Veejendra K. Yadav - Steric and Stereoelectronic Effects in Organic Chemistry

Veejendra
K. Yadav
Steric and
Stereoelectronic
Effects in Organic
Chemistry
Second Edition
Steric and Stereoelectronic Effects in Organic
Chemistry
Veejendra K. Yadav
Steric and Stereoelectronic

Effects in Organic Chemistry
Second Edition
Veejendra K. Yadav
Department of Chemistry
Indian Institute of Technology Kanpur
Kanpur, Uttar Pradesh, India
ISBN 978-3-030-75621-5 ISBN 978-3-030-75622-2 (eBook)

https://doi.org/10.1007/978-3-030-75622-2
1st edition: © Springer Science+Business Media Singapore 2016

2nd edition: © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2021
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To Arpita, Dhananjay, and Dhruv with love
Preface to the Second Edition
After the publication of the first edition of the book in 2016, some incorrect structures
and lack of emphasis, here and there, were noticed by the MSc and PhD students
whom I recently taught a course (Physical Organic Chemistry) and myself. All
such structures have been corrected and requisite emphasis laid to make the reading
enjoyable. The presentation has been toned up to prevent distractions.
The contents of the erstwhile Chap. 6 now appear in Chap. 10. However, torquose-
lectivity and Hammett Substituent Constants are now dealt with separately in Chaps. 7
and 8, respectively. The discussion on torquoselectivity has been expanded to include
recent developments in depth to give the reader a broader perspective. Hammett
Substituent Constants are relevant to theoretical chemists involved with Quantitative
Structure–Activity relationships. Now, Chap. 10 also includes a description of the
captodative effect, an area that is significant for specific materials research.
The relative aromaticity of pyrrole, furan, and thiophene has been a subject of
intense research for quite some time. Several new approaches have been designed
with the sole aim to prove that thiophene has the most aromatic character because it
undergoes Diels–Alder reactions with comparatively great difficulty. The designed
approaches are not consistent among themselves because the relative aromaticity
index changes with the approach used. It was therefore felt necessary to address this
issue from the viewpoint of non-experts in theory. The author has carried out intensive
computational research and arrived at pyrrole > furan > thiophene aromaticity order
by emphasizing R-factor and allylic interactions in the diene. R is the distance between
the reacting termini of the diene. Chapter 9 deals with this subject in detail. The author
is confident that the reader will find the arguments convincing.
This book aims to facilitate teaching the concepts to undergraduate and graduate
students, and also encourage research in areas such as torquoselectivity and relative
aromaticity index.
I dare not say that the script is completely error-free now. I would gratefully
acknowledge criticism and suggestions from the readers for further improvement.
Kanpur, India Veejendra K. Yadav
vii
Summary of Second Revised Edition
This edition of the book has been modified with the aim of making the reading enjoy-
able by laying emphasis and elaborating on topics relevant to the stereochemistry
of important organic reactions. While modifying, all errors noticed in structures and
text have been corrected.
The contents of the erstwhile Chap. 7 now appear in Chap. 10. Chapter 10 includes
a description of captodative effect, a subject of great significance for specific materials
research. Two topics, namely Torquoselectivity and Hammett Substituent Constants,
have been taken out and dealt with separately in Chaps. 7 and 8, respectively. The
discussion on torquoselectivity has been expanded to include recent developments
in depth to give the reader a broader perspective.
The relative aromaticity of pyrrole, furan and thiophene has been a subject of
intense research for quite some time. Different new approaches have been designed
with the sole aim to prove that thiophene has the most aromatic character because it
undergoes Diels-Alder reactions with comparatively great difficulty. The designed
approaches are not consistent among themselves because the relative aromaticity
index changes with the approach used. It was, therefore, felt necessary to address
this issue from the view-point of non-experts-in-theory.
This book aims to facilitate teaching the concepts to undergraduate and grad-
uate students, and encourage research in areas such as torquoselectivity and rela-
tive aromaticity index. Hammett substituent constants are relevant to the theoretical
chemistry audience involved with Quantitative Structure-Activity Relationships.
Veejendra K. Yadav
ix
Contents
1 Steric and Stereoelectronic Control of Molecular Structures

and Organic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1 Influence of Steric Effects on Structures . . . . . . . . . . . . . . . . . . . . . . . 1
2 Influence of Stereoelectronic Effects on Reactions . . . . . . . . . . . . . . 6
3 Evaluation of the Numerical Value of Anomeric Effect . . . . . . . . . . 30
4 Influence of Anomeric Effect on Conformational Preferences . . . . 31
5 Influence of Anomeric Effect on Conformational Reactivity . . . . . . 38
6 Conformations of Mono and Dithioacetals . . . . . . . . . . . . . . . . . . . . . 43
7 Conformations of Mono and Diazaacetals . . . . . . . . . . . . . . . . . . . . . 45
8 Antiperiplanar Effects Arising from C–Si, C–Ge, C–Sn,
and C–Hg Bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
2 Reactions on Saturated and Unsaturated Carbons . . . . . . . . . . . . . . . . 49
1 Inter- and Intramolecular Reactions on Saturated Carbons . . . . . . . 49
2 Intermolecular Reactions of Epoxides . . . . . . . . . . . . . . . . . . . . . . . . . 50
3 Intramolecular Reactions of Epoxides . . . . . . . . . . . . . . . . . . . . . . . . . 51
4 Baldwin Rules for Ring Closure on Saturated and Unsaturated
Carbons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
5 SN 2 Reaction (Reaction on Unsaturated Carbon) . . . . . . . . . . . . . . . 55
6 SN 2 Reaction of Cyclopropane Activated by Two Geminal
Carbonyl Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
7 Reactions Involving Consecutive Intramolecular SN 2
Reactions Leading to Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . 60
8 Dual Activation for Skeletal Rearrangement . . . . . . . . . . . . . . . . . . . 64
9 Solvolysis with Neighboring Group Participation . . . . . . . . . . . . . . . 65
10 Rearrangement Originating from Oxirane Under Lewis Acid
Condition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
11 Rearrangement via Classical Versus Nonclassical
Carbocations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
12 Tandem Skeletal Changes and Polyene Cyclization . . . . . . . . . . . . . 67
xi
xii Contents
13 Application of 5-Exo-Trig Cyclization Rule . . . . . . . . . . . . . . . . . . . . 70

14 Stereocontrol in Multi-cyclization Reactions . . . . . . . . . . . . . . . . . . . 71
15 Reaction on sp Carbons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
16 Stereoelectronic Control in Beckmann Rearrangement . . . . . . . . . . 73
17 Stereoelectronic Control in Curtius Rearrangement . . . . . . . . . . . . . 74
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
3 Diastereoselectivity in Organic Reactions . . . . . . . . . . . . . . . . . . . . . . . . 77
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
2 Cram’s Model for Asymmetric Synthesis . . . . . . . . . . . . . . . . . . . . . . 78
3 Anh–Felkin Modification of Cram’s Model for Asymmetric
Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
4 Cieplak’s Model for Diastereoselectivity . . . . . . . . . . . . . . . . . . . . . . 82
5 Houk’s Transition State and Electrostatic Models
for Diastereoselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
6 Cation Coordination Model (σ → π* Model)
for Diastereoselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
5-Aza-2-Adamantanone, 18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
N-Methyl-5-Aza-2-Adamantanone, 19 . . . . . . . . . . . . . . . . . . . . . . . . 97
5-Aza-2-Adamantanone N-Oxide, 20 . . . . . . . . . . . . . . . . . . . . . . . . . 97
5-Bora-2-Adamantanone, 21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
2,3-Endo,Endo-Dimethylnorbornan-7-One
and the Corresponding Diethyl Analog . . . . . . . . . . . . . . . . . . . . . . . . 99
4-Oxatricyclo[5.2.1.02,6 ]Decan-10-One, 9,
and 4-Oxatricyclo[5.2.1.02,6 ]Dec-8-En-10-One,
10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Trans-2-Heterobicyclo[4.4.0]Decan-5-Ones . . . . . . . . . . . . . . . . . . . . 103
3-Halocyclohexanones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
4 A(1,2) and A(1,3) Strains . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
2 A(1,2) Strain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
3 Stereocontrol in Reactions on Account of A(1,2) Strain . . . . . . . . . . . 113
4 A(1,3) Strain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
5 Stereocontrol in Reactions on Account of A(1,3) Strain . . . . . . . . . . . 117
6 A(1,3) Strain in Amides and Its Consequences
on Diastereoselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
5 The Conservation of Orbital Symmetry Rules (Woodward–
Hoffmann Rules) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
2 Orbitals and Symmetry Considerations . . . . . . . . . . . . . . . . . . . . . . . . 130
3 π2 + π2 Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
4 Electrocyclic Ring Closure and Ring Opening Reactions . . . . . . . . . 141
Contents xiii
1,3-Butadiene → Cyclobutene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

1,3,5-Hexatriene → 1,3-Cyclohexadiene . . . . . . . . . . . . . . . . . . . . . . 144
5 Diels–Alder Cycloaddition Reaction (π4 + π2 Reaction) . . . . . . . . 147
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
6 The Overlap Component of the Stereoelectronic Effect
vis-à-vis the Conservation of Orbital Symmetry Rules . . . . . . . . . . . . 149
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
2 Steric Effects in the Thermal Fragmentation
of cis-3,6-Dimethyl-3,6-Dihydropyridazine . . . . . . . . . . . . . . . . . . . . 150
3 Orbital Overlap Effects in the Thermal
Fragmentation of Cyclopropanated and Cyclobuanated
cis-3,6-Dimethyl-3,6-Dihydropyridazine . . . . . . . . . . . . . . . . . . . . . . 151
4 Orbital Overlap Effects in [1,5] Sigmatropic Shifts . . . . . . . . . . . . . . 152
5 Difficulties Experienced with [1,5]-Sigmatropic
in the Cyclobutanated Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
7 Torquoselectivity of Conrotatory Ring Opening
in 3-Substituted Cyclobutenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
1 Activation Barrier Approach to Torquoselectivity . . . . . . . . . . . . . . . 159
2 TS-NBO Approach to Torquoselectivity . . . . . . . . . . . . . . . . . . . . . . . 160
3 Restricted Conformational Effects on Torquoselectivity . . . . . . . . . . 171
4 Global Conformational Effects on Torquoselectivity . . . . . . . . . . . . 174
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
8 Hammett Substituent Constants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
1 Hammett Substituent Constants for Benzoic Acids (σm and σp ) . . . 180
2 Hammett Substituent Constants for Phenylacetic
and 3-Arylpropionic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
3 Hammett Substituent Constants and Free Energy Assessment . . . . 184
4 Hammett Substituent Constants and Reaction Pathway
Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
5 Hammett Substituent Constants σ+ and σ− . . . . . . . . . . . . . . . . . . . . . 185
6 Hammett Substituent Constants and Ester Hydrolysis
Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
9 Relative Aromaticity of Pyrrole, Furan, Thiophene
and Selenophene, and Their Diels–Alder Stereoselectivity . . . . . . . . . 191
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
2 Heteroatom Lone Pair Interaction with Ring π Bonds
in the Ground State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
3 DA Reactions of Pyrrole, Furan, Thiophene, and Selenophene
with MA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
4 DA Reactions of Cyclopentadiene, Silole, and Germole
with MA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
xiv Contents

with Acetylene-1,2-Bisnitrile and Acetylene . . . . . . . . . . . . . . . . . . . 197
6 DA Reactions of 1,3-Cyclohexadiene
and 1,3-Cycloheptadiene with MA . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
and 1,3-Cycloheptadiene with Acetylene-1,2-Bisnitrile
and Acetylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
and 1,3-Cyclooctadiene-6-Yne with Acetylene-1,2-Bisnitrile
and Acetylene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
9 Evaluation of Allylic Interaction in DA Reactions of Acyclic
Dienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
10 DA Reactions of 6-Oxa-, 6-Aza-, 6-Thia-,
and 6-Selena-1,3-Cycloheptadienes with MA . . . . . . . . . . . . . . . . . . 203
11 DA Reactions of 2,3-Cyclopropano-, 2,3-Cyclobutano-,
and 2,3-Cyclopentano-6-Oxa-1,3-Cycloheptadienes
with MA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
12 DA Reactions of Benzene, Pyridine, and 1,4-Diazine
with Acetylene-1,2-Bisnitrile and Acetylene . . . . . . . . . . . . . . . . . . . 205
13 DA Reactions of Naphthalene, 1-Azanaphthalene,
and 1,4-Diazanaphthalene with Cyclopropene . . . . . . . . . . . . . . . . . . 206
14 DA Reactions of Anthracene, 9-Azaanthracene,
and 9,10-Diazaanthracene with Cyclopropene . . . . . . . . . . . . . . . . . . 206
15 DA Reactions of Benzene, Naphthalene, and Anthracene
with Acetylene-1,2-Bisnitrile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
16 Deformation Energy Considerations in DA
Reactions of Five-Membered Heterocycles
with Acetylene-1,2-Bisnitrile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
17 DA Reactions of Thiophene 1,1-Dioxide with MA . . . . . . . . . . . . . . 210
18 Reaction Profile and Solvent Effects on Diastereoselectivity
of DA Reactions of Five-Membered Heterocycles with MA . . . . . . 211
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
10 Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
1 Spiroconjugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
2 Periselectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
3 Ambident Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
4 Ambident Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
α,β-Unsaturated Carbonyl Compounds . . . . . . . . . . . . . . . . . . . . . . . . 229
Aromatic Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Unsymmetrical Anhydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Arynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
5 α-Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
6 Carbenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
7 Hammond Postulate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
Contents xv
8 Curtin–Hammett Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

9 Diastereotopic, Homotopic, and Enantiotopic Substituents . . . . . . . 246
10 Captodative Effect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
About the Author
Veejendra K. Yadav earned his Ph.D.

under the mentorship of Dr. Sukh Dev
in 1982. He has carried out his postdoc-
toral research at University of Calgary,
Memorial University of Newfoundland,
University of Ottawa, and University of
Southern California over the years 1983–
1990 before joining Indian Institute of
Technology Kanpur (IITK) as Assistant
Professor in late 1990. Over the years, he
rose through ranks and became full professor
in 2001. He has taught undergraduate- and
postgraduate-level courses at IITK over the
past 30 years, and has remained a popular
teacher among the students throughout. His
research focuses on the development of new
reactions with emphasis on the construction
of pharmacophores, synthesis of biolog-
ically active molecules, computational-
cum-experimental investigation of facial
selectivity, and computational investigation
of reaction mechanisms. He has three inter-
national patents and over 100 research papers
to his credit. More details may be found on
the link http://home.iitk.ac.in/~vijendra or
by visiting: veejendrakyadav.com.
xvii
Chapter 1
Steric and Stereoelectronic Control
of Molecular Structures and Organic
Reactions
Abstract This chapter emphasizes the important aspects of steric and stereoelec-
tronic effects and their control on conformational and reactivity profiles. The confor-
mational effects in ethane, butane, cyclohexane, variously substituted cyclohexanes,
and cis- and trans-decalins allow a good understanding of the discussions that follow.
The application of these effects to E2 and E1cB reactions followed by the anomeric
effect and mutarotation is discussed. The conformational effects in acetal forma-
tion and the reactivity profile, carbonyl oxygen exchange in esters, and hydrolysis
of orthoester have been discussed. The application of the anomeric effect in 1,4-
elimination reactions, including preservation of geometry of the newly created double
bond, has been presented in detail. Brief discussions of the conformational profiles
of thioacetals and azaacetals, and rate acceleration on account of σC–Si , σC–Ge , σC–Sn ,
and σC–Hg bonds have also been explained.
1 Influence of Steric Effects on Structures
Consider the staggered and eclipsed conformers of ethane 1 as shown below. The
staggered conformer is more stable than the eclipsed conformer by 3.0 kcal/mol. The
electron pairs of the eclipsed bonds repel each other to raise the energy of the system
by 1.0 kcal/mol. Three such interactions make up to 3.0 kcal/mol.
H HH Me Me H
H H H H
H H
H H H H H H H H
H H
H H
1, ethane staggered eclipsed 2, propane staggered eclipsed
On replacing one hydrogen with methyl, we arrive at the staggered and eclipsed
conformers of propane 2. Other than the three repulsive electron pair−electron pair
interactions, each contributing 1.0 kcal/mol, there is also methyl-hydrogen steric
interaction (or van der Waals repulsion) that contributes 0.4 kcal/mol in the eclipsed
conformer. Thus, the eclipsed conformer is less stable by (3 × 1.0) + 0.4 =
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 1

V. K. Yadav, Steric and Stereoelectronic Effects in Organic Chemistry,
https://doi.org/10.1007/978-3-030-75622-2_1
2 1 Steric and Stereoelectronic Control of Molecular …
3.4 kcal/mol than staggered conformer. On either side of the methyl group in the
staggered conformer, there is hydrogen on the front carbon with a dihedral (torsion)
angle of 60°. The methyl and hydrogen are said to be gauche to each other with no
repulsive interaction between them. However, a gauche methyl−methyl interaction
contributes 0.9 kcal/mol. The eclipsing methyl−methyl repulsion is 2.5 kcal/mol
(bond pair−bond pair repulsion = 1.0 kcal/mol; van der Waals repulsion between
the two methyl groups = 1.5 kcal/mol). We encounter the last two interactions in the
conformations of butane.
Me Me H Me Me Me Me Me H Me
H H Me H H Me H H
Me H H
H H H H H H H H H H H H H H
H H Me
Me H H Me
3, butane a b c d e f a
kcal mol-1 0.0 3.8 0.9 4.5 0.9 3.8 0.0
Butane 3 can exist in different conformations 3a–f across the central σC–C bond
as shown. Beginning from the staggered conformer 3a that has both methyl groups
at a torsion angle of 180°, we can write other conformers by clockwise 60° rotation
each time about the central σC2–C3 bond, as shown. Note that the conformers 3b and
3f, and 3c and 3e are one and the same. There are no issues related to either the
eclipsing electron pair−electron pair repulsion or van der Waals repulsion in 3a.
Hence, 3a is the most stable conformer and lets us arbitrarily place its energy at
0.0 kcal/mol. Now, we can calculate the energies of other conformers as follows: 3b
and 3f: 3.8 kcal/mol; 3c and 3e: 0.9 kcal/mol; 3d: 4.5 kcal/mol. All these values are,
in fact, so small that butane exists as an equilibrium mixture of all the conformers at
Standard Temperature and Pressure (STP). The equilibrium distribution is a function
of the relative energies; the more stable a conformer, the more is its contribution.
a 1
1 5
5 6 6
3
2 b
4 3
c 4 2
4a 4b 4
Consider the structure 4a for the cyclohexane chair. The axial bonds on any two
adjacent ring positions are parallel and also anti to each other. The three bonds
involved in this relationship are a, b, and c, and they could also be viewed to be in
the same plane geometrically. The ‘anti’, ‘parallel’, and ‘same plane’ put together
is ‘antiperiplanar’. Thus, the axial bonds on two adjacent cyclohexane positions are
antiperiplanar.
The equatorial bonds on any two adjacent ring positions, such as C1 and C2,
are gauche to each other with a torsion angle of 60°, as shown in 4b. With these
substituents as methyl, the situation is exactly the same as in the gauche butane
1 Influence of Steric Effects on Structures 3
conformers 3c and 3e. This will raise the energy by 0.9 kcal/mol. Another important
structural feature stems from the observation that an equatorial bond is antiperiplanar
to two ring bonds. For instance, the equatorial bond on C1 is antiperiplanar to σC2–C3
and σC5–C6 . Likewise, the bond on C2 is antiperiplanar to σC3–C4 and σC1–C6 . A special
note should be taken of the orientations of equatorial bonds on C3 and C6. Other
than being antiperiplanar to each other across a hypothetical σC3–C6 bond, both the
bonds are also antiperiplanar to σC1–C2 and σC4–C5 bonds.
A good knowledge of the structural relationship of the axial and equatorial bonds
on the cyclohexane ring will help us understand the underlying stereoelectronic and
conformational effects on reactivity. Methylcyclohexane can adopt the two chair
conformations 5a and 5b. The conformer 5b is obtained from 5a on ring flip. The
conformer 5a is fully devoid of van der Waals interactions. However, one discovers
two butane gauche interactions in conformer 5b, as shown, each raising the energy
by 0.9 kcal/mol. Thus, 5b is less stable than 5a by 2 × 0.9 = 1.8 kcal/mol. In
other words, mono-substituted cyclohexane should prefer the conformer with the
substituent occupying the equatorial position.
H H
Me
Me
5a 5b
Consider trans-1,2-dimethylcyclohexane 6. In conformer 6a, the two equatorial

methyl groups are gauche to each other to raise the energy by 0.9 kcal/mol. In
conformer 6b, the product of ring flip in 6a, each axial methyl group is engaged
in two butane gauche interactions. This will raise the energy by 2 × (2 × 0.9) =
3.6 kcal/mol. The conformer 6a, therefore, is more stable than 6b by 3.6 − 0.9
= 2.7 kcal/mol. Thus, trans-1,2-disubstituted cyclohexane prefers the conformer in
which both the substituents occupy equatorial positions.
H H
Me
Me H
Me
H CH3
6a 6b
In either of the two conformations 7a and 7b of cis-1,2-dimethylcyclohexane 7,

one methyl is axial and the other equatorial. The two methyl groups are mutually
gauche to each other and the axial methyl is further gauche to two axial hydrogen
atoms, as shown. Both the conformers are one and the same. In the event that one
substituent is different from the other, the molecule will largely adopt the conformer
in which the larger substituent occupies an equatorial position.
H Me H H
H Me
Me Me
7a 7b
Trans-1,3-dimethylcyclohexane can adopt the conformations 8a and 8b. In both,

one methyl is axial and the other equatorial. Both the conformers, therefore, are one
and the same. While the equatorial methyl is not involved in any van der Waals inter-
action, the axial methyl is engaged in two butane gauche interactions, as indicated.
Thus, compared to methylcyclohexane, trans-1,3-dimethylcyclohexane is higher on
the energy scale by 2 × 0.9 = 1.8 kcal/mol.
H Me
H Me
H
Me H
Me
8a 8b
Cis-1,3-dimethylcyclohexane can adopt two conformations. In conformer 9a, both

the methyl groups are axial and, hence, gauche to each other. Each methyl is addi-
tionally gauche to an axial hydrogen, as shown. The total increase in energy of this
conformer will, therefore, be 2.5 + 0.9 + 0.9 = 4.3 kcal/mol. In 9b, both the methyl
substituents are equatorial and there are no issues arising from gauche interactions.
Thus, 9b is more stable than 9a by 4.3 kcal/mol. Also, the more stable conformer 9b
of cis-1,3-dimethylcyclohexane is more stable than trans-1,3-dimethylcyclohexane
8a/8b by 1.8 kcal/mol.
H Me
Me
Me Me
9a 9b
The two conformers of trans-1,4-dimethylcyclohexane are 10a and 10b. In view

of the foregoing discussions, the conformer 10b is more stable than 10a by 2 × (2
× 0.9) = 3.6 kcal/mol. In 10a, each axial methyl is engaged in two butane gauche
interactions, as shown.
H Me
H
Me
Me
H
Me H
10a 10b
1 Influence of Steric Effects on Structures 5
Each conformer of cis-1,4-dimethylcyclohexane, 11a or 11b, has one methyl

axial and the other equatorial. The axial methyl is engaged in two butane gauche
interactions as shown, raising the energy of the system by 2 × 0.9 = 1.8 kcal/mol.
In comparison, the more stable conformer of trans-1,4-dimethylcyclohexane, 10b,
is more stable than cis-1,4-dimethylcyclohexane 11 by 1.8 kcal/mol.
H Me Me H
H H
Me Me
11a 11b
Three different representations of trans-decalin are 12a–c. The bonds in both

red and blue colors are equatorial to the other ring, leaving the hydrogens on ring
junctions axial. We know that the 1,2-diequatorial substituents are gauche to each
other and two such interactions will raise the energy of the system by 1.8 kcal/mol.
These interactions are present in cis-decalin as well, but between axial and equa-
torial substituents (vide infra). For the purpose of relative energy calculations of
trans-decalin and cis-decalin, these gauche interactions are, therefore, ignored. The
ring flip in trans-decalin is not permitted for the reason that it requires two current
equatorial bonds to turn axial and still remain connected by a two-carbon chain
without subjecting the ring to strain, which is geometrically not possible.
H H H
H H H
12a 12b 12c
The three different representations of cis-decalin are 13a–c. Of the two red bonds,
one is axial and the other equatorial to the ring. The same is true of the two blue bonds
in the other ring. Consequently, one of the two hydrogen atoms on the ring junction
is axial and the other equatorial to any one of the two rings. Note the three distinct
gauche interactions present in the representation 13c. These are the interactions across
C1–C9–C10–C5, C1–C9–C8–C7, and C5–C10–C4–C3 for having the C1- and C5-
methylene groups axial to the other ring system. These gauche interactions may be
traced in other representations as well. Unlike trans-decalin, ring flip in cis-decalin
is allowed and it reduces the energy of the system by 0.4 kcal/mol. This lowering of
energy is called entropy gain. Thus, trans-decalin is more stable than cis-decalin by
(3 × 0.9) − 0.4 = 2.3 kcal/mol. The conformational mobility in cis-decalin is only
slightly below that of cyclohexane.
H H
2
3
H
4 1
H
5 10 9
H
6 7 8
H
13a 13b 13c
2 Influence of Stereoelectronic Effects on Reactions
We will first define the stereoelectronic effect by following the progress of the E2
(elimination bimolecular) reaction shown in Eq. 1. The following points are to be
noted:
(a) The axis of electron pair orbital on base B is collinear with σC–H to allow the
abstraction of H as H+ . It is a typical SN 2 reaction, wherein a base attacks H
from one side and the σC–H electron pair is released from the other side.
(b) The resultant carbanion has transient life as it undergoes another SN 2 reaction,
wherein the above electron pair orbital attacks the carbon bearing the leaving
group L, as shown, and an olefin is formed.
(c) It must be noted that the axes of the carbanion electron pair orbital (n) and
the electron-deficient σC–L bond in the transient species are antiperiplanar,
leading to strong n → σ*C–L interaction. An interaction of this sort is termed
an anomeric effect in the study of sugars and stereoelectronic effects elsewhere.
It may also be called the antiperiplanar effect for the antiperiplanar disposition
of the electron pair orbital (or electron-rich bond) and the electron-deficient
bond.
B:
H H H H H
H .. H (1)
E2 reaction
H H L
σC-H σ*C-L H L H H H
H H H H H H H
E1cB reaction H B: H .. H
n σ*C-L H L B-H+ H L rotation H L
H H H H
(2)
:B
H
H H H
(3)
H H
H H H
L
2 Influence of Stereoelectronic Effects on Reactions 7
(d) For the E2 reaction to succeed, σC–H and σC–L bonds must be antiperiplanar
to each other, as shown in Eq. 1. This structural feature allows σC–H → σ*C–L
interaction, which is responsible for the enhanced acidity of the hydrogen to
allow its abstraction as H+ by the base in the rate-determining step. The rate of
E2 reaction is, therefore, dependent on the concentrations of both the substrate
and the base. The E2 reaction using the Newman projection is shown in Eq. 3.
(e) In contrast to the E2 reaction, the rate of the E1cB reaction (elimination
unimolecular through the conjugate base) is dependent only on the concen-
tration of the carbanion formed from deprotonation of the substrate; see Eq. 2.
To begin with, the σC–H bond is not required to be antiperiplanar to the σC–L
bond. The resultant carbanion (conjugate base of the substrate) survives until
its collapse to olefin by ejecting the leaving group through a transition state
(TS) similar to that for the E2 reaction. The attainment of the TS requires
rotation around the σC–C bond.
From the above discussions of E2 and E1cB reactions, it is clear that an electron-
rich bond such as σC–H or an electron pair orbital antiperiplanar to an electron-
deficient bond such as σC–L constitutes an energy-lowering prospect. This is neces-
sarily because of the partial electron donation from the electron-rich bond or electron
pair orbital to the anti-bonding orbital corresponding to the electron-deficient bond
σC–L . It lowers the anti-bonding orbital and raises the corresponding bonding orbital
on the energy scale. Consequently, the bonding orbital is weakened and its cleavage
takes place with enhanced ease. We shall now exploit this information to understand
the reactivity profiles of a select class of molecules to strengthen our knowledge
base.
Note the antiperiplanar relationship of the axial electron pair orbital on the ring
oxygen O7 and σC1–O8 bond in (α)-D-glucopyranose 14. This relationship leads to
n → σ*C1–OH interaction, also called the anomeric effect. The consequence of this
interaction is the facile cleavage of the σC1–OH bond after protonation, leading to the
transformation 15 → 16, as shown in Eq. 4. Likewise, we notice an electron pair
orbital on O8, which is antiperiplanar to the σC1–O7 bond. This relationship results
in yet another anomeric effect, called the exo-anomeric effect in distinction from
the above anomeric effect that originates from the ring oxygen. The consequence of
the exo-anomeric effect is smooth cleavage of the σC1–O7 bond on the protonation
of ring oxygen and the transformation 17 → 18 is achieved, as shown in Eq. 5.
However, this cleavage will be less facile than the cleavage in Eq. 4 for additional
energy requirements for ring-cleavage.
HO 6 HO HO
4 5 7O O -H2O O
HO H+ HO HO
HO H HO H HO H
3 2 1
OH OH OH
8 OH OH2
14 15 16
(4)
6
HO HO HO
4 5 7O O H OH
HO H+ HO HO
HO H HO H HO H
2
3 OH 1 OH OH
8
O H O H O
H
14 17 18
(5)
HO 6 HO H HO
4
HO
5 O7 HO O HO OH
8
HO 2
O H HO O H HO O H
1
3 OH OH OH
H H H
19 20 21
(6)
An electron pair orbital that is not engaged in an anomeric effect is more electron-
rich than the one which is and, hence, vulnerable to faster protonation. This translates
into the understanding that two electron pair orbitals on the same heteroatom are
likely to be different from each other on account of whether or not they are engaged
in an anomeric effects.
We now consider β-(D)-glucose 19. It turns out from the given color coding
that neither of the two electron pair orbitals on ring oxygen is antiperiplanar to the
σC1–O8 bond. The cleavage of the σC1–OH bond after protonation will, therefore, occur
without anomeric assistance. In other words, this cleavage will be slower than the
cleavage 15 → 16 shown in Eq. 4. Alternatively, O8 consists of an electron pair
orbital antiperiplanar to the σC1–O7 bond. Therefore, the σC1–O7 bond can cleave after
protonation of O7 with anomeric assistance and lead to the transformation 20 → 21,
as shown in Eq. 6. The oxonium ion 21 is a rotamer of 18.
The species 18 is in equilibrium with α-(D)-glucose 14 and β-(D)-glucose 19 via
21. Thus, under slightly acidic conditions, α-(D)-glucose and β-(D)-glucose will be
predicted to equilibrate with each other and lead to what we popularly call mutarota-
tion. The specific optical rotation of α-D-glucose is different from that of β-D-glucose.
Thus, commencing from α-(D)-glucose in an aqueous solution, the optical rotation
will change with time and become static at equilibrium. Of course, the equilibrium
will be established fast when one begins with α-(D)-glucose because the changes 14
→ 17 → 18 → 21 lead to relief from the steric strain arising from the axial OH
group on the anomeric carbon C1.
Alternatively, the oxonium ion 16 could be attacked by water from both axial and
equatorial sites to generate, respectively, α-D-glucose and β-D-glucose. Of course,
the axial attack will be favored over the equatorial attack due to the stabilizing nature
of the resultant anomeric effect. In the transformation 16 → 14, water attacks the
oxonium ion on the axial face and the electron pair of the cleaved π bond ends up
axial on the ring oxygen to exert an anomeric effect on the very σC–O bond that is
formed in the process. An attack from the equatorial site will generate 19, where the
formed σC–O bond is not under the anomeric effect of any of the electron pair orbitals
on ring oxygen. Both the formation and cleavage of a bond under anomeric control
are more facile than when the anomeric effect is absent. We shall continue to learn
this aspect through the discussions below.
We know that the acid-catalyzed reaction of an aldehyde with an alcohol under
dehydrating conditions generates an acetal, as shown in Eq. 7. The progress of the
reaction is shown below in Eq. 7. One water molecule is released in the step 26 → 27
for every molecule of the acetal formed. Since the proton used at the beginning of the
reaction is released in the end, the reaction is catalytic in the proton source. It must
also be noted that each step leading to the acetal is reversible, which necessitates
the removal of water from the reaction mixture to drive it to completion. The proton
transfer from one oxygen to the other in the species 25, leading to 26, is very facile for
the geometrical closeness of the two oxygen atoms for being located on a tetrahedral
carbon.
RCHO + MeOH H+ RCH(OMe)2 (7)

22 23
OH H OH2
+ H+ R + MeOH
RCHO OH R O R OMe
..
- H+ H - MeOH Me
H H
24 25 26
OMe H OMe
- H2O R + MeOH - H+
OMe R O R OMe
+ H2 O H - MeOH Me + H+
H H
27 28 29
The true joy is in considering the reverse of acetal formation, i.e., acid hydrol-
ysis of an acetal within the ambit of stereoelectronic effects to explore the reactivity
characteristics. We begin by understanding the conformational profile and the asso-
ciated conformational effects by representing the acetal in such a way that it appears
to be part of the cyclohexane chair. We have already understood the geometrical
relationships of various cyclohexane ring bonds and also the bonds on the ring.
O O O
R O R O R O
H H H
30a 30b 30c
O O O
R O R O R O
H H H
30d 30e 30f
O O O
R O R O R O
H H H
30g 30h 30i
The acetal RCH(OMe)2 can adopt nine conformers 30a–i. Ignore the broken
bonds that are used to allow the reader a quick conformational match with that of
the cyclohexane chair to ascertain the geometrical relationships rather conveniently.
The following points must be noted:
(a) The conformers 30a and 30e have two methyl groups within the van der
Waals distance and, hence, their contributions to the overall equilibrium will be
small, if not zero. We can, therefore, eliminate these conformers from further
discussion.
(b) The conformers 30b and 30d, 30c and 30g, and 30f and 30h are mirror images
and, thus, we consider only one from each pair.
(c) We are left with four distinct conformers, 30b, 30c, 30f and 30i, to take forward
to consider acid hydrolysis. The relative contributions of these conformers may
be estimated from the realization that they are laced with two, one, one, and
zero stereoelectronic effects, respectively. The conformers 30b and 30i are,
respectively, the most and least contributing. The conformers 30c and 30f
contribute at the medium level.
The acid hydrolysis of the conformer 30b is presented in Eqs. 8 and 9. The
following specific points are to be noted:
(a) Of the two oxygen atoms in 30b, each has one electron pair orbital that does not
participate in any stereoelectronic effect. Protonation of such an electron pair
on the front oxygen leads to 31 that can undergo σC–O bond cleavage under the
anomeric effect arising from the other oxygen, as shown, to generate methanol
and the oxonium ion 32.
(b) Likewise, protonation of the rear oxygen followed by cleavage of the σC–O bond,
as in Eq. 9, will generate the oxonium ion 34 and methanol. The oxonium ions
32 and 34 are of E- and Z-configurations, respectively.
O O O
R O R O H
R + CH3OH (8)
H H H
30b 31 32
H
O
O
30b R O R + CH3OH (9)
H
H
33 34
H
O O O
R O R O R + CH3OH (10)
H
H H
30c 35 32
H
O O O
R O R O R + CH3OH (11)
H
H H
30f 36 34
(c) With R that is small in size and, thus, marginally contributing to van der Waals
repulsion with O-methyl in 34, both the cleavage pathways will be expected to
be, more or less, equally facile. However, with a large R, the pathway shown
in Eq. 8 will predominate.
The acid hydrolyses of the conformer 30c and 30f are shown in Eqs. 10 and 11,
respectively. Protonation of the front oxygen in 30c followed by cleavage of the σC–O
bond under stereoelectronic control of the rear oxygen will generate 32. Cleavage
of the rear σC–O bond after protonation will be relatively inefficient because it is not
supported by any stereoelectronic effect arising from the front oxygen. Likewise, 30f
can be argued to generate 34.
Finally, we discuss the cleavage of the conformer 30i that lacks a stereoelectronic
effect. The molecule has mirror plane symmetry and, hence, either σC–O bond can
cleave after protonation. However, this cleavage will take place without stereoelec-
tronic assistance and the species 38 formed, as shown in Eq. 12. The most notable
feature of 38 is the axis of the empty orbital which is antiperiplanar to the σO–C
bond and not to an electron pair orbital on the oxygen. The species 38 is, therefore,
a high-energy species. Conformational change, while keeping methyl as far from R
as possible (anticlockwise rotation) will allow the formation of the stable species 32
as it has an oxygen electron pair orbital antiperiplanar to the empty orbital required
for oxonium ion formation. Since the formation of a high-energy species is involved,
the conformer 30i may be safely predicted to be a neutral conformer or a conformer
that is resistant to hydrolysis.
H
O O R empty p orbital R O
R O R O O + CH3OH O R
H H H
H H
30i 37 38 32 32
(12)
We have learnt so far that protonation of one of the two oxygen atoms followed by
its cleavage in the reacting acetal conformers generates the oxonium ion 32 and/or 34,
depending upon the size of R. We will now consider reactions of these oxonium ions
with water. The reaction of 32 is outlined in Eq. 13. The capture of the empty orbital,
of course under the stereoelectronic effect of an oxygen electron pair, generates 39,
wherein the antiperiplanar relationship of R with methyl is firmly retained. Proton
transfer from one oxygen to the other, by taking advantage of 1,3-diaxial proximity,
will generate 40. Now, cleavage of the σC–O bond under the stereoelectronic effect,
as shown, will generate 41 which is actually the protonated aldehyde. Loss of proton
from 41 to another acetal molecule or even water, which is present in large excess,
will generate RCHO, the product of hydrolysis. Considering a similar pathway, the
reaction of 34 with water is shown in Eq. 14.
H
R R H
OH2 O H O H R O H
HO O R O R O O R
H
H H H H
H H
32 39 39 40 41 41
(13)
H H H
R R R H
OH2 O
H2O O H O
O O R O R O H O R
H H H H
H H
34 42 43 44 45 46
(14)
We have noted above that one of the two electron pair orbitals on the same oxygen
is engaged in stereoelectronic effect and the other is not. The electron density in the
latter orbital is, therefore, less than the former. Consequently, the latter orbital is
more basic and, thus, its protonation will be kinetically favored.
The stereoelectronic effect is a stabilizing effect as it lowers the energy of the
system by 1.4 kcal/mol. This effect originates from the interaction between oxygen
electron pair orbital and the σC–O bond. The following interaction energies must be
noted to begin calculating the relative energies of the conformers 48a, 48b, and 48c,
Eq. 15, to enable us to predict the predominant conformer at the equilibrium.
(a) An axial methylene group on the cyclohexane ring contributes equivalent to
two butane gauche interactions, i.e., 2 × 0.9 = 1.8 kcal/mol. The energy of the
system is raised.
(b) An axial oxygen atom on the cyclohexane ring contributes 2 × 0.4 =

