) with lithium aluminum hydride but only
the α alcohol (Example 20.43) under MPV conditions.62 The reversibility of the reaction
has also been exploited for oxidation, under the name of the Oppenauer oxidation.63
OH
Al(O-i-Pr)3 O (20.43)
O i-PrOH O N
O OH
O N
LiAlH4/Et2O O
(20.44)
O N
The reversibility of the MPV reduction affects the stereochemistry of the reduction in
hindered systems, as is illustrated by the reductions of camphor with lithium aluminum
hydride in THF and aluminum isopropoxide in isopropyl alcohol. Lithium aluminum
hydride, which reacts irreversibly from the less hindered face of the carbonyl group, leads
to the more hindered (less stable) exo isomer as the major product of the reaction. In con-
trast, MPV reduction, being reversible, eventually gives the less hindered (more stable)
endo isomer. When the energy difference between the two isomers of the product is small,
the difference between the use of lithium aluminum hydride and the MPV reduction are
also less pronounced, as shown by the reduction of 3-methylcyclohexanone. A milder,
modern variant of the MPV reduction that avoids the strongly basic reaction conditions of
the original reaction involves the use of samarium (II) iodide (e.g., Example 20.45).64
[H]
+
O HO HO
[H] = LiAlH4 89 : 11
[H] = Al(O-i-Pr)3, i-PrOH 10 : 90
[H]
+
O Me HO Me HO Me
[H] = LiAlH4 76 : 24
[H] = Al(O-i-Pr)3, i-PrOH 70 : 30
62. (a) Irie, H.; Uyeo, S.; Yoshitake, A. J. Chem. Soc., Chem. Commun. 1966, 635. (b) Irie, H.; Uyeo, S.; Yoshi-
take, A. J. Chem. Soc., C 1968, 1802.
63. (a) Oppenauer, R.V. Rec. Trav. Chim. 1937, 1937, 137. (b) Djerassi, C. Org. React. 1951, 6, 207. (c) Opppenauer,
R.V. Org. Syn. Coll. Vol. 3, 1943, 207.
Rupert Viktor Oppenauer (1910–1969) was born in Austria, and educated at the ETH, in Zürich (PhD, 1934,
under Nobel laureates Leopold Ruzicka and Tadeusz Reichstein). Following several academic appointments in
Europe, he worked for a time at Hofmann–La Roche and then moved to Buenos Aires, where he worked for the
Ministry of Public Health.
64. (a) Collins, J.; Namy, J.-L.; Hagan, H.F. Nouv. J. Chim. 1986, 10, 229. (b) Evans, D.A.; Kaldor, S.W.; Jones,
T.K.; Clardy, J.; Stout, T.J. J. Am. Chem. Soc. 1990, 112, 7001.

OSi(i-Pr)Et2 OSi(i-Pr)Et2
Me SmI2, i-PrOH Me
OPMB O OPMB O (20.45)
THF, 3 h, r.t.
O (quantitative) O
(d.r. 98.5:1.5)
O OH
Me Me
The Cannizzaro and Tishchenko Reactions (G = O, M = Na or Al)

In 1853, the Italian chemist Stanislao Cannizzaro noted that when aldehydes that lack an
α hydrogen were treated with strong base, a disproportionation reaction occurred. Half
the aldehyde was reduced to the corresponding alcohol, and the other half was oxidized to
the carboxylic acid.65 When the aldehyde molecules involved are identical (e.g., Example
20.46), the reaction is called the Cannizzaro reaction. When they are not (e.g., Example
20.47), the reaction is called the crossed Cannizzaro reaction. The crossed Cannizzaro
reaction with formaldehyde was widely used for reducing aldehydes, although it has been
largely superseded in modern organic synthesis by complex metal hydrides.
CHO CO2H CH2OH
KOH, H2O (20.46)

+
(79%) (88%)
CHO CH2OH
KOH, H2O
(20.47)
H2C=O
(72%)
Me Me
The crossed Cannizzaro reaction is still used in the industrial preparation of certain
alcohols. The industrial synthesis of pentaerythritol (Example 20.48), an important raw
material for plastics and explosives, from acetaldehyde and formaldehyde provides an ex-
cellent example. The reaction involves a sequential combination of three aldol additions
and a final crossed Cannizzaro reaction.
CHO CHO CHO
KOH/H2O KOH/H2O
Me
H2C=O H2C=O
(aldol) OH (aldol) OH OH
KOH/H2O
(20.48) H2C=O
(aldol)
OH OH OH
KOH/H2O CHO
H2C=O
OH OH (crossed OH OH
Cannizzarro)
65. (a) Cannizzaro, S. Ann. Chem. Pharm. 1863, 88, 129. (b) List, K.; Limpricht, H. Ann. Chem. Pharm. 1864, 90, 180.
Stanislao Cannizzaro (1826–1910) began as a medical student at Palermo, moving to Pisa in 1845. After the
collapse of the Sicilian revolution in 1849, he was condemned to death but escaped to France and entered
Chevreul’s laboratory. His subsequent career took him from Alessandria (1851) to Genoa (1855), Palermo (1861),
and finally Rome (1871). He ultimately became vice president of the Italian Senate. For a more complete biogra-
phy, see: Tilden, W.A. J. Chem. Soc., Trans. 1912, 101, 1677.

Redox III 909
In a series of papers in 1906, the Russian chemist V. E. Tishchenko described a similar

redox reaction of aldehydes catalyzed by aluminum isopropoxide.66 In this case, the prod-
uct of the reaction is an ester derived by condensation of two molecules of the aldehyde
with each other (e.g., Example 20.49). As in the Cannizzaro reaction, one molecule of al-
dehyde is reduced to the alcohol level and the other is oxidized to the carboxylic acid level.
A similar reaction, using the sodium alkoxide rather than the aluminum alkoxide, had
been noted by Claisen in 1887.67 A modern variant, known as the Evans-Tishchenko reac-
tion, involves the cross-reaction of an aldehyde and a β-hydroxyketone catalyzed by sa-
marium (II) iodide to give the monoester of a 1,3-anti-diol.68 Although the ester group
usually ends up at the site of the ketone carbonyl (e.g., Example 20.50), this is not always
the case (e.g., Example 20.51), so one must be prepared to determine its precise location
experimentally.
Me
CHO O
Al(O-i-Pr)3 O
(20.49)
i-PrOH
Me
Me
OH O
Me2CHCHO, SmI2 OH O O
(20.50)
THF, –10°C
(95%; d.r.>99:1)
PMP PMP O
O O O OH Me2CHCHO, SmI2 O O OH O
(20.51)
THF, –10°C
H (95%) H
R R
Worked Problem
20-3 What is the major product expected from the following reaction?
OH O
SmI2, EtCHO, THF
OPMB –20 to –10°C
66. (a) Tishchenko, V. Zh. Russ. Fiz.-Khim. Obshch. 1906, 38, 355. (b) Tishchenko, V. Zh. Russ. Fiz.-Khim.
Obshch. 1906, 38, 482. (c) Tishchenko, V. Zh. Russ. Fiz.-Khim. Obshch. 1906, 38, 540. (d) Tishchenko, V. Zh. Russ.
Fiz.-Khim. Obshch. 1906, 38, 547. (e) Tishchenko, V. Chem. Zentr. II 1906, 1309. (f) Tishchenko, V. Chem. Zentr.
II 1906, 1552. (g) Tishchenko, V. Chem. Zentr. II 1906, 1555. (h) Tishchenko, V. Chem. Zentr. II 1906, 1556.
Vyacheslav Yevgenievich Tishchenko (1861–1941) graduated from St. Petersburg in 1883 and was appointed
to the faculty in 1891. In 1901 he was appointed Professor of Chemistry at the Women’s Medical Institute con-
current with his position at the University. He remained in Russia after the revolution, becoming Director of
the Chemical Institute of Leningrad University. For more detail, see: Lewis, D.E. Early Russian Organic Chem-
ists and Their Legacy (Springer: Heidelberg, 2012), p. 114.
67. Claisen, L. Ber. Dtsch. chem. Ges. 1887, 20, 646.
68. Evans, D.A.; Hoveyda, A.H. J. Am. Chem. Soc. 1990, 112, 6447.