0.8 kcal/mol (1,3-diaxial steric interaction between oxygen and hydrogen =
0.4 kcal/mol) and the energy of the system is raised.
O
HO O O O O
O H+
HO O
47 48a 48b 48c

(15)
E48a: -(2 × 1.4) + (2 × 0.4) + (2 × 0.4) = -1.2 kcal/mol

E48b: -1.4 + (2 × 0.9) + (2 × 0.4) = 1.2 kcal/mol
E48c: (2 × 0.9) + (2 × 0.9) = 3.6 kcal/mol
Now, we can analyze the relative energetics of the above conformers as follows:
(a) The conformer 48a benefits from two stereoelectronic effects that contribute
−(1.4 × 2) = −2.8 kcal/mol. Each ring in this conformer also has an oxygen
atom axial to the other ring and it contributes 2 × (2 × 0.4) = 1.6 kcal/mol. The
net change in the relative energy, therefore, is −2.8 + 1.6 = −1.2 kcal/mol.
(b) The conformer 48b has only one stereoelectronic effect to contribute −
1.4 kcal/mol. One ring has an oxygen atom axial to the other ring and this
will contribute 2 × 0.4 = 0.8 kcal/mol. This conformer also has one methy-
lene group axial to the other ring to contribute 2 × 0.9 = 1.8 kcal/mol. Thus,
the net change in the relative energy is −1.4 + 0.8 + 1.8 = 1.2 kcal/mol.
(c) The number of stereoelectronic effects in conformer 48c is nil. However, each
ring has one methylene group axial to the other ring to collectively contribute
2 × (2 × 0.9) = +3.6 kcal/mol. Thus, the net change in relative energy is
3.6 kcal/mol.
It is clear that the conformer 48a will predominate and 48c contribute insignifi-
cantly to the equilibrium mixture. In other words, 1,9-dihydroxy-5-nonanone 47 will
generate, when subjected to intramolecular acetal formation reaction under acidic
conditions, an equilibrium mixture of three spiroacetals, wherein 48a predominates.
In the discussion of acid hydrolysis of acetals, cleavage of a σC–O bond with the
assistance of a single stereoelectronic effect was considered facile. However, the
leaving species was positively charged, which rendered the σ bond weak. Must the
leaving species be neutral, two stereoelectronic effects are required for cleavage.
We will demonstrate the essentiality of this requirement by considering the reac-
tion hydroxide ion with D-gluconolactone. To a good approximation, the weakness
rendered to a σ C–O bond by a positive charge on the oxygen is equal to the weakness
rendered by one stereoelectronic effect.
The reaction of D-gluconolactone 49 with O18 -labeled hydroxide ion under stereo-
electronic control (axial attack) will furnish 50. The new σC–O*H bond is antiperiplanar
not only to an electron pair orbital on the resultant oxy anion but also to the axial elec-
tron pair orbital on the ring oxygen. This reaction is reversible because σC–O*H can
cleave with the same ease as it was formed in the first place, being antiperiplanar to
two electron pair orbitals. Intramolecular proton transfer 50 → 51 is also reversible.
The σC–OH bond in 51 cannot cleave because it is antiperiplanar to only one elec-
tron pair orbital of oxy ion [O*]− and, thus, 53 that retains the labeled oxygen will
not form. In other words, if the hydrolysis reaction is interrupted (quenched before
completion by an aqueous acid) and the unreacted D-gluconolactone is examined for
the presence of O18 , it will be found absent.
HO HO HO HO
O - O O O-
HO [HO*] HO - HO HO
HO HO O HO O H HO OH
OH
OH O H O O* H O O* O*
H
49 D-gluconolactone 50 51 52
X
HO HO
HO O HO OH
HO HO
O-
OH O* OH
O*
53 54
However, the ring σC–O bond in 51 is under stereoelectronic control of two electron
pair orbitals (solid red) and, hence, it can cleave to generate 52. The transformation 51
→ 52 is also reversible because the intramolecular attack of oxy ion on the carbonyl
group to result in 52 → 51 conversion is just about as efficient as the conversion 51
→ 52 for exactly the same reasons. Intramolecular proton transfer from carboxylic
acid to the oxy ion in 52 will generate 54. The reversal 54 → 52 is difficult because
the carboxylate ion is resonance-stabilized and, hence, its electrophilic character is
considerably compromised.
D-Gluconolactone is an example of E-ester wherein the carbonyl oxygen and the
substituent on ethereal oxygen are anti to each other across the intervening σC–O
bond. In the hydrolysis of D-gluconolactone, we did not consider the ring flip from
one chair to the other because all the equatorial bonds will turn axial to cause large
steric interactions. To allow for such a conformational flip for the consideration of
carbonyl oxygen exchange during E-ester hydrolysis, we discuss below the simplest
instance of δ-lactone 55.
60 O*
X
O [HO*] O O O OH
O- O H OH O
O
O* H *O O* O*
55 56 58 59
57
H H
O O O
O*
O O O O O OH O*
X * *
62 61 63 64
An argument similar to the one for the hydrolysis of D-gluconolactone leads us to

59 as the final product, wherein the label O18 is incorporated. The transformation 57
→ 60 is not allowed for the lack of the requisite number of stereoelectronic effects.
Assuming that the ring flip 57 → 61 competes with the cleavage 57 → 58 and, thus,
61 is indeed formed, we consider its fate as follows:
(a) The σC–OH bond in 61 is antiperiplanar to two electron pair orbitals, one on
each of the other two oxygen atoms. It renders the cleavage of theσC–OH bond
facile, and the O18 -containing δ-lactone 62 is formed.
(b) A close inspection of 61 reveals an alternate possibility. Like the σC–OH bond,
the ring σC–O bond is also antiperiplanar to two electron pair orbitals. The ring
σC–O bond could, therefore, also cleave with as much ease as the σC–OH bond.
(c) There is a characteristic difference between the two processes above. The
cleavage of the ring σC–O bond leads to the formation of 63, wherein the
carboxylic acid function is in the Z-configuration and a Z-carboxylic acid (or
ester) benefits from two stereoelectronic effects unlike an E-ester such as 62
that benefits from only one such effect (vide infra). This allows the TS energy
for the change 61 → 63 to be smaller than 61 → 62. The pathway 61 → 63
→ 64 predominates. The label is incorporated in the carboxylic acid product
64, and the δ-lactone 62 with the O18 label is not formed.
(d) Overall, even if the ring flip 57 → 61 competes with the cleavage 57 → 58,
carbonyl oxygen exchange is not likely to occur. The E-esters indeed do not
undergo carbonyl oxygen exchange during base hydrolysis.
Acyclic esters such as 65 necessarily exist in Z-configuration and undergo
carbonyl oxygen exchange. The σC–OH bond in the tetrahedral conformer 67, obtained
on proton exchange in 66, is antiperiplanar to two electron pair orbitals, one on each
of the other two oxygen atoms, to allow its facile cleavage and O18 -incorporated
Z-ester 68 is formed, as shown in Eq. 16. Of course, cleavage of the σC–OMe bond
under the assistance of two stereoelectronic effects can also take place and lead to
O18 -containing carboxylic acid.
R O O
HO* O H
O R O R O R
O* (16)
O
*OH *O
65 66 67 68
Having understood the consequences of stereoelectronic effects and also the

requirement of minimum two such effects for the cleavage of a neutral σC–O bond,
we shall now attempt to understand the fate of an acetal on reaction with ozone and
discover yet another important feature. The two electron pair orbitals antiperiplanar
to σC–H could arguably polarize it to allow the carbon acquire partial positive charge
(δ+ ) and the hydrogen partial negative charge (δ− ). In the presence of a hydride
ion acceptor, the departure of the hydrogen as hydride, leading to the formation of
a stabilized carbocation shown in Eq. 17, is conceivable. Since a carbon-centered
radical is stabilized by a heteroatom on it, the radical character of the above σC–H
bond, as shown in Eq. 18, is also conceivable.
OR OR OR
R' OR R' OR R' OR + H
(17)
H
.
OR OR OR
. (18)
R' OR R' . OR R' OR + H
H
Ozone may be considered as either 1,3-dipolar or 1,3-diradical species. The

dipolar form of ozone will exploit the polar character of the σC–H bond and, likewise,
the diradical form of ozone will exploit the radical character of the σC–H bond. These
notions and their consequences are summarized in Eqs. 19–21.
O R O R
R' O + O O O R' O + O O OH (19)
R R
H
69 70
O R O R O R O R
R' O + O O O R' O H R' O H R'
R R - O2 R - ROH
..
..
O O O O- O
71a 71b 72
(20)
O R O R
R' O R' O (21)
..
+ O O O + O O OH
R R
H
73
OR OR
R' OR + O3 R' OR (Z)-R'CO2R + ROH + O2
H OOOH singlet
(22)
The dipolar ozone reacts by the abstraction of the acetal hydrogen as hydride ion
to generate hydrotrioxide ion and the carbocation 70, as shown in Eq. 19. A combi-
nation of these two species under the stereoelectronic control of both the oxygen
atoms of the acetal will generate the hydrotrioxide 71a, as shown in Eq. 20. Direct
insertion of dipolar ozone into the σC–H bond can also take place to generate the above
hydrotrioxide. Likewise, hydrogen atom abstraction by diradical ozone will generate
hydrotrioxy radical and the radical species 73, as shown in Eq. 21. A combination of
the two will form the hydrotrioxide 71a. Fragmentation of 71a in the manner shown
leads to the formation of the oxyanion 71b and dioxygen. Further cleavage in 71b
under stereoelectronic control forms the Z-ester 72. The net reaction is shown in
Eq. 22. The oxygen gas evolved has been found to be in a singlet excited state and
the hydrotrioxide formation has been confirmed by its detection at low temperatures
[1].
From the above discussions, it is easy to identify those acetals that will react with
ozone and also those that will either not react or react, but with difficulty. Note the
three different conformers of 74. The conformers 74a and 74b meet the requirement
for reaction with ozone for having two electron pair orbitals antiperiplanar to the σC–H
bond. The conformer 74c does not meet this requirement, as it has only one such
electron pair orbital. To test whether 74c indeed does not react or reacts with ozone
but slowly in comparison to the conformers 74a and 74b, we freeze the conformer
74c as in 75. The species 75 was indeed discovered to be inert to ozone. Likewise,
the reactive conformer 74b could be frozen as in 76 and 77. The stereo-functional
similarity between 75 and 78 must be noted; the σC–H bond in both is antiperiplanar
to one oxygen electron pair orbital and a σC–O bond. One may wish to reason that
the conformationally rigid α-glycosides will be expected to be inert to ozone.
O O O
O O O
H H H
74a 74b 74c
H
O O O
O O O O O
H H H H
75 76 77 78
Orthoesters such as 79 are protected forms of esters. The hydrolysis of orthoesters

to carboxylic acid esters is easily achieved on exposure to an aqueous acid as shown
in Eq. 23. The stepwise progress of hydrolysis, given in Eq. 24, is illustrative of the
possible stereoelectronic control elements.
(a) Protonation followed by bond cleavage under stereoelectronic control will
generate 81. The cleavage which takes place under two stereoelectronic effects
is arguably faster than the cleavage under only one such effect.
(b) The combination of 81 and water will generate 82. Undoubtedly, if the stere-
oelectronic effects are to control this addition, water must occupy the same
place that was vacated in the previous step.
(c) Intramolecular proton transfer from one oxygen to the other leads to 83. The
obvious fate of 83 is its cleavage under stereoelectronic control to generate the
ester 84 and alcohol.
(d) The initially engaged H+ is also released in the transformation 83 → 84 to
allow it to re-enter hydrolysis all over again. The catalytic nature of H+ is thus
established.
R'C(OR)3 + H2 O + H + R'CO2R + 2ROH + H+ (23)
OR OR R OR OR H
H+ - ROH H2O
R' OR R' O R' R' O
H H
OR OR OR OR
79 80 81 82
R H
R' O
ROH + O R' O
-H+
RO
OR H
84 83
(24)
The importance of the stereoelectronic effect in orthoester hydrolysis could be

gleaned from the reaction of 85. Should the stereoelectronic effects not be invoked,
the reaction could generate all three products 89–91. When R1 and R2 are the same,
there will be only two products, 89 and 90. We shall learn below from the considera-
tion of the prevailing stereoelectronic effects that only an 89-like product is expected
to predominate.
OR1
O
OR2
85
OH2 OR1 OR1

O HO H2O O
OR2 OR2 OH2
86 87 88
HO O OR2 O O HO O OR1
89 90 91
We will examine each step of orthoester hydrolysis under the operating stereo-
electronic effects that vary with the variation in the conformational profile. Consider
the orthoester 92 and the nine well-defined conformers 92a−i. The following specific
observations are made:
(a) The conformers 92c and 92e suffer from severe steric interactions between the
methyl groups as shown and, hence, their concentration at equilibrium will be
small or negligible.
(b) The conformers 92g−i also suffer from severe steric interactions between the
methyl of the axial methoxy group and axial hydrogen atoms on ring positions
4 and 6 as shown in 92g. The equilibrium concentration of each of these
conformers will also be expected to be small or negligible like those of 92c
and 92e.
(c) We, therefore, eliminate the conformers 92c, 92e, and 92g−92i and retain 92a,
92b, 92d, and 92f for further discussion.
CH3 CH3 CH3

O O O
CH3
CH3
O O O O O O
CH3
92a 92b 92c
CH3 CH3 CH3

O O O
CH3
CH3
O O O O O O
CH3
92d 92f
92e
H O H O H O
H1 H H CH3
6 2 CH3
O O O O O O
4 3
5 CH3
92g 92h 92i
The loss of an alkoxy group, after protonation, is the starting point of hydrolysis.
An orthoester can provide for this loss with assistance from one or two stereo-
electronic effects, the latter being more effective than the former. Consideration of
cleavage of the conformers 92a, 92b, 92d, and 92f leads to the following observations:
(a) The conformer 92d does not allow any σC–O bond to cleave with assistance from
two stereoelectronic effects. This conformer may, therefore, be treated as the
slow-reacting or even neutral conformer. This prediction has been experimen-
tally verified by studying the hydrolysis of 93, a rigid 92d conformer, which
was found to be stable to the normally employed mildly acidic condition for
orthoester hydrolysis [2–5].
(b) The conformer 92a is set to undergo cleavage of only the ring σC–O bond to
form 94, a species that still has one stereoelectronic effect as shown and will
be treated as an E,Z-dialkoxycarbonium ion.
(c) The conformers 92b and 92f will collapse to 95a and 95b, respectively, on the
loss of the axial methoxy group. These species can be regarded as E,E- and
E,Z-lactonium ions, respectively.
(d) The species 95b has one stereoelectronic effect still in it, whereas 95a has
none. Obviously, on account of the retained stereoelectronic effects, the trans-
formations 92a → 94 and 92f → 95b will be favored over the transformation
92b → 95a.
(e) There is no entropic gain in the transformation 92a → 94, as a single molecule
is formed from a single molecule and the ring is also cleaved. In contrast, in each
of the other two transformations 92b → 95a and 92f → 95b, two molecules
are formed from one. Consequently, there are entropic gains and, moreover,
the ring is not cleaved. Thus, the transformations 92b → 95a and 92f → 95b
are predicted to be energetically more favorable than the transformation 92a

→ 94, where the internal return 94 → 92a may be significant.
(f) Out of 92b → 95a and 92f → 95b, the latter transformation ought to more
efficient than the former for retaining one stereoelectronic effect.
(g) Overall, the orthoester 92 must undergo hydrolysis predominantly via the
conformer 92f.
CH3 CH3
CH3
O O O
CH3
O O O O CH3 O O
CH3
O 92a 92b 92f
O O
93 O CH3 CH3
O C O CH3 O C O
OH O
CH3
94 95a 95b
(h) Stereoelectronically controlled hydration of the E,Z-lactonium ion 95b will

generate the hemi-orthoester 96a, wherein the new σC–O bond is antiperiplanar
to the other two oxygen electron pair orbitals.
(i) In instances where the tetrahydropyran ring cannot easily undergo chair inver-
sion, 96a will exist in equilibrium with 96b and 96c. However, in instances
where the tetrahydropyran ring can easily flip, the conformers 97a, 97b, and
97c will also be present at equilibrium.
(j) The relative concentration of 97c will be negligible because of the strong steric
interactions between the methyl of the methoxy group and the axial hydrogens
on ring positions 4 and 6, as shown.
(k) The conformers 96a, 96b, and 96c resemble the conformers 92f, 92b, and 92a,
respectively. The exact orientation of σO–H is to be neglected because proton
exchange is fast and, as such, the O-H bond is considered equivalent to an
electron pair orbital.
H H
H
O O O
CH3
O CH3 O
95b O O O O
CH3
96a 96b 96c
5 1
O O 6 O
O O H 4 3
O H
2
H
O CHH O H
Me
O
3
CH3
97a 97b 97c
We will now consider the cleavage of each of the above hemi-orthoester

conformers under stereoelectronic control just as we dealt previously with the
cleavage of the important orthoester conformers. The following observations emerge:
(a) The conformer 96a will cleave to the hydroxy Z-ester 98 as shown in Eq. 25.
(b) The conformer 96b will not cleave and constitute the neutral conformer.
(c) The conformer 96c will cleave to the hydroxy E-ester 99, as shown in Eq. 26.
(d) Neither 96a nor 96c can cleave to lactone because no ring oxygen electron pair
orbital is in a stereoelectronic effect with the equatorial σC–OMe bond.
Overall, in instances where the tetrahydropyran ring cannot undergo chair inver-
sion, lactone will not be formed. Additionally, since the Z-ester is more stable than
E-ester, hydrolysis will take place preferentially via the hemi-orthoester conformer
96a and the hydroxy Z-ester 98 formed.
H
O O Me O
Me Me
O O OH O OH O (25)
96a 98 98
H
O O O
O O OH O OH O (26)
Me Me Me
96c 99 99
O OH OH O
O O O +
O (27)
H O O
O Me Me
97a 98 90
O O
O H (28)
O
O
97b 90
Me
The conformer 97a can cleave to both the hydroxy Z-ester 98 and lactone 90 as
shown in Eq. 27. The conformer 97b can cleave only to the lactone 90, Eq. 28. The
cleavage 97a → 98 will be favored over 97a → 90 because 98 enjoys one additional
stereoelectronic effect. Thus, even in instances where the tetrahydropyran ring can
easily flip, lactone will not be formed and the preferred product of hydrolysis will be
the hydroxy Z-ester 98. The overall hydrolysis pathway for conformationally labile
cyclic orthoesters, therefore, is 92f → 95b → 96a/97a → 98. However, keeping in
view that the formation of a hydroxy ester through ring opening is opposed by its
reversibility and assuming that the reversibility factor is as important as one stereo-
electronic effect, the lactone formation may compete to a varying extent depending
upon the orthoester in question and also the hydrolytic conditions.
Mild acid hydrolysis of the conformationally labile orthoesters 100 and 101 are
reported to yield 70:30 mixtures of the corresponding hydroxy Z-ester and lactone [6,
7]. The conformationally rigid orthoesters 102−104 furnish only the corresponding
hydroxy Z-esters. The orthoesters 102 and 103 are conformationally rigid because
chair inversion causes severe 1,3-diaxial interactions between the axial alkoxy group
with the axial methyl group in 102 and the isopropyl group in 103. The molecule 104
is conformationally rigid because it conforms to the trans-decalin system. The results
from the conformationally labile 100 and 101, and conformationally rigid 102−104
confirm the conclusions drawn above, i.e., mild acid hydrolyses of conformationally
rigid cyclic orthoesters generate hydroxy Z-esters exclusively. However, conforma-
tionally labile cyclic orthoesters may give both hydroxy Z-esters and lactones with
the former predominating.
OR OR OR
O OR O OR O OR
100 101 102
OR OR
H
O O OR
OR
H
103 104
In evidence for preferred cleavage of the axial alkoxy group, the results of hydrol-
yses of rigid conformers 105–108 are illustrative; see Eq. 29. The hydrolysis in
each instance generates the same hydroxy methyl ester 109. However, hydrolysis
of 108 generates the hydroxy ethyl ester 110. That the hydrolysis does not proceed
via the pathway 92a → 94 is conclusively demonstrated by the observation that
such a pathway for the orthoester 106a (an equivalent of the conformer 92a) will
furnish both the ethyl and methyl esters as shown in Eq. 30. Cleavage of ring oxygen,
after due protonation (not shown), under stereoelectronic control will generate 111.
Hydration of 111 under the same two stereoelectronic effects that allowed smooth
cleavage of the ring σC–O bond will lead to 112a, which will be expected to exist
in equilibrium with the conformer 112b. Further cleavage of 112a and 112b will
generate the ethyl ester 110 and methyl ester 109, respectively. Only the methyl ester
109 is obtained from experiments.
OR1 O
H H
O OR2 OH OR2 (29)
+ R1OH
H H
105, R1 = CD3, R2 = CH3 109, R2 = CH3

106, R1 = C2H5, R2 = CH3 110, R2 = C2H5
107, R1 = ClCH2CH2, R2 = CH3
108, R1 = CH3, R2 = C2H5
O O O O
HO HO HO
O O O HO O HO O
106a 111 112a 112b
O
HO HO
O O O
110 109
(30)
The bicyclic cis-ester 113 can exist as an equilibrium mixture of 113a and 113b.
The conformer 113b is non-reacting as it corresponds to 92d. The conformer 113a
can undergo cleavage of only one of the two ring σC–O bonds which, following
hydration, will form the hemi-orthoester 114. Further cleavage of 114 will lead to
dihydroxy Z-ester 115. It is to be noted that chair inversion in 114 is not allowed
because it will place the large hydroxyalkyl substituent axial and, thus, lead to severe
steric interactions.
H
O O
R
O O
O O O O R
OR
113 113a 113b
(31)
OH OH
OH O
R
O R
O
O OH
114 115
The trans-ester 116 will exist predominantly as the conformer 116a to allow
cleavage-cum-hydration to form 117, which can cleave only to the lactone 118.
However, the transformation 117 → 118 will take place with the assistance of only
one stereoelectronic effect arising from the external oxygen. The energy barrier for
the transformation 117 → 118 is, therefore, higher than that of the transformation
114 → 115.
H
O O O O
O HO
O O O O O
OR H
R
116 116a 117 118
(32)
The reaction of ozone with tetrahydropyranyl ethers is similar to the reaction

of ozone with acetals. Since the hydrotrioxide cleaves to an oxy anion, the control
elements that influence the chemistry of hemi-orthoesters will also control the chem-
istry of such hydrotrioxides. The relative orientation of the hydrotrioxide group is,
therefore, not important. However, the steric interactions guide us in arriving at the
predominant conformers 120a–c.
H H H CH3
CH3
O O O O O O
CH3
119a 119b 119c
x O3 O3 O3
O2H
O2H O2H
O O O CH3
CH3
O O O O O O
CH3
120a 120b 120c
5 1
6 O O O
4
O O O
3 2
H O2H
O2H O2H
H O O O
Me CH3
CH3
121a 121b 121c
The conformer 119a is non-reacting. The conformers 119b and 119c will react
with ozone to generate, respectively, 120b and 120c that will be in equilibrium with
each other and also 120a. These are the three important hydrotrioxide conformers
that we need to consider, must the chair flip be not allowed. The conformer 120a
will form, via the oxy anion 122a, the E-ester 123 on the cleavage of the ring σC–O
bond. The conformer 120b may break down to the oxy anion 122b, but 122b itself
cannot cleave any further due to the lack of the required number of stereoelectronic
effects on any of the two neutral σC–O bonds. The conformer 120c will cleave to the
Z-ester 124. Thus, for species that do not allow chair flip, the conformer 120c is the
most reacting conformer and the product formed from this conformer is a Z-ester.
We must remember that Z-ester is more stable than the corresponding E-ester on
account of one additional stereoelectronic effect present in the former.
O2 H
O2H
O O2H O O CH3
CH3
O O O O O O
CH3
120a 120b 120c
O O O CH3
CH3
O O O O O O
CH3
122a 122b 122c
O O CH3
OH O OH O
CH3
123 124
Must the chair flip be allowed, the other three conformers to consider would
be 121a−c. The conformer 121a suffers from severe steric interactions, as shown,
resulting in low concentration at the equilibrium. The conformer 121b can cleave
only to the δ-lactone 127, cyclic form of an E-ester, via the oxy anion 125b. Finally,
the conformer 121c can cleave to both the hydroxy Z-ester 126 and the δ-lactone
127, via the oxy anion 125c. Since the formation of an E-ester/δ-lactone is more
energy-requiring than the formation of a Z-ester, cleavage of 121c, via 125c, to the
hydroxy Z-ester 126 is expected to predominate.
O O O
O O O
H O2H
O2H O2H
H O O O
Me CH3
CH3
121a 121b 121c
O O O OH
O- O- O
O
127 O O CH3 O CH3
CH3
125b 125c 126
O O
O-
O
O CH3 127
125c
Also, must a hydrogen bond between the hydrotrioxide and leaving group be
preferred over steric interactions of the kind present in 92c and 92e, the reacting
conformer corresponding to 120c will be 128. Likewise, the hydrogen-bonded
conformer corresponding to 121c will be either or both of 129 and 130. Having
considered that the axial electron pair orbital on the ring oxygen is engaged in an
anomeric effect with the external σC–OMe bond, the equatorial electron pair orbital
on ring oxygen is more electron-rich and, hence, a 129-like arrangement will be
more suited than a 130-like arrangement. Additionally, a 129-like arrangement is
like trans-decalin and, hence, more favorable than a 130-like arrangement that is like
cis-decalin.
H O
O O O O O
O H O
H CH3 O O O
O O O CH
3 O CH
3
128 129 130
The reaction of ozone with simple tetrahydropyranyl ethers and conformationally

rigid β-glycosides was indeed discovered to furnish the corresponding hydroxy Z-
esters exclusively under kinetically controlled conditions; lactone formation was not
observed [8–10]. For instance, β-D-glucopyranoside 131 reacted under acetylating
conditions to form 132 exclusively, Eq. 33. The reactions of tetrahydrofuranyl ethers
133, Eq. 34, and 135, Eq. 36, were similar to that of 131; only the esters 134 and 136
were obtained, respectively.
AcO AcO
AcO O OAc
AcO OMe AcO
AcO CO2Me (33)
OAc OAc
H
131 132
O OMe OAc CO2Me

(34)
H
133 134
H
AcO OMe AcO CO2Me
AcOH2C O AcOH2C OAc (35)
OAc OAc
135 136
Hemiorthothiol esters, formed from the combination of hydrosulfide ion [HS− ]

and dialkoxycarbocations, also cleave under stereoelectronic control. The cyclic
dialkoxycarbocations 137, Eq. 36, 140, Eq. 37, and the acyclic dialkoxycarboca-
tion 143, Eq. 38, were reacted with sodium hydrosulfide to form 139, 142, and 145,
respectively [11–13].
CH2OH
O O O O O
S (36)
Ph Ph SH Ph
137 138 139
OH
O O O O O S
(37)
Ph Ph SH
Ph
140 141 142
OMe OMe OMe

Ph Ph OMe Ph
OMe (38)
SH S
143 144 145
Likewise, the reactions given in Eqs. 39–41 could be analyzed and the formation
of 148 and 149 from 146 and 152 from 150 understood [14]. The mixed hemi-
orthoesters 147 and 151 are formed from the axial attack of hydrosulfide ion on the
cationic species 146 and 150, respectively.
H H H
O O O
O OH
(39)
O S
H H H S H
146 147 148
H H H
O O OH
O O (40)
O S
H H H S H
146 147 149
H H H
O O OH
O OR (41)
R
OR S
H H S H
H
150 151 152
3 Evaluation of the Numerical Value of Anomeric Effect
We will now quantify the anomeric effect and ascertain that it indeed is −1.4 kcal/mol,
a number that we have previously used in some calculations. However, before we
proceed to achieve this, let us understand how we can calculate the energy difference
of any two conformers, given their equilibrium distribution under a set of experi-
mental parameters. From the law of thermodynamics, G = −RT lnK, where G is
Gibbs’ free energy difference in kcal/mol of the two conformers, R the gas constant
at 1.98 cal/K/mol, and T the reaction temperature in Kelvin at which the ratio of the
conformers at equilibrium is K.
Descotes and coworkers [15] studied the acid-catalyzed isomerization of the cis-
and trans-bicyclic acetals 153 and 154 at 80 °C and discovered the mixture to contain
57% of cis-153 and 43% of trans-154 at the equilibrium. This gives a value of 57/43
= 1.3256 to K. On substituting this value and also the values of R and T in the above
equation, a value of −0.17 kcal/mol for G was obtained. In other words, cis-153
is more stable than trans-154 at 80 °C by 0.17 kcal/mol.
Cis-153 has one stereoelectronic effect, as shown, and trans-154 none. Putting
together the stereoelectronic effect (say, x kcal/mol), steric interactions and confor-
mational effects, the energy of cis-153 will be x + 0.85 kcal/mol (one CH2 group
axial to the other ring) + 0.80 kcal/mol (one OR group axial to the other ring) −
0.42 kcal/mol (the stabilizing entropy factor associated with cis-decalin) as against
0.0 kcal/mol for trans-154 on a relative scale. Since cis-153 is more stable than trans-
154 by 0.17 kcal/mol, the mathematical correspondence x + 0.85 + 0.80 − 0.42 =
−0.17 holds and we obtain a value of x as −1.40 kcal/mol.
O
O O
153 154
Deslongchamps and coworkers [16] rigidified 153 and 154 as in structures 155
and 156 and found the equilibrium distribution (MeOH, p-TsOH, reflux) to be 45%
and 55%, respectively. The following observations are made:
(a) The distribution corresponds to an energy difference of 0.14 kcal/mol, i.e., 155
is less stable than 156 by 0.14 kcal/mol.
(b) Species 156 is free from stereoelectronic and steric effects and, thus, its energy
could be equated to 0.0 kcal/mol on a relative scale.
(c) The energy of 155 adds up to x kcal/mol (one stereoelectronic effect) +
0.85 kcal/mol (one CH2 group axial to the other ring) + 0.8 kcal/mol (one
OR group axial to the other ring).
3 Evaluation of the Numerical Value of Anomeric Effect 31
(d) On putting together the energies of 155 and 156, we arrive at the relationship
x + 0.85 + 0.8 = 0.14, which lends x a value of −1.51 kcal/mol. This value is
close to the value obtained previously by Descotes.
O
O O
155 156
From here onward, we shall take the stereoelectronic effect and the n-butane
gauche interaction to contribute −1.4 kcal/mol and 0.9 kcal/mol, respectively, and
use them to analyze conformational effects in molecules of other structural types.
4 Influence of Anomeric Effect on Conformational

Preferences
The spiroacetal 157 can exist as an equilibrium mixture of three conformers

157a−c. We will now calculate the relative energies of these conformers and see
how the numbers could reliably predict conformer distribution in compliance with
experiments.
(a) The conformers 157a, 157b, and 157c possess two, one, and zero stereoelec-
tronic effects, respectively, as shown.
(b) In conformer 157a, each ring has one OR axial to the other ring. This will raise
the energy of the conformer by 2 × (2 × 0.4) kcal/mol.
(c) In conformer 157b, there are two butane gauche interactions by virtue of having
an axial CH2 group, which will contribute 2 × 0.9 kcal/mol. The conformer
157b also has one OR group axial to the other ring and this will contribute 2
× 0.4 kcal/mol.
(d) In conformer 157c, each ring has one CH2 group axial to the other ring to
contribute 2 × (2 × 0.9) kcal/mol.
O
O O O O O O
157 157a 157b 157c
E157a = 2 (-1.4) kcal/mol + (2 × 0.4) kcal/mol + (2 × 0.4) kcal/mol = -1.2 kcal/mol

E157b = 1 (-1.4) kcal/mol + (2 × 0.9) kcal/mol + (2 × 0.4) kcal/mol = 1.2 kcal/mol
E157c = (2 × 0.9) kcal/mol + (2 × 0.9) kcal/mol = 3.6 kcal/mol
The relative energies of the conformers are given below the structures. The
conformer 157a is more stable than conformers 157b and 157c by 2.4 kcal/mol
and 4.8 kcal/mol, respectively. This conformational analysis allows us to predict that
the spiroacetal 157 must exist essentially as the conformer 157a. This result has
been verified by 13 C NMR study and also X-ray analysis by Deslongchamps and
coworkers [17, 18].
Deslongchamps and coworkers [17, 18] have also studied the methyl-substituted
spirosystem 158, formed from decan-1,9-diol-5-one, for which two isomers 158a and
158b are possible. While the methyl substituent is trans to σC–O bond of the other
ring at the spirojunction in 158a, it is cis in 158b. The isomer 158a can exist either
as conformer 158a1 or 158a2 or as an equilibrium mixture of both. The conformer
158a2 is obtained on flipping ring A in 158a1 . Likewise, the two different conformers
for the isomer 158b are 158b1 and 158b2 . The magnitude of steric interaction of a
methyl group 1,3-diaxial to another methyl (or methylene) group has been estimated
to be 4.0 kcal/mol. Likewise, the steric interaction of a methyl group 1,3-diaxial to
oxygen has been estimated to be 3.0 kcal/mol. Now, we can put together the operating
stereoelectronic and steric effects for each conformer and calculate the net relative
energies.
O O O O O O
158 158a 158b
O
B O B H B O
A A O A
O O O
H O
H H
158a1 158a2 158b1 158b2
158a1
4 Influence of Anomeric Effect on Conformational Preferences 33
(a) Two anomeric effects to contribute 2 × (−1.4) kcal/mol.

(b) Ring A’s OR in 1,3-diaxial interactions with two hydrogen atoms of ring B to
contribute (2 × 0.4) kcal/mol.
(c) Ring B’s OR in 1,3-diaxial interactions with two hydrogen atoms of ring A to
All the above interactions add up to −1.2 kcal/mol.
158a2
(a) One anomeric effect to contribute −1.4 kcal/mol.
(c) Ring B’s one CH2 group axial to ring A and in 1,3 diaxial interactions with a
hydrogen atom to contribute 0.9 kcal/mol and with a methyl group to contribute
4.0 kcal/mol.
(d) Ring A’s methyl in 1,3-diaxial interaction with a hydrogen in ring A itself to
contribute 0.9 kcal/mol.
All the above interactions add up to 5.2 kcal/mol.
158b1
(a) One anomeric effect to contribute −1.4 kcal/mol.
(b) Vertical ring’s OR in 1,3-diaxial interactions with two hydrogen atoms of the
horizontal ring to contribute (2 × 0.4) kcal/mol.
(c) Ring B’s one CH2 group is axial to the vertical ring and it is in 1,3-diaxial
interactions with two hydrogen atoms of ring A to contribute (2 × 0.9) kcal/mol.
158b2
(a) Two anomeric effects to contribute 2 × (−1.4) kcal/mol.
(c) Ring B’s OR in 1,3-diaxial interaction with a hydrogen atom of ring A to
contribute 0.4 kcal/mol and with a methyl group to contribute 3.0 kcal/mol.
(d) Ring A’s methyl in 1,3-diaxial interaction with a hydrogen in ring A itself to
contribute 0.9 kcal/mol.
Thus, 158a1 is more stable than 158a2 by 4.0 kcal/mol. With such a large energy
difference, the isomer 158a must exclusively exist as conformer 158a1 . Since the
conformers 158b1 and 158b2 differ from each other by 1.1 kcal/mol, the isomer 158b
will be expected to exist largely as 158b1 at the equilibrium. However, since the
isomers 158a and 158b are interconvertible through acid-catalyzed acetal-opening
to decan-1,9-diol-5-one and re-ring closure, and also since 158a1 is the most stable
of all the conformers, only 158a will be predicted to form under thermodynami-
cally controlled conditions, and it must exist exclusively as conformer 158a1 . This
prediction has been verified experimentally.
Cyclization of 159 can, in principle, give rise to a mixture of two conformation-
ally rigid isomeric acetals 160a and 160b. These isomers benefit from two and one
anomeric effects, respectively, as shown. In the isomer 160a, each acetal ring has an
axial OR, contributing 2 × 0.4 kcal/mol. In isomer 160b, while one ring has an axial
CH2 to contribute 2 × 0.9 kcal/mol, the other ring has an axial OR to contribute 2
× 0.4 kcal/mol. By taking the stereoelectronic and steric effects together for each
isomer, their relative net energies are given below.
OH O O O
HO +
O
O
159 160a 160b
E160a: 2 × (−1.4) + (2 × 0.4) + (2 × 0.4) = −1.2 kcal/mol

E160b: 1 × (−1.4) + (2 × 0.9) + (2 × 0.4) = +1.2 kcal/mol
The isomer 160a is more stable than 160b by 2.4 kcal/mol. Since 160a and 160b
are interconvertible under the acidic conditions of cyclization of 159, the isomer
160a will be predicted to form predominantly under thermodynamically controlled
conditions. Deslongchamps and coworkers have indeed shown that the cyclization
of 159 under acidic conditions (0.1N HCl/CH3 OH) furnished only 160a. From the
cyclization under mild acidic conditions (catalytic p-TSA in CHCl3 ), a small amount
of 160b was isolated and also shown to convert irreversibly and completely to 160a
on exposure to 1.0 N HCl in acetone [17].
The dihydroxy ketone 161, with (S)-configuration at the secondary carbinol center,
will be expected to yield a mixture of the two isomeric spiroacetals 162 and 163. The
acetal 162 can exist as an equilibrium mixture of 162a and 162b. Likewise, the acetal
163 also can exist as an equilibrium mixture of 163a and 163b. The conformational
isomers are achieved by flipping the methyl-containing ring from one chair to the
other. From the operating anomeric and steric effects, we calculate the net relative
energies of the conformers as follows:
H
O H
O
OH (S) OH O H
O
161 O
163
162
O
O O
O H H
O
O O O
H H
162a 162b 163a 163b
E162a: 2 × (−1.4) + (2 × 0.4) + (1 × 0.4) + 3.0 = 1.4 kcal/mol

E162b: 1 × (−1.4) + (2 × 0.4) + (2 × 0.9) = 1.2 kcal/mol
E163a: 1 × (−1.4) + (2 × 0.4) + (2 × 0.9) = 1.2 kcal/mol
E163b: 0 × (−1.4) + (2 × 0.9) + (1 × 0.9) + (1 × 4.0) = 6.7 kcal/mol
From the calculated relative energies, the isomers 162 and 163 are likely to form
in nearly equal amounts. Further, the isomer 162 should exist, within a small approx-
imation, as a 1:1 mixture of the conformers 162a and 162b due to the very small
energy difference of a mere 0.2 kcal/mol. Because of the significantly large energy
difference of 5.5 kcal/mol, the isomer 163 must exclusively exist as the conformer
163a. These predictions bear well with experiments [17].
Let us now consider the dihydroxy ketone 164, which is enantiomeric to 161 at
the secondary carbinol center. Cyclization is expected to furnish a mixture of the
isomeric acetals 165 and 166. The isomer 165 may exist as an equilibrium mixture
of 165a and 165b. Likewise, the isomer 166 may also exist as an equilibrium mixture
of 166a and 166b. Whether both 165 and 166 or just one of them is formed, and
also whether each of these would indeed exist as an equilibrium mixture of the two
possible conformers will be governed by their relative energy differences, calculated
below.
O H O
H
(R) OH + O
OH O O
164 165 166
O
O O
O H H
H O
H O O
O
165a 165b 166a 166b

E165a: 2 × (-1.4) + 0.8 + 0.8 = -1.2 kcal/mol
E165b: 1 × (-1.4) + 0.8 + 0.9 + 4.0 = 4.3 kcal/mol
E166a: 1 × (-1.4) + 0.4 + 3.0 + (2 × 0.9) = 3.8 kcal/mol
E166b: 0 × (-1.4) + (2 × 0.9) + (2 x 0.9) = 3.6 kcal/mol
Being the most stable, only the isomer 165 will be expected to form and,
also, it must exist predominantly as conformer 165a. Since 161 and 164 are non-
interconvertible, but 162 and 163, and 165 and 166 are interconvertible, one will
expect 162a, 162b, 163a, and 165a to form from an enantiomeric mixture of 161
and 164. This is corroborated by experiments [17]. Also, under the acidic conditions
of the reaction, while the isomer 162a or 163a was converted to an approximately
1:1 mixture of the two, the isomer 165a was found not to equilibrate. References 17
and 18 provide mines of information and may be referred by the reader with serious
stereochemical inclination.
We learnt above about the anomeric or stereoelectronic effect and its implications
on conformational preferences. Let us now consider the examples given in Eqs. 42–
45. The masked tetrahydroxyketone 167 [19], dibromodihydroxyketone 169 [20],
and masked pentahydroxyketone 171 [21, 22] cyclized exclusively to 168, 170, and
166, respectively. A cyclization similar to 171 → 172 was used by Kozikowski
and coworkers in the synthesis of (±)-talaromycin B [23]. In yet another successful
synthesis of talaromycin B, Kocienki and Yates have achieved the transformation
173 → 174 [24]. The stereochemistry at the spiro-carbon in the products 168, 170,
172, and 174 is always the same as that in the predicted predominant conformer
157a.
O OH
O (42)
O O SMe O O 168
OH
167
O Br
Br Br O 170 (43)
OH O OH
169
Br
OH
OH O
S S (44)
O O O
HO OH
O O
171 172
O O
(45)
O
O OH
HO OH
O 173 174
We have discussed above the conformational profile of 1,7-

dioxaspiro[5.5]undecane skeleton. There are examples of 1,6-dioxaspiro[4.5]decane
skeleton as well, a skeleton that has been encountered in products of natural origin
including but not limited to ionophores. Cottier and coworkers [25] have prepared
several derivatives of 1,6-dioxaspiro[4.5]decane and shown that 175 exited as
conformer 175a in preference to 175b. These authors have also reported that
176 existed in the conformation shown to allow each ring oxygen an electron
pair orbital antiperiplanar to the polar σC–O bond. The existence of the central
tetrahydropyran ring in a twist-boat conformation to accommodate as many as four
σC-O bonds antiperiplanar to different electron pair orbitals represents a strong case
of conformational control by the stereoelectronic effect.
O O O
O
O O H H
175 175a 175b
OH O
O
O HO
176
5 Influence of Anomeric Effect on Conformational

Reactivity
We will now analyze 1,4-elimination reactions shown in Eqs. 46–51. These elimina-
tions are rendered possible by the antiperiplanar relationship of the breaking central
σC–C bond with the electron pair orbital on the heteroatom and σC–X bond. Here, X
is a leaving group such as halogen and OTs. The salient points are as follows:
(a) While the species 183 generates 184 under solvolysis conditions, the species
185 undergoes SN 2 reaction, 1,2-elimination, and rearrangement to generate
species other than 184.
(b) The ring expansion through transformation 186 → 187 is remarkable. In
contrast, the isomer 189 undergoes alternate reactions such as SN 2, elimination,
and rearrangement.
(c) Compare the transformations 186 → 188 and 190 → 192 and note the geome-
tries of the resultant olefins. The geometry of the olefin is trans in 188 and
cis in 192 because of (a) the differences in the ring-junction geometry, and (b)
stereoelectronic control of the two intramolecular SN 2 processes.
(d) The iminium ions formed from the reactions were oxidized after hydrolysis to
isolate amides as the end products.
N a a c
b
N +
-Y - (46)
Y b d
c
d
178 179
177
N N N
Cl X H (47)
H Cl
180 181 182
N OTs N X N H
(48)
H H H H H OTs
183 184 185
H H
TsO
[O]
N N N (49)
H H O
H H
186 187 188
5 Influence of Anomeric Effect on Conformational Reactivity 39
H
H
only SN2 substitution, 1,2-elimination and
N (50)
other rearrangement products
TsO
H
189
H
TsO
H N [O] O N
N (51)
190 191 192
Equations 52 and 53 represent two pathways for 1,4-elimination in 193, leading to

different iminium ions 194 and 195, respectively. The distribution of these iminium
ions will depend on whether the reaction is performed under thermodynamic or
kinetic control. While the species 194 is a cyclooctene derivative, 195 is a cyclo-
hexane derivative. The cyclohexane derivative 195 must, of course, predominate
under thermodynamically controlled conditions. Like 193, the species 196 also repre-
sents two pathways for 1,4-elimination shown in Eqs. 54 and 55. Fortunately, both
the pathways yield the same product 197. The reactions shown in Eqs. 56 and 57 are
examples of elimination resulting from a 1,3-diol mono-tosylate system. An electron
pair orbital on the hydroxy oxygen is antiperiplanar to the cleaving central σC–C bond
and it provides the necessary electronic push for cleavage. The reaction shown in
Eq. 57 was used by Corey and coworkers in a synthesis of α-caryophyllene [26].
OTs
N N
(52)
193 194
OTs
N N
(53)
193 195
OTs
N N
(54)
196 197
OTs
N N
(55)
196 197
O H O
H (56)
OTs
198 199
H OTs H
H
(57)
O O
H H
O
200 201
In Eqs. 58 and 59, an oxy anion provides the necessary electronic push for 1,4-
elimination. In Eq. 58, this oxy anion was generated in situ by hydride reduction
of the carbonyl group [27]. Oxy anion generation in Eq. 59 was achieved in situ by
the cleavage of the ester group on reaction with an alkoxide in a protocol typical of
transesterification [28].
O O O
H (58)
H
TsO TsO
202 203 204
O
Cl OCOPh Cl O
RO
H - PhCO2R H H
205 206 207 CH2CHO
(59)
The reactions shown in Eqs. 60 and 61 also illustrate the power of the stere-
oelectronic effect. In Eq. 60, the attack of ethoxide ion on the carbonyl group in
208 generates the tetrahedral intermediate 209, wherein both the oxy anion and
the ethereal oxygen have one electron pair orbital antiperiplanar to a common ring
bond. Further, this ring bond is antiperiplanar to the equatorial σC–OTs bond. These
geometrical features together fulfill the necessary requirement for 1,4-elimination
and the cyclooctene 210 is formed. In the event that σC–OTs bond is axial as in 211,
1,4-elimination is prevented altogether and simple 1,2-elimination takes place under
otherwise identical reaction conditions to form 212 [29].
H H O O
O
TsO EtONa TsO O O
(60)
EtOH
208 209 210
OTs
O O
H
(61)
H
211 212
EtO
The reaction shown in Eq. 62 is an example of 1,4-elimination that is followed

by decarboxylation of the respective carboxylate to obtain the E,Z-macrolide 215
[30, 31]. This fragmentation was considered by Eschenmoser to take place in two
consecutive steps:
(a) Both the ring oxygen atoms have one electron pair orbital in an antiperiplanar
orientation to stereoelectronically eject tosylate via the cleavage of the ring
σC–C bond and generate the dipolar species 214.
(b) The πC8–C9 bond in 215 emerges from the stereoelectronically controlled
decarboxylation for having the σC8–CO2 bond antiperiplanar to the σC9–O bond.
O O O
H 9 9
9 O H
5 O CO2-X+ CO2-X+ O
8 8 5 6 8
TsO 6
H H H
213 214 215
(62)
As shown in Eq. 63, the bicyclic species 216 is quantitatively transformed into a
ω-cyanocarboxylic acid 218 [32]. The intermediate species 217 formed from reac-
tion with hydroxide ion has two electron pairs, one on each of the two oxygen
atoms located on C1, antiperiplanar to the σC1–C2 bond. The antiperiplanar relation-
ship between σC1–C2 and σC3–C4 , and also between σC3–C4 and σN–OTs, are the other
requirements for overall fragmentation. Note that the nitrile function emerges from
a process of anti-elimination.
Me Me Me
O O O
2 1
4
TsO N 3
(63)
TsO N N
H H OH H OH
216 217 218
The simultaneous cleavage of cyclopropane and cyclobutane rings in 219 in a

highly stereospecific manner leads to the formation of 221, wherein the double
bond has E-geometry, as shown in Eq. 64. Note that the anti-relationship of methyl
substituent on the cyclobutane ring and specifically shown hydrogen on the cyclo-
propane ring is retained in the product olefin. Compare this with a similar cleavage
of 222 that leads to 224 with Z-double bond, Eq. 65 [33]. Fragmentations of 219
and 222 proceed through stereoelectronically favored cleavages of the intermediate
species 220 and 223, respectively. The antiperiplanar relationship between σC1–C2
and σC3–C4 and also between σC1–C2 and the two electron pair orbitals, one on each
of the two oxygen atoms on C1, allow smooth cleavage. The reaction of 225 with
sodium borohydride in methanol in the presence of magnesium methoxide furnished
228, Eq. 66 [33]. This reaction involves trans-esterification from tert-butyl ester to
methyl ester, reduction of ketone to alcohol, fragmentation under full stereoelectronic
control, and reduction of the resultant aldehyde to alcohol.
O OMe CO2Me
H H O 1
3 2
CO2Me (64)
4
MeO2C CO2Me MeO2C CO2Me
CO2Me
219 220 221
O CO2Me
OMe
O 1
H H
3 2
4
CO2Me (65)
CO2Me
222 223 224
CHO CH2OH
O HO
H H
CO2Me CO2Me
-t
t-
BuO2C CO2Bu MeO2C CO2Me CO2Me CO2Me
225 226 227 228

(66)
Methoxide ion-catalyzed transformation of the tricyclic enedione 229 into an

isomeric mixture of the ester 232, Eq. 67, is yet another interesting example. The
σC1–C2 bond is weakened by two antiperiplanar electron pair orbitals, one on each
of the two oxygen atoms on C1. Moreover, the σC1–C2 bond is nearly parallel to the
p orbitals of the πC=C bond that allows their electron densities to mix well enough
to facilitate the formation of dienolate 231 [34]. Protonation on either face of the
dienolate is responsible for the formation of isomeric mixture of the end product
232.
O H
O 1 O H+
3
2 (67)
4 H H
CO2Me O- CO2Me O
O O
229 230
231 232
6 Conformations of Mono and Dithioacetals
2-Alkoxytetrahydro-2H-thiopyrans were studied by Zefirov and Shekhtman [35]

and the axial conformer 233 was found to predominate (90%) over the equatorial
conformer 234, when R was methyl or propyl group. The equilibrium of the isomeric
mixture of 235 and 236 under acidic conditions was studied by Eliel and Giza [36].
The axial isomer 235 was found to constitute approximately 65% of the mixture.
These examples indicate that the monothioacetal function benefits from the anomeric
effect arising from sulfur, which is largely the same as that from oxygen.
S S
H OR
OR H
233 (90%) 234 (10%)
O O
H SR
SR H
235 (65%) 236 (35%)
1-Oxa-7-thiaspiro[5.5]undecane 237 can exist in four different conformations

237a–d that possess two, one, one, and zero stereoelectronic effects, respectively.
By considering the stereoelectronic effect from sulfur the same as from oxygen, the
relative energies are calculated as 0.0, 2.4, 2.4, and 4.8 kcal/mol. On this account,
237 must exist predominantly as conformer 237a.
O
S O S S O S
237a 237b 237c 237d
E237a: 2 × (-1.4) + (2 × 0.4) + (2 × 0.4) = -1.2 kcal/mol

E237b: 1 × (-1.4) + (2 × 0.4) + (2 × 0.9) = 1.2 kcal/mol
E237c: 1 × (-1.4) + (2 × 0.4) + (2 × 0.9) = 1.2 kcal/mol
E237d: 0 × (-1.4) + (2 × 0.9) + (2 × 0.9) = 3.6 kcal/mol
The above analysis gains support from the cyclization results of 238 and 240. The
compound 238 furnished the conformer 239a rather than 239b. In conformer 239a,
each heteroatom exerts a stereoelectronic effect on the other, whereas only sulfur
exerts a stereoelectronic effect on oxygen in conformer 239b. The conformer 239a
is more stable than 239b by 2.4 kcal/mol. Likewise, the cyclization of 240 furnished
only the conformer 241a and none of 241b [18, 37]. The conformers 241a and 241b
may also be calculated, as above, to differ in energy by 2.4 kcal/mol.
H S
SH
O O S O
OH
H
238 239a 239b
H O
OH
O S O S
SH
H
240 241a 241b
E239a: 2 × (-1.4) + (2 × 0.4) + (2 × 0.4) = -1.2 kcal/mol

E239b: 1 × (-1.4) + (2 × 0.4) + (2 × 0.9) = 1.2 kcal/mol
1,7-Dithiaspiro[5.5]undecane 242 may be expected to adopt any or all of the three

conformers 242a−c. These conformers have two, one, and zero stereoelectronic
6 Conformations of Mono and Dithioacetals 45
effects, respectively. By taking into account the prevailing steric effects and also the
stereoelectronic effect worth 1.4 kcal/mol offered by sulfur, the relative energies of
these conformers are as follows:
S
S S S S S
S S
242 242a 242b 242c
H S
SH
O S S S
SH
H
243 244a 244b
E242a: 2 × (-1.4) + (2 × 0.4) + (2 × 0.4) = -1.2 kcal/mol

E242b: 1 × (-1.4) + (2 × 0.4) + (2 × 0.9) = +1.2 kcal/mol
E242c: 0 × (-1.4) + (2 × 0.9) + (2 × 0.9) = +3.6 kcal/mol
The conformer 242a is more stable than 242b and 242c by, respectively, 2.4
and 4.8 kcal/mol. On this basis, 242 must exist predominantly as conformer 242a.
This prediction has been verified experimentally. Additionally, the cyclization of 243
under acid-catalyzed conditions furnished predominantly the conformer 244a at the
equilibrium [18, 37]. Conformer 244a is 2.4 kcal/mol more stable than 244b. Thus,
the stereoelectronic effect due to sulfur must also be of the order of −1.4 kcal/mol.
7 Conformations of Mono and Diazaacetals
The acetals 245 and 246 have been discovered from low-temperature NMR studies
to exist largely as conformers 245a and 246a, respectively [38]. Each of these
conformers benefits from two stereoelectronic effects in contrast to 245b and 246b
that have only one such effect. The additional stereoelectronic effect in conformers
245a and 246a is responsible for higher stability. The conformer 247a with an axial
alkyl substituent, methyl or benzyl, on the nitrogen has been suggested to be more
stable than conformer 247b with the substituent on nitrogen equatorial [39]. Again,
247a benefits from one additional stereoelectronic effect than 247b.
H H
O O O O
N N H3C N H3C N
H H
245a 245b 246a 246b
Me H
R
O O O O
N N R N R N
R Me
R = CH3, PhCH2 R = H, p-NO2-C6H4CH2
247a 247b 248a 248b
The acetal 248 bears a methyl group on nitrogen, and either an equatorial hydrogen
or p-nitrobenzyl group on ring carbon bearing the two heteroatoms was discovered to
exist as a 1:1 equilibrium mixture of the conformers 248a and 248b [40]. This result
demonstrates that both the conformers are of equal energy and, hence, it was used
for the evaluation of the anomeric effect arising from nitrogen. The conformer 248a
is raised in energy due to one butane gauche interaction (0.9 kcal/mol) as shown and
another interaction due to the gauche form of CH3 –N–CH2 –O (0.4 kcal/mol). Let us
assume that the contribution from the stereoelectronic effect caused by the equatorial
electron pair orbital on nitrogen is x kcal/mol, then x + 0.9 + 0.4 = 0. This lends x a
value of −1.3 kcal/mol. This value is very close to the stereoelectronic effect arising
from oxygen, −1.4 kcal/mol.
R NO2 NO2
R R
O N R O N O O
N O N N
R
249 250 251a 251b
1-Oxa-3,5-diaza- and 1,3-dioxa-5-azacyclohexanes exist as conformers 249 and

250, respectively [41]. With the axial alkyl group on nitrogen, both the conformers
gain two stereoelectronic effects as shown. The conformer 251a with an axial methyl,
ethyl, or propyl substituent on nitrogen is favored over the conformer 251b possessing
the substituent on nitrogen equatorial. However, the conformer 251b is favored over
251a when the substituent on nitrogen is a large isopropyl, cyclohexyl, or tert-butyl
group [39].
8 Antiperiplanar Effects Arising from C–Si, C–Ge, C–Sn, and C–Hg Bonds 47
8 Antiperiplanar Effects Arising from C–Si, C–Ge, C–Sn,

and C–Hg Bonds
The σC–Si , σC–Ge , and σC–Sn bonds provide significant stabilization to positive charge
[42–46]. The donor ability of the σC–Si bond is as good as that of a lone pair. The rate
enhancement in the elimination proceeding through the stabilized carbocation 253
is of the order of 1012 on substitution of the trimethylsilyl (TMS) group [44]. Hyper-
conjugative interaction with the antiperiplanar TMS group has been suggested to be
responsible for 1010 fold rate acceleration and the remaining 102 fold originating
from inductive interactions. The diminished reactivity of the conformer 255 is asso-
ciated with the less-favorable gauche arrangement of the departing group relative to
TMS.
H/TMS H/TMS
But But But

OCOCF3
252 253 254
12
kSi / kH = 2.4 x 10
H/TMS H/TMS
But But But
OCOCF3
255 256 254
kSi / kH = 4.0 x 104
The donor ability of σC–Ge and σC–Sn bonds is greater than that of the σC–Si bond. For
instance, the corresponding trimethylgermyl (Me3 Ge) and trimethylstannyl (Me3 Sn)
trifluoroacetates react 1014 and >>1014 times faster than the metal-free analog [46].
Mercury displays similar characteristics. However, its effect is larger than that of
silicon and comparable to germanium. In fact, the effect of mercury increases with
the nucleophilicity of solvent, suggesting that coordination of solvent with mercury
increases the polarizability of the σC–Hg bond [47, 48].
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17. P. Deslongchamps, D.D. Rowan, N. Pothier, G. Sauvé, J.K. Saunders, Can. J. Chem. 59, 1105
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Chapter 2
Reactions on Saturated and Unsaturated
Carbons
Abstract This chapter uncovers the geometrical requirements for reactions on satu-
rated and unsaturated carbons in both acyclic and cyclic systems with the related stere-
ochemical features. The nucleophilic attacks in SN 2 and SN 2 processes, involving the
necessary geometrical requirements, are discussed. The resonance-driven activation
of cyclopropane is of much significance in synthetic chemistry. The mode of activa-
tion and its consequences on product profile are amply reasoned. The SN 2-originated
1,2-migration within geometrical constraints of the reactant and neighboring group
participation under solvolysis conditions have been explained with emphasis on
product distribution. The activation of oxirane by Lewis acid, followed by rear-
rangement under stereochemical effect, is discussed. Given the suitable geometrical
disposition of substituents and functional groups in a given molecule, several 1,2-
migrations can take place in tandem to generate fascinating skeletons. This chemistry
has been described with examples of the construction of several steroidal skele-
tons. Baldwin rules and the preferred exo-trig over endo-trig cyclization are demon-
strated with examples using geometrical analysis. The stereoelectronically controlled
addition reactions are also highlighted.
1 Inter- and Intramolecular Reactions on Saturated

Carbons
The concerted bond formation and bond cleavage in SN 2 reactions proceed with full
stereoelectronic control. In transition structure 2 for the reaction, both the nucleophile
and the leaving group are bonded to the central carbon atom, which has acquired
an sp2 character. One lobe of the p orbital on carbon overlaps with an incoming
nucleophile and the other with the leaving group. Since the nucleophile approaches
the carbon from the direction opposite to the leaving group, the result is Walden
inversion or inversion of configuration. The reaction is, thus, controlled by electronic
effects that impose certain geometrical restraints on the TS structure.

https://doi.org/10.1007/978-3-030-75622-2_2
50 2 Reactions on Saturated and Unsaturated Carbons
R R2 R1
R1 2 R2
R1
Nu - + L Nu L Nu
R3 R3 R3
1 2 3
The evidence to the fact that the nucleophile is indeed aligned collinearly with
the leaving group comes from the transformation 4 → 5, which takes place via an
intermolecular process rather than the formally appealing intramolecular process
shown in structure 6. The intramolecular process does not allow the said collinear
arrangement [1]. Indeed, the transformation 4 → 5 was found to be bimolecular.
O O
SO2OMe SO3 S
O
X
Me Me
Ts Ts Ts
4 5 6
2 Intermolecular Reactions of Epoxides
It is for the collinear requirement that epoxides react with nucleophiles and open up to
give products of well-defined stereochemistry. We will investigate this by considering
the conformationally rigid unsymmetrical epoxide 7, which may form two different
products, 9 and 11, by following different pathways. The following points must be
noted:
(a) While the diaxial product 9 results from axial attack at C3 and proceeds through
chair-like intermediate 8, the diequatorial product 11 results from equatorial
attack at C2 and proceeds through twist boat-like intermediate 10.
(b) Since the equatorial attack at C2 proceeds through a higher energy twist-
boat TS structure, product 9 must form in preference to 11 under kinetically
controlled conditions, i.e., when reaction equilibration has not been allowed.
(c) It must be noted that the 1,2-diequatorial product 11 is thermodynamically
more stable than the 1,2-diaxial product 9 on account of 1,3-diaxial interactions
present in the latter.
(d) Indeed, epoxides open to form 1,2-diaxial products.
2 Intermolecular Reactions of Epoxides 51
O- OH
H H
H H H
6 O Nu Nu
3 4 8 9
1 2
H 5 O-
H
H
7
OH
H Nu
Nu H
10 11
3 Intramolecular Reactions of Epoxides
The intramolecular SN 2 opening of epoxide also follows the above stereoelectronic

requirement within the geometrical constraints of the system. It was solely based
on the collinear requirement of the SN 2 reaction that Stork favored intramolecular
opening leading to a six-membered ring more than a five-membered ring for the
following reasons:
(a) While the nucleophile is perfectly aligned for the rear collinear attack in 12,
it is poorly aligned in 13. The trajectory requires the nucleophile to be on the
dotted line which, in turn, requires considerable bond distortion or bending in
13.
(b) From reactions of the epoxynitriles 14 and 16 under basic conditions, it was
indeed discovered that the transformation 14 → 15 was significantly faster
than 16 → 17 [2].
CN CN
H
O O O
OH
12 13 14 15
H CN
CN
O
OH
16 17
A similar analysis of transition state requirement allowed Stork to realize that it

was easier to achieve collinearity in the formation of a four-membered ring than a
five-membered ring. Thus, in a given situation where both four- and five-membered
rings could form, the former may prevail. The following observations are illustrative:
(a) The reaction of epoxynitrile 18 with a base (required for deprotonation to
generate the requisite carbanion) in benzene furnished 95:5 mixture of the
isomeric cyclobutanes 19 and 20 [3]. No five-membered ring product was
formed.
(b) The major isomer 19 is less stable than minor isomer 20 because the two large
substituents are cis in 19 and cause steric interactions. This result indicates that
the TS structure resembling 21, leading to 19, is of lower energy than the TS
structure resembling 22 and leading to 20.
(c) In the TS structure resembling 22, the nitrogen atom along with the large
solvated metal ion comes close to the methyl-bearing carbon of epoxide to
cause significant van der Waals repulsion.
CN OH OH
OTHP CN
O OTHP
+
H CN H OTHP
18
19 20
R = CH2CH2OTHP
M O O
N H H
C R R M
C N
21 22
In yet another interesting example, the iodolactonization of the β,γ-unsaturated

carboxylic acid salt 23 was found to yield the butyrolactone 24 in preference to
the otherwise more stable γ-lactone 25. The internal opening of the iodonium ion
(equivalent to an epoxide) by carboxylate ion leading to the four-membered ring
product 24 is preferred over five-membered ring product 25.
3 Intramolecular Reactions of Epoxides 53
R1 R1
I
I R2
R2 O R3
R1 O
R3 O O
24
R2 O
R3 O R1 R1
I
I
23 R2
R2 O
O
R3 O R3 O
25
In regard to the internal opening of epoxide, cyclopropane formation is preferred

over cyclobutane, regardless of the relative degree of substitution of the ring. For
instance, the reaction of 26 with a suitable base generates cyclopropane 27 exclu-
sively [3]. The transition state structure for this transformation resembles the transi-
tion state structure 21 above, but with one carbon less in the chain linking the nitrile
group and the ring.
O HOH2C H
CN CN
26 27
In summary, in internal epoxide opening, six-membered ring formation does not

require bending of any of the σ bonds of the chain, while the formation of five-,
four-, and three-membered rings requires simultaneous bending of four, three, and
two such σ bonds, respectively, in addition to the carbanion electron pair orbital.
Though the degree of bending is more pronounced in the formation of a three-
membered ring than others, the number of bonds that must bend simultaneously is
more important than the degree of bending. Thus, the simultaneous bending of three σ
bonds leading to cyclobutane formation is less difficult than bending of four σ bonds
leading to cyclopentane formation, but more difficult than bending of two σ bonds
leading to cyclopropane formation. In other words, the facility of ring formation
from the internal opening of epoxide decreases in the order: six-membered ring >
three-membered ring > four-membered ring > five-membered ring.
4 Baldwin Rules for Ring Closure on Saturated

and Unsaturated Carbons
We now turn to an internal SN 2 reaction on sp3 carbon. Purely on account of geomet-

rical constraints imposed in achieving the collinear alignment, Baldwin proposed a
set of rules for such ring-closing reactions [4]. The reactions were designated by a
numerical prefix which denotes the size of the ring to be formed, followed by the
term exo or endo depending upon whether the breaking bond is exocyclic or endo-
cyclic to the ring under construction. Now, a suffix such as tet (for a tetrahedral or
sp3 carbon), trig (for a trigonal or sp2 carbon), or dig (for a diagonal or sp carbon)
describes the state of hybridization of the electrophilic carbon. A collection of several
such reactions is given as follows:
Y X
X X X X
Y Y Y Y
3-exo-tet 4-exo-tet 5-exo-tet 6-exo-tet 7-exo-tet
X X
Y Y
5-exo-trig 5-exo-dig
Y Y Y
X X Y X X
5-endo-tet 6-endo-tet 5-endo-trig 5-endo-dig
While all the reactions from 3-exo-tet to 7-exo-tet are favored, 5-endo-tet and 6-
endo-tet are not favored on stereoelectronic grounds, i.e., on account of the collinear
requirement of the SN 2 reaction. The relative ease of these processes is 3-exo-tet
> 4-exo-tet < 5-exo-tet > 6-exo-tet > 7-exo-tet. It is important to recognize that
the intramolecular SN 2 process proceeding through the TS structure resembling 6
constitutes a 6-endo-tet process and, hence, is unfavorable.
5 SN 2 Reaction (Reaction on Unsaturated Carbon) 55
5 SN 2 Reaction (Reaction on Unsaturated Carbon)
The SN 2 reaction involves a nucleophilic attack on the terminal sp2 carbon, resulting
in a shift of the π bond and departure of the leaving group from the allylic position.
The nucleophile may attack either anti or syn to the leaving group as shown in the
transformations 28 → 29 and 28 → 30, respectively. The syn attack is preferred over
the anti attack because the syn attack displaces the π electrons in direction anti to
σC–Y bond and, thus, is suitable for the next rear side attack.
X X
syn attack Y
28 29
anti attack Y
X
X
28 30
In confirmation of preferred syn attack, reactions of cyclohexenyl dichloroben-

zoates 31 (R = Me, i-Pr, t-Bu; R = C6 H3 Cl2 ) with piperidine afforded 32. Likewise,
the mesitoates 31 and 33 (R = i-Pr, R = C6 H2 Me3 ) reacted with piperidine to
afford 32 and 34, respectively [5, 6]. Different dispositions of the substituents on the
cyclohexene ring in 31 and 33 must be noted.
R
OCOR'
R H
N
H
31 32
R
OCOR'
R H
N
H
33 34
The story of the cyclohexenyl system is a bit complicated compared to the above
two reactions because the cyclohexenyl system can adopt two conformations 35a and
35b. Syn attack on 35a will proceed through a chair-like TS structure resembling 36
and generate 37. In TS structure 36, the electron pair orbital is disposed anti to leaving
group Y and, thus, the subsequent elimination (or intramolecular SN 2 reaction) is

facile. In the alternate anti attack, the TS structure resembles twist-boat structure 38,
wherein the electron pair orbital is syn to the leaving group and, thus, the elimination
is rendered difficult. The difficulties in the transformation 35a → 39b relative to 35a
→ 37 are the following:
(a) The energy demand to achieve the twist-boat TS structure 38 is more than that
for the chair TS structure 36.
(b) While the stereoelectronic requirement for elimination is not met in the syn-
elimination 38 → 39a, it is rigidly in place for the anti-elimination 36 →
37.
(c) While the flip of the twist-boat olefin 39a to the half-chair olefin 39b is energy-
requiring, no such event is required in the transformation 36 → 37.
Thus, the pathway 35a → 36 → 37 is energetically favored over the pathway 35a
→ 38 → 39a → 39b.
Y
Y X X
H
H H
35a 36 37
Y H
Y
H H
X
35a X X
38 39a 39b
X X
X
Y Y
H H
H
35b 40 41a 41b
Y
H Y H
H
X H X
35b 42 43
5 SN 2 Reaction (Reaction on Unsaturated Carbon) 57
In the alternate conformer 35b, syn attack proceeds through the twist-boat TS
structure resembling 40, wherein the axes of the electron pair orbital and σC–Y bond
are not antiperiplanar to allow smooth elimination to 41a, going over to 41b after ring
flip. However, in comparison, this transformation must be more facile than 35a →
39b. Though the anti attack to 35b does proceed through the chair-like TS structure
resembling 42, and the elimination to 43 is not supported stereoelectronically for the
syn dispositions of the electron pair orbital and leaving group Y.
It is also conceivable that the twist-boat TS structures 38 and 40 may ring-flip
to 38a and 40a before collapsing through elimination to 39b and 41b, respec-
tively. However, both 38a and 40a lack the requisite antiperiplanar relationship for
elimination.
Y
Y H H
H
H X
H X
X
38 38a 39b
X
Y H X
X Y
H
H H H
40 40a 41b
Overall, the syn process 35a → 36 → 37 is the most energy-conserving pathway

and it will be expected to prevail.
A fascinating example of two consecutive syn additions is expressed from the
transformation 42 → 44 via 43, the product of the first syn addition, on the reaction
of 42 with sodium methoxide [7]. Note that the methoxy substituents in the product
are syn, a relationship secured by nuclear Overhauser effect (nOe) measurements.
MeO MeO
Y Y D
MeO
Y D D
D Y = Cl D D
42 43 44
6 SN 2 Reaction of Cyclopropane Activated by Two

Geminal Carbonyl Groups
Cyclopropane 1,1-dicarboxylate can, in principle, adopt three conformers exo,exo-

45, endo,exo-45, and endo,endo-45. When the carbonyl group and the cyclopropane
ring are opposite across the intervening σC–C bond, we consider the orientation exo.
Likewise, when the carbonyl group and the cyclopropane ring are on the same side of
the intervening σC–C bond, the orientation is considered endo. All these conformers,
however, are disfavored on grounds of dipolar and steric interactions.
RO O O O OR O
OR
O OR OR
O O OR OR O
RO RO O O RO
exo,exo-45 endo,exo-45 endo,endo-45 45a 45b
O OR O
OR
O Nu O
Nu RO RO
45b 46
It is assumed that 45 preferably adopts the conformer 45a or 45b to avoid the
above destabilizing interactions and yet has the p orbital of the in-plane carbonyl
function parallel to the adjacent σC–C bond orbital of cyclopropane. This arrangement
activates the σC–C bond of cyclopropane and allows a nucleophilic attack on the
remote carbon. The resultant carbanion delocalizes into the carbonyl group as shown
in the transformation 45b → 46. The conformer 45b is preferred over 45a in obeyance
of anti-transition state structure theory. It is also apparent that must the compound be
restrained in either of the conformations exo,exo-45, endo,exo-45, and endo,endo-45
for geometrical reasons, it will display heightened reactivity toward nucleophiles.
Indeed, when 47 is mixed with piperidine in benzene at room temperature, an
exothermic reaction takes place to form 48 [8]. For substrates under activation by a
single carbonyl group, see the transformations 49 → 50 [9] and 51 → 52 [10].
6 SN 2 Reaction of Cyclopropane Activated by Two Geminal … 59
O O
O O
N
+
H
O N O
O H O
47 48
Nu Me
H
X + Me2CuLi H X
RO2C
RO2C O O
49 (X = O, CH2) 50
O O
CO2R + ArS-Na+ CO2R
O O
H H H
CO2R SAr CO2R
CO2R CO2R
51 52
It is the consequence of the above activation mechanism that 53 equilibrates with

56 via 54 and 55, and 57 with 60 via 58 and 59 on mixing with a catalytic amount
of dimsyl sodium [CH3 S(O)CH2 Na] in DMSO as solvent [11, 12].
CO2Et CO2Et
CO2Me CO2Me
EtO2C CO2Me EtO2C CO2Me
53 54
CO2Et CO2Me CO2Et CO2Me
EtO2C CO2Me EtO2C CO2Me