Problems
20-4 What is the structure of the product of the following reaction (only a catalytic
amount of DIBAL-H instead of a stoichiometric quantity is used)? How is the
product formed?
MeO O CHO
cat. DIBAL-H
H H C18H28O10
O O n-pentane, 0°C to r.t.
[Tetrahedron 2007, 63, 11325]

OH O
Me2CHCHO, SmI2 MeCHO, SmI2
(a) THF, –10°C
(b)
THF, –10°C
OH O OTBS
Reference for problems: J. Am. Chem. Soc. 1990, 112, 6447.
Reaction Synopses
Reduction of Aldehydes and Ketones by Hydrogen Transfer
R R
O H OH
R R
Reagents: R 2CH–CR 2–MgX; R 2CH–CR 2–ZnX; etc.

or R 2CH-CR 2–BR 2';
or (R 2CH–O)3Al, R 2CHOH; SmI2, i–PrOH, THF; etc.
or H2C=O, KOH (Cannizzaro)
Reduction with organometallic reagents: occurs when the systems are hindered
20.3 Stereochemistry and Stereoselectivity in Hydride Reductions
The addition of hydride to a ketone carbonyl group has the potential for generating a
new stereogenic center, so the reduction of ketones has been the subject of extensive
stereochemical studies, and there is a voluminous literature on the stereochemistry of
reduction by hydride reagents. Despite this intensive activity, the origins of the stereo-
chemistry of complex hydride reductions remain in some doubt, although the stereo-
chemical preferences themselves are now fairly clear. Thus, it is apparent that sodium
borohydride (as well as other complex metal hydrides) exhibits an inherent preference

This is an Evans-Tishchenko reaction, and it gives the monopropionate of the anti-1,3-diol. In this particular
reaction, the ester group actually ends up at the position of the original alcohol (i.e., the lefthand product is the
one isolated).
[Org. Lett. 2013, 15, 3118]
Et Et
OH O O O OH OH O O
SmI2, EtCHO, THF or
OPMB –20 to –10°C OPMB OPMB

Redox III 911
for axial attack on the carbonyl group of a cyclohexanone, a generalization first pro-
posed by Barton.69
The first serious attempts to rationalize why there is this stereochemical bias in the
reduction of cyclohexanone derivatives led to two models of reduction: the “product de-
velopment control” model and the “steric approach control” model.70 Both these models
have been strongly criticized.71 Explanations based on parameters including torsional
strain,72 orbital symmetry control,73 dissymmetry in the π orbital of the carbonyl group,74
and charge-transfer stabilization of the transition state75 have been advanced to rational-
ize the stereochemistry obtained. The controversy over the stereochemistry of nucleop-
hilic addition to the carbonyl group of cyclohexanone derivatives continues.76
Hydride addition to the carbonyl group may be viewed as a typical nucleophilic
addition to the π bond. Bürgi and Dunitz studied nucleophilic addition to carbonyl
compounds and observed that there was a favored trajectory of approach of the nucle- Figure 20.5 Bürgi-Dunitz
ophile to the carbonyl group.77 In this preferred approach trajectory, the nucleophile trajectory for the addition of
makes an O—C—Nu angle of approximately 110° with the C=O axis perpendicular to borohydride anion to acetone
the plane of the carbonyl group. The Bürgi-Dunitz trajectory (Figure 20.5) has become
one of the foundations on which stereochemical predictions in the reduction of car-
bonyl groups is based.
The reactions of acyclic ketones are generally adequately predicted by applying the
Cram78 and Felkin-Anh79 models that were discussed at length in Chapter 2. In the case of
complex metal hydrides, both the reducing agent and the substrate affect the stereochem-
ical outcome of the reaction. This is illustrated by the results in Table 20.2, where the re-
duction of a series of structurally related α-substituted acyclic ketones is summarized.80
The data in Table 20.2 show that, as the reducing agent becomes more sterically
demanding, the proportion of the Cram isomer increases rapidly. As the steric bulk of
the α′ substituent increases, there is also an increase in the proportion of the Cram
isomer in the product. However, it is much more modest in scope (each methyl branch
at the α′ position increases the percent of the major isomer by approximately 10%). As
with other nucleophilic additions to chiral ketones and aldehydes, a substituent at the
α position capable of coordinating the cation by chelation leads to a general reversal of
the observed stereochemical bias, and the anti-Cram product is usually observed as the
major product.
69. Barton, D.H.R. J. Chem. Soc. 1953, 1927.

70. (a) Dauben, W.G.; Fonken, G.J.; Noyce, D.S. J. Am. Chem. Soc. 1956, 78, 2579. (b) Dauben, W.G.; Blanz,
E.J., Jr.; Jiu, J.; Micheli, R.J. J. Am. Chem. Soc. 1956, 78, 3752. (c) Dauben, W.G.; Bozak, R.E. J. Org. Chem. 1959,
24, 1596. (d) Dauben, W.G.; Bozak, R.E.; Ellis, R.; Willey, F. Rev. Chim. Acad. Roumaine 1962, 7, 803 [cf Chem.
Abstr. 1964, 61, 4424].
71. Wigfield, D.C.; Phelps, D.J. Can. J. Chem. 1972, 50, 388.
72. Chérest, M.; Felkin, H. Tetrahedron Lett. 1971, 383.
73. (a) Klein, J. Tetrahedron Lett. 1973, 4307. (b) Klein, J. Tetrahedron 1974, 30, 3349.
74. (a) Liotta, C.L. Tetrahedron Lett. 1975, 519. (b) Anh, N.T.; Eisenstein, O.; Lefour, J.-M.; Trân Huu Dâu,
M.-E. J. Am. Chem. Soc. 1973, 95, 6146. (c) Ashby, E.C.; Noding, S.A. J. Am. Chem. Soc. 1976, 98, 2010.
75. Cieplak, A.S. J. Am. Chem. Soc. 1981, 103, 4540.
76. (a) Gung, B.W. Tetrahedron 1996, 52, 5263. (b) Tomoda, S.; Senju, T. Tetrahedron 1999, 55, 3871. (c) Yadav,
V.K.; Jeyaraj, D.A.; Balamurungan, R. Tetrahedron 2000, 56, 7581.
77. (a) Bürgi, H.B.; Dunitz, J.D.; Schefter, E. J. Am. Chem. Soc. 1973, 95, 5065. (b) Bürgi, H.B.; Dunitz, J.D.;
Lehn, J.M.; Wipff, G. Tetrahedron 1974, 30, 1563. (c) Bürgi, H.B.; Dunitz, J.D. Acc. Chem. Res. 1983, 16, 153.
78. (a) Cram, D.J.; Abd Elhafez, F.A. J. Am. Chem. Soc. 1952, 74, 5828. (b) Cram, D.J.; Knight, J.D. J. Am.
Chem. Soc. 1952, 74, 5835. (c) Curtin, D.Y.; Harris, E.E.; Meislich, E.K. J. Am. Chem. Soc. 1952, 74, 2901.
(d) Leitereg, T.J.; Cram, D.J. J. Am. Chem. Soc. 1968, 90, 4019.
79. (a) Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199. (b) Anh, N.T.; Eisenstein, O. Nouv.
J. Chem. 1977, 1, 61.
80. Yamamoto, Y.; Matsuoka, K.; Nemoto, H. J. Am. Chem. Soc. 1988, 110, 4475.

Table 20.2 Reduction of α-Substituted ketones with Complex Hydrides
Minor Major: Yield

Reducing Agent Ketone Major (Cram) (Anti-Cram) Minor (%)
LiAlH4, Et 2O, 0°C 74:26 97

O OH OH
L-Selectride > 99:1 80

O OH OH
LiAlH4, Et 2O, 0°C 77:23 74

O OH OH
L-Selectride > 99:1 80

O OH OH
LiAlH4, Et 2O, 0°C 58:42 92

O OH OH
LiAlH4, Et 2O, 0°C 68:32 99

O OH OH
LiAlH4, Et 2O, 0°C 81:19 99

O OH OH
20.4 Reduction Using Metals81
The reduction of carbonyl compounds with active metals is a reaction of considerable long
standing. Sodium,82 sodium amalgam,83 zinc,84 and magnesium85 have been used to reduce
ketones and carboxylic acid derivatives for more than a century. In the ensuing time,
several low-valent metal species (e.g., Li°, Na°, K°, Zn°, Mg°, Ca°, Ti°, Cr+2, Sm+2) have been
used in organic synthesis. The common feature of dissolving metal reductions is that they
proceed through free radical intermediates. Depending on the exact reaction conditions,
81. Monographs: (a) House, H.O. Modern Synthetic Reactions, 2nd ed. (Benjamin Cummings: Menlo Park,
1972), ch. 3.
82. (a) Bouvealt, L.; Blanc, G. Compt. rend. 1903, 136, 1676. (b) Bouveault, L.; Blanc, G. Bull. Soc. Chim. France
1904, 31, 666. (c) Adkins, H.; Gillespie, R.H. Org. Syn., Coll. Vol. 3 1955, 671. (d) Bouveault, L.; Loquin, R.
Compt. rend. 1905, 140, 1593. (e) Finley, K.T. Chem. Rev. 1964, 64, 573. (f) Rühlmann, K. Synthesis 1971, 236.
83. (a) Saytzeff, A. Ann. Chem. Pharm. 1873, 171, 258. (b) Saytzeff, A. Z. Chem., N.F. 1869, 5, 551. (c) Saytzeff,
A. Z. Chem., N.F. 1870, 6, 105. (d) Saytzeff, A. J. prakt. Chem. [2] 1871, 3, 76. (e) Saytzeff, A. J. prakt. Chem.
[2] 1871, 3, 427.
84. (a) Clemmensen, E. Ber. Dtsch. chem. Ges. 1913, 46, 1837. (b) Clemmensen, E. Ber. Dtsch. chem. Ges. 1914,
47, 51. (c) Clemmensen, E. Ber. Dtsch. chem. Ges. 1914, 47, 681. (d) Martin, E.L. Org. React. 1942, 1, 155. (e) Vedejs,
E. Org. React. 1975, 22, 401.
85. Fittig, R. Ann. Chem. Pharm. 1859, 110, 17.