56 55
MeO2C CO2Et MeO2C CO2Et

CO2Et CO2Et
CO2Me CO2Me
57 58
MeO2C CO2Et MeO2C CO2Et
CO2Me CO2Et CO2Me CO2Et

60 59
7 Reactions Involving Consecutive Intramolecular SN 2

Reactions Leading to Rearrangement
Let us consider rearrangements that involve two or more intramolecular SN 2

processes to furnish products by beginning with the reaction of tertiary alcohols
bearing a leaving group at β-carbon. Note that in the representative transformation
61a → 62, group R1 that migrates from oxygen-bearing carbon to carbon bearing
leaving group Y is disposed antiperiplanar to both σC–Y and electron pair orbital on
oxygen. If for some reason, steric or otherwise, the molecule adopts conformer 61b,
it is R2 that will migrate to yield 63, which is isomeric to 62. Finally, the conformer
61c, wherein σC–O is anti to σC–Y , will form the epoxide 64 in a clean SN 2 process.
O Y O R3
R3
R2 R2 H
H R1
R1
61a 62
R1 Y
R3 R1 R3
O H
H O
R2
R2
61b 63
R2 Y R2 R3
R3
R1 R1 H
O H O
61c 64
We can now apply the above general concepts to a system wherein both the
hydroxy group and leaving group Y are located at positions 1 and 2 of a ring system,
as in 65, and also a system wherein the hydroxy group is located on a ring carbon and
leaving group Y on a carbon outside the ring, as in 67. The following two distinct
scenarios, therefore, emerge:
7 Reactions Involving Consecutive Intramolecular SN 2 Reactions … 61
(a) There is ring contraction in the transformation 65 → 66 and ring expansion in

67 → 68.
(b) The carbon bearing the hydroxy group in 65 relocates outside the ring in product
66 and, thus, the number of atoms in the ring is reduced by one.
(c) There is ring expansion in the transformation 67 → 68. The carbon outside the
ring in 67 relocates and becomes part of the ring and, thus, the ring is enlarged
by one carbon.
OH R O R O
R
Y Y H
H H
65 66
O
OH O
Y Y
67 68
Interesting features emerge from applying the above concepts to the deamination
of vicinal aminoalcohols on a cyclohexane backbone. The amino group is trans-
formed into a diazonium group to act as the leaving group as in structures 70, 73,
75, and 78, respectively. Four different situations arise from consideration of the
isomeric structures 69, 72, 74, and 77.
(a) Note the antiperiplanar relationship of a ring bond with electron pair orbital on
oxygen and σC–N bond (all in green color) in structure 70. The rearrangement
occurs to furnish ring-contracted aldehyde 71.
(b) As above, note the antiperiplanar relationship of a ring bond on carbinol
carbon is antiperiplanar to electron pair orbital on oxygen and also σC–N
bond (all in green color) in structure 73. The rearrangement occurs to furnish
ring-contracted aldehyde 71.
(c) In diazonium species 75, the axial hydrogen on carbinol carbon is antiperiplanar
to σC–N bond and, thus, it migrates and cyclohexanone 76 is formed.
(d) In diazonium species 78, the carbinol oxygen itself is antiperiplanar to
σC–N bond, which allows an intramolecular nucleophilic displacement of the
diazonium group and epoxide 79 is formed.
H H H H
OH O O
t-Bu NH2 t-Bu N2 t-Bu
H H H H H H
69 70 71
H
OH O H
H H O
t-Bu NH2 t-Bu N2 t-Bu
H H H H H H
72 73 71
H H H O
OH
t-Bu H t-Bu H
O t-Bu H
H NH2 H N2 H H
74 75 76
OH OH O
H H
t-Bu H t-Bu H H t-Bu
H
H NH2 H N2 H
77 78 79
We will consider some more examples. Attempted reduction of 80 with LiAlH4

furnishes the ring-contracted product 83 [13]. The base-like character of LiAlH4 is
responsible for deprotonation of carbinol to generate the oxy anion 81, which triggers
rearrangement to 82. The carbonyl product 82 was further reduced by the hydride to
alcohol 83.
H H
H H
TsO TsO
O O
O HO
BH H
80 81 82 83
The transformations 84 → 86, 87 → 89, and 90 → 92 are steroid skeleton-based

examples, wherein one ring is contracted and the other enlarged by virtue of the
structural design of the substrates [14].
7 Reactions Involving Consecutive Intramolecular SN 2 Reactions … 63
Me Me Me
Me
O O O
H H H
TsO TsO H H
B O
84 85 86
Me Me Me Me
H H H
TsO TsO O
O O H
O
B H
87 88 89
Me Me Me Me
H H
TsO TsO O
O O H
B H O
90 91 92
A consequence of the relative orientational differences could also be seen in the

changes 93 → 94 and 95 → 96 [15]. The changes are brought about on treatment with
AgBF4 , which weakens the σC–Cl bond by coordination and allows the antiperiplanar
σC–C bond (green color) to migrate. Of course, in each substrate, one electron pair
orbital on oxygen is also antiperiplanar to the migrating bond to provide an additional
push for the overall reaction.
Cl CN CN
OMe O CN
O
93 94
Cl CN
NC
OMe O CN O
95 96
8 Dual Activation for Skeletal Rearrangement
We learnt above that an oxygen atom on one carbon and a leaving group on the
adjacent carbon constituted a situation for bond migration from the oxygen-bearing
carbon to the carbon bearing the leaving group, with loss of the latter. Throughout,
an electron pair orbital on oxygen was antiperiplanar to the migrating bond and the
migrating bond, in turn, was antiperiplanar to the bond connecting the leaving group
to the adjacent carbon. We can imagine a situation wherein there are two oxygen
atoms on the same carbon and each oxygen has an electron pair orbital antiperiplanar
to a migrating bond on the same very carbon. This allows the migration to occur
faster. Such situations arise in reactions of α-halo ketones and aryl-substituted 1,2-
dicarbonyl compounds with oxygen-based nucleophiles such as hydroxide ion.
For instance, 97 generates 98 on reaction with sodium hydroxide, wherein each
oxygen has one electron pair orbital antiperiplanar to σC–Ar bond to make it labile for
cleavage. Further, the σC–Ar bond is antiperiplanar to the σC–Br bond on the adjacent
carbon. The consequence of the two mutual dispositions is the cleavage of the σC–Ar
bond and the attack of the resultant aryl anion on the carbon-bearing bromine in SN 2
fashion in quick succession to form 99 as the sole product. The reaction, therefore, is
stereo-electronically controlled. The story with transformation 100 → 102 is similar.
The transformation 103 → 105 constitutes benzil-benzilic acid rearrangement.
Br Br O CO2
Ar O
Ar
t-Bu t-Bu t-Bu
O Ar
H H H
97 98 99
O
O Ar O
Ar Ar
Br Br CO2
t-Bu t-Bu t-Bu
H H H
100 101 102
O O OH
HO O O O Ar O Ar
ArCOCOAr
Ar HO O
Ar Ar Ar
103 104 105a 105b
9 Solvolysis with Neighboring Group Participation 65
9 Solvolysis with Neighboring Group Participation
Solvolysis with neighboring group participation may be viewed as a reaction on satu-

rated carbon. We will understand this phenomenon by considering the solvolysis of
erythro-tosylate 106 in comparison to threo-tosylate 110 in acetic acid. Neighboring
group participation in 106 leads to chiral phenonium ion 107, which is captured by
acetate ion on either carbon atom of the three-membered ring, and a 50:50 mixture
of the erythro-acetates 108 and 109 is formed. Note that 108 and 109 are the same
product (try superimposing one onto the other) and, thus, the resultant product is
optically active. A similar analysis of the solvolysis of 110 allows us to arrive at the
threo-products 112 and 113 through the achiral phenonium ion 111. Since 112 is the
mirror image of 113, the resultant product is optically inactive.
H + H
H
H H H
OTs OAc AcO
H H
106 107 108 109
H H + H
H H H H H
OTs OAc AcO
110 111 112 113
Solvolysis of the iodoacetate 114 in wet acetic acid containing silver acetate
furnished a mixture of the cis-diol monoacetates 117a and 117b. Weakening of
the σC–I bond on the association of silver ion with iodine is closely followed by
intramolecular capture of the incipient carbocation by the neighboring acetoxy group
to generate acetoxonium ion 115. This is captured by water to generate 116, which
collapses to a mixture of 117a and 117b. The compound 117 has been used in the
synthesis of (+)-crotanecine, a naturally occurring alkaloid [16].
I CH2CN O CH2CN HO O CH2CN R1O CH2CN
NZ O NZ O NZ NZ
AcO R2O
114 115 116 117a, R1 = H, R2 = Ac

117b, R1 = Ac, R2 = H
10 Rearrangement Originating from Oxirane Under Lewis

Acid Condition
The rearrangement of oxiranes to carbonyl species on treatment with Lewis acids

provides yet another elegant example of neighboring group participation that results
in excellent diastereocontrol. For instance, oxirane 118 is smoothly transformed
into 120 on treatment with BF3 .OEt2 . The key to the formation of a single product
is concurrent heterolysis of σC–O bond from β-face and migration of hydrogen as
hydride on the α-face, as shown. Contrast this with the formation of both 123 and
125 from 121. In this instance, a small time lag between the cleavage of σC–O bond
and migration of hydrogen allows the transient formation of the discrete carbocation
122, which allows migration of the angular methyl group as well, as shown, to form
a new carbocation 124. Loss of proton from 124 forms 125.
O O O
O O O O O O
O O O O H
H H O BF3 O
118 119 120
OR OR OR
O O O
O O O O H
H H O BF3 O
121 122 123
OR OR
H
O O
O O
H O BF3 H OH
124 125
11 Rearrangement via Classical Versus Nonclassical

Carbocations
In optically active exo-2-norbornyl brosylate 126, the σC–OBs bond is antiperiplanar

to the σC1–C6 bond. This allows acetolysis to proceed with neighboring group partic-
ipation, as shown, and a 50:50 mixture of 129a and 129b is formed. Since 129a
is the mirror image of 129b, the product is optically inactive overall. Cleavage of
11 Rearrangement via Classical Versus Nonclassical Carbocations 67
σC–OBs bond under neighboring group participation of σC1–C6 allows the formation of
nonclassical carbocation [17, 18] 127, which is viewed as a fast equilibrating 50:50
mixture of the classical carbocations [19] 128a and 128b, one being the mirror image
of the other. The exo-capture of 128a and 128b forms 129a and 129b, respectively.
7 7 7 7 3
4
5 4 3 5 3 5 3 3 7 5
1 4 4 5
1
4
6 * OBs 6 6 6 1
1 2 1 2 2 2 6
2
126 127 128a 128b
7 3
5 4 3 7 4 5
6 * OAc AcO *
1 1 2 6
2
129a 129b
12 Tandem Skeletal Changes and Polyene Cyclization
The effect of the antiperiplanar arrangement of an electron-deficient bond and an

electron-rich bond is so dramatic that several migrations occur, one after the other, in
quick succession. The acid-catalyzed transformation 130 → 134 is one such example
among many. Protonation of carbinol oxygen converts it into a strong leaving group.
The α-hydrogen on C4, which is anti to σC–O bond, migrates and leads to the tertiary
cation 132. Soon after, many angular group migrations take place to arrive at tertiary
cation 133. The sole fate of 133 is deprotonation to form 134.
OH OH2
3 2 1
H 10 9 11 12 H H H
4 5 13 18
H H H H 6 H
7 8 14 17 H H
16
H 15 H
131
HO 130
H
H
H
H
H H H
H
H
132 133 134
The enzyme-catalyzed polycyclization of squalene 135 produces 138, which is

known to be a precursor of cholesterol. In the process, squalene oxide is an interme-
diate, which adopts conformation 137 and rearranges, under acid catalysis, to 138
[20, 21]. In the transformations 131 → 133 and 137 → 138, many SN 2 reactions
take place in tandem for the sole reason of stereoelectronically driven well-organized
geometrical orientations of the reacting functional groups. Note that all the double
bonds are trans and that any two such consecutive bonds are 1,5-related to each other.
H
H
H
135 136
H
H
HO H HO
H H
H H
137 138
A cationic center may be derived from a variety of other sources such as acetal and
alcohol on mixing with acids. Treatment of the polyolefinic acetal 139 with stannic
chloride in pentane gives a racemic mixture of the tetracyclic isomer 142. The first
formed cationic species 140 is not chiral and, hence, either face of the nearest π bond
can react with it at equal ease. Conversion of the open-chain species 139 having no
chiral center into tetracyclic species 142 having seven such centers and yet producing
only two out of the total possible 64 racemates (27 = 128 diastereomers) is a striking
tribute to the power of the stereoelectronic effect [22].
H H
O O O OH HO(H2C)2O H
H
139 140 141
H
H
H H
OH
HO(H2C)2O H O H H
H H
142
12 Tandem Skeletal Changes and Polyene Cyclization 69
The allylic alcohol 143 furnishes tetracyclic product 146 on treatment with stannic
chloride in nitroethane at −80 °C. The first formed allylic cation 144 undergoes
tandem cyclization with remaining π bonds to form the tertiary cation 145, which
loses a proton to generate 146 [23].
H H
OH
143 144 145
H H
H H
H H
146
In a more impressive polyene cyclization, the reaction of optically active allylic

alcohol 147 with trifluoroacetic acid and ethylene carbonate followed by workup with
K2 CO3 in aqueous methanol furnished the optically active ketone 150. The reaction
is initiated by a syn-selective SN 2 reaction and proceeds to the carbonate-trapped
intermediate 149. Likewise, the reaction of the enantiomer of 147 furnished the
enantiomer of 150. The cyclization step is completely enantiospecific. The process
is a very fine example of total asymmetric synthesis due to a single chiral center in
the reacting allyl alcohol [24].
O O
O O
O O
H
HO H2O
H H
H H H
147 148 149
O
H O
H H H
H H
H
150 150
13 Application of 5-Exo-Trig Cyclization Rule
We learnt above the following three principles:

(a) The dihedral angle requirement for SN 2 reactions is 180°.
(b) The reaction in the 5-exo-trig mode is favored over the 5-endo-trig mode.
(c) Axial attack on cyclohexene π bond is favored over the equatorial attack.
While keeping these principles in mind, we proceed to analyze reactions that
involve attack on the sp2 centers. Substrates such as 151 and 153 fail to react under
basic conditions to form 152 and 154, respectively. Obviously, the oxy anion formed
from alcohol does not react with the enone in a 5-endo-trig manner, a pathway that is
formally appealing. Remember that oxy anion adds rapidly to enone in a bimolecular
process under otherwise similar reaction conditions. In contrast, 152 and 154 are
formed readily under acidic conditions, and we must understand the cause for the
same. Under the acidic condition, protonation of carbonyl oxygen in 151 leads to
a resonance mixture of 155a and 155b, and 155b allows 5-exo-trig closure to form
152 with great ease [25, 26].
O O O O
OH X O OH X O
151 152 153 OMe 154 OMe
OH OH
151 OH OH 152
155a 155b
In yet another revelation of the strong stereoelectronic requirement for intramolec-

ular SN 2 reaction, the hydroxy ester 156 furnished lactone 157 only, and none of
158, on reaction with a base. While the product 157 arises from 5-exo-trig closure
involving the attack of oxy ion on carbonyl function, 5-endo-trig closure featuring
attack of the oxy ion at olefinic carbon in a conjugate manner to form 158 is difficult
[25, 26].
13 Application of 5-Exo-Trig Cyclization Rule 71
CO2Me
CO2Me
OH O O O
156 157 158
OH O
O O
O O O O
156 157
O HO
OMe OMe CO2Me
OH O O
156 158
14 Stereocontrol in Multi-cyclization Reactions
When the species 159 and dimethyl acetone 1,3-dicarboxylate are taken together in
aqueous acid, 164 is formed as the sole product. Hydrolysis leads to dialdehyde 160,
which undergoes intramolecular condensation to generate the iminium ion 161a,
rewritten in 3D form as 161b. The enol from the dicarboxylate acts as a nucleophile,
and it reacts with the above iminium ion on the axial face to generate 162 and release
the secondary amine simultaneously. Intramolecular condensation of this secondary
amine with the other aldehyde group forms iminium ion 163, which is captured by
the other enol form of the dicarboxylate, again on the axial face, and 164 is formed
[27].
CH(OR)2 CHO H
NH2 NH2 N N
H
CH(OR)2 CHO CHO CHO
159 160 161a 161b
H
N N N
O O O
CHO
O O O
O O O O O O
O O O
162 163 164
15 Reaction on sp Carbons
The addition of a nucleophile to a triple bond such as in 165 may, in principle, lead to
two different products 166a and 166b. The added nucleophile is anti to the released
electron pair orbital in 166a and syn in 166b. The stereoelectronic effect favors the
formation of 166a. That being the case, process 166a → 165 must also be faster than
process 166b → 165. Both of these processes are E1cB reactions. Following this, the
transformation 167 → 168 under basic conditions was indeed discovered to be 50
times faster than 169 → 168 [28, 29]. Also, cis-dichloroethylene 170 is transformed
into chloroacetylene 171 approximately 20 times faster than trans-dichloroethylene
172 [30].
R R R
R R + Nu +
Nu R Nu
165
166a 166b
H CO2H H Cl
C C O2C C C CO2 C C
HO2C Cl HO2C CO2H
167 168 169
H H H Cl
C C Cl C C H C C
Cl Cl Cl H
170 171 172
The cis-dichloroethylene 170 reacts with sodium p-toluenethiolate (p-

CH3 C6 H4 SNa) in the presence of sodium ethoxide to give cis-1,2-bis-p-
tolylmercaptoethylene 175. This contrasts the behavior of trans-dichloroethylene,
which is recovered unchanged. The transformation 170 → 175 proceeds as shown,
and there is evidence in favor of 171, 173, and 174 as intermediates during the course
of the reaction [31, 32]. Trans-elimination is, therefore, favored over cis-elimination,
indicating a decisive role of stereoelectronic effects in such reactions.
EtO H H H H OEt
C C Cl C C H C C
Cl Cl Cl SAr
SAr
170 171 173
ArS ArS SAr

H C C SAr C C
H H
174 175
15 Reaction on sp Carbon 73
The addition of a nucleophile to nitrilium ion generates a product in which the

released electron pair on nitrogen occupies position anti to the nucleophile. For
instance, the N-anilinonitrilium ion 177, formed from solvolysis of the hydrazonyl
bromide 176 in the presence of sodium acetate, gives Z-178. On heating, Z-178 is
rapidly converted to the amide 179 via isomerization to E-178 [33, 34]. Note that
the acyl group migration from oxygen to nitrogen takes place in the last step of the
overall process.
R CH3 CH3 R
N N C6H3X2 R N N C6H3X2 N
Br AcO N(CH3)C6H3X2
176 177
Z-178
R N(CH3)C6H3X2 R N(CH3)C6H3X2
N N
AcO O COCH3
E-178 179
16 Stereoelectronic Control in Beckmann Rearrangement
Beckmann rearrangement [35] converts oximes and derivatives into amides. The
group that migrates is one that is anti to σN–O bond. The stereochemical integrity of
the migrating group is fully retained in the product. Thus, the migration of R1 in 180
generates the nitrilium ion 182, which hydrolyzes, via 183, to amide 184. When the
migrating group can form a stable cation, fragmentation to the corresponding nitrile
such as 180 → 185 takes place instead of migration.
R1 R1
C N C N R2 C N R1
R2 OR3 R2 OR3
180 181 182
HO R1 O
C N NHR1
R2 R2
183 184
R1
C N R1+ + R2 C N + R3O
R2 OR3
185
180
17 Stereoelectronic Control in Curtius Rearrangement
In Curtius rearrangement, the acylazide 186 is transformed into isocyanate 187 and
molecular nitrogen. The migrating group retains its stereochemical integrity just as
in Beckmann rearrangement. Stereoelectronic effects, therefore, control the reaction
because the migrating group is necessarily anti to σN−N2+ bond and also an electron
pair orbital on carbonyl oxygen as illustrated in 188.
O
R O C N + N2
N N N R
186 187
O
R C
N N N
188
Thus, both trans-addition and trans-elimination are strongly favored over the
corresponding cis-variants due to stereoelectronic effects. In 1,2-migrations, the
migrating group is always anti to the leaving group on the adjacent carbon. An
electron pair orbital anti to the migrating bond facilitates migration. Having had two
electron pairs anti to the migrating bond, the migration is rendered even more facile.
References
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References 75
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2994 (1968)
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Chem. Commun. 736 (1976)
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Chapter 3
Diastereoselectivity in Organic Reactions
Abstract This chapter deals with the facial selectivity of nucleophilic additions
to carbonyl compounds. This is explained using models such as Cram’s model,
Anh–Felkin modification of Cram’s model, Houk’s transition state model, Houk’s
electrostatic model, Cieplak’s σ → σ*# model, and cation coordination model. The
intricacies, variations, and predicted selectivities are elaborated with examples. It
has been argued that Cieplak’s σ → σ*# model is applicable to only those reac-
tions that proceed through product-like transition structures. Using the cation coor-
dination model, the facial selectivities of a number of substrates, including better
anti-selectivity of endo,endo-2,3-diethyl-7-norbornanone in comparison to that of
endo,endo-2,3-dimethyl-7-norbornanone, have been convincingly explained.
1 Introduction
The addition of a nucleophile to a carbonyl compound with an adjacent chiral center

can generate, in principle, a mixture of two diastereoisomers. The ratio of these
diastereoisomers depends on the relative bulks of non-coordinating substituents on
chiral center, the effective bulk of the nucleophile, and the reaction conditions. From
effective bulk, we mean the bulk of the solvated nucleophile, if eminent. The reaction
is schematically represented by Eq. 1.
a O a Nu a OH
b b OH b Nu
+ (1)
c d c d c d
Several models have been proposed to predict the formation of the predomi-
nant diastereoisomer. We present below a critical analysis of often used models and
explore features to assess the broadness of applicability.

https://doi.org/10.1007/978-3-030-75622-2_3
78 3 Diastereoselectivity in Organic Reactions
2 Cram’s Model for Asymmetric Synthesis
From close scrutiny of the results of several reactions, Cram proposed a model to
explain the predominant diastereoselectivity [1]. The model relies on the relative
bulks of substituents on the α carbon and envisages the approach of a nucleophile
to the carbonyl group syn to the small substituent. The carbonyl species itself was
presumed to adopt a conformation wherein it was flanked by the small- and medium-
sized groups as shown in Eq. 2. The attack syn to the medium-sized group gener-
ates the minor diastereoisomer. Understandably, the difference between the rela-
tive bulks of small- and medium-sized groups is the sole determinant of observed
diastereoselectivity. This model was so successful at reliably predicting the major
diastereoisomer from a host of reactions that came to be known as Cram’s model for
asymmetric synthesis. The reaction expressed by Eq. 2 could also be expressed by
using Newman projections of both the reactant and product as shown by Eq. 3.
MS O M
S Nu
OH M
S OH
Nu
+ (2)
L R L R L R
O
M S Nu M M
HO Nu Nu OH (3)
S + S
RL
LR LR
The difficulty with Cram’s model, however, was threefold as follows:

(a) The product was formed in eclipsed conformation, which is higher in energy
than the product in staggered conformation.
(b) The alkyl group R sterically interacts with the large substituent L in the
suggested reactant conformer.
(c) The angle of nucleophilic attack at the carbonyl carbon (Nu…C…O) is less
than 90° , which supposedly leads to substantial rise in the energy of the tran-
sition structure due to electrostatic repulsion between the similarly charged
nucleophile and carbonyl oxygen (both carry net negative charges).
It was later that the quantum chemical calculations suggested the angle of
nucleophilic attack at the carbonyl carbon to be close to the tetrahedral angle.
3 Anh–Felkin Modification of Cram’s Model

for Asymmetric Synthesis
Even if one ignores the difficulty related to the angle of attack, the first two factors
that destabilize the transition structure were serious liabilities of the Cram’s model
and needed to be addressed. The following two points need to be noted:
3 Anh–Felkin Modification of Cram’s Model for Asymmetric Synthesis 79
(a) Anh and Felkin considered a different reactant conformer in which the large
substituent was disposed orthogonally to the carbonyl group and the nucle-
ophile was allowed to approach along a trajectory opposite to it, rather some-
what closer to the small substituent to render tetrahedral attack as shown in
Eq. 4 [2, 3].
(b) The above geometrical arrangement avoids steric interactions between the
nucleophile and large group by keeping them opposite to each other and also
allows the product to be formed directly in staggered conformation.
This approach came to be known as the Anh–Felkin modification of Cram’s model
for asymmetric synthesis. The minor diastereoisomer is derived from the alternate
conformer shown in Eq. 5. However, this conformer is of higher energy for the
geometrical closeness of R and M.
O M HO S
L L Nu (4)
Nu R M
R S
O M OH
S
L Nu L (5)
Nu
M R S R
Let us consider the reaction of (S)-3-phenyl-2-butanone, 1. The two conformers of

the reactant following the Anh–Felkin modification of Cram’s model are 1a (Eq. 6)
and 1b (Eq. 7). The conformer 1a will predominate over 1b because the latter suffers
from steric interactions between the methyl groups that are gauche to each other. The
conformers 1a and 1b will generate (S,S)-2a and (R,S)-2b, respectively, on reaction
with ethyl magnesium iodide. Since 1a is the predominant conformer, (S,S)-2a is
formed as the major product.
O Me OH
Me
Ph Et Ph
Et H (6)
Me H Me
1a 2a
O
H
HO H
Ph
Me
Et Ph Et (7)
Me Me Me
1b 2b
For (R)-3-phenyl-2-butanone, 3, the two reacting Anh–Felkin conformers are 3a

and 3b. These conformers are expected to generate (S,R)-4a and (R,R)-4b as shown
in Eqs. 8 and 9, respectively, on reaction with ethyl magnesium iodide. Since the
conformer 3b is more stable than 3a on account of methyl–methyl interaction in
the latter, (R,R)-4b predominates. Note that the products (S,S)-2a and (R,R)-4b and
(R,S)-2b and (S,R)-4a are enantiomers of each other.
O H OH
H
Ph Et Ph
Et (8)
Me Me Me Me
3a 4a
O HO Me
Me
Ph Ph Et
Et (9)
Me H Me H
3b 4b
Let us extend the above analysis to (R)-3-cyclohexyl-2-butanone, 5. The two

reacting Ahn–Felkin conformers are 5a (Eq. 10) and 5b (Eq. 11), with the latter
predominating. The predominant product expected from these conformers on reac-
tion with a hydride reagent is (R,R)-6a and (S,R)- 6b, respectively. Because the
conformer 5b is more stable than 5a due to methyl–methyl gauche interaction in the
latter, the product (S,R)-6b must predominate over (R,R)-6a. Indeed, (S,R)-6b and
(R,R)-6a are formed in a 72:28 ratio on reduction using lithium aluminum hydride
(LiAlH4 ) [1].
O H OH
H
C6H11 H C6H11
H Me (10)
Me Me Me
5a 6a
O Me HO Me
C6H11 C6H11 H
H (11)
Me
Me H H
5b 6b
O OH
C6H11 C6H11
Me Me
H Me H (12)
HMe H
5c 6c
Although the predominant product from the reaction of 5 with LiAlH4 is well
explained by the Anh–Felkin modification of Cram’s model, the question arises as to
what guaranteed the conformer 5b? An ab initio calculation of (R)-5 at HF/6-31G(d)
level of theory predicts conformer 5c (Eq. 12) to be the lowest on potential energy
surface. Some more comments on conformer 5c are as follows:
3 Anh–Felkin Modification of Cram’s Model for Asymmetric Synthesis 81
(a) In this conformer, the σC–H bond on the asymmetric carbon is nearly eclipsing
with the σC–Me bond on the carbonyl carbon (torsion angle = 16° ).
(b) This is not the conformer which Cram had considered to be the reacting
conformer either.
(c) It turns out that while Cram used a much less-stable conformer to explain the
predominant product, Anh and Felkin’s reacting conformer was close to the
most stable conformer.
(d) Arguably, the conformers are in dynamic equilibrium with one another. It
is, therefore, likely that somewhat less-stable conformer 5b assumes the
significance of being the reacting conformer.
One may be tempted to consider 5c react with nucleophiles along the trajectory
shown by the arrow. This trajectory is not only anti to the largest substituent, cyclo-
hexyl, on the asymmetric carbon but it also fulfills the need for tetrahedral angle
attack. The product is directly formed in staggered conformation as we allow for
a small gradual rotation (clockwise in the present instance) during the event the
carbonyl carbon changes its hybridization from sp2 to sp3 . The product 6c is the
same as 6b.
In the indicated approach of the nucleophile to conformer 5c, it is gauche to
the methyl group on the adjacent sp3 carbon to raise the energy of the transition
structure. Such an energy contribution will be higher in the alternate transition struc-
ture, wherein the nucleophile will be gauche to the large cyclohexyl group. Thus, the
reaction represented by Eq. 12 may constitute the minimum energy reaction pathway.
One may also wish to invoke competitive σ → π*C=O interactions arising from
substituents on the α-carbon to control conformer distribution of the reactant and,
thus, the selectivity of nucleophilic addition. Since it is an established fact that the
σC–H bond is more electron-donating than the σC–C bond [4–6], the possible options
are 5d (Eq. 13) and 5e, (Eq. 14), wherein σC–H and πC=O are parallel to each other to
allow the σC–H → π*C=O interaction. The nucleophile enters from the opposite side,
as shown by the arrows [7, 8].
This model favors the approach of a nucleophile to an electrophilic center from
the direction opposite to the most electron-donating substituent at adjacent carbon.
However, from the discussion above, both 5d and 5e are high-energy conformers.
While both methyl groups are gauche to each other in 5d, methyl on carbonyl carbon
is gauche to the cyclohexyl group in 5e. For the differential bulks of methyl and
cyclohexyl groups, the conformer 5d will be expected to be lower in energy than
conformer 5e. Two interesting points emerge:
(a) Both 5d and 5e converge to 5c on geometry optimization. Thus, 5c is the most
stable conformer with a torsion angle of 99° between the two methyl groups.
(b) The product 6d is the same as 6b above for having the same configuration.
Likewise, products 6e and 6a are the same. This could be taken to suggest that
conformer 5d may as well be the reacting conformer, which is different from
the conformers considered by Cram and also Anh–Felkin previously.
O HO C6H11
C6H11
H H H
H
Me
(13)
Me Me Me
5d 6d
O OH
Me Me
H H H
H (14)
C6H11 Me C6H11 Me
5e 6e
In maintaining the tetrahedral angle of attack, nucleophiles must approach the

carbonyl carbon from the direction which is in between the methyl and cyclohexyl
groups, closer to the methyl group, on the sp3 carbon. Such a transition structure has
not been calculated to warrant further comment. We will learn, later in this chapter,
more about σ → π*C=O control on diastereoselection.
4 Cieplak’s Model for Diastereoselectivity
To explain the stereochemical outcome in nucleophilic additions to substituted cyclo-

hexanones, Cieplak advocated for the σ → σ*# interaction (σ# is the incipient bond
that is being formed between the nucleophile and carbonyl carbon in the transition
structure (TS) and σ*# the corresponding antibonding orbital) as a TS-stabilizing
factor and, thus, suggested the approach of nucleophile from the direction anti to
more electron-donating σ bond on α-carbon. For instance, nucleophiles will approach
largely on axial face to result predominantly in equatorial alcohol, as indeed observed
from experiments, for the fact that axial σC–H bonds are better electron donors than
σC2–C3 and σC5–C6 ring bonds. The σ → σ*# concept invited many researchers to
explore new substrates to judge its applicability. Cieplak’s σ → σ*# approach to
discern axial versus equatorial selectivity of cyclohexanone is summarized in Fig. 1.
The reduction of 4-tert-butylcyclohexanone by LiAlH4 in tetrahydrofuran at 0
°C affords a mixture of trans- and cis-alcohols in an 88.5:11.5 ratio, Table 1 [9].
The predominant attack takes place from the axial direction as predicted above by
Fig. 1 Cieplak’s σ → σ*# Nu

model to explain axial versus 3 1 O
equatorial selectivity of 2
cyclohexanone in reaction O
4 5 6 Nu
with nucleophiles H
H
4 Cieplak’s Model for Diastereoselectivity 83
Table 1 Relative yields of the equatorial approach of the nucleophile in nucleophilic additions to
4-tert-butyl-, 3-methyl- and 3,5-dimethylcyclohexanones (reproduced from Ref. 7)
Nucleophile and reaction condition O O O
t-Bu
LiAlH4 , THF, 0 °C 11.5 [9] 15.4 [9] 17.0 [9]

MeLi, Et2 O, 0 °C 65 [9] 66 [9]
EtMgBr, Et2 O, 0 °C 69 [10] 72 [11]
the Cieplak model. This selectivity is expected to diminish when the ring carries an
equatorial methyl group on C3 for the following reasons:
(a) The C3-methyl group does not introduce elements of steric interaction during
the course of nucleophilic addition.
(b) The C3-methyl group raises the electron-donor ability of σC2–C3 to support the
equatorial attack. The axial attack is, therefore, diminished at the expense of
an equatorial attack.
In other words, the difference of the sum of σC2–H → σ*# and σC6–H → σ*#
interactions, which supports the axial attack, and σC2–C3 → σ*# and σC5–C6 → σ*#
interactions, which support the equatorial attack, is diminished, leading to a reduced
equatorial attack. Indeed, within a small approximation, 3-methylcyclohexanone
exhibits a 15.4% preference for the equatorial attack as compared to 11.5% for
4-tert-butylcyclohexanone under otherwise identical reaction conditions [9]. From
extrapolation of this argument, cis-3,5-dimethylcyclohexanone is expected to exhibit
a better preference for the equatorial attack in comparison to 3-methylcyclohexanone
and, hence, the axial selectivity must diminish further. Indeed, the observed equatorial
preference of cis-3,5-dimethylcyclohexanone is 17.0, 1.6% more than that of 3-
methylcyclohexanone [9].
Since the nucleophile must approach the carbonyl group at a tetrahedral angle,
the axial substituents on C3 and C5 offer resistance to the reaction on the axial face.
The following two scenarios emerge:
(a) An increase in the size of nucleophiles may lead to enhanced equatorial attack
for a given set of axial substituents, including hydrogen atoms on C3 and C5.
(b) An axial substituent larger than hydrogen may cause enough steric resistance
to the axial approach of even a relatively small nucleophile and, thus, promote
equatorial attack.
In support of the first scenario, the reaction of 4-tert-butylcyclohexanone
with MeLi in Et2 O at 0 °C generates a 65:35 mixture of cis-4-tert-butyl-
1-methylcyclohexanol (product of equatorial attack) and trans-4-tert-butyl-1-
methylcyclohexanol (product of axial attack). Compare this with 11.5:88.5 compo-
sition of cis- and trans-4-tert-butylcyclohexanols obtained on reaction with LiAlH4
in THF at 0 °C [9]. Like the reaction with MeLi, reaction with C2 H5 MgBr in Et2 O at
Table 2 The yields of the

Grignard
axial approach of Grignard O 1 O
reagent 6
reagents to O
t-Bu Ph O 5
4-tert-butylcyclohexanone 3
2 4
and
2-phenyl-1,3-dioxan-5-one CH3 MgI 45 98
(reproduced from Ref. 7)
CH3 CH2 MgI 31 98
(CH3 )2 CHMgI 18 96
(CH3 )3 CMgCl 0 no addition
0 °C generates a 69:31 mixture of cis- and trans-4-tert-butyl-1-ethylcyclohexanols

[10]. The dimeric and/or multimeric nature of alkyllithiums and Grignard reagents
increase their bulk enough to turn the attack on the equatorial face significantly.
The effect of a gradual increase in the bulk of a given type of nucleophile on
the facial selectivity of a given cyclohexanone derivative could be gleaned from the
measurement of the relative axial approach. The axial selectivity decreases in the
order 45% → 31% → 18% → 0% on changing the nucleophile from CH3 MgI
→ CH3 CH2 MgI → (CH3 )2 CHMgI → (CH3 )3 CMgCl in reaction with 4-tert-
butylcyclohexanone as shown in Table 2. The steric effect arising from (CH3 )3 CMgCl
is so high that absolutely no reaction tales place on the axial face and cis-alcohol is
formed as the sole product from 100% attack on the equatorial face.
Let us consider 2-phenyl-1,3-dioxan-5-one and compare its selectivity profile with
that of 4-tert-butylcyclohexanone in reactions with Grignard reagents; see Table 2. In
2-phenyl-1,3-dioxan-5-one, σC4–O3 → σ*# and σC6–O1 → σ*# interactions destabilize
the equatorial TS because the participating σ bonds are electron-deficient due to the
significantly high electronegative character of oxygen [12]. Since σC4–Hax → π*C=O
and σC6–Hax → π*C=O interactions stabilize the axial TS, the corresponding product is
formed almost exclusively. However, in reaction with tert-butylmagnesium chloride,
the axial addition is denied completely because the steric interaction between the
phenyl group on C2 and large tert-butylmagnesium chloride is significant.
On replacing the ring oxygen in 6-phenyl-1-oxan-3-one by sulfur, the selectivity
profile is expected to change in favor of equatorial attack because the σS–C bond
is strongly electron-donating. The direction of electron donation is from sulfur to
carbon. Likewise, on replacing both ring oxygen atoms in 2-phenyl-1,3-dioxan-5-
one by sulfur, the equatorial approach of the nucleophile is expected to constitute the
major pathway. In relative terms, (σS–C2 → σ*# + σC4–C5 → σ*#) > (σC2–Hax → σ*#
+ σC4–Hax → σ*#) in 6-phenyl-1-thian-3-one and (σS–C4 → σ*# + σS–C6 → σ*#)
(σC4–Hax → σ*# + (σC6–Hax → σ*#) in 2-phenyl-1,3-dithian-5-one. These predictions
are also in good qualitative and quantitative agreement with the experimental results
collected in Fig. 2 [13, 14].
The electron-donating power of σC2–C3 and σC5–C6 bonds in cyclohexanone could
also be modified by incorporating equatorial electron-withdrawing substituents on
C3 and C5 positions. The consequent decrease in σC2–C3 → σ*# and σC5–C6 →
σ*# interactions implies more axial than equatorial attacks of nucleophiles. This
exclusive
O S
O O
81%
88% S
O O
76%
Ph 96% Ph S
O S O
85%
Fig. 2 The axial versus equatorial approach of nucleophile in reduction with a metal hydride
O O O 1 O
2 3
6
H 5 4
15% H 9% NC 3%
Fig. 3 The relative equatorial approach of nucleophile in reduction of trans-decalones
explains the opposite effects of methyl and cyano substituents on the stereochemistry
of reduction of trans-decalones by LiAl(OCMe3 )3 H. While the methyl derivative
allows 15% equatorial attack, it is diminished to just 3% for the nitrile; see Fig. 3
[15].
Why does the methyl derivative allow a larger equatorial attack (15%) than the
unsubstituted derivative (9%) even when σC–H is a better electron donor than σC–C ?
The origin of the observed effect may be traced to the stereoelectronic effect arising
from the σC–H bond of the methyl group, which is antiperiplanar to the σC4–C5 bond,
as shown in the last structure in Fig. 3. This results in the σC–H → σ*C4–C5 interaction
worth approximately 3.3 kcal/mol. This interaction raises the electron density of the
σC4–C5 bond, which supports an enhanced equatorial approach of the nucleophile.
Different heteroatoms in 4-heterocyclohexanones alter the electron densities of
σC2–C3 and σC5–C6 bonds differently. However, Cieplak invoked transannular electron
delocalization of the sort depicted in Fig. 4 and argued in favor of increased axial
attack as a consequence of increasing the electron-donating ability of heteroatom
lone pair. It must be remembered that the electron-donating ability of a heteroatom
lone pair is opposite to its electronegativity, i.e., less-electronegative the heteroatom,
more electron-donating is its lone pair, and vice versa. Accordingly, sulfur, nitrogen,
and oxygen display decreasing donor ability. Following the Cieplak model, the ease
of axial approach of a given nucleophile must decrease in the same order. However,
from the experimental results collected in Table 3, the relative trend for axial approach
Fig. 4 Cieplak’s n → σ*#

overlap hypothesis to explain
axial versus equatorial O
selectivity of
X
4-heterocyclohexanones; Sax
and Seq indicate axial and O
X
equatorial approaches,
respectively
Sax Seq
Table 3 Experimental selectivities of trans-2-heterobicyclo[4.4.0]decan-5-ones in reduction with