Redox III 913
these radicals may yield either the alcohol or other reduction product, or a dimeric prod-
uct formed by combination of two radicals.
The initial step of these reductions (Example 20.52) requires the transfer of a single
electron from the metal atom to the lowest energy unoccupied molecular orbital (π*) of
the carbonyl compound, resulting in rupture of the π bond and formation of a radical
anion. Note that the singly occupied 2p orbital on carbon is coplanar with the orbital
carrying the non-bonding lone pair on oxygen. Thus, the possibility for electron delocal-
ization (similar to hyperconjugation in alkanes) exists.
e
C O C O (20.52)
If the metal is a very strong reducing agent (typically a Group IA metal or a Group IIA
metal below magnesium), the radical anion may accept another electron to give a dianion
that is protonated on carbon by a protic solvent (including such poor proton donors as
liquid ammonia). The acid added during product isolation protonates the oxygen to give
the alcohol product (Example 20.53). In the absence of a proton source, the radical anion
may dimerize to give the dianion of a diol; protonation during isolation gives the diol
(Example 20.54).
R R R R
M• M•
O O O OH (20.53)
R R R R
R R R R
O O HO OH (20.54)
R R R R
Dissolving Metal Reduction of Carbonyl Compounds

The oldest useful reduction of carbonyl compounds with metals is the reduction of esters
by sodium metal in refluxing ethanol (e.g., Example 20.55), first published by French
chemist Louis Bouveault86 and his students in a series of papers beginning in 1903.87 It is
now known as the Bouveault-Blanc reduction. This permits the selective reduction of the
ester group of diacid half-esters (e.g., Example 20.56) and the reduction of conjugated
ketones to the saturated alcohol (e.g., Example 20.57).
H (CH2)7CO2Et H (CH2)7CH2OH
Na, EtOH, ∆ 88
(20.55)
(49-51%)
H (CH2)7Me H (CH2)7Me
86. Louis Bouveault (1864–1909) was born in Nevers, and educated at the Sorbonne (Dr ès-sc phys, 1890).
On graduating, Bouveault became Professor of Organic Chemistry at the Institut Chimique de Nancy, and then
Maître de Conférences at the University of Lyons. In 1894 Bouveault was appointed to the University of Nancy
and in 1902 to the Sorbonne. In 1904 he was appointed as Maître de Conférences. He died prematurely in 1909
in the midst of a flourishing career. For more details, see; Nye, M.J. Science in the Provinces (University of
California Press: Berkeley, 1986), p. 166 ff.
87. (a) Bouvealt, L.; Blanc, G. Compt. rend. 1903, 136, 1676. (b) Bouveault, L.; Blanc, G. Bull. Soc. Chim. France
1904, 31, 666. (c) Bouveault, L.; Loquin, R. Compt. rend. 1905, 140, 1593.
88. Adkins, H.; Gillespie, R.H. Org. Syn., Coll. Vol. 3 1955, 671.

H
CO2Me 1) Na, NH3, EtOH 89
O (20.56)
CO2H 2) H3O+
(72%) H O
Na, EtOH, ∆ 90
(20.57)
R R = H, Me, OMe
O HO R
The reduction of carbonyl compounds by solutions of metals in ammonia gives the

corresponding primary or secondary alcohol if the carbonyl group is not conjugated with
a double bond. If the carbonyl group is conjugated with a double bond, the products are
derived by initial reduction of the carbon-carbon double bond. Reduction of α-substituted
ketones proceeds predominantly with anti-Cram selectivity, although the level of diaste-
reoselectivity is usually lower than the Cram selectivity with lithium aluminum hydride.91
Simple alkenes are not reduced by dissolving metals in alcohol or ammonia solvent. How-
ever, reduction of α,β-unsaturated carbonyl compounds with lithium in ammonia in the
absence of a stronger proton source gives a single regioisomer of the lithium enolate,
which can then be used in an alkylation reaction or an aldol addition reaction (e.g., Exam-
ple 20.58). In the presence of a proton source, the saturated alcohol is the usual product
(e.g., Example 20.59). When the enone is a cyclohexenone, the two hydrogens are intro-
duced from the axial direction, so the stereochemistry of the reaction can be predicted
(e.g., Example 20.60).
1) Li, NH3, Et2O 92

(20.58)
O 2) NH4Cl, H2O O
H
OMe
OMe 1) Li, NH3, Et2O, EtOH 93
(20.59)
2) NH4Cl, H2O HO
O H
(94%)
H
1) Li, NH3 94
(20.60)
2) NH4Cl
H
Ph O Ph O
The Pinacol Reaction and Related Reactions

The reaction between a carbonyl compound and an active metal in a protic solvent usually
results in reduction to the primary alcohol if the carbonyl compound is an aldehyde or to
89. Paquette, L.A.; Nelson, N.A. J. Org. Chem. 1962, 27, 2272.
90. (a) Seo, B.-I.; Lewis, D.E.; Wall, L.K.; Lee, H.; Buttrum, J.W. Synth. Commun. 1993, 23, 15. (b) Seo, B.-I.;
Suh, I.-H.; Jensen, W.P.; Lewis, D.E.; Wall, L.K.; Jacobson, W.P. Tetrahedron: Asymmetry, 1992, 3, 367.
91. Yamamoto, Y.; Matsuoka, K.; Nemeto, H. J. Am. Chem. Soc. 1988, 110, 4475.
92. (a) Halsall, T.G.; Theobald, D.W.; Walshaw, K.B. J. Chem. Soc. 1964, 1029. (b) Chen, Y.; Xiong, Z.; Zhou,
G.; Yang, J.; Li, Y. Chem. Lett. 1997, 1289.
93. Stork, G.; Darling, S.D. J. Am. Chem. Soc. 1964, 86, 1761.
94. House, H.O.; Thompson, H.W. J. Org. Chem. 1963, 28, 360.

Redox III 915
the secondary alcohol if the carbonyl compound is a ketone. However, if the reaction is
carried out in an aprotic solvent such as diethyl ether, another reaction can occur. In this
reaction, two molecules of the carbonyl compound become bonded together at the car-
bonyl carbons, as discovered by Rudolf Fittig (Examples 20.61 to 20.63).95 The product is a
vicinal diol called a pinacol (Greek πιναξ, pinax, a table, referring to the tabular form of
the crystals obtained from acetone).
Me
O Mg(Hg) Me OH
96
(20.61)
Me Me C6H6, ∆
Me OH
(43-50%) Me
Ph Ph
97
HO OH (20.62)
(18%)
Ph
O Al(Hg), EtOH
C6H6, 50°C
Ph
HO
(20.63)
OH (27%)
Ph
Historically, the most popular metal for carrying out the pinacol reaction has
probably been magnesium. The modern variants of the pinacol reaction are most
f requently based on metals other than magnesium, and titanium-based reagents are
especially popular for carrying out the reaction. The key step (Example 20.64) in the
first total synthesis of the plant hormone gibberellic acid (gibberellin A 3), for example,
involved a pinacol reaction using titanium metal.98 Where the double bond does not
occupy a position prohibited by Bredt’s rule, titanium metal can also reduce carbonyl
compounds to alkenes, a reaction known as the McMurry reaction.99 As illustrated in
the reactions of cyclohexanone, t itanium-based reactions (Example 20.65) often give
much higher yields than the corresponding magnesium-based pinacol reactions
(Example 20.66). For this reason, the titanium-based reagents have gained considerable
popularity.
H H
Ti, THF
(55%) OH (20.64)
O
CHO OH
THPO THPO
95. Wilhelm Rudolf Fittig (1835–1910) was educated at Göttingen (PhD, 1858); he was appointed to the
faculty in 1860. He subsequently moved to Tübingen (1870) and Strasbourg (1876). Fittig was awarded the Davy
medal by the Royal Society in 1906. He was also a teacher of some note, publishing two widely-used textbooks.
For more information, see: Witt, O.N. J. Chem. Soc., Trans. 1911, 99, 1646.
96. Adams, R.; Adams, E.W. Org. Syn., Coll. Vol. 1 1944, 459.
97. Vigevani, A.; Pasqualucci, R.; Gallo, G. Tetrahedron 1969, 25, 573.
98. Corey, E.J.; Danheiser, R.L.; Chandrasekaran, S.; Siret, P.; Keck, G.E.; Gras, J.-L. J. Am. Chem. Soc. 1978,
100, 8031. (b) Corey, E.J.; Danheiser, R.L.; Chandrasekaran, S.; Keck, G.E.; Gopsalom, B.; Larsen, S.D.; Siret, P.;
Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8034.
99. (a) McMurry, J.E. Acc. Chem. Res. 1974, 7, 281. (b) McMurry, J.E.; Rico, J.G. Tetrahedron Lett. 1989, 30,
1169.

(20.65)
Ti (85%)
O
OH
Mg(Hg)
(20.66)
HO (30%)
One particularly useful application of the titanium-based reductive coupling of car-

bonyl compounds is the reduction of dicarbonyl compounds with titanium (III) chloride
and a zinc-copper couple. This reaction provides an excellent method for the formation of
compounds with medium-sized rings that are extremely difficult to obtain by other cy-
clization methods (e.g., Example 20.67).100 Similar reactions of aldehydes with low-valent
titanium (prepared from titanium tetrachloride and manganese metal) give anti-1,2-diols
in a crossed pinacol reaction (e.g., Example 20.68).101
O Bu
TiCl3, Zn(Cu) Bu
O
(20.67)
DMF
Bu (76%) Bu
PhCHO, Mn (10 eq.) OH

CHO TiCl4 (5 eq)
X (20.68)
THF, –10°C X
OH
(d.r. 4:1)
Reductive Elimination: The E1cb Elimination

If an organometallic reagent is to be formed either by direct combination or by metal-
halogen exchange with another metal alkyl, it is also important that there be no group at
the β carbon that might conceivably act as a leaving group—even a poor leaving group. In
such compounds, the reaction with the metal leads not to the formation of the expected
organometallic compound but rather to elimination of the halogen and the leaving group,
a reaction known as reductive elimination. The reaction is also promoted by low-valent
metal ions (e.g., Sm2+).
Several groups can function as the leaving group at the β carbon, including halogens,
oxygen-containing functional groups, and even some nitrogen functional groups; they
are summarized in Table 20.3. When the leaving group is a halogen, reductive elimina-
tion proceeds readily with anti stereochemistry by a mechanism that is basically the
same as the E2 mechanism. However, when the leaving group is relatively poor, other
factors come into play. As the leaving group becomes more difficult to remove, the reac-
tion mechanism changes to E1cb. As a result, the stereochemistry becomes less rigidly
defined. This is illustrated in Example 20.69, where the product ratio is independent of
the stereochemistry of the starting bromoether. Reductive elimination of β-haloethers
often occurs during the attempt to prepare organometallic reagents (e.g., Example 20.70).
Reductive elimination does not always require a metal. For example, the formation of
100. McMurry, J.E.; Fleming, M.P.; Kees, K.L.; Krepski, L.R. J. Org. Chem. 1978, 43, 3255.
101. Duan, X.-F.; Feng, J.-X.; Zi, G.-F.; Zhang, Z.-B.Synthesis, 2009, 277.

Redox III 917
Table 20.3 Reactant and Reagent Combinations for Reductive Elimination
X Y R R
reagent
R R
R R solvent R R
X Y Reagent/Solvent
Halogen Halogen Li, NH3; Na, NH3

OR Na, ROH; Mg, ROH
OH (acid conditions) Mg, Et 2O; Li, Et 2O
NHCOR Zn, AcOH, ∆; n-BuLi, THF
OH OH (1) MeLi; (2) K 2WCl6, THF, ∆
OH OH (1) Im2C=S; (2) P(OR)3, ∆
OH OH TsOH, NaI
OH OH Ti, THF
OTs OTs NaI, DMF
1,2-diodoalkanes is always followed by attack of iodide ion to give iodine and the alkene
(Example 20.71).
Zn, EtOH 11
Br
H2O H 102
(20.69)
∆
OMe 9
H H
Cl OH
O
1) BuLi, Et2O, C6H14 103
(20.70)
2) NaHCO3, H2O
(90-95%)
X I
(20.71)
X I
X = Cl, Br, OTs.

OH2+, etc.
102. (a) House, H.O.; Ro, R.S. J. Am. Chem. Soc. 1958, 80, 182. (b) Cristol, S.J.; Rademacher, L.E. J. Am. Chem.
Soc. 1959, 81, 1600.
103. Schöllkopf, U.; Paust, J.; Patsch, M.R. Org. Syn. 1969, 49, 86.

An important method for the stereospecific formation of alkenes is the reductive elim-
ination of vicinal diols through their cyclic thionocarbonates, known as the Corey-Winter
reaction.104 The reaction involves the abstraction of the sulfur atom from the thionocar-
bonate by trivalent phosphorus (usually a phosphite ester) to generate a cyclic carbene that
rearranges to the alkene with loss of carbon dioxide. The overall reaction is stereospecific
and suprafacial (syn), as illustrated by the formation of trans-cyclooctene from trans-
cyclooctane-1,2-diol (Example 20.72).105
S
1) N N
HO N N
HO 2) (C8H17)3P, 130°C, 17 h
(84%)
(20.72)
O O O
S S
O R3P O O
PR3
Wurtz Coupling
The reaction between an alkyl halide and sodium metal is almost always complicated by a
coupling reaction called the Wurtz coupling (after the French chemist Charles Adolphe
Wurtz,106 who discovered it). The net result of the Wurtz coupling is that two of the alkyl
groups of the alkyl halide become bonded to each other to form the alkane. Thus, if one
attempts to prepare butylsodium by the direct reaction between sodium and 1-bromobu-
tane, one obtains octane as the major organic product, not butylsodium. The intramolec-
ular version of the Wurtz coupling is a reductive elimination of a non-vicinal dihalide,
and it has been used to form cycloalkanes by the reaction b etween a dihalide and sodium
metal or a sodium-potassium alloy in a hydrocarbon solvent. This reaction is an extremely
important method for the preparation of small-ring compounds (e.g., Example 20.73) and
compounds with extreme ring strain (e.g., Example 20.74).
Cl
Na, dioxane
(20.73)107
∆
(78-94%)
Br
Na-K (20.74)
108
Br heptane
Br ∆
104. (a) Corey, E.J.; Winter, R.A.E. J. Am. Chem. Soc. 1963, 85, 2677. (b) Block, E. Org. React. 1984, 30, 457.
(c) Sonnet, P.E. Tetrahedron 1980, 36, 557.
105. Corey, E.J.; Shulman, J.I. Tetrahedron Lett. 1968, 3655
106. Charles Adolphe Wurtz (1817–1884) graduated from Strasbourg (MD, 1843). After study with Liebig at
Giessen and with Dumas in Paris, he became Dumas’ assistant in 1845 and his successor in 1853. In 1879, he
became the first professor of organic chemistry at the Sorbonne. For much more detail, see: (a) Rocke, A.J.
Nationalizing Science: Adolphe Wurtz and the Battle for French Chemistry (MIT Press: Cambridge, 2001);
(b) Williamson, A.W. Proc. Roy. Soc. 1885, 38, xxiii.
107. Lampman, G.M.; Aumiller, J.C. Org. Syn., Coll. Vol. 6 1988, 133.
108. Pincock, R.E.; Torupka, E.J. J. Am. Chem.Soc. 1969, 91, 4593.