NaBH4 and Na(CN)BH3
H H H
6
5 X X + X
4 HO H
2 3
O 1 H H H
H OH
Heteroatom X Hydride Temperature (oC) Time (min) Aack (ax:eq)

NBn NaBH4 0 60 >30:1
Na(CN)BH3 25 60 >34:1
O NaBH4 0 30 6.3:1
Na(CN)BH3 25 60 13:1
S NaBH4 0 40 3.9:1
Na(CN)BH3 25 60 9.5:1
is N > O > S [16]. Cieplak’s hypothesis based on n → σ*# overlap, thus, fails to
explain the observed trend in stereoselectivity.
There is variation in the electron densities of the ring bonds in cyclohexanone
on introducing a polar substituent on C4 as well. According to Cieplak, the impact
of such a substituent is controlled by through-space n → σ*# overlap as shown in
Fig. 5, and the predominance of axial attack is expected for both axial and equatorial
O O O O
Seq.ax > Seq.eq Sax.ax > Sax.eq
Fig. 5 Pictorial presentation of the effect of polar C4-substituents on cyclohexanone on axial versus
equatorial diastereoselectivity based on n → σ*# interaction (reproduced from Ref. [7])
Table 4 Stereoselectivity in the reduction of 4-substituted trans-decalones with NaBH4 in MeOH

at 25 °C
H OH
O
2
3 1 OH + H
5 6
X 4 X X
eq-alcohol ax-alcohol
X (eq:ax)-alcohol X (eq/ax)-alcohol
H 60:40
eq-OH 61:39 ax-OH 85:15
eq-OAc 71:29 ax-OAc 83:17
eq-Br 66:34
eq-Cl 71:29 ax-Cl 88:12
ax-F 87:13
substituents. The experimental results obtained by Houk for substituents such as

OH, OAc, Br, Cl, and F support this hypothesis; see Table 4 [17]. A substituent
occupying axial position was found to be better axial director than when occupying
an equatorial position. The through-space n → σ*# overlap, however, has not been
confirmed by quantum chemical calculations. Having allowed σ → σ*# interaction
as a more significant control, a polar electron-attracting substituent on C4 should be
expected to inductively reduce the electron density in σC2–C3 and σC5–C6 bonds to
discourage equatorial attack and, thus, lead to enhanced axial selectivity. The axial
selectivity is primarily supported by σC2–Hax → σ*# and σC6–Hax → σ*# interactions.
5-Substituted 2-adamantanones constitute a class of molecules belonging to 2,4,6-
trisubstituted cyclohexanones. William le Noble has studied the reduction of several
of this class of molecules by different hydride sources and noted the selectivity
profiles [18]. The results are collected in Table 5. Although the reaction conditions
are not exactly the same for direct comparison with the results in Table 4, the following
observations may still be noted:
(a) The observed axial preferences of 2-adamantanones are not as high as those
of 4-substituted cyclohexanones.
(b) The strong σC2/C6–Hax → σ*# interactions in 4-substituted trans-decalones vis-
à-vis the corresponding but relatively weak σC–C → σ*# interactions in 5-
substituted 2-adamantanones are likely to contribute to higher axial selectivity
of the former class of molecules.
(c) 5-Hydroxy-2-adamantanone exhibits largely equatorial selectivity. This cannot
be explained within the ambit of the n → σ*# hypothesis. An alternate rationale,
therefore, is desirable. It is likely that the carbinol function is transformed into
Table 5 Stereochemical outcome of nucleophilic additions to 5-substituted 2-adamantanones

media
O
H OH HO H
2
1 3
6
4 7
9 +
10
R 5 8 R R
ax-attack eq-attack
R Reacon condions ax:eq selecvity

C6H5 LiAlH4, Et2O, rt 56:44
C6H5 LiAl(OBut)3H, Et2O, rt 49:51
F NaBH4, i-PrOH, rt 62:38
Cl NaBH4, i-PrOH, rt 59:41
OH NaBH4, MeOH, 0 oC 43:57
CF3 NaBH4, i-PrOH, 0 C o
59:41
CO2Me NaBH4, MeOH, 0 oC 61:39
alkoxide under the alkaline conditions of NaBH4 reduction. It renders the σC–O
bond electron donor, which raises electron density in the ring σC–C bonds and
the equatorial attack is enhanced.
In order to explain the selectivity observed with cyclohexanones bearing polar
substituents at position 4, Cieplak cited the reactions of 5-phenyl-2-adamantanone
with sodium acetylide in liquid NH3 shown in Eq. 15 and 5-carbomethoxy-2-
adamantanone with LiAl(Ot Bu)3 H in THF as shown in Eq. 16. These reactions
proceed with 66:34 and 83:17 selectivity in favor of an axial attack. While the
example in Eq. 15 may conform to πAr → σ*# overlap as depicted in Fig. 5, it
is not clear which nonbonding orbital of the carbomethoxy group is so engaged.
In view of vicinal overlap, phenyl and carbomethoxy groups are electron-attracting
and, thus, reduce the electron density in σC3–C4 and σC1–C6 bonds to destabilize the
equatorial TS. The carbomethoxy group, being more electron-attracting than phenyl,
is expected to cause improved axial selectivity, which is indeed the case.
H
Ph 6 Ph
5 1 2 (15)
NaCCH, NH3
4 O
3 - 78 oC
OH
O O-
syn Nu
anti 7
4
5 3 7a: R1 = R2 = CH2OMe
1 2
6 7b: R1 = R2 = CH=CH2
R2
7c: R1 = R2 = CO2Me
R1
7 8
Fig. 6 The structures of selected norbornan-7-ones 7 and the proposed rigid conformer 8 for the
species 7b
MeO2C MeO2C
LiAl(OtBu)3H H (16)
O
THF, reflux
OH
Norbornan-7-one has been the subject of intense experimental study of

facial selectivity caused by endo substituents at positions 2 and 3; see Fig. 6.
The impetus arose primarily because, unlike cyclohexanone, norbornan-7-one
is rigid and also devoid of significant geometrical distortion around carbonyl
function [19, 20]. While 2,3-bis(methoxymethyl)norbornan-7-one (7a) and 2,3-
divinylnorbornan-7-one (7b) show anti preference for addition of nucleophiles,
2,3-bis(methoxycarbonyl)norbornan-7-one (7c) exhibits syn preference.
All the three substituents are electron-withdrawing and, thus, the Cieplak model
predicts predominantly syn addition to all. Mehta and le Noble [21] have attributed
the anti-selectivities of 7a and 7b to through-space donations from the substituents in
rigid conformers such as 8 for the divinyl species. In 8, the vinyl π bonds lie parallel
to σC1–C2 and σC3–C4 bonds. Though this geometrical assumption may appear logical
[22, 23], the rigid conformer premise required verification.
5 Houk’s Transition State and Electrostatic Models

for Diastereoselectivity
From the TS structures for the addition of LiH to a series of 2,3-disubstituted

norbornan-7-ones, Houk has concluded that (a) Cieplak’s premise of stereoselection
based on σ → σ*# interaction is not important, and (b) the electrostatic effect consti-
tutes the sole control element [14, 24–26]. Electron-attracting substituents induce
positive charges on C2 and C3, which electrostatically attract the nucleophile on the
syn face. In contrast, electron-donating substituents induce negative charges, which
electrostatistically repel the nucleophile and an attack on the anti face is realized.
The question arises as to why 7a and 7b favor anti addition and 7c syn addition
when the substituents in all of them are electron-withdrawing? Houk considered
electrostatic repulsion between the nucleophile and the substituents in 7a and 7b,
and electrostatic attraction in 7c. The differential treatment of otherwise electron-
withdrawing substituents may, at best, be considered an anomaly.
The rigid conformer argument for 2,3-bis-methoxymethyl derivative 7a with the
attendant n → σ*C1–C2 and n → σ*C3–C4 interactions and 2,3-divinyl species 7b with
the attendant πC=C → σ*C1–C2 and πC=C → σ*C3–C4 interactions, as assumed by
Mehta and le Noble, was examined by natural bond orbital (NBO) analysis [27–29].
While the assumption for 7b was found true, it was not so for 2,3-bis-methoxymethyl
derivative 7a.
The ring oxygen in 4-oxatricyclo[5.2.1.02,6 ]decan-10-one (9) and 4-
oxatricyclo[5.2.1.02,6 ]dec-8-en-10-one (10) is indeed held in such a rigid conformer
that donation from one of the two electron pair orbitals to σ*C1–C2 and σ*C6–C7
appears a distinct possibility. Alternatively, the electron-withdrawing nature of
the ring oxygen will be expected to reduce the residual charges on C2 and C6,
and support syn-selectivity in compliance with Houk’s electrostatic model. The
experimental selectivities of these molecules under different conditions are collected
in Table 6 [30]. While the general trend for both the molecules under normal reaction
conditions favors anti-selection, the selectivity of 10 is much higher than that of 9
(see the footnotes of Table 6 for details).
NBO analysis does not show n → σ*C1–C2 and n → σ*C6–C7 interactions in both 9
and 10. Clearly, an interpretation of anti-selectivity based on electron donation from
ring oxygen is erroneous. Further, C2 and C6 on a syn face and C8 and C9 on an
anti face carry NBO charges of −0.29 and −0.47 in 9, and −0.28 and −0.22 in 10
[31–33]. These charges predict syn addition to 9 and anti addition to 10, according
to Houk’s electrostatic model. The difference of charges in 10 is too small to explain
its high anti-selectivity. The weak anti-selectivity of 9 observed from reaction with
LiAlH4 is also alarming and against the model. An alternate rationale is, therefore,
required to explain the observed anti-selectivities.
Mehta and coworkers have introduced 5-substituted bicyclo[2.1.1]hexan-2-ones
11 as new probes for experimental as well as a computational study of electronic
effects on π-selectivity; see Table 7 [34]. Houk’s TS model was discovered to fail in
correctly treating the carbomethoxy and acetylenic substrates. The residual charges
on C5 and C6 are collected in Table 8. C5 is always less negatively charged than C6
and, thus, nucleophiles must always approach the carbonyl group from the direction
syn to C5. However, this is not the case always. The electrostatic model, therefore,
also failed in correctly predicting the diastereoselectivity.
It is amply clear from the foregoing discussions that no single model is sufficient
to rationalize the observed facial selectivities of substrates of different skeletal types
under varying reaction conditions. Some models have larger applicability and, hence,
greater appeal than others. For instance, the Cieplak model based on the σ → σ*#
interaction has been verified by many researchers based on the study of different
substrate types. The TS model must conceivably work all the time. However, it also
fails in select instances. Why does the TS model fail at all? LiH is not known to act
as a nucleophile. Is the use of LiH as a nucleophile in the calculation of transition
states the source of discrepancy? Does the calculated TS closely represent the true
5 Houk’s Transition State and Electrostatic Models for Diastereoselectivity 91
Table 6 The π-Selectivities of hydride reductions of 9 and 10

O 11 O 11
anti syn anti 10 syn
7 7
8 6 8 6
2 2
9 1 9 1
5 5
O 3 O 3
4 4
9 10
_________________________________________________________________________________________________________________________
entry 9/10 Hydride Solvent Lewis acid Time (h) Yield (%) an:syn
__________________________________________________________________________________________________________________________
1 9 NaBH4 MeOH 0.5 >95 1.0:1.0
2 9 NaCNBH3 MeOH pH 3−4 0.5 >95 2.1:1.0
3 9 LiAlH4 Et2O 2.0 >80 1.1:1.0
4 9 DIBAL-H toluene 2.0 >85 2.0:1.0
5 9 DIBAL-H toluene TiCl4 (3 equiv) 0.5 >85 4.8:1.0
6 9 L-Selectride THF 1.0 >95 1.0:1.5
7 9 L-Selectride toluene 1.0 >85 1.0:8.0
8 9 L-Selectride toluene TiCl4 (3 equiv) 2.0 >80 1.3:1.0
9 10 NaBH4 MeOH 1.0 >85 23:1.0
10 10 NaCNBH3 MeOH pH 3−4 1.0 >95 25:1.0
11 10 LiAlH4 Et2O 2.0 >95 4.5:1.0
12 10 DIBAL-H toluene 2.0 >75 1.8:1.0
13 10 DIBAL-H toluene TiCl4 (3 equiv) 0.5 >85 >20:1.0
14 10 L-Selectride THF 1.0 >85 15:1.0
15 10 L-Selectride toluene 1.0 >85 2.3:1.0
There is a strong dependence of selecvity on the specific hydride used and the solvent employed. The selecvity of 9 is reversed
with the use of L-Selectride. Unlike most other reducing species that favor an addion, L-Selectride favors syn addion. The effect
of solvent on reacon with L-Selectride is phenomenal; the selecvity changes from 1:1.5 in THF (entry 6) to 1:8 in toluene (entry 7).
Compound 10 exhibited an-selecvity throughout. The magnitude of selecvity is, again, highly dependent on the source of hydride
and the solvent. Throughout, there is no reversal in selecvity of 10. This contrasts the results for 9 and demonstrates a controlling
role of the π-bond. Coordinaon of π-bond to the nucleophile, through caon, followed by delivery of nucleophile to carbonyl group
syn to it appears reasonable. Saturaon of π-bond in the products formed from 10 generates the same product mixture as that from
9, in different proporons though. Lewis acids promote an addion to both 9 and 10. The exclusive an addion of DIBAL-H to 10 in
presence of TiCl4 in toluene (entry 13) is indeed remarkable in comparison to 1.8:1 selecvity observed in its absence (entry 12).
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
TS for the reaction under consideration? What is the nature of the TS structure? Is it
reactant-like or product-like? Is there a need to include solvent effects in calculations?
We shall try to find answers to several of these questions in the sections below.
6 Cation Coordination Model (σ → π* Model)

for Diastereoselectivity
A rather simple premise to understand facial selectivity may be to consider geomet-

rical changes around carbonyl carbon on coordination of oxygen with a positively
charged species before the reaction with nucleophile. The positively charged species,
Table 7 The π-selectivities of different 5-substituted bicyclo[2.1.1]hexan-2-ones

O HO H H OH
anti 3 2 syn
1 NaBH4
6 +
4 5 MeOH, 0 oC
11 R R R
-------------------------------------------------------------------------------------------------
11a, R = CN 75% 25%
11b, R = CO2Me 66% 34%
11c, R = CCH 60% 40%
11d, R = CH2OH 48% 52%
11e, R = CH2CH3 47% 53%
11f, R = CH=CH2 44% 56%
-------------------------------------------------------------------------------------------------
Table 8 The residual charges on C5/C6 of 11 at B3LYP/6-31G* level

----------------------------------------------------------------------------------------------------------------
11, R= Charge at C5 Charge at C6
----------------------------------------------------------------------------------------------------------------
CN −0.362 − 0.454
CO2Me − 0.351 − 0.453
CCH − 0.316 − 0.454
CH2OH − 0.271 − 0.453
CH2CH3 − 0.244 − 0.451
CHCH2 − 0.270 − 0.454
----------------------------------------------------------------------------------------------------------------
in effect, is the cation companion of the true nucleophile. This premise is fortunately
based on the very fact that such a coordination has previously been demonstrated to
constitute the initial step [35].
Coordination with cations will reduce the πC=O bond order to usher in pyramidal-
ization at carbonyl carbon. This will change the torsion angle of carbonyl oxygen with
a select ring position. The nucleophile will then preferentially attack the carbonyl
carbon on the face with an increased torsion angle. Since the change in torsion angle
will depend on the nature, orientation, and relative position of a given substituent,
the approach is likely to hold promise for the prediction of selectivity. In applying
this concept to cyclohexanone, while considering tetrahedral pyramidalization at
6 Cation Coordination Model (σ → π* Model) for Diastereoselectivity 93
O-M+
O 5
6
+ M+ 1 O-M+ +
4 3 2
H H
H H
12a 12b
Nu OH
OH Nu
13a 13b
Fig. 7 Pyramidalization scenarios on coordination of carbonyl oxygen in cyclohexanone with metal

ion M+
carbonyl carbon for the sake of simplicity, two distinct scenarios emerge and 12a
and 12b are formed as shown in Fig. 7.
In 12a with axial pyramidalization, the empty orbital is antiperiplanar to σC2–Hax
and σC6–Hax bonds. Likewise, in 12b with equatorial pyramidalization, the empty
orbital is antiperiplanar to σC2–C3 and σC5–C6 bonds. Since the σC–H bond is a better
electron donor than the σC–C bond, the principle of stereoelectronic effect dictates
12a of lower energy than 12b. An electron-rich nucleophile (a Lewis base) is thus
expected to be electrostatistically drawn to the empty orbital (a Lewis acid) on the
axial face in 12a, leading to the formation of the equatorial alcohol 13a. The axial
alcohol 13b will likewise be formed from 12b. Support for this analysis comes from
the observation that conformationally locked and sterically unbiased cyclohexanone
generates equatorial alcohol predominantly.
In 3-oxacyclohexanone 14, Fig. 8, interactions of σC2–Hax and σC6–Hax with the
axially oriented empty orbital on carbonyl carbon are more energy-lowering than the
interactions of σC2–O3 and σC5–C6 with the equatorially oriented empty orbital. The
σC2–O3 bond is electron-withdrawing for the electron-attracting nature of oxygen.
Consequently, axial pyramidalization [36, 37] and, thus, predominantly axial attack
take place. This is in excellent agreement with experiments [7, 8]. From the extrapo-
lation of these arguments to 3,5-dioxacyclohexanone 15, one will predict better axial
selectivity than 3-oxacyclohexanone 14, which also is in agreement with experiments
[36–38].
5 O
6 O O O
O 1 O S
4 3 2 O
H S S
H
14 15 16 17
Fig. 8 Structures of 3-oxacyclohexanone, 3,5-dioxacyclohexanone and the corresponding thia-

analogs
A σS–C bond is so highly electron-donating from sulfur to carbon that the sum of
(antiperiplanar) interactions of one σC–C bond and one σS–C bond with an equatorially
oriented empty orbital is significantly larger than the sum of antiperiplanar interac-
tions of the two σC–Hax bonds with an axially oriented empty orbital. This being so,
the situation reverses from 3-oxacyclohexanone 14 to 3-thiacyclohexanone 16, and
from 3,5-dioxacyclohexanone 15 to 3,5-dithiacyclohexanone 17. Both 16 and 17
have been found to exhibit high equatorial selectivity [7, 8]. Indeed, cation coordina-
tion allows axial pyramidalization in 14 and 15 as opposed to significant equatorial
pyramidalization in 16 and 17 [38].
As the Lewis acid strength of the cation increases, its complexation with the
carbonyl oxygen becomes stronger with a corresponding increase in pyramidaliza-
tion. This, in turn, leads to better diastereoselectivity. Conversely, cation remaining
the same, selectivity must not vary significantly for insignificant changes in steric
requirement of nucleophiles. The following observations vindicate these arguments:
(a) The ax:eq selectivity varied from 7.7:1 to 16:1 to >25:1 in the reaction of 3,5-
dioxacyclohexanone derivative shown in Eq. 17 with LiAlH4 , DIBAL-H, and
a Grignard reagent, respectively [36]. The intensity of coordination is expected
to improve in the same order by following the HSAB principle.
(b) The selectivity remained at >25:1 when nucleophile was varied from MeMgX
to n-BuMgX to PhMgX [36].
Nu OH
O
O O OH O Nu
O O O (17)
+
In the event the cation possesses poor coordinating ability because of either
diffused positive charge or large size, the level of diastereoselection will be low
due to reduced pyramidalization and, thus, poorly defined axial versus equatorial
disposition of the electron-deficient orbital on carbonyl carbon. In conformity with
this argument, the following examples are noteworthy:
(a) 3-Oxacyclohexanone exhibits 90 and 85% axial selectivity when reacted with
AlH4 − possessing, respectively, Li+ and (n–C8 H17 )3 (n–Pr)N+ as the cations.
Li+ complexes better with the carbonyl oxygen than the large ammonium ion
[37].
(b) 4-Methylcyclohexanone predominantly exhibits axial selectivity in reactions
with LiAlH4 and NaBH4 . However, the selectivity turns equatorial in reactions
with K-Selectride (88%) and Li-Selectride (80.5%) due largely to their very
large sizes that cause significant steric crowding in the TS for the axial attack
[39]. The marginally higher equatorial selectivity, i.e., less-axial selectively
observed with K-Selectride is likely due to the relatively inferior coordinating
ability of K+ over Li+ .
O 11 O O O O
eq attack 2 ax-attack
1 3
8 10 9 4
7 6 N5 N N B B
O- Nu
18 19 20 21 22
D1 = O11-C2-C3-C4, D2 = O11-C2-C3-C10
The axial and equatorial attacks are in respect of heteroatom-containing cyclohexanone.
Fig. 9 The 5-aza- and 5-bora-2-adamantanones and derivatives studied for the selectivity profile
Table 9 Selected torsion angles of 5-aza- and 5-bora-2-adamantanones and their cation complexes
Entry Substrate D1 D2
1 5-aza-2-adamantanone 120.88 122.10
5-aza-2-adamantanone; C = O…H+ 108.53 137.77
5-aza-2-adamantanone; C = O…H+ and N…H+ 135.50 107.55
2 N-methyl-5-aza-2-adamantanone 123.00 117.87
N-methyl-5-aza-2-adamantanone; C = O…H+ 135.30 107.70
3 5-aza-2-adamantanone N-oxide 123.66 117.98
5-aza-2-adarnantanone N-oxide; C = O…H+ 128.82 114.99
4 5-bora-2-adamantanone 118.17 122.18
5-bora-2-adamantanone; C = O…H+ 123.27 119.40
5-bora-2-adamantone; B…H− and C = O…H+ 100.91 142.88
Let us consider diastereoselectivities of 5-aza-2-adamantanone 18, N-methyl-

5-aza-2-adamantanone 19, 5-aza-2-adamantanone N-oxide 20, and 5-bora-2-
adamantanone 21, Fig. 9. 5-Substituted 2-adamantanones, investigated thoroughly
by le Nobel [40, 41], allow us to test the validity of the model. In the application of
the model, we are required to estimate the torsion angles D1 and D2. An increase in
D1 with a corresponding decrease in D2 supports an axial attack for the heteroatom-
containing ring. On the contrary, an increase in D2 with a corresponding decrease
in D1 supports the equatorial attack. By taking H+ as a representative cation, the
torsion angles D1 and D2 are collected in Table 9. H+ was used as a substitute for
metal cation for computational simplicity.
5-Aza-2-Adamantanone, 18
The reduction in torsion angle D1 by >12° and enhancement in torsion angle D2 by

>15° on carbonyl protonation as shown in Fig. 10b suggests equatorial pyramidaliza-
tion and, hence, preference for equatorial nucleophilic attack. The bonds σC3–C4 and
Fig. 10 a 18, b 18 with C=OH+ , c 18 with C = OH+ and NH+
σC1–C9 are more electron-rich than σC1–C8 and σC3–C10 consequent to being antiperi-
planar to equatorial lone pair orbital on nitrogen. This situation is similar to those in
5-trimethylsilyl- and 5-trimethylstannyl-2-adamantanones, which have been shown
to exhibit, respectively, 45:55 and 43.5:56.5 selectivity in favor of an equatorial attack
on reduction with NaBH4 in isopropanol [40]. The selectivity is slightly higher at
35:65 in the reaction of tin-derivative with MeLi in Et2 O. Both σC–Si and σC–Sn bonds
are good electron donors.
The above trend with 5-aza-2-adamantanone reverses on protonation of nitrogen
as well. This results in enlarged D1 by >14° and correspondingly reduced D2 as
shown in Fig. 10c. If so, the axial attack will prevail, as observed by le Noble. The
68:32 (ax:eq) distribution on reduction by NaBH4 in both methanol and water was
considered by le Noble to have involved hydrogen-bonded amine center [40, 41].
The overall effect of hydrogen-bonding is akin to protonation. In fact, in a dynamic
situation, protonation is the end game of hydrogen-bonding. Why must one consider
the protonation of nitrogen at all?
From NBO analysis, nitrogen bears nearly as much negative charge (−0.50)
as carbonyl oxygen (−0.54). As such, a healthy competition between the two
heteroatoms for a given cation appears a genuine possibility. Protonation or, for that
matter, hydrogen-bonding makes nitrogen electron-deficient, which renders σC3–C4
and σC1–C9 bonds electron-poor in comparison to σC1–C8 and σC3–C10 bonds. This
allows preferred axial orientation of empty orbital on carbonyl carbon and, thus, the
axial attack of the nucleophile is enhanced.
The Cieplak model fails at predicting correct selectivity in the reduction of 5-aza-
2-adamantanone because it predicts equatorial selectivity by considering the electron-
donating nature of nitrogen lone pair. This model, however, appears to succeed when
only the electron-attracting character of the σC–N bond is considered important. The
calculated geometry of carbonyl-protonated 5-aza-2-adamantanone, Fig. 10b, estab-
lishes firmly that the stereoelectronic effect caused by nitrogen lone pair is more
significant than the electron-attracting nature of the σC–N bond.
Fig. 11 a N-methyl-5-aza-
2-adamantanone,
b protonated N-methyl-5-
aza-2-adamantanone
N-Methyl-5-Aza-2-Adamantanone, 19
On carbonyl protonation, >12° increase in D1 and >10° decrease in D2 support

axial selectivity. This is in agreement with the observed 96:4 selectivity on reduction
with NaBH4 in isopropanol. Like N-protonated 5-aza-2-adamantanone above, the
positively charged nitrogen renders σC3–C4 and σC1–C9 bonds electron-deficient in
comparison to σC1–C8 and σC3–C10 bonds. It allows the empty orbital to the orient
antiperiplanar to latter bonds and, thus, the nucleophile attacks predominantly axial.
The computed 3D structures of N-methyl-5-aza-2-adamantanone and its protonated
derivative are shown in Fig. 11.
5-Aza-2-Adamantanone N-Oxide, 20
On carbonyl protonation, a 5° increase in D1 and 3° decrease in D2 indicate a pref-

erence for axial selectivity. This selectivity may be supplemented additionally by
the coordination of N-oxide oxygen with a cation, a prospect that appears genuine
because the residual charge on this oxygen, −0.71, is significantly larger than the
charge on carbonyl oxygen, −0.52. The additional coordination renders σC3–C4 and
σC1–C9 bonds even more electron-poor and, thus, results in enhanced axial selec-
tivity. The high axial selectivity expected from 5-aza-2-adamantanone N-oxide is in
agreement with experiments [41].
5-Aza-2-adamantanone N-oxide exhibits axial selectivity by a margin of 96:4 on
reduction with NaBH4 in isopropanol. The Cieplak model predicts axial selectivity
for the overall electron-attracting character of the N+ –O− bond. The Anh–Felkin
model fails as it is opposite to the Cieplak model in concept and allows the attack
of nucleophile anti to more electron-deficient bond on α carbon. The computed 3D
structures of 5-aza-2-adamantanone N-oxide and its protonated derivative are shown
in Fig. 12.
Fig. 12 a 5-aza-2-adamantanone N-oxide, b 5-aza-2-adamantanone with C=OH+
5-Bora-2-Adamantanone, 21
This molecule is interesting because a nucleophile is expected to add on to boron

before addition to the carbonyl group [16]. It is so because boron is >1.5 times more
electron-deficient than carbonyl carbon. This will have consequences on observed
selectivity. In having hydride ion as a nucleophile to add to boron and H+ for carbonyl
protonation, D2 turned >40° larger than D1 and, hence, the eminent equatorial selec-
tivity [17]. This analysis is in agreement with the result from the capture of deuterium
from n-Bu3 SnD by 5-pyridyl-5-bora-2-adamantyl radical. Equatorial capture of the
radical was almost twice as large as the axial capture. An orbital with one electron in it
is similar to an empty orbital because both are electron-poor and, thus, the same stere-
oelectronic arguments apply. The computed 3D structures of 5-bora-2-adamantanonc
and its above derivatives are shown in Fig. 13.
The Cieplak model fails as it predicts axial attack for the electron attracting nature
of boron. For the same reason, however, the Anh–Felkin model succeeds in predicting
equatorial selection. Houk’s TS model also succeeds in predicting equatorial pref-
erence. Since D2 is 4° larger than D1 in 5-bora-2-adamantanone, less-destabilizing
interactions in the TS for equatorial attack over those in the axial attack are expected.
Fig. 13 a 21, b 21 with C=OH+ , c 21 with C=OH+ and BH−

Depending upon substituents in the vicinity of the carbonyl group, the carbonyl
carbon is expected to undergo pyramidalization due to σ → π*C=O type interactions.
This pyramidalization is enhanced on the coordination of carbonyl oxygen with a
cation. Thus, it is possible that one can look at simply σ → π*C=O interactions in
the ground state structure of a given molecule and predict its diastereoselectivity. We
will see the successful application of this concept to other structural types below.
2,3-Endo,Endo-Dimethylnorbornan-7-One
and the Corresponding Diethyl Analog
Both 2,3-endo,endo-dimethylnorbornan-7-one 23 and 2,3-endo,endo-

diethylnorbornan-7-one 24, Fig. 14, are anti-selective. However, the anti-selectivity
of diethyl derivative is significantly superior to that of dimethyl derivative. For
instance, on reduction with LiAlH4 , the anti:syn selectivity is 79:21 for 24 and only
55:45 for 23. If the σ → σ*# interaction, as advocated by Cieplak, is indeed the
control element, both molecules will be predicted to exhibit syn-selectivity because
(a) σC–H is more electron-donating than σC–C and (b) anti side has two endo σC–H
bonds in lieu of two endo σC–C bonds on the syn side. Consequently, σC1–C6 and
σC4–C5 bonds, both on the anti side, must be more electron-rich than σC1–C2 and
σC3–C4 bonds on the syn side. Obviously, the Cieplak model, in its original form, fails
at not only predicting the correct selectivity of these molecules but also explaining
the differential selectivity profile.
In conformer 24a, σC8–C9 and σC10–C11 bonds are antiperiplanar to the σC2–C3
bond. However, σC8–C9 is nearly antiperiplanar to the σC1–C2 bond and σC10–C11
synperiplanar to the exo σC3–H bond in conformer 24b. The conformer 24a is more
stable than 24b by approximately 3.4 kcal/mol. In the application of the cation
coordination model, the torsion angles D1–D4, both before and after carbonyl proto-
nation, are found to support anti-pyramidalization [42]. These torsion angles are
collected in Table 10. The calculated 3D structures of 23 and 24, and their H+ - and
Li+ -coordinated species are shown in Fig. 15 for ready visualization of expected
diastereoselectivity.
O O O
anti 7 syn 7 7
4 4 4 H
5 3 5 3 5
11 3
2 2 6 2 11
6 1 6 1 1
10 10
8
8 9
23 24a 24b
9
Fig. 14 Structures of 2,3-endo,endo-dimethylnorboranan-7-one 23 and two low energy conformers

24a and 24b of 2,3-endo,endo-diethylnorbornan-7-one 24
Table 10 Calculated torsion angles D1–D4 in 23, 24 and their protonated derivatives at the
B3LYP/6-31G* level (D1 = O–C7–C1–C2, D2 = O–C7–C1–C6, D3 = O–C7–C4–C3, and D4
= O–C7–C4–C5)
Substrate D1 D2 D3 D4
23 121.63 125.06 121.63 125.06
23-H+ 115.33 132.28 115.69 131.97
24a 121.22 125.59 121.22 125.59
24a-H+ 112.57 135.20 113.18 134.60
24b 122.46 124.50 120.75 126.40
24b-H+ 114.21 133.68 112.34 135.86
The origin of anti-selectivity is in the antiperiplanar interactions collected in

Table 11. In 23, one σC-H bond of each methyl group is antiperiplanar to σC1–C2 and
σC3–C4 bonds, which allows interaction worth 3.5 kcal/mol each. This interaction
increases to about 4.2 kcal/mol on the protonation of carbonyl oxygen. The increased
electron densities of σC1–C2 and σC3–C4 bonds allow increased anti-pyramidalization
of the carbonyl group and, thus, anti-selectivity is enhanced. A similar situation
exists in 24a. One methylene σC–H bond is antiperiplanar to σC1–C2 and σC3–C4 bonds.
However, the resultant σC–H → σ*C1–C2 or σC–H → σ*C3–C4 interaction is somewhat
higher at 3.9 kcal/mol and increases to 4.6–4.7 kcal/mol on protonation of carbonyl
oxygen. The stronger interactions in 24a and its protonated derivative over those in
23 and its protonated derivative ensure larger anti-pyramidalization in the former
and, thus, the selectivity is improved.
We noted above that the sum of σC1–C2 → π*C=O and σC3–C4 → π*C=O interactions
is more than the sum of σC1–C6 → π*C=O and σC4–C5 → π*C=O interactions in both 23
and 24, and also their protonated species to warrant anti-selectivity. Since the differ-
ence of anti- and syn-favoring interactions is more in protonated 24 than protonated
23, a larger anti-selectivity of 24 is in order. Thus, σC–C → π*C=O interaction alone
is a good tool to predict and also explain the observed differential selectivity [42].
The effect of the interaction of remote bonds is embedded in vicinal σC–C bonds.
4-Oxatricyclo[5.2.1.02,6 ]Decan-10-One, 9,
and 4-Oxatricyclo[5.2.1.02,6 ]Dec-8-En-10-One, 10
Let us return to the substrates 9 and 10 wherein n → σ*C1–C2 and n → σ*C6–C7

interactions, as previously speculated by Mehta and le Noble, were found absent from
NBO analysis. The prominent σC–C → π*C=O interactions relevant to the selectivity
are listed in Table 12. The sum of interactions σC1–C2 → π*C=O and σC6–C7 → π*C=O
(6.64 kcal/mol in 9 and 7.02 kcal/mol in 10) is superior to the sum of interactions
σC1–C9 → π*C=O and σC7–C8 → π*C=O (6.38 kcal/mol in 9 and 5.52 kcal/mol in 10)
in both species [30]. Notably, the differential interaction is larger in 10 (1.5 kcal/mol)
Fig. 15 Calculated 3D structures: a 23, b 23-H+ , c 23-Li+ , d 24a, e 24a-H+ , f 24a-Li+ , g 24b, h
24b-H+ , and i 24b-Li+
than in 9 (0.26 kcal/mol). This could be taken to support a larger anti-selectivity of 10

compared to 9. Additional factors, however, may also contribute to higher selectivity
of 10 over 9 (wide infra).
We will now try to understand why σC1–C2 → π*C=O and σC6–C7 → π*C=O inter-
actions are superior to σC1–C9 → π*C=O and σC7–C8 → π*C=O interactions. Both 9
and 10 have mirror plane symmetry passing through the carbonyl group and, hence
σC1–C2 → π*C=O interaction is the same as σC6–C7 → π*C=O interaction and, likewise,
Table 11 σ → π*C=O interactions in 23 and 24, and their protonated species

Substrate σC1–C2 σC1–C6 σC3–C4 σC4–C5 σC8–H σC10–H σC8–C9 σC10–C11 → σ*C3–C4
→ → → → → → →
π*C=O π*C=O π*C=O π*C=O σ*C1–C2 σ*C3–C4 σ*C1–C2
23 3.43 3.27 3.43 3.27 3.53 3.53
23-H+ 8.60 5.66 8.82 5.66 4.24 4.16
24a 3.48 3.25 3.38 3.25 3.93 3.93
24a-H+ 9.20 5.30 9.39 5.32 4.71 4.61
24b 3.33 3.45 3.69 3.06 1.83 1.24
24b-H+ 8.42 5.79 10.3 4.79 2.19 1.57
Table 12 Interactions relevant to π-selectivities of 9 and 10