Redox III 919
Birch Reduction
Carbon-carbon π bonds are usually inert to reduction by metals. However, in several
papers starting in 1944, Australian chemist Arthur Birch 109 described the reduction of
aromatic rings by a solution of an alkali metal in liquid ammonia in the presence of a
proton donor such as ethanol or tert-butyl alcohol.110 This reaction, which is carried
out with lithium (occasionally sodium or potassium) in liquid ammonia in the pres-
ence or absence of a proton source or an organic cosolvent is now known as the Birch
reduction.111 More than 60 years after its development, the Birch reduction remains
one of the most useful methods for the reduction of aromatic rings. The key to
the Birch reduction is the fact that alkali metals dissolve in liquid ammonia to give
deep blue, electrically conductive solutions containing the metal ion and solvated
electrons.
In the absence of the proton donor, the reduction of aromatic rings is quite slow
because the addition of the second electron to the cyclohexadienyl radical anion gener-
ates a d ianion—an extremely powerful base. Protonation of the radical anion (20.75),
however, leads to the cyclohexadienyl radical (20.76), which readily accepts a second
electron to give the cyclohexadienyl anion (20.77). Depending on the exact reaction
conditions, this anion may be protonated to give the 1,4-cyclohexadiene or it may give
the 1,3-cyclohexadiene, which is then reduced to the cyclohexene. Under kinetic condi-
tions (in the presence of a proton donor strong enough to irreversibly protonate the
cyclohexadienyl anion), the thermodynamically less stable nonconjugated diene is pro-
duced (Figure 20.6).
Ring substituents also play an important role in determining the regiochemistry and
rate of a Birch reduction. Electron-releasing groups result in products that carry the sub-
stituent on one of the residual π bonds (e.g., Example 20.78); alkyl groups tend to retard
H H H H Figure 20.6 The mechanism

ROH of the Birch reduction of
aromatic rings in the
presence and absence of a
proton source
NH3
e NH3 e
H H H H NH2
repeat
etc etc etc
(20.75) (20.76) (20.77)
109. Arthur John Birch (1915–1995) was educated at Sydney (MSc, 1937) and Oxford (D Phil, 1941). He
stayed in Britain until 1952, working on the synthesis of steroid hormones. His career then took him to Sydney
(1952), Manchester (1955), and the Australian National University (1967). For more biographical detail, see: (a)
Birch, A.J. To See the Obvious. (Oxford University Press: New York, 1995); (b) Rickards, R.W.; Cornforth, J.
Biogr. Mem. Fell. Roy. Soc. 2007, 53, 21.
110. (a) Birch, A.J. J. Chem. Soc. 1944, 430. (b) Birch, A.J. J. Chem. Soc. 1945, 809. (c) Birch, A.J. J. Chem. Soc.
1946, 593. (d) Birch, A.J. J. Chem. Soc. 1947, 102. (e) Birch, A.J. J. Chem. Soc. 1947, 1642. (f) Birch, A.J. J. Chem.
Soc. 1949, 2531.
111. Reviews: (a) Birch, A.J. Quart. Rev. (London) 1950, 4, 69. (b) Birch, A.J.; Smith, H. Quart. Rev. (London)
1958, 12, 17. (c) Watt, G.W. Chem. Rev. 1950, 46, 317. (d) Caine, D. Org. React. 1976, 23, 1. (e) Hook, J.M.; Mander,
L.N. Nat.Prod. Rep. 1986, 35. (f) Rabideau, P.W. Tetrahedron 1989, 45, 1579. (g) Rabideau, P.W.; Marcinow, Z.
Org. React. 1992, 42, 1. (h) Subba Rao, G.S.R. Pure Appl. Chem. 2003, 75, 1443. (i) For a review of the mecha-
nism, see: Zimmerman, H.E. Acc. Chem. Res. 2012, 45, 164.

the rate of the reduction, whereas alkoxy and amino groups tend to accelerate the reduc-
tion slightly.112 Electron-withdrawing substituents on the ring change the regiochemistry
of the reduction, with the major product being that in which the substituent is not on a
double bond but on one of the two sp3-hybridized carbons (Example 20.79). Phenols are
rapidly deprotonated under Birch reduction conditions to give phenoxide anions that
resist reduction with lithium. Yet, the substituted ring of β-naphthols is rapidly reduced to
give the corresponding tetralone (Example 20.80).
OMe OMe
Na, NH3 (20.78)
EtOH
(79%)
CO2Na CO2Na
Na, NH3 (20.79)
EtOH
(89-95%)
OH Na, NH3 O
(20.80)
EtOH
The Birch reduction of aromatic ethers is an especially important reaction syntheti-

cally because the products of the reduction are enol ethers. These compounds may be
hydrolyzed to cyclohexenone derivatives, thus making aromatic ethers a useful “masked”
enone for synthesis where the reactivity of the carbonyl group or the alkene double bond
would be undesirable. Hydrolysis of the enol ether with a weak acid such as aqueous oxalic
acid gives the non-conjugated enone (Example 20.81). Hydrolysis of the enol ether with a
stronger acid usually results in migration of the double bond into the conjugated position
(Example 20.82; the more common situation).
(CO2H)2
(20.81)
OMe OMe
H2O
Li, NH3
O
ROH
HCl/H2O (20.82)
In the absence of a proton source, the reduction of benzoate esters with lithium in
liquid ammonia gives an intermediate cross-conjugated ester enolate anion. The similar
reduction of a benzoate anion gives the analogous cross-conjugated dianion of the carbox-
ylic acid. Like all enolates, these anions can be trapped with an alkyl halide to give the
alkylated product (e.g., Example 20.83).113
112. Krapcho, A.P.; Bothner-By, A.A. J. Am. Chem. Soc. 1959, 81, 3658.
113. For examples, see: (a) Overman, L.E.; Ricca, D.J.; Tran, V.D. J. Am. Chem. Soc. 1997, 119, 12031. (b) Hook,
J.M.; Mander, L.N.; Woolias, M. Tetrahedron Lett. 1982, 23, 1095. (c) Taber, D.F. J. Org. Chem. 1976, 41, 2649.
(d) Schultz, A.G.; Pettus, L. J. Org. Chem. 1997, 62, 6855.

Redox III 921
OMe OMe OMe
Li, NH3 1) MeI, 0°C (20.83)

H H H
THF 2) HCl, H2O
HO2C OH OLi HO2C OH

LiO OLi
One of the most spectacular applications of the Birch reduction in synthesis is from a
steroid synthesis by W. S. Johnson. This chemist used the Birch reduction to introduce no
less than five new chiral centers into a molecule in a single step with complete control over
the relative stereochemistry (Example 20.84).114
Me H (31%)
OMe H
HO (20.84)
1)Li, NH3, EtOH H
Me
2) HCl, H2O, EtOH O
H
O Me H (7%)
H H
HO
H
The Birch reduction of conjugated dienes gives simple alkenes, whereas the Birch re-
duction of nitriles and imines gives amines. Reduction with sodium or lithium in liquid
ammonia may be used for hydrogenolysis of benzyl esters, ethers, and amines as well as for
hydrogenolysis of alkyl halides to hydrocarbons. Internal alkynes are reduced to E alkenes
using the Birch reduction. Here, virtually none of the Z isomer is produced, as illustrated
by the reduction of the C2 -symmetric alkyne shown in Example 20.85. Beginning in 1952,
a useful modification of the original Birch procedure was developed by Benkeser, who
initially replaced the liquid ammonia with a low-boiling amine115 and then replaced the
alkali metal with calcium (Example 20.86).116 This latter version of the Benkeser reduction
has become very popular due to its much improved performance over the classical Birch
reduction in large-scale applications.
H H
O O
O Na, NH3, THF
O H O (20.85)
O (92%) H
O O
H H
114. (a) Johnson, W.S.; Bannister, B.; Pappo, R. J. Am. Chem. Soc. 1956, 78, 6331. Earlier papers in this series
address the stereochemistry of the reduction of the enone and styrene moieties: (b) Johnson, W.S. J. Am. Chem.
Soc. 1956, 78, 6278. (c) Johnson, W.S.; Szmuszkovicz, J.; Rogier, E.R.; Hadler, H.I.; Wynberg, H. J. Am. Chem.
Soc. 1956, 78, 6285. (d) Johnson, W.S.; Ackerman, J.; Eastham, J.F.; DeWalt, H.A., Jr. J. Am. Chem. Soc. 1956, 78,
6302. (e)
115. (a) Benkeser, R.A.; Robinson, R.E.; Landesman, H. J. Am. Chem. Soc. 1952, 74, 5699. (b) Benkeser, R.A.;
Robinson, R.E.; Sauve, D.M.; Thomas, O.H. J. Am. Chem. Soc. 1955, 77, 3230. (c) Benkeser, R.A.; Agnihotri,
R.K.; Burrous, M.L. Tetrahedron Lett. 1960 (16), 1.
116. Benkeser, R.A.; Belmonte, F.G.; Kang, J. J. Org. Chem. 1983, 48, 2796.

Ca, MeNH2 (20.86)

+
(CH2NH2)2
(71%) (21%)
A Final Word on Dissolving Metal Reductions

The alkali metals always pose a threat of fire or explosion, so for process chemistry,
especially, a less pyrophoric alternative is always being sought. In recent years, the use
of s ilica-supported alkali metals has begun to supersede the use of alkali metals in
many reactions because the need for cryogenic conditions and solvents such as liquid
ammonia is eliminated by these reagents. The momentum toward using these reagents
as the first choice in reactions such as the Bouveault-Blanc and Birch reductions, as
well as in reductive dehalogenation and desulfurization is increasing. More of these
supported alkali metals, which are mobile black powders, are becoming commercially
available.117
Worked Problem
20-4 What are the intermediate compounds in the following sequence? Why is step
B → C necessary?
N N
O OMe K, t-BuOH Br HCl, MeOH O O
∆
A B C
NH3-THF H2O
Me Me
§Answer below.
117. (a) Shatnawi, M.; Paglia, G.; Dye, J.L.; Cram, K. C.; Lefenfeld, M.; Billinge, S.J.L. J. Am. Chem. Soc. 2007,
129, 1386. (b) Dye, J.L.; Cram, K.D.; Urbin, S.A.; Redko, M.Y.; Jackson, J.E.; Lefenfeld, M. J. Am. Chem. Soc.
2005, 127, 9338. (c) Nandi, P.; Redko, M.Y.; Petersen, K.; Dye, J.L.; Lefenfeld, M.; Vogt, P.F.; Jackson, J.E. Org.
Lett. 2008, 10, 5441. (d) Bodnar, B.S.; Vogt, P.F. J. Org. Chem. 2009, 74, 2598. (e) Nandi, P.; Dye, J.L.; Jackson, J.E.
J. Org. Chem. 2009, 74, 5490. (f) Costanzo, M.J.; Patel, M.N.; Petersen, K.A.; Vogt, P.F. Tetrahedron Lett. 2009,
50, 5463.

The initial step is the Birch reduction to give the potassium salt of the amide enolate, A, which is then al-
kylated to give the product B. The next step is hydrolysis of the enol ether, which is essential to prevent the
possibility of regioisomeric rearrangement products. The [3,3]-sigmatropic rearrangement of the 1,5-diene then
completes the sequence. [Tetrahedron Lett. 2004, 45, 8183]
N N N N N
O OMe KO OMe O OMe O O O O
Me Me Me Me Me
A B C

Redox III 923
Problem

CO2Me
1) Li, NH3, t-BuOH
Na, NH3 MeO THF
N
(a) (b)
MeO i-PrOH-THF 2) BrCH2CO2But
OTBS
1) Li, NH3, THF
(c)
2) isoprene
3) BrCH2CH=CH2
O
References: (a) J. Am. Chem. Soc. 2006, 128, 8734. (b) Org. Lett. 2006, 8, 831. (c) J. Org. Chem. 2009,
74, 6623.
Reaction Synopses
Reductive Elimination
X Y
X, Y: Cl, Br, I, OSO2R, NR 3+, etc.

Reagents: Li, NH3; Mg, Et2O; Zn, EtOH, ∆; Zn, AcOH, ∆;
or BuLi, Et2O; etc.
or NaI, DMF, ∆; etc.
Mechanism: E1cb or E2
Stereochemistry: anti (E2); mainly anti (E1cb)
Birch and Benkeser Reductions
M/NH3 M/NH3
ROH
M: Li, Na, K, etc.; ROH: EtOH, Me3COH, etc.

Reagents: Li, NH3, t-BuOH, THF; etc. (Birch reduction)
or Ca, MeNH2, (CH2NH2)2; etc. (Benkeser)
Reduction of Conjugated Carbonyl Compounds
(a) To Saturated Ketones
R R R R
R O R O
R R
Reagents: H2, Pd-C; etc.

or Li, NH3 (no proton source); etc.
(b) To Saturated Alcohols
R R R R
R O R OH
R R
Reagents: Li, NH3, ROH; etc.

or NaBH4, MeOH; LiAlH4, Et2O, extended time
(continues)

Pinacol Reaction
R R R
O HO OH
R R R
Reagents: Mg(Hg), Et2O; Zn(Hg), Et2O; Al(Hg), Et2O; etc.

or Ti, THF, TiCl3, K, THF; etc. (provided any alkene would
violate Bredt’s rule)
or Mn, TiCl4, THF; etc. (allows the diastereoselective crossed
pinacol reaction of aromatic aldehydes)
McMurry Reaction
Reagents: Ti, THF, TiCl3, K, THF; etc.
20.5 Reduction of Carbonyl Compounds to Hydrocarbons
Deoxygenation is carried out using three major reactions. The first is the Wolff-Kishner
reduction, in which hydrazone is treated with a strong base at elevated temperature; the
second is the Clemmensen reduction, in which the carbonyl compound is reduced with zinc
amalgam and concentrated hydrochloric acid; and the third is reductive desulfurization, in
which a dithioketal is reduced under catalytic hydrogenation or Birch reduction conditions.
The Wolff-Kishner Reduction and Related Reactions

The Wolff-Kishner reduction118 was originally carried out by heating the hydrazone of
the carbonyl compound with potassium hydroxide or by heating the carbonyl com-
pound with potassium hydroxide in hydrazine. However, in 1946 Chinese chemist
Huang Ming-long reported a modified version of the reaction,119 now known by his
name, which involved a high-boiling protic solvent (he used ethylene glycol, but dieth-
ylene glycol is now more widely used). The overall yields are higher than the original
Wolff-Kishner procedure (e.g., Examples 20.87 and 20.88). The Huang Minlon proce-
dure (the name of the reaction is based on the name used in the original paper, not on
more modern transliterations of the Chinese) has itself been modified by Barton, who
118. Todd, D. Org. React. 1948, 4, 378.

Ludwig Wolff (1859–1919) was educated at Würzburg, Munich, and Strasbourg (PhD, 1882 under Fittig).
Wolff became Fittig’s assistant on graduating, and he was appointed privatdozent at Strasbourg in 1885. In 1891,
he was appointed extraordinary professor of analytical chemistry at the University of Jena, where he spent the
rest of his working life. His major works involved the study of hydrazines and diazo compounds. A plaque in
his honor was unveiled at Jena in 2012.
Nikolai Matveyevich Kizhner (1867–1935) was educated in Moscow (Dr Khim, 1900) and was immediately
appointed inaugural Professor of Organic Chemistry at the Tomsk Technological Institute, in Siberia. His
decade at Tomsk was tumultuous. He resigned under duress in 1912 and left Tomsk in 1914. He taught at Sha-
nyavskii People’s University in Moscow until 1918, when he became director of the Aniline Trust Research In-
stitute, in Moscow. For more detail, see: Lewis, D.E. Angew. Chem. Int. Ed. 2013, 52, 11704.
119. (a) Huang-Minlon J. Am. Chem. Soc. 1946, 68, 2487. (b) Huang-Minlon J. Am. Chem. Soc. 1949, 71, 3301.
The fortuitous discovery of this reaction is related in: Ma, S.; Craig, G.W. Helv. Chim. Acta 2013, 96, 1822.
Huang Ming-long (1898–1979) was educated at Zhejiang Medical College (graduated 1918) and at the Uni-
versity of Berlin (PhD, 1924). He worked in the West during 1935–1940 (Schering AG in Berlin) and 1946–1952
(Harvard and Merck). From 1925–1934 he served as professor of chemistry at Zhejiang Medical College and
from 1940–1946 was at the Academia Sinica in Kunming. In 1952 he returned to the PLA Academy of Medical
Sciences, and in 1956, he moved to the Academia Sinica in Shanghai. For more detail, see: (a) Han, G.; Jin, S.;
Wu, Y. Progr. Chem. 2012, 24, 1229 (in Chinese); (b) Ma, S.; Craig, G.W. Helv. Chim. Acta 2013, 96, 1822.