O 11 O 11
anti 10 syn anti 10 syn
7 7
8 6 8 6
2 2
9 1 5 9 1 5
4O 3 H 4O 3 H
H H
9 10
σC1–C9 → π*C=O and σC7–C8 → π*C=O interactions. The followings are highlights of
the interactions and their consequences:
(a) The geometrical feature of a heterocyclic ring in both 9 and 10 is such that
one electron pair orbital on ring oxygen is antiperiplanar to σC2–C3 and σC5–C6
bonds, and the other to a σC-H bond on both C3 and C5.
(b) The above stereo-relationship results in n → σ*C2 πC3 and n → σ*C5–C6 inter-
actions (1.9 kcal/mol in 9 and 2.2 kcal/mol in 10) and also n → σ*C3–H and n
→ σ*C5–H interactions (7.2 kcal/mol in 9 and 7.5 kcal/mol in 10).
(c) The interactions n → σ*C3–H and n → σ*C5–H raise the electron densities of
σC–H bonds. Since these σC–H bonds are antiperiplanar to σC1–C2 and σC6–C7
bonds, they interact in σC3–H → σ*C1–C2 and σC5–H → σ*C6–C7 manner and
raise the electron densities of σC1–C2 and σC6–C7 bonds by 2.9 kcal/mol in 9 and
2.8 kcal/mol in 10.
(d) The interactions n → σ*C3–H and σC3–H → σ*C1–C2 ensure anti-selectivity, as
observed from experiments.
The π-route predicts syn-selectivity for 10 by consideration of the π → π*C=O
interaction. The π → π*C=O barrier must be disrupted by the nucleophile to enter the
anti face [43, 44]. Additionally, the electrostatic repulsion between olefin and nucle-
ophile, both electron-rich, also disfavors the anti approach [45]. However, there exists
a good possibility for olefin-cation coordination to guide the delivery of nucleophile
syn to π bond itself and, thus, account for the very high anti-selectivity observed
from this molecule in comparison to 9.
Trans-2-Heterobicyclo[4.4.0]Decan-5-Ones
The axial TSs with LiH were computed for aza-, oxa-, and thia-derivatives and
subjected to NBO analysis to explore the n → σ*# interaction advocated by Cieplak
in support of axial preference. However, such an interaction was found absent. The
corresponding equatorial TSs also were devoid of the n → σ*# interaction. The
energy differences in axial and equatorial TSs, collected in Table 13, signal axial
selectivity, which is poorest for thia- and highest for oxa-species. The axial selec-
tivity of the aza-species is predicted to be intermediate to the other two. However, it
contrasts experimental findings in as much as the aza-species exhibited the highest
selectivity.
The inductively electron-withdrawing N and O atoms are expected to reduce the
electron densities of the ring bonds σC3–C4 and σC1–C6 . This reduces the magnitudes
of σC3–C4 → π*C=O and σC1–C6 → π*C=O interactions, leading to axial selectivity. On
the contrary, σC–S is electron-donating. The consequent increase in electron densi-
ties of σC3–C4 and σC1–C6 bonds results in increased σC3–C4 → π*C=O and σC1–C6 →
π*C=O interactions and supports the equatorial attack, i.e., loss in axial selectivity.
The higher axial selectivity of aza-species in comparison to oxa-species is likely due
to hydrogen bonding of nitrogen with the reaction medium (methanol for borohy-
dride reduction), which renders nitrogen effectively more electron-withdrawing than
Table 13 Energy differences in axial and equatorial TS structures for the reactions of trans-2-
heterobicyclo[4.4.0]decan-5-ones with LiH
H H H
6
1 X X + X
2 HO H
4 3
O 5 H H H
H OH
Substrate [Eax-TS - Eeq-TS] kcal/mol [Eax-TS – Eeq-TS] kcal/mol

X HF/6-31G* HF/6-31+G*
NMe - 1.26 - 1.10
O - 1.58 - 1.47
S - 1.07 - 0.83
oxygen. The prospect of such hydrogen bonding has previously been suggested by
le Noble to explain the predominantly syn-selectivity of 5-aza-2-adamantanone [41,
46–48]. The decrease in electron densities of σC3–C4 and σC1–C6 bonds of aza-species
has been suggested by computational investigations, wherein nitrogen was allowed
for hydrogen bonding with water [16].
3-Halocyclohexanones
Finally, we consider the selectivity of 3-halocyclohexanones in reactions with nucle-

ophiles. The Cieplak model predicts axial attack irrespective of whether the halogen
is axial or equatorial for similar inductive electron-withdrawal from the σC2–C3
bond. From TS calculations, Frenking has predicted the equatorial attack in 3-ax-
fluorocyclohexanone and axial attack in the corresponding 3-eq-species [49]. The
equatorial attack on 3-ax-fluorocyclohexanone is favored over the axial attack by
2.3 kcal/mol. Likewise, the axial attack on 3-eq-fluorocyclohexanone is favored over
the equatorial attack by 2.7 kcal/mol. While the preferred axial attack on cyclo-
hexanones bearing equatorial electron-withdrawing substituents on position 3 is
known experimentally [7, 8], equatorial attack in 3-ax-fluorocyclohexanone cannot
be verified due to conformational mobility of the ring system.
In the application of the cation coordination model, the carbonyl groups in 3-
chloro- and 3-fluorocyclohexanones were allowed for protonation and the torsion
angles O7–C1–C2–C3 and O7–C1–C6–C5 were estimated [50]. These torsion angles
are collected in Table 14. The interpretation of data is as follows:
Table 14 The torsion angle changes on protonation of carbonyl group in 3-ax- and 3-eq-
halocyclohexanones
5 X 1 O7 5 1 O7
6 6
4 3 4 3
2 2
X
3-ax-halocyclohexanone 3-eq-halocyclohexanone
Substrate Torsion angle O7-C1-C2-C3 Torsion angle O7-C1-C6-C5
3-ax-chlorocyclohexanone 140.47 138.27
3-ax-chlorocyclohexanone, protonated 133.93 135.62
3-eq-chclorocyclohexanone 134.33 134.18
3-eq-chlorocyclohexanone, protonated 145.64 144.89
3-ax-fluorocyclohexanone 139.77 138.07
3-ax-fluorocyclohexanone, protonated 136.68 139.44
3-eq-fluorocyclohexanone 134.59 133.58
3-eq-fluorocyclohexanone, protonated 149.67 147.04
(a) The reduction in torsion angles in protonated 3-ax-chlorocyclohexanone

predicts an equatorial attack. In contrast, the torsion angles increase in
protonated 3-eq-chlorocyclohexanone to suggest an axial attack.
(b) The increase in torsion angles in protonated 3-eq-chlorocyclohexanone is
considerably larger than the corresponding reduction in protonated 3-ax-
chlorocyclohexanone. Consequently, 3-eq-chlorocyclohexanone is predicted
to exhibit improved selectivity in comparison to 3-ax-chlorocyclohexanone.
(c) Like the above chloro-species, 3-ax- and 3-eq-fluorocyclohexanones are
predicted for equatorial and axial preferences, respectively.
(d) The selectivity predictions above are in excellent agreement with those based
on TS calculations.
The transition structure is known to be of two types, the early transition struc-
ture and the late transition structure. The early transition structure is reactant-like,
wherein the incipient bond (σ#) has not begun to form. In contrast, the incipient bond
formation has taken place to a reasonable extent in the late transition structure and,
hence, it is product-like. In view of this, Cieplak’s σ → σ*# model need not apply
to those reactions that proceed through the early transition structure. Indeed, the σ
→ σ*# interaction has been found absent in several early transition structures with
the σ → π*C=O interaction controlling the selectivity. In contrast, the late transition
structures have been found devoid of the σ → π*C=O type interaction with the σ →
σ*# interaction controlling the selectivity [51].
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4178 (2006)
Chapter 4
A(1,2) and A(1,3) Strains
Abstract The A(1,2) and A(1,3) strains and their control on conformational and reac-
tivity profiles are discussed. The application of A(1,3) strain to facial selectivity of
reactions such as [2,3]- and [3,3]-sigmatropic shifts, intramolecular SN 2 reactions,
hydroboration, and enolate alkylation is highlighted. The high diastereoselectivity
observed in the reactions of enolates derived from 4-substituted N-alkanoyl-1,3-
oxazolidinones (Evans enolates) with electrophiles is also discussed.
1 Introduction
The most preferred form of a transition state structure is a six-membered ring because
it is intrinsically strain-free. It allows us a comprehensive discussion of stereochem-
istry and steric interactions because the stereo-relationships of substituents among
themselves and also with ring bonds are clearly understood. Chair → twist boat →
boat → twist boat → chair are the recognized events enroute ring flip from one chair
to other. In this process, a substituent changes its orientation from axial to equatorial
and equatorial to axial. In between chair and twist boat, there is half-chair.
The twist boat and boat conformers are, respectively, 5.5 and 6.5 kcal/mol above
the chair conformer. The two hydrogens in red color in the boat conformer, called
flagpole hydrogens, come close enough to raise its energy by 1.0 kcal/mol. This
energy is the same as the σC–H –σC–H bond pair repulsion in the eclipsed conformer
of ethane. The positions bearing flagpole hydrogens are called flagpole positions.
The highest energy difference, 10.5 kcal/mol at STP, between the chair and boat
conformers is the energy required to flip one chair to the other.
https://doi.org/10.1007/978-3-030-75622-2_4
108 4 A(1,2) and A(1,3) Strains
Ha
Ha' H H H
He
H H H
He' H
H
H
H
He'
H He
Ha'
Ha
H
a = axial, e = equatorial, a' = pseudoaxial, e' = pseudoequatorial
Cyclohexene exists in half-chair [1] conformation 1a as confirmed from X-ray

structures of many species, including morphine [2] and cholesteryl iodide [3]. Rela-
tive to cyclohexane, cyclohexene is flattened and only C4 and C5 bear truly axial
and equatorial bonds. The bonds on C3 and C6, which are slightly off from truly
axial and equatorial positions, are called pseudo-axial (a ) and pseudo-equatorial (e ),
respectively. The dihedral angle between a substituent on C1 (like R1 in structure 1b)
and an equatorial substituent on position C6 (like equatorial R2 in structure 1b) is
about 43°−44° (significantly less than the normal gauche value of 60°). This allows
them to sterically interfere with each other.
a R1 R1
a' 1 e 2 2
'e e 4 1 R 1 R2
6 2 6 3
3 e e'
2 5
'a 3 5
a 4
1a 1b 1c
The magnitude of the above interaction depends on the size of the substituents.
With each of these substituents being larger than hydrogen, the resultant interaction
is called the A(1,2) interaction or A(1,2) strain as the substituents are positioned on
atoms 1 and 2 of the allylic system. The numbering commences from the allylic
position and moves to the olefinic linkage as demonstrated in structure 1c. Some
conformational change must occur to avoid or minimize such an energy-enhancing
interaction.
A similar picture emerges from consideration of cyclohexane bearing an exocyclic
methylene group. The substituents R1 and R2 in the 3D conformer 2a or planar
conformer 2b are nearly coplanar with the dihedral angle within a few degrees
and, thereby, dangerously close to result in steric interactions. As above with the
conformer 1b, the severity of the interaction will increase with the size of R1 and R2 .
This interaction is called A(1,3) interaction or A(1,3) strain because the substituents
involved are located on positions 1 and 3 of the allylic system. The system will,
therefore, tend to adopt a conformer different from 2a, wherein the substituents
1 Introduction 109
R1 and R2 are held as far apart as geometrically possible. The obvious choice is
conformer 2c with R2 held axially.
H H R1 H
H
5 1
R2
6 R1 e R2
R2
4 3 2
H H
H
R1
2a 2b 2c
2 A(1,2) Strain
The molecule 1c, with both R1 and R2 larger than hydrogen, is expected to exist as
an equilibrium mixture of the conformers 1c1 and 1c2 . This equilibrium involves a
flip from one half-chair to the other. It is to be noted that unlike conformer 1c2 , 1c1
benefits from an additional energy-lowering hyperconjugation effect arising from
the interaction of π bond with axial σC–H bond on allylic carbon (σC–H → π*C=C ).
Must the size of substituents R1 and R2 be such that the steric interaction between
them in conformer 1c1 minus the above stabilizing hyperconjugative interaction be
larger than the sum of steric interactions between R1 and H, and also R2 and axial H
as shown in conformer 1c2 , the conformer 1c2 will predominate. From here onward,
we shall ignore the hyperconjugative effects from further discussions to keep the
matter simple.
3 2 H
1
R1 R2
H R2 H
4 5 6 R1
H H H
1c1 1c2
Garbisch demonstrated, from the application of NMR spectroscopy, that many

1,6-disubstituted cyclohexenes existed predominantly in the conformer with C6-
substituent axial [4]. He also demonstrated that the 6-equatorial substituent in 1-
arylcyclohexenes was held more nearly in the C2–C1–C6 plane (due to conjugation
effects) than the 6-equatorial substituent in 1-alkylcyclohexenes. The interaction
between the aryl group and the C6-equatorial substituent leads to a preference for
the conformer bearing C6-substituent axial, i.e., 1c2 . The results for specific examples
of general structure 3 are collected in the table below. From examples at entries 4
and 6, it is clear that the 1,3-diaxial interaction (between Me2 COH and Me in entry
4 and between COMe and Me in entry 6) is stronger than the A(1,2) interaction, so
much so that the C6-substituent occupies an equatorial position preferentially.
110 4 A(1,2) and A(1,3) Strains
R3
R
R2
R1
3
Entry R R1 R2 R3 Preferred orientation of R1

1 Ph Me3 C H H axial
2 Ph Ph H H axial
3 Ph Me2 COH H H axial
4 Ph Me2 COH Me Me equatorial
5 Ph COMe H H ncp*
6 Ph COMe Me Me equatorial
7 Me COMe H H ncp*
8 Ph NO2 H H axial
9 Me NO2 H H axial
10 Me Br H H axial
11 OMe Br H H axial
*ncp = No conformational preference
There could be four conformers in all for a molecule of type 4. Beckett et al. [5–7]
have observed that the conformer 4a is preferred over conformers 4b−d. 1,3-Diaxial
interaction between the electron pair orbital on nitrogen and methyl group in 4a is
considered to be small. Conformer 4b is destabilized by the 1,3-diaxial interaction
between the methyl group and substituent R on nitrogen. Likewise, the conformer
4c is destabilized by 1,3-diaxial interaction between axial H on C5 and axial R on
nitrogen. Both the conformers 4c and 4d are destabilized by the A(1,2) strain as well.
2 3
1
R N 4
Ar
6 5
Me
4
R
Me Me Ar Ar
R N Ar
N
Ar N Me R N Me
H H R H H
4a 4b 4c 4d
Beckett and coworkers also discovered that protonation reduced population of the
conformer with C5-axial methyl to less than 50% of the total mixture [5–7]. Only
conformers 5a and 5b (5a:5b = 43:57) were detected. The increased interaction
of C5-axial methyl with axial hydrogen on nitrogen as against electron pair orbital
2 A(1,2) Strain 111
in 4a was considered as the primary cause for the shift in conformer distribution.
The conformers 5c and 5d are destabilized due to severe 1,3-diaxial interactions as
shown. The conformer 5d is also destabilized by the A(1,2) strain.
H Et
Me 3 Ar Ar
N 2 Me
Et 4 Et Me N H Me
1 Ar N H N
H Ar
6 5 H H Et H
H
5a 5b 5c 5d
Beckett et al. [5–7] also found that quaternization of 4 with alkyl halides reversed
the conformational equilibrium even further. For a system like 6, the conformer 6a
with the C5-substituent occupying the equatorial position predominated. Obviously,
the A(1,2) strain present in 6a is less than the steric strain arising from the 1,3-diaxial
interaction between ethyl and methyl substituents in conformer 6b.
Ph
4 Me
5 Et
3 Ar Me
2 6
Et N Me Me N Ar
N Me H H
Et 1 Me
6 6a 6b
The conformational profile of cis,trans,cis-1,2,3,4-

tetrachlorotetrahydronaphthalene 7 is influenced by the A(1,2) strain. Of the
two conformers 7a and 7b, 7a constitutes the nearly exclusive conformer at equilib-
rium [8]. It is important to note that both chlorine atoms on the allylic positions in
7a are axial and, thus, significantly away from the hydrogens on peri positions C5
and C8 to avoid the otherwise eminent A(1,2) strain.
Cl H Cl
8 1 2 Cl Cl H
7 H Cl H Cl
Cl H Cl H
6 3
5 4 Cl Cl H
Cl H Cl
7 7a 7b
Enamine constitutes an excellent example of A(1,2) strain. Because of 8a ↔ 8b

resonance involving the overlap of lone pair orbital on nitrogen with the π-bond, the
bonds shown in green color in 8a are, more or less, in a single plane. This brings
the methylene group attached to nitrogen and the substituent R, must it be oriented
equatorial, very close to each other to result in severe steric interaction. Consequently,
the enamine 8a adopts a conformation wherein the substituent R occupies an axial
position [9–11].
112 4 A(1,2) and A(1,3) Strains
N N
Re R
8a 8b
The enolates formed from certain substituted cyclohexanones are very close to
enamines in their display of the A(1,2) strain and, hence, the preferred conformer
distribution. The equilibrium composition of the potassium enolate conformers 9a
and 9b is solvent-dependent [12]. The bulkier and more cation-coordinating solvent,
the larger is the concentration of conformer 9a. The interaction of solvated ion pair
O− K+ with the equatorial methyl group at C6, as in 9b, is the apparent cause. The
greater this interaction is, the greater will be the contribution of 9a to the equilib-
rium. However, there ought to be a point where the solvated O− K+ may begin to
substantially interact with the axial methyl group as well. In this instance, the system
is said to have reached the limiting equilibrium point.
O OK OK
Me a 1 Me
Me Me Me e Me
6 2
5 3
4
9 9a 9b
A similar effect has been noted in the generation of potassium enolate of 2α-
methyl-androst-4-ene-3,17-dione 10b. This enolate was discovered to be about
1.4 kcal/mol less stable than 10a, the enolate without the 2α-methyl substituent
[13] is to be recognized that the 2α-methyl substituent in 10b is located at an equa-
torial position and, hence, is in steric interaction with the solvated ion pair O− K+ as
discussed above. A 2β-methyl group occupies the axial position in which it is free
from interaction with the ion pair, i.e., devoid of A(1,2) strain, but in severe 1,3-diaxial
interaction with the nearby angular methyl group.
O O
H H
H H H H
KO KO
10a 10b
The methyl ester of bicyclofarnesic acid 11a was recovered unchanged on being
treated with sodium methoxide at 150–160 °C for 24 h [14]. The necessity of an
2 A(1,2) Strain 113
axial carbomethoxy group in 11a is the interaction between the methyl group on the
olefinic bond and the carbomethoxy group in the equatorial isomer 11b.
CO2Me H
H MeO2C
11a 11b
Base-catalyzed isomerization of 12a furnished 12b wherein the large side chain
on ring D was axially positioned to avoid the A(1,2) strain with the methyl group on
the adjacent sp2 carbon [15].
AcN AcN
O H O
HO D HO
base C
H H
A B
HO HO
H H
12a 12b
3 Stereocontrol in Reactions on Account of A(1,2) Strain
An interesting aspect of 1c1 /1c2 conformational change is the steric resistance offered
to an approaching reagent when the substrate is a reactive species such as an enamine
or enolate. This approach will be controlled by two factors: (a) the stereoelectronic
effect which requires as much continuous orbital overlap as possible in the TS
structure, and (b) the steric resistance that will be offered to a reagent’s approach.
In 1c1 (R1 = O− M+ and R2 = R), there is absolutely no resistance to a reagent’s
axial approach, and an electrophile is expected to attack C2 on the lower face to
generate 13, as shown in Eq. (1). In 1c2 (R1 = O− M+ and R2 = R), attack on C2 on
the upper face will be favored on account of the stereoelectronic effect to generate
14, as shown in Eq. (2). The direction of attack by the nucleophile being axial, the TS
structure is chair-like. It is to be noted that the upper face approach to 1c2 is opposed
by R on account of steric interactions. Thus, must R be very large, attack on the
lower face may prevail to generate 15b, as shown in Eq. (3). However, this attack
requires the adoption of the boat conformer 15a by the ring at some point during
the course of the reaction which is energy-demanding. The lower face attack will
therefore be expected to prevail only if the energy required for the adoption of this
114 4 A(1,2) and A(1,3) Strains
boat conformer is lower than the energy required for the reagent to pass by R in its
approach to 1c2 on the upper face.
O
O- M+
H R H R
E+ H E
(1)
H H H
1c1 13
H E+ H E
R
R
H
O- M+ H H (2)
H
H O
1c2 14
H H H H
R O R
H H
O- M+ R H E (3)
H
E H O
1c2 15a H 15b
In a smart application of the effect of the A(1,2) strain on conformer distribu-

tion, Brown studied Rh-catalyzed hydrogenation of the chiral allylic alcohol 16 and
discovered a very high degree of diastereocontrol in obtaining 17 and 18 in a 99:1
ratio [16]. The catalyst must form a complex with the carbinol function in 16 for the
reaction to occur. For being coplanar, the A(1,2) strain present between the methyl
substituent and carbonyl oxygen in 16b causes it to be much less populated than 16a
wherein the hydrogen is placed syn to the carbonyl group to avoid A(1,2) interaction.
O H2 O O
+
Rh catalyst
O OH O OH O OH
16 17 18
H R H R
Rh
O OH O OH O
CH3
O H O H O OH
16a 17 17
H R H R
Rh
O OH O OH O
H X H
O CH3 O O OH
16b 18 18
4 A(1,3) Strain 115
4 A(1,3) Strain
With R1 = H and R2 = CH3 in 2, the conformer 2a is more stable than 2c by

approximately 0.9 kcal/mol at the 6-31G(d) level of Hartree–Fock theory. This result
may be taken to understand that the A(1,3) strain in conformer 2a is not significant
enough to subvert the conformer distribution in favor of 2c [17].
With R1 = R2 = CH3 in 2, the net energy difference between the conformers
2a and 2c is about 3.7 kcal/mol at the 6-31G(d) level of Hartree–Fock theory. The
energy of conformer 2c with the methyl group axial is lower than conformer 2a
with the methyl group equatorial. The axial methyl group in conformer 2c faces
two 1,3-diaxial interactions with hydrogens, each raising the energy by 0.9 kcal/mol.
Were these 1,3-diaxial interactions absent in 2c, its energy would have been lower by
−(3.7 + 1.8) = −5.5 kcal/mol in respect of 2a. Thus, the CH3 –CH3 interaction in 2a
will be estimated at >5.5 kcal/mol to allow 2c to prevail. Clearly, with an increase in
the bulk of either R1 or R2 or both, the conformer 2c will become even more favored
[17]. Since the conformer 2a is also stabilized by an additional hyperconjugative
interaction arising from the axial σC–H bond on C2 (σC–H → π*C=C interaction), the
A(1,3) interaction must be larger than even the above value.
NMR studies have revealed that syn-2-methylcyclohexylideneacetic acid 19
predominantly exists as the conformer 19a wherein the methyl group has occupied
axial position. In contrast, the corresponding anti-isomer 20 predominantly adopts
the conformer 20a with the methyl group in an equatorial position [18].
H CO2H CH3 HO2C H CO2H
CH3 CH3 H
H CH3
HO2C H
19 19a 20 20a
The phenyl group in 21 is twisted out of the plane of π bond by ~50° in an apparent
attempt to avoid steric interaction between the phenyl group and equatorial hydrogen
on C2, had the phenyl group been planar with the π bond [17]. Such a subtle but
definite manifestation of the A(1,3) strain was indeed demonstrated in instances such
as 22 and 23. The phenyl group in 22 [19] and acetyl group in 23 [20] were found,
from ultraviolet measurements, twisted out of the plane of π bond to varying degree
[19, 20]. The phenyl group in 22 is twisted out of π plane by ~53° at the 6-31G(d)
level of Hartree–Fock theory [17].
116 4 A(1,2) and A(1,3) Strains
OH
NC
H
H H
1
2 O
6 N
5
4
3 H
Me O
21 22 23
From the examination of a number of 6-substituted 4-methylcholest-4-enes, it was

noted that the isomerization of 24a (R = Br/CH2 OAc), through hydrolysis of the
corresponding dienol acetates 24b, failed as only the 6β-isomer was recovered [21].
Also, attempted isomerization of 24a (R = Br) on treatment with hydrogen chloride
in glacial acetic acid returned the isomer. In contrast, the 6α-hydroxy species 25
isomerized completely to the 6β-hydroxy species 26 when simply left in contact
with silica gel. The lability of the 6α-isomer is apparently due to the A(1,3) strain
between the methyl group on C4 and α-substituent on C6. While the α substituent
on C6 is equatorial, β-substituent is axial. Clearly, the gain from avoiding the A(1,3)
strain is more than the loss due to 1,3-diaxial interaction between the angular methyl
substituent on C10 and β-substituent on C6.
C8H17 C8H17 C8H17 C8H17
1 1
2 9 2 9
10 8 10 8
H
7 7
O 3
4
5
6 AcO 3
4
5
6 O O
R R Me OH Me OH
24a, R = Br, CH2OAc 24b, R = Br, CH2OAc 25 26
A solution of hydrogen chloride or hydrogen bromide in dimethylformamide

causes smooth isomerization of (-)-α-santonin 27 into santonin-C 28. Likewise, α-
dihydrosantonin 29 also isomerizes to 30. Although the conversion of trans-lactone
to cis-lactone itself is an exothermic process, a good part of the driving force for
these isomerizations must come from the A(1,3) strain that exists between the C4-
methyl group and C6-equatorial oxygen. It must be noted that the products 28 and
30 themselves have fairly strong 1,3-diaxial interaction between C6-axial oxygen
and the C10-axial methyl group.
4 A(1,3) Strain 117
1
2 9 8
10
3 HCl/HBr
O 5
6
7 H DMF O H
4
CH3 O CH3 CH3 O CH3
O O
27 28
1 9
2 10 8
3
HCl/HBr
6 7 H H
O 4
5 DMF O
CH3 O CH3 CH3 O CH3
O O
29 30
5 Stereocontrol in Reactions on Account of A(1,3) Strain
The A(1,3) strain is capable of destabilizing the transition state of a reaction and, thus,
influence the product distribution. The compound 31 can organize in two different
ways, 31a and 31b, to undergo [3,3] sigmatropic shift and generate 32 and 33,
respectively. However, since the transition state resembling 31b is of higher energy
than 31a due to the A(1,3) strain between the two methyl groups as indicated, the
reaction funnels through 31a and 32 are formed exclusively [22]. Thus, one of the
two faces of the alkene in the allyl unit reacts in preference to the other.
O O
O [3,3] shift
O O
CH3 H O
31a 32
O O
H [3,3] shift
O O X O
O
31b 33
Claisen rearrangement of 34 proceeds through a transition state resembling 34a

to generate 35, wherein the two methyl substituents on the resultant cyclopentane
ring are syn oriented. The transition state resembling 34b encounters the A(1,3) strain
between a methyl substituent and oxygen of the vinyl ether unit as shown and, thus,
the product 36 is not formed. Note that the two methyl substituents are now anti to
each other [23, 24].
118 4 A(1,2) and A(1,3) Strains
Me3SiO Me3SiO
[3,3] shift
Me3SiO O H O H
34a 35
O
34 O O
[3,3] shift
H H
Me3SiO X Me3SiO
34b 36
The A(1,3) strain determines the degree of selectivity in the intramolecular alkyla-
tion of 37. The enolate formed from the carbanion 38 can adopt two different transi-
tion state conformations 39a and 39b, leading to 40 and 41, respectively. However,
the transition state resembling 39b is destabilized by the A(1,3) interaction between
the 3-butenyl group and either ethoxy group (as shown) or oxy anion in the Z-enolate
(not shown). The transition state resembling 39a is therefore favored over 39b and
it predominantly leads to 40 [25].
TsO Me TsO OEt H OEt

CO2Et CO2Et TsO OTs
O O
H
Me Me
37 38 39a 39b
H
EtO2C CO2Et
Me H
Me
40 41
[2,3] Sigmatropic rearrangement proceeds through a conformationally flexible

five-membered transition state and, hence, it is difficult to attain a high degree of
stereocontrol. In certain instances, however, the A(1,3) strain may be the only reliable
control to achieve a high level of diastereoselection. Accordingly, the level of chirality
transfer from the allylic carbon in the reactant to the allylic carbon in the product was
discovered to increase from an (E)-allylic system to the corresponding (Z)-allylic
system, as evident from the reactions of 42 and 44 [26, 27]. The species 42 reacted
with full diastereocontrol and 43 was formed as the sole product. The conformer 42b
is destabilized by the A(1,3) strain between the methyl and isopropyl substituents and,
hence, its concentration at equilibrium is little. Only the conformer 42a is available
for reaction and 43 is exclusively formed. In contrast, 44 was transformed into a
50:50 mixture of 45a and 45b. The conformers 44a and 44b contributed equally due
to the lack of A(1,3) strain.
5 Stereocontrol in Reactions on Account of A(1,3) Strain 119
O CH Li
2
CH2Li H H H
O H
OLi
H
42a 42b 43
CH2Li O CH Li
2
O H H OLi
OLi +
H H H H H
44a 44b 45a 45b
Iodolactonization is often used to functionalize a double bond with the gener-

ation of a new stereocenter. Kinetically controlled iodolactonization (I2 , CH3 CN,
NaHCO3 , 0 °C) of 46 results in a 70:30 mixture of 47 and 48 [28, 29]. The major
product 47 is formed through a six-membered transition state, wherein the iodonium
ion is formed under steric guidance of the methyl group, i.e., on the anti face of the
double bond as in 47a. The minor product 48 could be envisioned to have derived
from the transition state resembling 48a. The transition state 47a is favored over 48a
for the absence of the A(1,3) strain due to axial positioning of the methyl substituent.
In comparison, the 1,3-diaxial interaction in 47a is relatively small.
O O
O
O O
HO I I
H H
46 47 48
H
H I H
I
O O
NaO O
47a 47
H H
O O I
H
NaO I O H
48a 48
In comparison, iodolactonization of 49 proceeds with very high diastereoselec-

tivity as a 95:5 mixture of 50 and 51 is obtained [28, 29]. The diastereoselectivity
is tightly controlled by the A(1,3) strain between the methyl on the terminal olefinic
carbon and the other methyl on allylic carbon, so much so that it allows the reaction to
proceed primarily through the transition state structure resembling 50a. The minor
120 4 A(1,2) and A(1,3) Strains
isomer is obtained from reaction through the less stable transition state structure
resembling 50b, wherein the above A(1,3) could be seen.
O O
O
O O
HO +
H H
I I
49
50 51
H I
H O
O - I
O O
H
O H
O
H
50a 50 I
O
H H
O O
O
H
I - O
O
I H
H
50b 51 I
Hydroboration of a double bond next to stereocenter results in high diastereose-

lectivity. One substituent at the stereocenter shields one face of the double bond to
allow an attack on the other preferentially. It requires the fixation of the conformation
around the bond between the stereocenter and the π bond. The A(1,3) strain plays an
important role as demonstrated from the reactions of 52 and 54 [30, 31]. The coopera-
tive effect of the bulk and stereoelectronic effect due to the dimethylphenylsilyl group
(σC–Si orients perpendicular to the π bond for an effective σC–Si → π* interaction)
allows a selective attack on one face of the π bond. Possibly, the A(1,3) strain rigidifies
the conformation as in 54 and then the large bulk of the dimethylphenylsilyl group
directs the reagent to the opposite less-hindered face of the π bond. With the bulky
9-BBN as hydroboration reagent, high asymmetric induction has been achieved with
E-olefins also [30, 31].
PhMe2Si 1.hydroboration PhMe2Si

2. oxidation
H H OH
ds = 50%
52 53
PhMe2Si 1.hydroboration PhMe2Si OH

2. oxidation
H ds = > 95% H
54 55
ds = diastereoselectivity
The allyl alcohol 56 furnished 58 predominantly on oxymercuration in aqueous

tetrahydrofuran followed by reductive demercuration using NaBH4 [32]. Assisted by
chelation with both the ring oxygen and the carbinol function, mercuration on α-face
allows water to approach from β-face, as shown in 57, to form 58 selectively. In
aligning the methyl group on π bond with the axial hydrogen on allylic ring carbon,
the molecule in conformation 56 avoids the A(1,3) strain.
OH OH Hg OH
O OBn O OBn O OBn
H OR H OR HO H OR
H2O
56 57 58
Admixture of unsaturated ester 59 with the K-enolate 60 generates yet another

K-enolate, which could exist as a mixture of the conformers 61a, 61b, and 61c. On
account of the A(1,3) interaction between either substituent, except hydrogen, on the
allylic carbon and solvated OK (or even OMe if one considers the other geometry
of the enolate), the conformer 61c will be considered to be the most stable. In this
conformer, σC–H at the allylic carbon is cisoid to the π bond of enolate, which avoids
the A(1,3) strain. The electrophile, MeI in the present instance, approaches the π bond
from anti to the large CH2 CO2 But substituent and 62 is formed predominantly [33].
H t-BuO2CH2C H CH2CO2But
OK t
CO2Bu
+ H
t
CO2Me OBu
MeO OK MeO OK MeO OK
59 60 61a 61b 61c
CH2CO2But CH2CO2But
MeI CO2But
H H
H CO2Me
MeO OK CO2Me
61c 62 62
122 4 A(1,2) and A(1,3) Strains
The Li-enolate formed from tert-butyl acetate reacts with the unsaturated ester
63 in a conjugate manner to generate another Li-enolate, which must adopt the
conformation 64 to avoid A(1,3) interaction between CH2 CO2 But and OEt in the E-
enolate, as shown, or solvated OLi in the Z-enolate (not shown). The intramolecular
SN 2 reaction with the alkyl iodide through a transition state resembling 64 generates
65a, which ring-flips to the more stable conformer 65b. In the said transition state
structure, the axis of the p orbital on internal enolate carbon must be parallel to the
σC–I bond for an effective SN 2 reaction. The trans-disposition of the ring substituents
may be noted [34].
t-BuO2C I
I H
H t-BuO2C
CO2Et
CO2Et
H
OLi CO2Bu-t
EtO CO2Et H
63 64 65a 65b
The Li-enolate of 66 adopts the conformation 67 with the π bond syn to the σC–H
bond on the adjacent ring carbon to avoid the otherwise strong A(1,3) interaction with
either of the other two substituents. Since one face of the enolate is blocked by the
quaternary carbon, an electrophile such as MeI approaches from the front, i.e., from
the direction opposite to the quaternary carbon, and 68 is formed exclusively [35].
Me Me Me
TBSOCH2 TBSOCH2 TBSOCH2
R2NLi MeI H
H
Me
H H H
CO2Me CO2Me
LiO OMe
66 67 68
Alkylation of the lithium enolate formed from N-propanoyl-1,3-oxazolidinone

69 proceeds with very high selectivity to result largely in a single diastereomer.
The Z-enolate 70 is generated in preference to the E-enolate (not shown) on reac-
tion with LDA to avoid the A(1,3) interaction between the methyl group on olefinic
bond and isopropyl-containing substituent on nitrogen. The predominant formation
of Z-enolate and steric resistance offered by the isopropyl group to approach an elec-
trophile from the top face controls the transition state so very well that 71 and 72
are formed in a 96:4 ratio on reaction with propanoyl chloride [36, 37]. The absolute
stereochemistry of the product is thus determined by the absolute stereochemistry of
the isopropyl-containing carbon in N-alkanoyl-1,3-oxazolidinone.
O O O OLi O O O O
O N LDA O N EtCOCl O N O N
+
COEt COEt
69 70 71 72
The consequences of the A(1,3) strain could also be seen under hydroboration
conditions. For instance, the conformers 73 and 76 are preferred to any alternate
conformer to avoid the A(1,3) strain by having the smallest substituent hydrogen
in the plane of the π bond. Hydroboration is expected to occur on the side of the
medium-size group (RM ) to generate, after oxidative cleavage of the σC–B bond, 75
and 78, respectively. Note that hydroboration takes place in a Markovnikov fashion,
wherein boron is attached to the lesser substituted olefinic carbon.
BR2 OH
RL RL RL
R2BH H 2 O2
RM RM RM OH
OH OH
NaOH
H H H H H
73 74 75
BR2 OH
RL RL RL
RM R2BH H 2 O2
RM RM OH
OH NaOH
H H H H H
OH
76 77 78
Indeed, 79, which must exist predominantly in the conformation 79b to avoid the
A(1,3) strain with the methyl substituent on olefinic carbon, allows the approach of a
hydroboration reagent on the face syn to methyl on the allylic carbon and, thus, the
product 80 is formed with a selectivity of 8:1 after oxidative cleavage of the σC–B
bond. A similar analysis applied to 81 guides us to consider 81b as the preferred
conformer. Hydroboration syn-to-methyl on the allylic carbon followed by oxidative
cleavage of the σC–B bond leads to 82 as the predominant product [38]. Indeed, 82a
and 82b are formed as a 12:1 diastereomeric mixture.
OH
CH2OBn CH2OBn CH2OBn
O O O
H
79a 79b 80 (ds = 8:1)
OH
O O O
H H
OH OH OH
81a 81b 82 (ds = 12:1)
124 4 A(1,2) and A(1,3) Strains
Having controlled the preferred geometry of an allylic system, the A(1,3) strain
influences the stereochemistry of catalytic hydrogenation of allylic alcohols. With
the prior coordination of the carbinol function with a metal catalyst, Rh(Diphos-4)+ ,
the high diastereoselectivities of the transformations of 83, 85, 87, and 89 into 84,
86, 88, and 90, respectively, can be easily understood. The conformers 83a, 85a, 87a,
and 89a are free from the A(13) strain and, therefore, constitute the preferred reacting
conformers.
OH OH OH
OTBDMS OTBDMS OTBDMS