Redox III 925
Figure 20.7 The generally

:OR accepted mechanism of the
OR Wolff-Kishner reduction of
H H H H aldehydes and ketones
R N2H4 R N H R N R N
O N N N
R R R R
RO
OR H
R R H R N R N
H H H H N H N
R R R R
used anhydrous hydrazine and sodium metal in diethylene glycol for the reduction of
highly hindered ketones.120
The generally accepted mechanism of the Wolff-Kishner reaction is given in Figure 20.7.
O
NH2NH2, KOH
(20.87)122
O(CH2CH2OH)2
∆
(84%)
NH2NH2, KOH (20.88)

121
HOCH2CH2OH
O ∆
(76%)
The strongly basic conditions of the Wolff-Kishner reduction can make it unsuitable
for use in the presence of sensitive functional groups. In such cases, a modification of this
reaction based on the tosylhydrazone (e.g., Examples 20.89 and 20.90) is often the
method of choice for deoxygenation.122 In this variation of the Wolff-Kishner reaction,
the tosylhydrazone is formed first, and this is then subjected to reduction by a nucleop-
hilic hydride nucleophile or a borane123 (the sulfur is actually reduced from the +6 to the
+4 oxidation state during this reaction). The overall effect is to allow the Wolff-Kishner
reduction to be carried out under much milder reaction conditions. When this reaction
is used to reduce α,β-unsaturated ketones, the product is an alkene. The double bond is
located between the original carbonyl carbon and the α carbon, even if this results in loss
of conjugation of the double bond with an aromatic ring.124
120. (a) Barton, D.H.R.; Ives, D.A.J.; Thomas, B.R. J. Chem. Soc. 1954, 903. (b) Barton, D.H.R.; Ives, D.A.J.;
Thomas, B.R. J. Chem. Soc. 1955, 2056.
121. White, J.D.; Somers, T.C. J. Am. Chem. Soc. 1994, 116, 9912.
122. (a) Hutchins, R.O.; Maryanoff, B.E.; Milewski, C.A. J. Am. Chem. Soc. 1971, 93, 1793. (b) Hutchins, R.O.;
Milewski, C.A.; Maryanoff, B.E. J. Am. Chem. Soc. 1973, 95, 3662.
123. Greco, M.N.; Maryanoff, B.E. Tetrahedron Lett. 1992, 33, 5009.
124. (a) Kabalka, G.W.; Yang, D.T.C.; Baker, J.D., Jr. J. Org. Chem. 1976, 41, 574. (b) Taylor, E.J.; Djerassi, C.
J. Am. Chem. Soc. 1976, 98, 2275. (c) Hutchins, R.O.; Natale, N.R. J. Org. Chem. 1978, 43, 2299. (d) Greene, A.E.
Tetrahedron Lett. 1979, 63.

O
1) TsNHNH2, TsOH
n-C11H24 (20.89)125
n-C9H19 CH3 2) NaBH3CN, TsOH
DMF, sulfolane, ∆
(86%)
CHO 1) TsNHNH2, MeOH, ∆ Me 123(b)

(20.90)
2) LiAlH4, THF, ∆
(70%)
A more recent approach to effecting the Wolff-Kishner reduction under mild condi-
tions has involved exploiting two facts. First, silyl compounds are often more stable than
their hydrogen counterparts (a fact routinely exploited in synthesis). Second, cleavage of a
σ bond to silicon by oxyanions or fluoride anion gives anions. In this modification of the
Wolff-Kishner reduction, a tert-butyldimethylsilyl hydrazone is formed and, in the same
vessel, is then treated with potassium tert-butoxide at temperatures more than 70°C lower
than most Wolff-Kishner reductions (e.g., Example 20.91).126 In this system, aromatic ke-
tones and aldehydes are reduced at 100°C, whereas aliphatic ketones are reduced at room
temperature.
1) (HNTBDMS)2
Sc(OTf)3 (cat)
(20.91)
MeO O 2) KOBut, HOBut
MeO
Me2SO, 23°C
(93%)
Wolff-Kishner reductions of carbonyl compounds carrying a heteroatom substituent

at the α carbon lead to the formation of alkenes via alkenyl anion intermediates (Example
20.92). This results from a simple modification of the reaction mechanism. The initial
anion formed by deprotonation of the hydrazone leads to elimination of the leaving group
to give the azoalkane, which then loses nitrogen through either anionic (shown) or free
radical intermediates to give the alkene. When the leaving group at the α position is an
epoxide oxygen, the reaction leads to ring opening, with the formation of an allylic alco-
hol. This variation of the Wolff-Kishner reduction is known as the Wharton reaction (e.g.,
Example 20.93).127
R' R'
N N
X N R N H :Base
R R H R
(20.92)
R' R'
H
R R
R R
125. Caglioti, L.; Magi, M. Tetrahedron, 1963, 19, 1127.

126. Furrow, M.E.; Myers, A.G. J. Am. Chem. Soc. 2004, 126, 5436.
127. Wharton, P.S.; Bohlen, D.H. J. Org. Chem. 1961, 26, 3615.

Redox III 927
O
H
NH2NH2 128
(20.93)
O (96%) PhOCO OH
PhOCO H
H H
A similar reaction is observed when the hydrazone carries a substituent on nitrogen

capable of elimination as a leaving group. One such class of compounds is the sulfonylhy-
drazones. Treating a sulfonylhydrazone with a base gives an alkene with rearrangement of
one of the groups bonded to the carbonyl carbon. When the base used is an alkoxide, the
reaction is known as the Bamford-Stevens reaction,129 and the more substituted alkene is
formed as the major product. When an alkylithium is used as the base, the reaction is
known as the Shapiro reaction,130 and the less substituted alkene is obtained as the major
product. It appears clear that the mechanism of the Shapiro reaction (Example 20.94)
proceeds through a vinyllithium formed by loss of nitrogen from an azovinyl anion.131 In
fact, this reaction is a useful method for the preparation of vinyllithium reagents.132 The
mechanism of the Bamford-Stevens reaction is less clearcut,133 and it may involve carbene
(shown as Example 20.95) or carbocation intermediates.
R' R'
N N
R" H N Ts R N
R R R
(20.94)
R' R'
H
R R
R R
R' R'
N R'
N
R N Ts N N
R N
R H R
R H
R H
(20.95)
R' R'
H
R R
R R H
128. Ziegler, F.E.; Hwang, K.-J.; Kadow, J.F.; Klein, S.I.; Pati, U.K.; Wang, T.F. J. Org. Chem. 1986, 51, 4573.
129. Bamford, W.R.; Stevens, T.S. J. Chem. Soc. 1952, 4735.
130. (a) Shapiro, R.H. Tetrahedron Lett. 1968, 345. (b) Shapiro, R.H.; Heath, M.J. J. Am. Chem. Soc. 1967, 89,
5734. (c) Shapiro, R.H. Org. React. 1976, 23, 405. (d) Adlington, R.M.; Barrett, A.G.M. Acc. Chem. Res. 1983, 16,
55. (e) Chamberlin, A.R.; Bloom, S.H. Org. React. 1990, 39, 1.
131. (a) Casanova, J.; Waegell, B. Bull. Soc. Chim. France 1975, 922. (b) Lipton, M.F.; Shapiro, R.H. J. Org.
Chem. 1978, 43, 1409.
132. See, for example, (a) Traas, P.C.; Boehlens, H.; Takken, H.J. Tetrahedron Lett. 1976, 2287. (b) Stemke, J.E.;
Chamberlin, A.R.; Bond, F.T. Tetrahedron Lett. 1976, 2947.
133. (a) Powell, J.W.; Whiting, M.C. Tetrahedron 1959, 7, 305. (b) Powell, J.W.; Whiting, M.C. Tetrahedron
1961, 12, 168. (c) De Puy, C.H.; Froemsdorf, D.H. J. Am. Chem. Soc. 1960, 82, 634. (d) Bayless, J.H.; Friedman, L.;
Cook, F.B.; Shechter, H. J. Am. Chem. Soc. 1968, 90, 531. (e) Nickon, A.; Werstiuk, N.H. J. Am. Chem. Soc. 1972,
94, 7081.

The possible involvement of carbenes in the Bamford-Stevens reaction is illustrated by

the reaction of camphor tosylhydrazone with hydroxide anion (Example 20.96). One of
the products is a tricyclane, which could come from carbene insertion. In contrast to this,
when the same hydrazone is treated with methyllithium (Example 20.97), the alkene is the
only product formed.
KOH (20.96)134
+
ROH
NNHTs ∆
MeLi (20.97)135
(98-99%)
NNHTs
The reaction between a sulfonylhydrazide and an α,β-epoxyketone represents the

hybrid of both these types of reduction. In the reaction (e.g., Example 20.98), α-substi-
tuted carbonyl compounds and functionalized hydrazines are both used. In this situation,
the reaction leads to fragmentation to give an alkyne and a ketone. The reaction is gener-
ally known as the Eschenmoser-Tanabe fragmentation.136 It has been especially success-
fully applied to the synthesis of medium-ring alkynes.
O O TsNHNH2 O
(20.98)137
EtOH, 50°C
(50%)
Problem
HO
O
NH2NH2 (8 eq) NH2NH2
N H
KOH (4 eq, powdered) NaOH
(a) CF3 (b) CO2H
N HO OH OHC HO
O OH
∆ H ∆
CO2H
O
O
O NsNHNH2
(c) H
O AcOH-THF
N 60°C
Ns O OMe
Me
References: (a) Org. Proc. Res. Dev. 2009, 13, 576. (b) Aust. J. Chem. 1996, 49, 249. (c) Org. Lett. 2008,
10, 3251.
134. Clark, P.; Whiting, M.C.; Papenmeier, G.; Reusch, W. J. Org. Chem. 1962, 27, 3356.
135. Shapiro, R.H.; Duncan, J.H. Org. Syn. 1971, 51, 66.
136. Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1957, 50, 708.
137. Tanabe, M.; Crowe, D.F.; Dehn, R.L. Tetrahedron Lett. 1967, 3943.