H
83 83a 84 (ds = 95%)
OH OH OH
H
OTBDMS OTBDMS OTBDMS
85 85a 86 (ds = 90%)
OH OH
OH OTBDMS
OBn OTBDMS
OBn
OTBDMS H OTBDMS
87 87a 88 (ds = 97%)
OBn OBn OH OBn
OBn OBn OTBDMS

H
OH OTBDMS
89 89a 90 (ds = 97%)
In tune with hydroboration and hydrogenation above, the A(1,3) strain controls
the diastereoselectivity of epoxidation reaction as well by exercising control on
conformer distribution. Epoxidation by m-CPBA is additionally controlled by its
coordination to a nearby heteroatom. For instance, conformational equilibrium
between 91a and 91b favors 91b in order to avoid the A(1,3) strain by virtue of having
the σC–H bond syn to the CH2 OH group. Coordination of m-CPBA with the ethe-
real oxygen followed by delivery of peroxygen to the syn face allows the exclusive
formation of the epoxide 92.
Like 92 above, 93 exists predominantly in the conformer 93b to avoid the A(1,3)
interaction of the methyl on π bond with either methyl and CH2 OBn on the allylic
carbon. Coordination-controlled epoxidation leads to the formation of 94 with >96%
diastereoselectivity.
OBn OBn OBn OBn

O O
H H
OH OH OH OH
91a 91b 92, ds = > 97%
OBn OBn OBn OBn

O O
OH OH OH OH
H H
93a 93b 94, ds = > 96%
The A(1,3) strain in trans-olefin is not as high as in cis-olefin. Accordingly,

the conformer 95c competes well with the conformer 95b at the equilibrium and
coordination-controlled delivery of peroxygen generates a mixture of the epoxides
96 and 97 with 60% diastereoselectivity.
OBn OBn
H
OH OH BnO OH
H H H H
95a 95b 95c
OBn O
O H
OH BnO OH
H H H
96 ds = 60% 97
6 A(1,3) Strain in Amides and Its Consequences

on Diastereoselectivity
The A(1,3) strain is experienced by amides as well. This is on account of conjugation

of nitrogen lone pair with the carbonyl group to generate enolate-like species such as
98a and 98b from 98. The A(1,3) interactions present in these species are as shown.
When applied to cyclic systems such as 99, the conformers 99a and 99b, both with
the substituent R1 equatorial, are expected to suffer from strong A(1,3) strain, so much
so that the conformer 99c, which is equivalent to 99d, is the most favored conformer.
126 4 A(1,2) and A(1,3) Strains
O R1 O R1 R1 O
N R3 N R3 N R3
R2 R2 R2
R4 R4 R4
98 98a 98b
O R2 R2 R2
H H
R1 N N N O N O N
O R1 R2 R1 H H
R2 O R1 R1
99 99a 99b 99c 99d
The A(1,3) strain experienced by amides is so very strong that cis-2,6-disubstituted

amide 100 exists exclusively as the conformer 100b. In this conformer, both the
CH2 CO2 Me substituents are axial to cause a strong 1,3-diaxial interaction. Appar-
ently, the rise in energy due to 1,3-diaxial interaction in 100b is less than the A(1,3)
strain present in 100a [39].
Ph
O O H
H H
MeO2C O N
O N O Ph N H
CO2Me CO2Me
Ph O O CO2Me
100 100a 100b
Treatment of 101 with formic acid furnished the tricyclic lactam 103 exclusively
[40]. Cyclization proceeds through an N-acyliminium ion, which can adopt either
of the conformations 102a and 102b. The transformation 102a → 103 is faster than
102b → 104a owing to the development of the A(1,3) strain in the latter product.
On mixing the electron pair on nitrogen with π electrons of the adjacent carbonyl
group, we construct the π bond in 104b. The oxy anion and the methylene group of
the non-nitrogen-containing cyclohexane ring, as shown in 104b, are close enough
to result in serious A(1,3) interactions. Consequently, the equilibrium between 102a
and 102b is expected to largely favor 102a.
6 A(1,3) Strain in Amides and Its Consequences on Diastereoselectivity 127
H O
X N N
N O
H
O 102a 102b
101, X = H, OH
OCHO H H
O
OHCO OHCO
N N N
H O O
103 104a 104b
There are many examples of other reaction types that proceed with a high level of
selectivity on account of allylic strain. The reader is directed to an exhaustive review
[41] and other sources [42] for more detailed studies.
References
1. C.W. Beckett, N.K. Freeman, K.S. Pitzer, J. Am. Chem. Soc. 70, 4227 (1948)
2. J.M. Lindsay, W.H. Barnes, Acta Cryst. 8, 227 (1955)
3. C.H. Carlisle, D. Crowfoot, Proc. R. Soc. Lond. 64, A184 (1945)
4. E.W. Garbisch Jr, J. Org. Chem. 27, 4249 (1962)
5. A.H. Beckett, A.F. Casy, M.A. Iorio, Tetrahedron 22, 2745 (1966)
6. A.H. Beckett, A.F. Casy, H.Z. Youssef, Tetrahedron Lett. 537 (1965)
7. A.F. Casy, A.H. Beckett, M.A. Iorio, H.Z. Youssef, Tetrahedron 3387 (1966)
8. P.B. de la Mare, M.D. Johnson, J.S. Lomas, V.S. del Olmo, J. Chem. Soc. B 827 (1966)
9. W.R.N. Williamson, Tetrahedron 3, 314 (1958)
10. F. Johnson, A. Whitehead, Tetrahedron Lett. 3825 (1964)
11. S.K. Malhotra, F. Johnson, Tetrahedron Lett. 4027 (1965)
12. S.K. Malhotra, F. Johnson, J. Am. Chem. Soc. 87, 5513 (1965)
13. G. Subramaniam, S.K. Malhotra, H.J. Reingold, J. Am. Chem. Soc. 88, 1332 (1966)
14. G. Stork, A.W. Burgstahler, J. Am. Chem. Soc. 77, 5068 (1955)
15. O. Wintersteiner, M. Moore, Tetrahedron 21, 779 (1965)
16. J.M. Brown, Angew Chem. Int. Ed. Engl. 26, 190 (1987)
17. These calculations were performed using the Gaussian16 program
18. H. Hauth, D. Stauffacher, P. Nicklaus, A. Melera, Helv. Chim. Acta 48, 1087 (1965)
19. C.M. Lee, A.H. Beckett, J.K. Sugden, Tetrahedron Lett. 2721 (1966)
20. M. Gorodetsky, Y. Mazur, J. Am. Chem. Soc. 86, 5213 (1964)
21. C.W. Shoppee, F.P. Johnson, R.E. Lack, R.J. Rawson, S. Sternhell, J. Chem. Soc. 2476 (1965)
22. T. Takahashi, H. Yamada, J. Tsuji, Tetrahedron Lett. 23, 233 (1982)
23. M.M. Abelman, R.L. Funk, J.D. Munger Jr, J. Am. Chem. Soc. 104, 4030 (1982)
24. P. Beslin, S. Perrio, J. Chem. Soc. Chem. Commun. 414 (1989)
25. S.H. Ahn, D. Kim, M.W. Chun, W.-K. Chung, Tetrahedron Lett. 27, 943 (1986)
26. T. Nakai, K. Mikami, Chem. Rev. 86, 885 (1986)
27. K.K. Chan, G. Saucy, J. Org. Chem. 42, 3828 (1977)
128 4 A(1,2) and A(1,3) Strains
28. P.A. Bartlett, D.P. Richardson, J. Meyerson, Tetrahedron 40, 2317 (1984)
29. D.R. Williams, M.H. Osterhout, J.M. McGill, Tetrahedron Lett. 30, 1327 (1989)
30. I. Fleming, Pure Appl. Chem. 60, 71 (1988)
31. I. Fleming, N.J. Lawrence, Tetrahedron Lett. 29, 2077 (1988)
32. M. Isobe, Y. Ichikawa, T. Goto, Tetrahedron Lett. 26, 5199 (1985)
33. M. Yamaguchi, M. Tsukamoto, I. Hirao, Chem. Lett. 375 (1984)
34. M. Yamaguchi, M. Tsukamoto, I. Hirao, Tetrahedron Lett. 26, 1723 (1985)
35. J.H. Hutchinson, T. Money, Chem. Commun. 288, (1986)
36. D.A. Evans, M.D. Ennis, T. Le, J. Am. Chem. Soc. 106, 1154 (1984)
37. D.A. Evans, J.S. Clark, R. Metternich, V.J. Novack, G.S. Sheppard, J. Am. Chem. Soc. 112,
866 (1990)
38. G. Schmid, T. Fukuyama, Y. Kishi, J. Am. Chem. Soc. 101, 259 (1979)
39. J. Quick, C. Mondello, M. Humora, T. Brennan, J. Org. Chem. 43, 2705 (1978)
40. D.J. Hart, J. Am. Chem. Soc. 102, 397 (1980)
41. R.W. Hoffmann, Chem. Rev. 89, 1841 (1989)
42. http://euch6f.chem.emory.edu/allylicstrain.html
Chapter 5
The Conservation of Orbital Symmetry
Rules (Woodward–Hoffmann Rules)
Abstract A discussion on conservation of orbital symmetry and its application

to select pericyclic reactions is presented. Early on, effort is made to explore the
symmetry characteristics of σ, σ*, π, and π* molecular orbitals. This is followed by
a discussion of molecular orbitals and their symmetry characteristics for allyl cation,
allyl radical, allyl anion, and 1,3-butadiene. The symmetry concept is applied to π2
+ π2 , π4 + π2 , and electrocyclic ring closing and ring opening reactions.
1 Introduction
In the projected synthesis of vitamin B12 , the plan called for the construction of a key
intermediate by stereospecific cyclization of a stereochemically well-defined 1,3,5-
triene to the corresponding 1,3-cyclohexadiene. From the inspection of molecular
models, Woodward and his colleagues were confident that the minimization of angle
strain coupled with appropriate orbital overlap would favor conrotatory cyclization.
While the reaction was indeed highly stereospecific, it took the disrotatory path
instead. To explain the observed contradiction, it was necessary to recognize a new
control element that Woodward and Hoffmann christened ‘conservation of orbital
symmetry rules’ [1–3].
Reactions occur readily when there is congruence between the orbital symmetry
characteristics of the reactants and products, and only with difficulty when that
congruence does not obtain. In other words, the orbital symmetry is conserved in
concerted reactions. How exactly is the orbital symmetry conserved and what are
its further ramifications are important issues which we will examine in detail by
considering examples. For a good grasp of the subject, let us first understand the
orbitals and their interactions in relation to π and σ bond formation.
https://doi.org/10.1007/978-3-030-75622-2_5
130 5 The Conservation of Orbital Symmetry Rules …
2 Orbitals and Symmetry Considerations
A π bond is formed from the overlap of two p orbitals that are adjacent and parallel
to each other across a σ bond, and a σ bond is the result of coaxial interaction of two
atomic orbitals such as s and s, s and p, and p and p. A molecular orbital (MO) is the
result of a linear combination of the constituent atomic orbitals and each MO can be
populated by a maximum of two electrons. For a total of n atomic orbitals and n being
an even number, there are n/2 bonding and an equal number of antibonding MOs.
With n as an odd number, there shall be (n−1)/2 bonding MOs, an equal number of
antibonding MOs, and one nonbonding MO.
For atomic orbitals x 1 and x 2 ,
(a) x 1 + x 2 represents bonding combination, which is characterized by positive
overlap with maximum electron density localized in the region between the
two nuclei, and
(b) x 1 − x 2 represents antibonding combination, which is characterized by negative
overlap with a nodal plane in the region between the two nuclei where the
electron density is nil.
For example,
x1 + x2
x1 and x2 are s orbitals
x1 - x2
x1 + x2
x1 and x2 are p orbitals and interact in σ manner
x1 - x2
x1 + x2
x1 and x2 are p orbitals and interact in π manner
x1 - x2
Because an orbital is a mathematical representation of a wave function and also

because multiplying an entire wave function by −1 does not change its energy char-
acteristics, overlap of a minus lobe with another minus lobe is precisely the same as
the overlap of a plus lobe with another plus lobe, i.e., x 1 + x 2 is the same bonding
molecular orbital as −x 1 − x 2 . In the construction of a σ bond from the overlap of
two p orbitals, this can be represented as follows:
2 Orbitals and Symmetry Considerations 131
(x1 + x2) = (-x1 - x2)
The overlap of hydrogen s orbital with a carbon p orbital to result in σC–H and
σ*C–H MOs is represented as follows. Here, it must be clearly understood that two sp3
orbitals may also combine to result in either π or σ bond, depending upon whether
they approach, respectively, parallel or collinear to each other.
In understanding conservation of orbital symmetry rules, we also need to compre-

hend various MO energy levels in a chemical entity and their symmetry properties
in respect of symmetry operators such as mirror plane and C 2 axis. For the sake of
discussion, let us consider the simple molecule of ethylene, which has four σC–H
bonds, one σC–C bond, and one πC=C bond. The four σC–H bonds are undoubtedly of
equal energy and, hence, they are placed at a single energy level. Because the energy
of σC–C bond is expected to be only a little different from that of σC–H bond, σC–C
level may also be placed at the σC–H level. Corresponding to these five bonding σ
levels, we shall have five antibonding levels to designate σ*. For the remaining πC=C
bond, we shall have bonding π and antibonding π* levels. On relative energy scale,
π level is higher than σ level in the bonding domain but lower in the antibonding
domain. Given below is a graphical representation of this analysis. The symmetry
properties of all the MOs (bonding and antibonding) in respect of two symmetry
elements, namely mirror plane m and C 2 axis, are also given.
MOs of ethylene and their symmetry characteristics

(A = antisymmetric, S = symmetric)
The mirror plane m is perpendicular to the plane of the molecule/orbital, which

also bisects it. The C 2 axis of symmetry is a line that bisects the molecule/orbital
through the center and is also perpendicular to it. We will understand these symmetry
elements more by considering the MOs of the allyl system.
Consider all the three carbons of an allyl system in the plane of the paper with the
p orbital on each carbon also in the same plane. All the substituents are therefore in
a perpendicular plane by virtue of resonance. The following points are in order:
(a) The mirror plane is placed orthogonal to the plane of the three carbons and it
passes through the central carbon atom. The mirror plane shall, therefore, be
parallel to the p orbitals on either side.
(b) The C 2 axis is perpendicular to the plane of the three carbons and it passes
through the central carbon atom. The C 2 axis is, therefore, orthogonal to the p
orbitals.
(c) If the reflection to the right of an orbital on the left of the mirror is the same,
the orbital is said to be symmetric. In the absence of such a relationship, the
orbital is antisymmetric.
(d) In order to determine the symmetry property of a MO with respect to C 2 axis,
the MO in question is rotated, clockwise or anticlockwise, around this axis by
180° to see whether or not the same MO is generated. When the same MO is
generated, it is said to be symmetric. Otherwise, it is antisymmetric.
(e) Generally, a given MO is symmetric with respect to mirror plane and antisym-
metric to C 2 axis and vice versa. The symmetry characteristics with respect to
a given symmetry element also alternate in moving from the lowest lying to
higher lying molecular orbitals.
2 Orbitals and Symmetry Considerations 133
C2
Two electrons in the lowest MO with the other two MOs empty is what character-
izes an allyl cation. Allyl radical has an additional one electron in the middle orbital,
and the same shall possess two electrons in allyl anion. In all of these allylic systems,
the highest level MO is always empty in the ground state of the species.
We are now equipped to consider the MOs and their symmetry characteristics
in s-cis-butadiene. The two π bonds are derived from four atomic p orbitals, their
allowed linear combinations give rise to a set of four MOs, two bonding and two
antibonding. These MOs and their symmetry properties with respect to m and C 2 are
given below.
m C2
---- A S
---- S A
---- A S
---- S A
Once again, it should be noted that the symmetry of the orbital alternates and also
the energy increases with number of nodes. In moving from the lowest MO to the
highest, the nodes increase in number from 0 to 3. These nodal points are shown by
thick dots on the C–C bonds. The symmetry properties with respect to mirror plane
are clearly opposite to those with respect to C 2 axis. In the ground state 1,3-butadiene,
the two lower MOs are filled, each by two electrons, and the higher levels are empty.
3 π2 + π2 Reaction
We will now consider some pericyclic reactions to see how best we can implement the
rules of conservation of orbital symmetry. For this, we need to ascertain correspon-
dence of reactant orbitals with product orbitals in respect of a symmetry element. Let
us first consider the π2 + π2 reaction of two ethylene molecules to form cyclobutane
as shown below. We create two σ bonds in the product at the expense of two π bonds
in the reactants. The energy level correlation is as follows. As a general practice, the
σ and σ* and also π and π* levels are represented equidistant from the nonbonding
level.
reaction of two alkenes to form cyclobutane
The transition state of a pericyclic reaction has cyclic geometry and the reaction
progresses in a concerted fashion, i.e., the breaking of some bonds and formation
of others take place simultaneously without any discrete intermediate ever being
involved. The reactant passes through a single transition state before collapsing to
the product. The major classes of pericyclic reactions are electrocyclic reactions
such as 1,3-butadiene → cyclobutene, cycloadditions such as π2 + π2 and π4 + π2
cycloadditions, and sigmatropic shifts such as [1,5] hydrogen shift. In general, these
reactions are considered to be equilibrium processes. However, it is possible to push
the reaction in a single direction by designing a reactant that generates a product of
significantly large stability (lower energy) in comparison to the reactant.
3 π2 + π2 Reaction 135
σ*
π*
π
σ
Approximate energy levels of the MOs involved in

cycloaddion. The dashed horizontal line represents nonbonding level.
The and levels, both bonding and anbonding, for ethylene will be
approximately the same as for other symmetrically substuted
alkenes but slightly different for unsymmetrical alkenes.
The two localized π bonds, π1 and π2 , of the two reactant ethylene molecules
are shown below. Corresponding to these, there are π1 * and π2 * levels, also shown
below. The orbital cross section is shown in the plane of the paper.
1 1 1 1
2 2 2 2
Consider the MOs of two ethylene molecules approaching each other. There are
a total of four combinations: the plus (+) and minus (–) combinations of the two
bonding levels, i.e., π1 + π2 and π1 − π2 , respectively, and, likewise, the plus
and minus combinations of the two antibonding levels, i.e., π1 * + π2 * and π1 * −
π2 *, respectively. These combinations are shown below. For each combination, let us
consider two mirror planes represented by the encircled digits 1 and 2. The following
observations in order:
(a) The π1 + π2 combination is symmetric with respect to reflections in both the
mirror planes.
(b) While π1 − π2 combination is symmetric with respect to reflections in mirror
plane 1, it is antisymmetric with respect to reflections in mirror plane 2.
(c) While π1 * + π2 * combination is antisymmetric with respect to reflections in
mirror plane 1, it is symmetric with respect to reflections in mirror plane 2.
(d) The π1 * − π2 * combination is antisymmetric with respect to reflections in
both the mirror planes.
The symmetry elements are given below each combination. The first symmetry
element is with respect to the mirror plane 1 and the second with respect to the mirror
plane 2. It is important to recognize that on the energy scale, the π1 + π2 combination

is lower than π1 − π2 combination in the bonding region. Likewise, in the antibonding
region, π1 * + π2 * combination is lower than π1 * − π2 * combination.
1 1 1 1
2 2 2 2
The criterion to make the above energy distinction is simple. Think of the situation
where the two π bonds have come close enough to begin interaction for σ bond
formation.
(a) In π1 + π2 combination, not only the interactions for the formation of σ bonds
(vertical coaxial overlap shown by broken green lines) are constructive but also
the p orbitals of each alkene are suitably disposed for constructive π-overlap
(horizontal blue lines). For π1 − π2 combination, π-overlap is present but σ-
overlap absent. The π1 + π2 combination is therefore more energy-lowering
than π1 – π2 combination. Thus, π1 + π2 MO shall appear below π1 – π2 MO
on the relative energy scale.
(b) Both the antibonding combinations are devoid of π-overlap. However, π1 * +
π2 * combination benefits from constructive σ-overlap, but π1 * − π2 * does
not. The combination π1 * + π2 * is, therefore, lower on the energy scale than
π1 * − π2 * combination.
(c) The combinations of antibonding MOs remain in the antibonding region and,
likewise, the combinations of bonding MOs remain in the bonding region. The
energy of a bonding level MO is always lower than that of antibonding MO.
In brief, we have the following overlaps across four MOs of the reactants.
orbital combination overlaps (constructive) overlaps (constructive)
2 2
2 0
0 2
0 0
σ1 σ2 σ1* σ2*
Now, we can analyze the situation in cyclobutane in an analogous manner. The

two localized σ orbitals, σ1 and σ2 , and their antibonding levels σ1 * and σ2 * are
given above. The allowed combinations σ1 + σ2 , σ1 − σ2 , σ1 * + σ2 * and σ1 * − σ2 *,
and their symmetry properties in respect of the same two mirror planes are shown
below. As above, the σ1 + σ2 combination is lower than σ1 − σ2 combination in
the bonding region and, likewise, the σ1 * + σ2 * combination is lower than σ1 * −
σ2 * combination in the antibonding region. For relative energy considerations, the
criteria discussed above apply.
σ1 + σ2 σ1− σ2 σ1* + σ2* σ1* − σ2*

SS AS SA AA
The correspondence or correlation diagram for the reaction of two ethylene

molecules to form cyclobutane can now be drawn. We must bear in mind that the σ
level is lower than π level on relative energy scale. By the same token, σ* level is
higher than π* level. For the reaction in direction of cyclobutane, we focus on the
two bonding MOs of cyclobutane, σ1 + σ2 and σ1 − σ 2 , and then search for their
symmetry correspondence (match) with MOs on the reactant side. The following
discrete observations emerge:
(a) While the SS symmetry of the lowest bonding cyclobutane orbital σ1 + σ2
corresponds to that of the bonding reactant orbital π1 + π2 , the symmetry
of the bonding orbital σ1 – σ2 corresponds to that of the antibonding reactant

orbital π1 * + π2 *.
(b) To conserve orbital symmetry, it is desirable that the bonding σ1 + σ2 and σ1 −
σ2 MOs be derived, respectively, from the bonding π1 + π 2 and antibonding
π 1 * + π2 * MOs of ethylene. The π1 * + π2 * MO is the first excited state
of ethylene. The reaction, therefore, is photochemical. It cannot be thermal
because it is impossible to promote a bonding level orbital to its first excited
state thermally due to very high energy requirement.
AA σ1* - σ2*
SA σ1* + σ2*
π1* - π2* AA
π1* + π2* AS
π1 - π2 SA
π1 + π2 SS
AS σ1 - σ2
SS σ1 + σ2
Following the principle of microscopic reversibility, the transformation of

cyclobutane into two ethylene molecules must also be photochemical. This notion
is beautifully borne out from the above correlation diagram. Whereas π1 + π2 is
derived from the still lower lying reactant orbital σ1 + σ2 , π1 − π2 is derived from
σ1 * + σ2 *. Since the energy difference between σ and σ* levels is larger than the
energy difference of π and π* levels, the transformation of cyclobutane into two
ethylene molecules will be expected to be more energy requiring than the coupling
of two ethylene molecules to form cyclobutane. Consequently, with a light of suit-
able wavelength, it should be possible to prepare cyclobutane from ethylene in good
quantum yield. There is symmetry-imposed barrier in either direction for the reaction
to occur in the ground state.
One may be tempted to use the following localized π1 and π2 orbitals. It must be
understood that this will not change the overall analysis because only the placement
of MOs on the relative energy scale will change. The four possible π-combinations
and their symmetry properties in respect of the same mirror planes 1 and 2 are given
below.
1 1 1 1
2 2 2 2
1 1 1 1
2 2 2 2
Now, π1 − π2 is lower than π1 + π2 and, likewise, π1 * − π2 * is lower than π1 * +

π2 *. These situations were opposite in the analysis above. These π combinations and
their symmetry properties are placed together with the previously taken combinations
of π1 and π2 , and their antibonding levels in the following correlation diagram.
AA σ1* - σ2*
SA σ1* + σ2*
π1* + π2* AA
π1* - π2* AS
π1 + π2 SA
π1 - π2 SS
AS σ1 - σ2
SS σ1 + σ2
In a fashion similar to the above, one may like to consider the following localized
σ orbitals for their possible combinations. Their respective antibonding variants are
also shown.
σ1 σ2 σ 1* σ 2*
The σ combinations in the increasing order of energy and the correlation of these
with the π combinations used in the very first instance above are the following. The
overall analysis and the photochemical nature of the reaction remain unchanged.
σ1 −σ 2 σ1 +σ 2 σ1*− σ 2* σ1* + σ 2*
SS AS SA AA
AA σ1* + σ2*
SA σ1* - σ2*
π1* - π2* AA
π1* + π2* AS
π1 - π2 SA
π1 + π2 SS
AS σ1 + σ2
SS σ1 - σ 2
The correlation diagram for the second sets of π and the σ combinations given
above shall be as follows. Clearly, no matter in which way we perceive the localized
reactant and product orbitals, the eventual correlation feature remained unchanged.
By recognizing the fact that the energy levels remained unaltered, we can confidently
conclude that nothing ever changed except our perception of the localized orbitals.
AA σ1* + σ2*
SA σ1* - σ2*
π1* + π2* AA
π1* - π2* AS
π1 + π2 SA
π1 - π2 SS
AS σ1 + σ2
SS σ1 - σ 2
4 Electrocyclic Ring Closure and Ring Opening Reactions
Let us consider the interaction of two p orbitals in the construction of a σ bond. We

begin with two p orbitals that are joined together by a tether and are also parallel to
each other. Two situations, A and B, arise.
(a) In situation A, one p orbital rotates clockwise and the other anticlockwise to
place same phase lobes coaxial and result in σ bond. This rotation is known as
disrotation because the two orbitals rotate in mutually opposite directions.
(b) In situation B, a σ bond results when both the p orbitals rotate either clockwise
or anticlockwise. This rotation is known as conrotation because the two orbitals
rotate in the same direction.
(c) Whereas mirror plane symmetry is conserved during disrotation, it is C 2
symmetry that is conserved during conrotation. A σ orbital is symmetric to
both the mirror plane and C 2 axis.
A : disrotation
B: conrotation
We extend the argument to the transformation of conjugated kπ (k = 4q or 4q

+ 2, q = 1, 2, 3 … etc.) polyenes to cyclic products. Such a reaction is popularly
known as electrocyclic ring closing reaction in which rotation of the two terminal p
orbitals at the termini is either disrotatory or conrotatory. Either mode of ring closure
is symmetry allowed. Note that mirror plane symmetry during disrotation and C 2
symmetry during conrotation is preserved. Let us explore the conditions for both
ring closing pathways by invoking conservation of orbital symmetry rules.
1,3-Butadiene → Cyclobutene
Let us first consider the conversion of 1,3-butadiene into cyclobutene. In this trans-
formation, two new bonds, one σ and the other π, are generated at the expense of
two π bonds in butadiene. All the other bonds in butadiene remain unaltered but for
changes in hybridization, bond lengths, and bond angles. The most important point
to note is that their symmetry properties remain unchanged. Thus, for simplicity of
the correlation diagram, we consider only the two π bonds on the reactant side and
one π and one σ bond on the product side. The MOs of the reactant and product, and
their symmetry properties in respect of mirror plane and C 2 axis are given below.
Φ1 Φ2 Φ3 Φ4
disrotation conrotation disrotat ion conrotation

m S A S A
C2 A S A S
σ π π* σ*
m S S A A
C2 S A S A
4 Electrocyclic Ring Closure and Ring Opening Reactions 143
1 and 2 are the bonding and 3 and 4 antibonding MOs of the reactant. The
energies of these MOs increase from 1 to 4 . The ring closing mode to result in
σ bond is indicated below each MO. Now, we can separately draw the correlation
diagram between the orbitals of 1,3-butadiene and cyclobutene in respect of mirror
plane and C 2 axis.
A σ* A σ*
Φ4 A Φ4 S
Φ3 S A π* Φ3 A S π*
Φ2 A S π Φ2 S A π
Φ1 S Φ1 A
S σ S σ
Orbital symmetry correlation diagram Orbital symmetry correlation diagram
with respect to mirror plane, S = with respect to C2 axis, S = Symmetric, A =
Symmetric, A = Antisymmetric Antisymmetric
Again, for cyclobutene formation, we must focus on its two bonding MOs (σ and
π) and then search for symmetry correspondence among the MOs of 1,3-butadiene.
(a) In reference to mirror plane symmetry, which amounts to disrotation, the
symmetry of the lower lying antibonding MO 3 is the same as that of the
higher lying bonding MO π of cyclobutene. Therefore, in order for cyclobutene
to form from 1,3-butadiene, the bonding 2 level must first be promoted to
antibonding 3 level. The reaction, therefore, is photochemical.
(b) Likewise, for the reverse reaction, we concentrate on the bonding MOs 1 and
2 of 1,3-butadiene and find their symmetry correspondence with σ and π*,
respectively. The π of cyclobutene must, therefore, be promoted to π* before
the reaction could take place. This reaction therefore is also photochemical.
(c) We, thus, conclude that the disrotatory ring closure of 1,3-butadiene to
cyclobutene and also disrotatory ring opening of cyclobutene to 1,3-butadiene
may be accomplished only photochemically.
In the other correlation diagram, where C 2 symmetry has been preserved, we note
that the symmetry properties of both the bonding MOs on either side correlate and
that there is no crossover to the antibonding level. The reaction in either direction,
therefore, proceeds thermally. Thus, the conrotatory ring closure of 1,3-butadiene to
cyclobutene and also the conrotatory ring opening of cyclobutene to 1,3-butadiene
takes place thermally. In other words, the thermal ring closure of 1,3-butadiene
to cyclobutene and also the thermal ring opening of cyclobutene to 1,3-butadiene
involve conrotatory motions.
Overall, the transformation of any 1,3-diene into cyclobutene or vice versa takes
disrotatory pathway under photochemical conditions and conrotatory pathway under
thermal conditions. The choice of the reaction condition is solely to meet the stere-
ochemical requirement of the product. This notion becomes amply clear from the
following transformations.
E A conrotatory ring closure under thermal conditions

E E will furnish the cyclobutene derivative with the two
heat E
E E ester groups cis as shown. A photochemical
H disrotatory ring closure will have these ester groups
H trans to each other
Ph Ph
Ph H O
heat MA These reactions involve conrotatory ring opening of
Ph O the benzocyclobutanes, which differ in the relative
Ph stereochemistry of the two phenyls. The resultant
H O quinodimetanes are trapped by MA in Diels-Alder
Ph fashion to furnish the adducts wherein the relative
stereochemistry of the phenyl groups in each case is
Ph Ph easily determined as shown. The observed
Ph H O stereochemical relationships confim the predictions
heat MA based on conrotatory ring openings. MA = maleic
H O anhydride
Ph H O
Ph Ph
H
O
H X
O
O Although both reactions are symmetry allowed,
H the thermal pathway is disfavored simply for the
O H geometrically impossible trans-ring junction.
O
H hν
O
H
H If the requirement is that of trans-3,4-dimethyl-1-

cyclobutene, one will choose to perform the
reaction thermally. The reaction must be
achieved photochemically for the generation of
hν the cis-isomer.
O
O Ph
Ph We understand the photochemical forward
hν reaction in view of what has been discused
N N above. However, if we were to believe in the
principle of microscopic reversibility, the reverse
N NH H
thermal reaction does not seem to fit. Inversion at
O the ring junction nitrogen to produce trans-fused
ring followed by thermal conrotatory ring opening
explains the observation. The inversion at N is
easy.
N N
H
1,3,5-Hexatriene → 1,3-Cyclohexadiene
Next, we consider the conversion of 1,3,5-hexatriene into 1,3-cyclohexadiene and

explore the thermal and photochemical modes of cyclization by imposing symmetry
considerations. In this reaction, we derive one σ and two new π bonds in the product
1,3-cyclohexadiene from a total of three π bonds in the reactant 1,3,5-hexatriene.
Given below are the six MOs (1 –6 ) of 1,3,5-hexatriene and their symmetry
properties in relation to mirror plane and C 2 axis.
Φ1 Φ2 Φ3 Φ4 Φ5 Φ6
m S A S A S A
C2 A S A S A S
For an easier depiction of the MOs and recognition of their symmetry char-
acteristics, the above six MOs may be represented in the following fashions as
well.
Φ1 Φ2 Φ3
Φ4 Φ5 Φ6
Now, we have one σ and two π orbitals in the bonding region and the corresponding
antibonding levels on the product side. The four π levels are the same as in 1,3-
butadiene discussed above. These six MOs along with their symmetry properties in
respect of mirror plane and C 2 axis are given below.
σ Φa Φb Φc Φd σ*
m S S A S A A
C2 S A S A S A
The separate correlation diagrams of the above reactant and product MOs in
respect of mirror plane and C 2 axis are shown below.
A σ*
Φ6 A A σ* Φ6 S
Φ5 S A Φd Φ5 A S Φd
Φ4 A S Φc Φ4 S A Φc
Φ3 S A Φb Φ3 A S Φb
Φ2 A S Φa Φ2 S A Φa
Φ1 S Φ1 A
S σ S σ
orbital symmetry correlation diagram orbital symmetry correlation diagram

with respect to mirror plane with respect to C2 axis
S = Symmetric, A = Antisymmetric S = Symmetric, A = Antisymmetric
Obviously, while the disrotatory ring closure with conservation of mirror plane
symmetry is predicted to take place thermally, the conrotatory ring closure with
conservation of C 2 axis of symmetry is expected to be photochemical. The predicted
mode of ring closure can be deduced easily from the stereochemistry of the product. It
must be noted that there is a switch in the mode of ring closure in switching from 1,3-
butadiene → cyclobutene to 1,3,5-hexatriene → 1,3-cyclohexadiene transformation.
It is important for the central π bond in 1,3,5-hexatriene to have Z-geometry for
its transformation to 1,3-cyclohexadiene succeed. From several such cases, the
following general understanding has emerged.
kπ electron system Thermal reaction Photochemical reaction

k = 4q (q = 1, 2, 3, 4, …) Conrotatory Disrotatory
k = 4q + 2 (q = 0, 1, 2, 3, …) Disrotatory Conrotatory
The ring closing transformations allyl anion → cyclopropyl anion, 1,3-

pentadienyl cation → cyclopentenyl cation, 1,4-pentadienyl cation → cyclopentenyl
cation, and 1,3,5,7-octatetraene → 1,3,5-cyclooctatetraene fall in the category of kπ,
k = 4q, electron system. In the category of kπ, k = 4q + 2, electron system, we
can quote the transformations allyl cation → cyclopropyl cation, 1,3-pentadienyl
anion → cyclopentenyl anion, and 1,4-pentadienyl anion → cyclopentenyl anion.
The chemical equations for these transformations are given below.
kπ, k = 4q, q = 1, 2, 3,..... kπ, k = 4q+2, q = 0, 1, 2, 3,.....
5 Diels–Alder Cycloaddition Reaction (π4 + π2 Reaction)
Diels–Alder reaction involves cycloaddition of 1,3-dienes with alkenes in pericyclic

manner to generate six-membered ring products. We now know that the reaction is
thermal and is never accomplished photochemically. Now, we seek a rational to the
only thermal nature of the reaction. For the sake of simplicity, let us consider the
reaction of 1,3-butadidne with ethylene to result in cyclohexene. Let us also impose
mirror plane symmetry on the course of the reaction.
We have six MOs coming from the reactants, four from 1,3-butadiene comprising
two bonding and two antibonding MOs and two from the alkene comprising one π and
the other π*. In product cyclohexene, we have constructed two new σ bonds, say σa
and σb , to lead to the bonding combinations σa + σb and σa − σb and the antibonding
combinations σa * + σb * and σa * − σb *. For the new π bond in cyclohexene, there
are π and π* molecular orbitals. It is to be understood that the energy levels of the π
MOs of the reactant alkene will be almost the same as those of the product π MOs of
the product. For substituted alkenes and 1,3-dienes, these levels will be different. The
overall symmetry-driven conclusion, however, does not change. The entire picture
of this reaction and the symmetry correlation is given below.
'a'
+
4π+ 2π = 6π electrons 2σ + 1π bonds
'c' 1,3-Butadiene and ethylene are both planar molecules and they are
shown to lie in two separate planes marked 'a' and 'b', but parallel to
'b' each other. The third plane marked 'c' is the mirror plane which is
orthogonal to the plane of the paper and also to the above two
planes. During the reaction, bond formation occurs between the
terminal sp2 carbons of the diene and alkene. Because these bonds
are σ bonds, the overlap of the involved p orbitals must be coaxial.
A σ1* = σa* - σb*
S σ2* = σa* + σb*