Redox III 929
The Clemmensen Reduction

The final method of deoxygenation of aldehydes and ketones that we will discuss is the
Clemmensen reduction,138 which involves heating the aldehyde or ketone with zinc amal-
gam and concentrated hydrochloric acid (e.g., Example 20.99).139 The strongly acidic con-
ditions of this reaction are tolerated by relatively few functional groups, and they tend to
promote rearrangement reactions.
CHO CH3
Zn(Hg) (20.99)
HCl, ∆
OMe OMe
(60-67%)
OH OH
A more modern version of the reaction (Example 20.100) involves the use of hydrogen
chloride and zinc dust in an organic solvent.140
O
Zn, HCl (g) (20.100)

Ac2O
AcO (70%) AcO
Reductive Desulfurization of Dithioketals and Dithioacetals

In the previous chapter, we saw that both sulfur atoms of a dithioketal or dithioacetal can
be replaced by hydrogen when the dithioketal is reduced with hydrogen-saturated Raney
nickel. The same reduction can also be accomplished using the Birch reduction, as shown
in Example 20.101.141 This combination of dithioacetal formation and desulfurization is
often used as a simple two-step alternative to the Wolff-Kishner and Clemmensen reduc-
tions and their variants.
C8H17
C8H17
Na, NH3 (20.101)

Et2O, EtOH
S
(89%)
S
Silicon-Based Deoxygenations
A potentially very useful deoxygenation reaction has been reported by Nimmagadda and
McRae.142 In this reaction, oxygenated organic compounds are treated with excess butylsilane
138. (a) Martin, E.L. Org. React. 1942, 1, 155. (b) Vedejs, E. Org. React. 1975, 22, 401. (c) Buchanan, J.G.St.C.;
Woodgate, P.D. Quart. Rev. Chem. Soc. 1969, 23, 522.
Erik Christian Clemmensen (1876–1941) was born in Odensee, Denmark and educated at the Royal Poly-
technic Institute. He left school in 1891, at age 15 and in 1900, he emigrated to the United States, after his grad-
uation. In 1903, he joined Parke, Davis & Company in Detroit, where he discovered (but never patented!) the
reaction named for him; it did, however, earn him a PhD from the University of Copenhagen in 1913. Clem-
mensen’s career was spent entirely in industry. In 1914, he founded the Commonwealth Chemical Corporation,
which was acquired by Monsanto in 1929. In 1935, he left Monsanto and founded the Clemmensen Chemical
Corporation. Up to his death at age 65, he was carrying out research at the Clemmensen Chemical Company.
139. Schwartz, R.; Hering, H. Org. Syn., Coll. Vol. 4 1963, 203.
140. Yamamura, S.; Hirata, Y. J. Chem. Soc. C 1968 2887.
141. Ireland, R.E.; Wrigley, T.I.; Young, W.G. J. Am. Chem. Soc. 1958, 80, 4604.
142. Nimmagadda, R.D.; McRae, C. Tetrahedron Lett. 2006, 47, 5755.

in the presence of 5 to 10 mol % tris-(pentafluorophenyl)borane in d ichloromethane. The

reaction showed remarkable selectivity for the reductive cleavage of carbon-oxygen bonds,
as shown in Examples 20.102 to 20.104. It is noteworthy that even the carboxyl group is re-
duced to a methyl group by this reagent.
O BuSiH3, B(C6H5)3
(20.102)
CH2Cl2, r.t.
(81%)
CHO Me
BuSiH3, B(C6H5)3
(20.103)
CH2Cl2, r.t.
(87%)
NO2 NO2
CO2H Me
BuSiH3, B(C6H5)3
(20.104)
CH2Cl2, r.t.
(67%)
OH OH
Reduction of Halides and Alcohols to Alkanes

The cleavage of carbon-heteroatom σ bonds is not restricted to dithioketals and sulfides.
Alkyl halides can be reduced chemoselectively by means of tributylstannane; the reaction
occurs by a free radical mechanism through tributylstannyl radicals (Figure 20.8). The
reaction is driven by the fact that the tin-halogen bond is much stronger than the tin-
hydrogen bond. A similar situation occurs with sulfur (C=S) and selenium compounds,
which also react with stannanes to give alkyl free radicals.
Stannane reductions are especially useful for deoxygenation of alcohols through
thiocarbonyl intermediates, a reaction known as the Barton-McCombie reaction or the
Barton deoxygenation.143 In these reductions (Examples 20.105 and 20.106), the tribu-
tylstannyl radical adds to the C—S π bond, and the alkyl free radical is generated by
elimination of a carbonyl compound. Example 20.105 is particularly interesting. The
attempted Wolff-Kishner deoxygenation of the corresponding ketone failed under
Huang-Minlon conditions, and the preparation of the dithioketal for reductive desul-
furization also failed.
OTHP OTHP
1) NaHDMS, CS2
MeI, –78°C (20.105)144
H H 2) Bu3SnH, AIBN H H
OH OMOM 150°C, 1.5 h OH OMOM
H (67%) H
OH
Ts Ts
N H 1) NaH, CS2 N H
MeI, THF
(20.106)145
2) Bu3SnH, AIBN
MeO2C N O PhMe, ∆ MeO2C N O
Boc (72%) Boc
143. Barton, D.H.R.; McCombie, S.W. J. Chem. Soc., Perkin Trans. 1 1975, 1974.
144. Basabe, P.; Martín, M.; Bodero, O.; Blanco, A.; Marcos, I.S.; Díez, D.; Urones, J.G. Tetrahedron 2010, 66, 6008.
145. Deng, H.; Yang, X.; Tong, Z.; Li, Z.; Zhai, H. Org. Lett. 2008, 10, 1791.

Redox III 931
Bu3SnH RH Bu3SnH RH Figure 20.8 The free radical

chain reaction for reduction
of halides (left) or thioesters
(right) with tributylstannane
R• Bu3Sn• R• Bu3Sn•
SnBu3
SnBu3
S X

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8.10 The Reactivity-Selectivity Principle 308

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Chapter Summary 935

Appendix 1: Named Reactions, Named Reagents, and Named Rules 1095

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The Fundamentals Revisited

1.1 Organic Structure: A Brief History

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01-Lewis-Chap01.indd 2 14/08/15 8:05 AM

Formal charge = (number of valence electrons in the neutral atom)

1. Electrons in a molecule have no memory. One cannot assign an electron in a molecule

01-Lewis-Chap01.indd 3 14/08/15 8:05 AM

1. Determine the total number of valence electrons.

Representing Organic Compounds: Structural Formulas

§ Answers for Worked Problem:

(i) (ii) (iii) (iv) (v)

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01-Lewis-Chap01.indd 5 14/08/15 8:05 AM

§ Answers for Worked Problems:

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1.2 Proton Transfers Revisited: Acids and Bases

Arrhenius Acids and Bases

Acid + Base → Salt + Water (Eq. 1.1)

This simple equation defines neutralization: the destruction of an acid by an equivalent

An acid is a substance that functions as a source of hydrogen ions in aqueous solution.

A base is a substance that functions as a source of hydroxide ions in aqueous solution.

01-Lewis-Chap01.indd 7 14/08/15 8:05 AM

Lowry-Brønsted Acids and Bases

A simple example of an acid-base reaction by the Lowry-Brønsted definition is the

01-Lewis-Chap01.indd 8 14/08/15 8:05 AM

HA + H2O → H3O+ + A– (Eq. 1.2)

The equilibrium constant for this reaction is given by Equation 1.5.

[HB][A2 ][H3O1 ] (Eq. 1.6)

Reorganization of Equation 1.6 gives the particularly useful Equation 1.7.

[H3O1 ][A2 ] [HB] K aHA (Eq. 1.7)

01-Lewis-Chap01.indd 9 14/08/15 8:05 AM

log( K eq ) 5 pK aHB 2 pK aHA (Eq. 1.8)

Example 1. CH3Li + H2O →

Table 1.1 Typical Ranges of pKa Values for Representative Acids

01-Lewis-Chap01.indd 10 14/08/15 8:05 AM

CH3– + Li + H2O → CH4 + Li+ OH–

K eq 5 10(45 2 18) 5 1027 and K eq 5 10(60 2 15) 5 1045

1.2 Proton Transfers Revisited: Acids and Bases