Φ 1∗ A
π∗ A A π∗
Φ 2∗ S
Φ2 A
π S S π
Φ1 S
A σ2 = σa - σ b
S σ 1 = σ a + σb
As there is no symmetry-imposed barrier in the ground state MOs of the reactants

and product, the reaction is thermal. Although there is one-to-one symmetry corre-
spondence among the antibonding MOs of the reactants and product, there is a huge
energy-imposed barrier to the reaction because the first excited state of the diene,
i.e., 2 *, does not correlate with the first excited state of cyclohexene, which is π*.
The π levels on both sides being more or less the same, the fact that the σ1 and
σ2 levels are considerably lower than 1 and 2 , the reaction will be expected to
be exothermic. The reaction, however, still requires some 20 kcal/mol as activation
energy. This energy requirement is not related to orbital symmetry conservation but
to factors such as energy changes accompanying re-hybridization in the levels, bond
length alterations, and angle distortions.
References
1. R.B. Woodward, In Aromaticity, Special Publication No. 21 (The Chemical Society: London,
1967), p 217
2. R.B. Woodward, R. Hoffmann, The Conservation of Orbital Symmetry (Academic Press, New
York, 1970). and references cited therein
3. R.B. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. Engl. 08, 781 (1969)
Chapter 6
The Overlap Component
of the Stereoelectronic Effect vis-à-vis
the Conservation of Orbital Symmetry
Rules
Abstract The integration of conservation of orbital symmetry and the orbital overlap
effect serves as a powerful tool to reliably predict the stereochemical course of
pericyclic reactions as exemplified in this chapter. The orbital overlap factor has been
discussed with examples such as the thermal fragmentations of cyclopropanated and
cyclobutanated cis-3,6-dimethyl-3,6-dihydropyridazine, and [1,5] sigmatropic shifts
in cis-2-alkenyl-1-alkylcyclopropanes and cis-2-alkenyl-1-alkylcyclobutanes.
1 Introduction
We have understood the stereoelectronic factor as a tool to cause reactions occur fast
when certain spatial relationships exist between the bonds formed and broken [1].
The “certain spatial relationships” of the bonds formed and broken are, in fact, their
mutual orientations such as collinearity of the three atoms involved in SN 2 reaction
and coplanarity of the four ligands on developing π bond in vicinal elimination to
allow orbital overlap throughout. By combining orbital overlap with conservation
of orbital symmetry, we have an extremely powerful tool in our hands to assist us
delineate the stereochemistry of reactions that would otherwise be difficult to explain.
The significance of combining the conservation of orbital symmetry rules with
orbital overlap was felt first from the observation that the cyclization of a stereo-
chemically well-defined 1,3,5-triene to the corresponding 1,3-cyclohexadiene in a
projected synthesis of vitamin B12 took exclusively the disrotatory pathway instead
of the expected conrotatory ring closure. The conrotatory ring closure was expected
on account of minimization of angle strain and π-uncoupling. To explain this contra-
diction, it was necessary to recognize a new control element which Woodward and
Hoffmann called “conservation of orbital symmetry”. Today, we know that 1,3,5-
triene undergoes disrotatory ring closure under thermal conditions and conrotatory
ring closure under photochemical conditions.
In the backdrop of orbital symmetry rules, need was felt to evaluate the strength
of the orbital overlap component of the stereoelectronic effect by designing experi-
ments in which both the competing pathways are orbital symmetry-allowed, but one
pathway is preferred over the other for better orbital overlap. Berson has explored
https://doi.org/10.1007/978-3-030-75622-2_6
150 6 The Overlap Component of the Stereoelectronic Effect …
this avenue exclusively by replacing one double bond in a simple model system by
cyclopropane ring because such a structural change was expected to cause one of
the two orbital symmetry-allowed pathways to enjoy better orbital overlap than the
other.
+ +39.4 kcal/mol
(1)
+ +37.5 kcal/mol (2)
N N (3)
+ -55 kcal/mol
N N
N N (4)
+ -53 kcal/mol
N N
N N (5)
+ -26 kcal/mol
N N
We first collect some background information to help us understand the orbital

overlap issue better. The following points must be noted:
(a) The fragmentation of cyclohexene into 1,3-diene and an alkene takes place in
a process called retro-Diels–Alder reaction as shown in Eq. (1). The unsubsti-
tuted version of the reaction is endothermic by 39.4 kcal/mol, a number that is
considerably high to make the reaction very slow. A similar difficulty is present
in the retro-homo-Diels–Alder reaction shown in Eq. (2).
(b) In contrast, the corresponding fragmentations of 3,6-dihydropyridazine,
Eq. (3), and its homologue, Eq. (4), proceed rapidly because formation of
the very stable N2 makes the reaction > 90 kcal/mol more exothermic than the
reaction in Eq. (1) [2, 3].
(c) The extraordinary rate enhancement associated with 3,6-dihydropyridazine,
whose fragmentation is many orders of magnitude faster than that of 3,4,5,6-
tetrahydropyridazine, Eq. (5), is consistent with concerted mechanism for the
reactions given in Eqs. (3) and (4).
2 Steric Effects in the Thermal Fragmentation

of cis-3,6-Dimethyl-3,6-Dihydropyridazine
3,6-Dihydropyridazines are appropriate substrates to bring the steric and orbital

overlap effects together with the maintenance of the conservation of orbital symmetry
rule. We bring in the steric effect first and note the following points:
2 Steric Effects in the Thermal Fragmentation of … 151
N N H H
= H H
N N N N
1 1a 1b
H H
H H
2 3
< 0.1% > 99.9%
Scheme 1 Thermal fragmentation of cis-3,6-dimethyl-3,6-dihydropyridazine
(a) The fragmentation of cis-3,6-dimethyl-3,6-dihydropyridazine 1 (Scheme 1)

can proceed through two different symmetry-allowed pathways. While the
reaction proceeding through the transition structure resembling conformation
1a will generate cis,cis-2,4-hexadiene 2, the reaction proceeding through the
transition structure resembling conformation 1b will generate trans,trans-2,4-
hexadiene 3.
(b) Since the two methyl groups sterically interfere with each other in conformer
1a, the reaction will be expected to proceed largely through the conformer 1b.
(c) The sole product of fragmentation is trans,trans-2,4-hexadiene 3. The steric
effect is so large that one of the two orbital symmetry-allowed pathways is
preferred over the other by a factor of 10 [3].
3 Orbital Overlap Effects in the Thermal Fragmentation

of Cyclopropanated and Cyclobuanated
cis-3,6-Dimethyl-3,6-Dihydropyridazine
We now couple the above steric effect with the overlap effect by replacing the πC=C
bond in 1 by cyclopropane ring such that it acts in tandem with the steric effects
arising from methyl substituents to allow the evaluation of the strength of the orbital
overlap effect as in the substrate 4 (Scheme 2). The following analysis is in order:
(a) The conformer 4a suffers from severe steric interactions involving the methyl
groups and the methylene group of cyclopropane ring to allow preference for
the uncrowded conformer 4b.
(b) The preference for 4b over 4a ought to be significantly larger than the prefer-
ence for 1b over 1a and, thus, 4 will be expected to fragment exclusively to the
trans,trans-diene 6, if the steric factors were the sole control. It was actually
cis,cis-diene 5 that predominated over 6 by a margin of about 200:1.
N N H H
= H H
N N N N
4 4a 4b
5 6
> 99.5% < 0.5%
N N
H H
7 8
Scheme 2 Thermal fragmentation of cyclopropanated and cyclobutanated 3,6-dimethyl-3,6-

dihydropyridazines
(c) Obviously, there has to be some very powerful effect at work in the transition
structure resembling 4a that reversed the normal steric preference.
The above “very powerful effect” has been shown to have its origin in superior
orbital overlap in a 4a-like transition structure, wherein the breaking σC–N bonds are
aligned parallel to the canted orbital axes of the cleaving cyclopropane ring bond
(dashed lines in 4a). In the alternate 4b-like transition structure, orbital overlap is
unsatisfactory because the axes of the involved orbitals are essentially orthogonal.
Thus, the cyclopropane ring has synthetically forced the choice of one fragmentation
pathway over the other and also controlled the stereochemical course of the reaction
at the sites of the two newly generated π bonds.
The above feature was observed from the cyclobutane derivative 7 as well as it
fragmented to the cis,cis-diene 8 with stereospecificity that was too high to measure.
However, the reaction 7 → 8 was considerably slower than 4 → 5 for the compar-
atively poorer parallel alignment of the cleaving cyclobutane ring orbitals with the
cleaving σC–N bonds.
4 Orbital Overlap Effects in [1,5] Sigmatropic Shifts
The overlap effect generated by the anisotropic influence of a small ring applies
to other concerted reactions as well. Let us consider [1,5] hydrogen shift in cis-
1-alkenyl-2-alkylcyclopropane (9 → 10, Eq. 6) and analogous cis-1-alkenyl-2-
alkylcyclobutanes (11 → 12, Eq. 7). Both the reactions are analogous to [1,5]
4 Orbital Overlap Effects in [1,5] Sigmatropic … 153
hydrogen shift 13 → 14 (Eq. 8) [4, 5].
(6)
H
9 10
(7)
H
11 12
(8)
H
13 14
Note the steric effects during [1,5] hydrogen shift in 6(S),2(E),4(Z)-2-deuterio-6-

methyl-2,4-octadiene, which can exist as an equilibrium mixture of the conformers
15a and 15b (Scheme 3) [6]. The sigmatropic shift is suprafacial from orbital
symmetry considerations and, thus, it can generate the products 16 and 17. The
electron distribution above and below the plane of the reactant diene is essentially
isotropic. The product 17 is favored over 16 by a factor of 1.5 probably because
of the slightly smaller steric requirement of methyl over ethyl group. Against the
ethyl group in 15a, it is methyl group in 15b that is closer to D-containing terminus
of the π bond. The migration origin and migration terminus must be close to each
other by being cis on the central π bond for the process to occur. The migration
terminus-derived π bond always has Z-geometry.
Now, we bring in the overlap effect by replacing the central π bond with cyclo-
propane and consider the optically homogeneous molecule 18 [7, 8]. This molecule
may be considered to undergo [1,5] hydrogen shift through the conformers 18a and
18b (Scheme 4). The following three significant points emerge.
Scheme 3 [1,5] Hydrogen H 4

shift in 6 S
S 5 3 Et
6(S),2(E),4(Z)-2-deuterio-6- H D
methyl-2,4-octadiene Et D 2 1
15a 15b
H Et
D
Et S R
D
H
16 17
H CH3
D3 C
H3C D3 C
D CH3
CD3 D HD CH3
CH3
H
18a 18b 20
H3 C
H CO2H
H
CD3
D CH3 D S CH3
19 21
Scheme 4 [1,5] Hydrogen shift in cis-2(S)-[2(S)-isopropyl-1-d 3 ]-1(S)-[1-(E)-propenyl-2-d]-

cyclopropane 18
(a) The conformer 18a will lead to the formation of 19, wherein the newly
generated asymmetric center has S-configuration.
(b) The conformer 18b will lead to the formation of 20, wherein the newly
generated asymmetric center has R-configuration.
(c) In conformer 18a, the breaking σC–H bond at the asymmetric center and σC–C
bond orbital on the adjacent cyclopropane carbon are parallel to each other
to allow their effective overlap to culminate into a π bond. These orbitals are
orthogonal in conformer 18b to allow very slow reaction, if at all.
The product obtained was subjected to oxidative π bond cleavage to isolate a
carboxylic acid with S-configuration. Very clearly, 18 reacted exclusively through the
conformer 18a and the orbital overlap factor tightly controlled the reaction pathway.
Only the isotopic difference between the two substituents at the donor site (CH3 vs
CD3 ) minimized any steric bias to the configuration of the donor-derived π bond in
the product.
In application of the above knowledge to hydrogen shift in the corresponding
cyclobutane derivative 22 (Scheme 5), one expects 22a as the most reactive conformer
on account of better orbital overlap of the breaking σC–H bond with the cyclobutane
σC–C bond, as shown by parallel dotted lines in red color, required for π bond forma-
tion to generate 23. The conformer 22b will be least reactive to generate 24 for
having the two breaking bonds orthogonal. The difference in the geometries of the
donor-derived π bonds and the reversal in the configuration of the acceptor-derived
carbon may specifically be noted.
5 Difficulties Experienced with [1,5]-Sigmatropic … 155
R1
R1 H R3
R2
R2 H R4
R3
R4
22a 22b
R1 R2
H R4
R2 R1 R3
R3 R4
H
23 24
Scheme 5 [1,5] Hydrogen shift in cis-2-alkenyl-1-alkylcyclobutane 22
5 Difficulties Experienced with [1,5]-Sigmatropic

in the Cyclobutanated Species
The following factors make a realization of the reaction of cyclobutanated species

to be more difficult than the corresponding cyclopropanated:
(a) The reverse ene-reaction of a cis-1-alkeneyl-2-alkylcyclobutane is much
slower than that of the cyclopropane counterpart. Consequently, fragmenta-
tion, epimerization, and sigmatropic rearrangement, which are not seen from
the cyclopropane system, compete with the reverse ene-reaction and their
products are depositories of the required stereochemical information in the
corresponding reactants.
(b) Since the primary product of the reverse ene-reaction is 1,5-diene, one may
expect a secondary transformation via Cope rearrangement.
(c) At the high temperature (250 °C and above) at which the reaction is carried
out, E/Z-isomerization is also highly likely and, in fact, an observed event.
Fortunately, the problem arising from secondary Cope rearrangement could be
suppressed by the choice of a methoxy group as a stereochemical marker as in 22
(R1 = CH3 , R2 = OMe, R3 = R4 = H), 22 (R1 = OMe, R2 = CH3 , R3 = R4 = H),
22 (R1 = CH3 , R2 = OMe, R3 = D, R4 = CH3 ), and 22 (R1 = OMe, R2 = CH3 ,
R3 = D, R4 = CH3 ). This is so because hydrogen shift leads to an enol ether whose
subsequent Cope rearrangement is insignificant under the reaction conditions [9, 10].
Although investigation of the full stereochemical feature of this reaction requires a
substrate with specified configuration at the three stereocenters such as in 22 (R1 =
CH3 , R2 = OMe, R3 = D, R4 = CH3 ) and 22 (R1 = OMe, R2 = CH3 , R3 = D, R4
= CH3 ), the substrates 22 (R1 = CH3 , R2 = OMe, R3 = R4 = H) and 22 (R1 =
OMe, R2 = CH3 , R3 = R4 = H) that terminate in stereochemically uninformative
CH2 group can provide valuable partial solutions in as much as the stereochemistry
of the donor-derived π bond is concerned.
Berson has studied the thermal reaction of the substrate 22 (R1 = OMe, R2 =
CH3 , R3 = R4 = H) and identified the products arising from different channels such
as fragmentation to 25 and 26, [1,3] sigmatropic shift to 27, single epimerization to
28 and 29, double epimerization to 30, and the desired [1,5] hydrogen shift leading to
all possible double-bond isomers of 31 as outlined in Scheme 6. From temperature
dependence of the overall rate of disappearance of the reactant and the composition
of product distribution, the activation parameters for the individual pathways were
determined. It was discovered that the activation energy of [1,5] hydrogen shift was
lower than those of the other competing pathways, i.e., epimerization, fragmentation,
and [1,3] sigmatropic shift. This finding is consistent with the difference in the
mechanism for two sets of reactions, the concerted pathway for [1,5] hydrogen shift
and the stepwise diradical pathway for some or all other pathways.
The epimerization at both the ring stereogenic centers causes the diastereomeric
interconversion 22↔30. Since the rates of [1,5] hydrogen shifts in these two diastere-
omers are comparable, some of the products formed from pyrolysis of 22 are consid-
ered to actually arise from 30 and vice versa. After making corrections for the
concurrent double epimerization by following an established procedure [9, 10], it
has been shown that the mechanistically significant ratio of the products (E,Z)-31
and (Z,Z)-31 formed directly from 22 was > 220:1. Very clearly, the orbital overlap
controlled the reaction of stereochemically well-defined reactant 22 and allowed one
symmetry-allowed pathway to take prominence over the other.
R S
S O fragmentation
+
OMe
H
22 25 26
R 1 1S
3 [1,3]-shift H
S O S
2 MeO
H
22 27 R H
MeO S
double single R R S
S R 22 S O +
S O epimerization epimerization
H
H 28 29
30
MeO + MeO
[1,5] hydrogen shift E,Z-31 E,E-31
22
OMe OMe
+
Z,Z-31 Z,E-31
Scheme 6 [1,5] Hydrogen shift and various other reactions of cis-1-alkenyl-2-alkylcyclobutane 22

(R1 = OMe, R2 = CH3 , R3 = R4 = H)
5 Difficulties Experienced with [1,5]-Sigmatropic … 157
In summary, we have witnessed that the orbital overlap component of the stere-
oelectronic effect is indeed a very powerful tool as it controls the stereochemistry
and also the rates of a range of pericyclic reactions by allowing exclusively one of
the two symmetry-allowed pathways for the reason of better overlap of the breaking
bonds.
References
1. E. L. Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, New York, 1962), p. 227

2. J.A. Berson, E.W. Petrillo, Jr. J. Am. Chem. Soc. 96, 636 (1974)
3. J.A. Berson, S.S. Olin, E.W. Petrillo Jr., P. Bickart, Tetrahedron 30, 1639 (1974)
4. J. Wolinsky, B. Chollar, M.B. Baird, J. Am. Chem. Soc. 84, 2775 (1962)
5. J.J. Gajewski, Hydrocarbon Thermal Isomerizations (Academic Press, New York, 1981), p. 106
6. W.R. Roth, J. König, K. Stein, Chem. Ber. 103, 426 (1970)
7. P.A. Parziale, J.A. Berson, J. Am. Chem. Soc. 112, 1650 (1990)
8. P.A. Parziale, J.A. Berson, J. Am. Chem. Soc. 113, 4595 (1991)
9. S.J. Getty, J.A. Berson, J. Am. Chem. Soc. 112, 1652 (1990)
10. S.J. Getty, J.A. Berson, J. Am. Chem. Soc. 113, 4607 (1991)
Chapter 7
Torquoselectivity of Conrotatory Ring
Opening in 3-Substituted Cyclobutenes
Abstract In the thermal conrotatory ring opening of 3-substituted cyclobutene,

the substituent may rotate either inward or outward to be, respectively, on a cis or
trans-double bond. The inward or outward rotation of the substituent, called torqu-
oselectivity, depends on its electronic nature. A sufficiently electron-withdrawing
substituent is known to rotate inward and, likewise, electron-rich or electron-donating
substituent outward. There is no known exception to the outward rotation of the
electron-rich or electron-donating substituent. However, there is no such consis-
tency in regard to electron-deficient or electron-withdrawing substituents because
some such substituents have been predicted from transition structure studies to rotate
outward as well. NBO interaction, i.e., orbital overlap in the transition structure is
an alternate approach to study torquoselectivity. It must clearly be understood that
the prediction by either transition structure model or NBO approach is applicable
to kinetically controlled reactions only because neither takes reaction equilibration
into consideration. An account of prediction of torquoselectivity and also reaction
equilibration with its effect thereon has been discussed in this chapter.
1 Activation Barrier Approach to Torquoselectivity
The ring opening of cyclobutene proceeds in conrotatory fashion under thermal

conditions to form 1,3-butadiene [1, 2]. Electron-rich substituents (ERS), such as
methyl and those with lone pair of electrons, selectively rotate outwards (1 → 2). In
contrast, electron-withdrawing substituents (EWS) rotate inwards (3 → 4). Such an
outward or inward rotation is controlled by the phenomenon called torquoselectivity.
Houk’s seminal work predicts the selectivity extensively based on relative activation
barriers for the inward and outward opening reactions [3–10]. Of course, opening
with lower activation barrier constitutes the preferred pathway.
https://doi.org/10.1007/978-3-030-75622-2_7
160 7 Torquoselectivity of Conrotatory Ring Opening …
ERS ERS
4 3
1 2
1 2
EWS EWS
3 4
Electron-rich and electron-releasing substituents are predicted, in conformity with

experiments, to rotate outwards. However, the trend is not so straightforward with
electron-withdrawing substituents. For instance, while CHO is predicted to rotate
inward, groups such as COMe, CO2 Me, CN, NO2 , NO, and CF3 are favored to rotate
outwards [3–10]. While the COMe and CO2 Me groups may obviously not be as
powerful π-acceptors as CHO group [11], the predicted turn-around in selectivity
from inward for CHO to outward for NO2 is not understood. This, and such other
observations, necessitated the search for an alternate approach. It is significant to note
that the experimental torquoselectivities of 3-CN-, 3-NO2 -, and 3-NO-cyclobutenes
are not known.
2 TS-NBO Approach to Torquoselectivity
An alternate approach to torquoselectivity is based on the understanding that the

selectivity may very well be a consequence of the electronic interplay between the
cleaving σC3C4 bond and substituent (S) in the transition structure (TS). This elec-
tronic interplay can be estimated by natural bond orbital (NBO) analysis [14] of the
TS. The following four different scenarios are likely:
(a) σS → σ*C3C4 interaction in substrates with electron-releasing substituents such
as methyl,
(b) nS → σ*C3C4 interaction in substrates with the substituents possessing lone
pair of electrons,
(c) σC3C4 → πS * interaction in substrates with resonance-accepting substituents,
and
(d) σC3C4 → σS * interaction in substrates with σ-acceptor substituents such as CF3 .
In 2001, Murakami and co-workers observed 83:17 kinetic distribu-
tion of the inward and outward opened products on heating 1-octyl-3-
dimethylphenylsilylcyclobutene 5 at 140 °C in m-xylene for 1 h [15]. Likewise,
the reaction of 1-dimethylphenylmethy-3-trimethysilylcyclobutene 8 at 140 °C in
m-xylene for 9 h generated 69:31 mixture of the inward and outward opened prod-
ucts, respectively. The preference for inward rotation of the silyl substituent was
proposed to result from a favorable overlap of the low-lying σ* orbital of the silyl
2 TS-NBO Approach to Torquoselectivity 161
substituent with the occupied σC3-C4 orbital of the breaking bond in the TS. Both
the differential activation energy and NBO interaction predict inward opening of
3-trimethylsilylcyclobutene. The differential activation free energy is 2.0 kcal/mol
in favor of inward opening at M06-2X/6-31G(d) level of theory. In parallel, the
σC3-C4 → σ*Si-C interaction was 11.3 kcal/mol in the inward opening TS compared
to only 5.0 kcal/mol in outward opening. Thus, the differential activation energy
and differential NBO interaction in the TS go hand-in-hand and predict the same
selectivity.
SiMe2Ph PhMe2Si
140 oC, 1 h SiMe2Ph
+
m-xylene
n-C8H17 n-C8H17 n-C8H17
5 6 7
SiMe3 Me3Si
o
140 C, 9 h SiMe3
+
m-xylene
PhMe2C PhMe2C PhMe2C
8 9 10
The development of differential NBO interaction approach is very interesting. It

has led even the proponent of the differential activation energy approach to concede
to the differential NBO interaction approach and, thus, opened the door for better
understanding.
In 2003, Houk and co-workers observed from calculations at B3LYP/6-31G(d)
level of theory that the filled orbital of a donor substituent experienced closed-shell
repulsion with the filled orbital of the breaking bond over inward rotation and,
therefore, it preferred to rotate outward. In contrast, a vacant acceptor orbital on
the substituent was expected to constructively interact with the filled orbital of the
breaking bond and, thus, rotate inward [10]. Since the electronic as well as steric
effects are well embedded in the TS, focus on closed-shell repulsion separate from
the differential activation energy is unwarranted. The differential activation energy
approach is an excellent approach, but the orbital interaction approach is probably
better.
In application of the differential activation energy approach, in its purest form,
to 3-CF3 -, 3-CF2 H-, and 3-CH2 F-substituted cyclobutenes, the outward opening
was favored over inward opening by 2.3, 0.3, and 2.0 kcal/mol, respectively, at
B3LYP/6-31G(d) level of theory in using the most stable conformers of the substrates.
However, in a small departure, calculations at M06-2X/6-311+G(2d,p) level of theory
by Barquera-Lozada favored inward opening of 3-CF2 H-cyclobutene by 2.5 kcal/mol
[16]. Dolbier and co-workers have experimentally observed 3-CF3 -cyclobutene to
open predominantly outward from gas-phase reaction [17, 18]. The relative concen-
tration of the inward product, however, was found to significantly increase at the
expense of the outward product on raising the reaction temperature. For instance, the
ratio of outward and inward products changed from 43.5:1 at 56.5 °C to 13.2:1 at
188.5 °C. The outward product was measured to be 2.5 ± 0.4 kcal/mol more stable
than inward product.
In 2011, Mikami and co-workers studied the ring opening of 2-CO2 Et-2-CF3 -3-
dimethylphenylsilyl-4-aryloxetene 11 under thermal conditions (toluene-d6 , 110 °C,
48 h) and observed its quantitative transformation to 12 with exclusive inward rotation
of CF3 group [19]. The researchers also observed predominance of inward rotation
of CF3 group on ring opening in the closely related 2-CO2 Et-2-CF3 -3-methyl-4-
phenyloxetene by a margin of 81:19 at 70 °C and 77:23 at 100 °C [20]. The results
were supported by σC-O → σ*C-F interaction, which was larger in the TS for inward
rotation of CF3 over its outward rotation. Going by the learnings of the original differ-
ential activation barrier approach, CF3 will be considered more electron-deficient
than CO2 Et and, thus, it rotated inward. Given a completion between CF3 and H,
CF3 will therefore be expected to rotate inward.
CF3 CF3
2 EtO2C O
EtO2C O1 110 oC, 48 h
3 4
toluene
PhMe2Si Ar PhMe2Si Ar
11 12
In 2015, Houk and Mikami concluded from TS calculations at M06-2X/6-

31+G(d,p) level of theory that the torquoselectivies of a series of mono-, di-, and
trifluoromethylcyclobutenes and also oxetenes resulted from the interplay of favor-
able orbital interactions and closed-shell repulsions [21]. These authors discovered
favorable interactions between σC-O and σ*C-F (σC-O → σ*C-F ) in fluoromethylox-
etenes when the substituents rotated inwards. Also, the preference for inward rotation
of the fluoromethyl group decreased because the closed-shell repulsions n F−σC-O
competed with σC-O → σ*C-F interactions. The closed-shell repulsion arises when
the distance between the oxygen and fluorine is less than the sum of their van der
Waals radii (2.99 Å). The attempt to first amalgamate the differential activation
energy approach with the orbital interaction approach and then turn completely to
the orbital interaction regime for a solid rationale to the observations is obvious.
Like the interaction σC-O → σ*C-F in oxetenes, σC-C → σ*C-F interaction may also
be expected in the ring openings of 3-fluoroalkyl cyclobutenes.
In 2015, Akilandeswari and Prathipa studied 3-OCH3 - and 3-OSiH3 -substituted
cyclobutenes by NBO analysis at B3LYP/6-31G(d) level of theory and found that
the interaction of the electron pair orbital on oxygen interacted with LUMO of the
breaking bond to support outward opening [22]. When the two substituents were
geminally substituted, OSiH3 was judged more electron donating than OCH3 and,
hence, it preferentially moved outward. The outward rotations of OCH3 and OSiH3
supported by the NBO interactions corroborated well with the predictions from
differential activation energies.
In 2016, Saal and Merzoud used the NBO interaction approach to the ring openings
of 3-OMe- and 3-CHO-cyclobutenes and found the results in line with those predicted
from differential activation energies. The 3-OMe- and 3-CHO-cyclobutenes were
favored, respectively, for outward and inward openings [23].
In 2017, in an exhaustive study, Yadav and co-workers investigated substrates
bearing several electron-rich and electron-withdrawing substituents, including 7-
CO2 Me- and 7-CONMe2 -benzocyclobutenes, and presented a critical compara-
tive analysis of the differential activation energy and NBO interaction approaches,
including comments on experimental results, wherever available [24]. Quantum
chemical calculations were carried out at different high levels of theory to study
consistency. Irrespective of the level of theory used, same trend was discovered.
The activation barriers for both outward and inward openings of several substituted
cyclobutenes are collected in Tables 1 and 2. These results qualitatively corroborate
with the findings based on relative activation energies [25, 26]. The initial hypoth-
esis based on steric factors, allowing a large substituent to rotate outward to avoid
the increasing steric congestion during inward rotation, has been dismissed previ-
ously by other investigators [3–10]. For instance, 3-tert-butyl-3-methoxycyclobutene
exclusively opens to (E)-1-tert-butyl-1-methoxybutadiene, 13 → 14, even when the
large tert-butyl substituent is placed in a highly hindered position [5]. The electronic
effect, thus, dominates over steric effect. Such a dominance is also supported from
the opening of trans-3,4-dimethylperfluorocyclobutene 15, which exclusively forms
(E,E)-perfluorohexa-2,4-diene 16 [4]. The CHO group in 3-CHO-cyclobutene and
both CF3 groups in 15 move inwards despite large steric interactions.
Table 1 Gibbs free energies

Substituent G‡outward G‡inward G‡
of activation (G‡ ), kcal/mol
for opening of cyclobutenes OMe 22.7 38.4 −15.7
substituted by heteroatoms t-Bu, OMe 30.0 35.3 −05.3
and other electron-donating
Me, OMe 27.5a 35.7 −08.2
groups. G‡ = G‡outward
OCOMe 26.7 40.6 −13.9
− G‡inward
F 27.0 42.6 −15.6
Me 29.9 36.9 −07.0
a The 2.5 kcal/mol lower G‡ , when Me moves inward in
comparison to t-Bu, suggests the differential steric effects arising
from these substituents
Table 2 Gibbs free energies of activation (G‡ ), kcal/mol, for opening of cyclobutenes possessing
electron-withdrawing substituents. G‡ = G‡outward − G‡inward
Substrate G‡outward G‡inward G‡ G‡cis-trans
CHO 29.7 25.1 4.6 79.6
COMe 28.4 30.0 −1.6 50.8
CN 29.1 33.6 −4.5 85.1
CN,CH3 33.4 31.0 2.4 – a
15 31.1 50.2 −19.1 – b
CF3 33.2 36.3 −3.1 83.5

NO2 30.5 36.5 −6.0 41.5
NO 28.1 24.6 3.5 74.9
CO2 Me 29.5 31.4 −1.9 –
BH2 28.0 10.4 17.6 57.4
17 37.4 39.7 −2.3 54.6c
20 40.6 40.8 −0.2 – c
a The inward and outward openings refer to rotation of CN group. b MP2/6-31G* results. The outward
and inward refer to rotation of F. c Total electronic energies as frequency calculations to arrive at
activation free energies were not successful
OMe OMe
CMe3 CMe3
13 14
F F F F
CF3 CF3
CF3 CF3
F F F F
15 16
In contrast to the electron-rich substituents such as those with lone pair of elec-
trons, the outward rotation of a resonance-accepting substituent is rate-retarding. For
instance, the TS for outward opening of 3-formylcyclobutene is 4.6 kcal/mol higher
than inward opening. This general observation, however, is not without exceptions.
For instance,
(a) Even though the acetyl group is resonance-accepting, 3-acetylcyclobutene
furnishes 3:2 mixture of outward and inward opened products, respectively [7].
Outward opening is favored over inward opening by a margin of 1.6 kcal/mol.
It must be noted that this energy difference corresponds to approximately
15:1 ratio of the outward and inward openings in contrast to the observed
3:2. The significantly larger predominance of outward opening than expected
raises an important question: what factor controlled the largely outward
opening of 3-acetylcyclobutene vis-à-vis the exclusive inward opening of

3-formylcyclobutene?
(b) The CN, CO2 Me, and NO2 groups are resonance-accepting like CHO group,
yet the TS energies predict outward openings. The TSs for outward openings
are, respectively, 4.5, 2.0, and 6.0 kcal/mol lower than the corresponding inward
openings.
(c) The predicted outward opening of 3-NO2 -cyclobutene contrasts the inward
opening of 3-NO-cyclobutene because NO2 group is a better resonance-
acceptor than NO group [11–13]. However, it must be noticed that the exper-
imental selectivity of neither of these substrates has hitherto been reported in
the literature.
(d) TS calculation favors outward opening of 3-CF3 -cyclobutene over inward
opening by 3.1 kcal/mol even when the CF3 group is a sufficiently strong
σ-acceptor.
A clear understanding of how the electron-rich and electron-withdrawing
substituents controlled the selectivity was, therefore, necessary. Since the electronic
effects of a substituent are at full display in the TS, there is an excellent opportunity
to identify this control element from NBO analysis, which gives a direct measure of
the orbital–orbital interactions. In this context, interaction of σC3C4 with a resonance-
accepting substituent orbital such as π* and that of σ*C3C4 with a lone pair orbital
n on a heteroatom substituent is significant. Both the interactions weaken σC3C4
bond and facilitate its cleavage. The weakening of σC3C4 bond through the interac-
tions πC1C2 → σ*C3C4 and σC3C4 → π*C1C2 is at the ring opening. However, these
interactions are generally not likely to control the torquoselectivity. The important
orbital–orbital interactions present in the TSs for outward and inward openings of
cyclobutenes bearing a range of substituents are collected in Tables 3 and 4.
In substrates bearing electron-rich heteroatoms such as those in Table 3, n →
σ*C3C4 interaction is significantly larger in the outward than inward opening TS and,
thus, outward opening, as indeed observed from experiments, is predicted [3, 5].
In 3-Me-cyclobutene, an example of substrates bearing a σ-donor substituent, σCH
Table 3 The NBO interactions (kcal/mol) in the TSs for opening of cyclobutenes containing
electron-rich heteroatom and σ-donor substituents. The values in the parentheses are for the inward
opening TSs
Substrate πC1C2 →σ*C3C4 σC3C4 →π*C1C2 n →σ*C3C4
OMea 50 (59) 75 (81) 43 (23)
t-butyl, OMea 66 (52) 91 (71) 37 (21)
Me, OMea 56 (53) 83 (75) 46 (23)
OCOMea 57 (64) 80 (89) 32 (14)
Fa 60 (65) 85 (91) 25 (14)
Me 57 (64) 82 (89) – b
a The n→ π*C2C3 interaction was absent in both the modes of ring opening. b The σCH → σ*C3C4
interaction in the outward and inward opening TSs is 11 and 6 kcal/mol, respectively
Table 4 The NBO interactions (kcal/mol) in the TSs for opening of cyclobutenes possessing
electron-withdrawing substituents. The values in parentheses are for the inward opening TSs
Substrate πC1C2 →σ *C3C4 σC3C4 →π*C1C2 σC3C4 →π*NO/CO πNO/CO →σ*C3C4
CHO 52 (54) 68 (68) 23 (64) 6 (2)
COMe 57 (66) 65 (71) 25 (55) 6 (1)
CN 56 (57) 68 (68) 24 (47) 11 (4)
CN, Mea 62 (56) 74 (68) 22 (48) 12 (4)
15 0 (0) 0 (0) – b – b
CF3 64 (71) 78 (84) – c – c
NO2 64 (72) 71 (78) 31 (50) 5 (3)

NO 50 (45) 63 (52) 24 (82) 8 (2)
CO2 Me 58 (63) 68 (71) 27 (59) 5 (0)
BH2 47 (32) 60 (30) – d – d
17 0 (0) 0 (0) 36 (72) 5 (1)

20 0 (74) 0 (108) 7 (0) 0 (0)
a The interaction σCH → σ*C3C4 was 6 (11) kcal/mol. b MP2/6-31G* results: πC1C4 /π*C2C3 =
85 (90) kcal/mol. c σC3C4 → σ*C-F = 11(21); σC-F →σ*C3C4 = 1.9 (1.7). d The most important
interaction is σC3C4 → lpB * which is 26 and 285 kcal/mol strong in the TSs for outward and inward
openings, respectively
→ σ*C3C4 interaction is important. This interaction is stronger in the outward than

inward opening TS by 5 kcal/mol.
The NBO interactions in the TSs for the opening of cyclobutenes bearing σ-
and π-accepting substituents are collected in Table 4. The instance of trans-3,4-
dimethylperfluorocyclobutene 15 is also included in this table as it involves the
competing effects of the electron-rich F and σ-accepting CF3 substituents. F is
electron-rich for its lone pairs of electrons.
In 3-CF3 -cyclobutene, an example of substrates bearing a σ-acceptor, σC3C4 →
σ*CF interaction is responsible for the control of selectivity. This interaction is larger
in inward than outward opening by 10 kcal/mol. This substrate, however, is reported
to open outward to form (E)-olefin [17, 27]. Since the (E)-olefin is more stable than
(Z)-olefin by 3.8 kcal/mol, it is likely that, under the severe conditions of the reaction
(gas phase, 3−4 mm pressure, 146-186 °C) with enough energy available, (Z)-olefin
reverts to cyclobutene (G# = 38 kcal/mol) more rapidly than (E)-olefin (G# =
38.8 kcal/mol) and then open again in an equilibrium process to allow a raise in the
concentration of the (E)-olefin over the course of the reaction [28]. It is important
to note that the reaction to (Z)-olefin is less exothermic (1.8 kcal/mol) than to (E)-
olefin (5.6 kcal/mol). The reaction profiles for the inward and outward openings of
3-CF3 -cyclobutene are shown in Fig. 1.
The observed inward openings of 3-CHO- and 3-CN-3-Me-cyclobutenes bear well
with the predictions from the NBO interactions. While the inward opening of 3-CHO-
cyclobutene is exclusive at 50−70 °C [29–31], it is 4:1 (in favor of inward rotation
of CN) for 3-CN-3-Me-cyclobutene at 79 °C [8]. 3-COMe-cyclobutene generates
Fig. 1 Reaction profile for

inward (solid green line) and
outward (dashed red line)
openings of
3-CF3 -cyclobutene at
MP2/cc-pVTZ//MP2/6-
31G* level of
theory
3:2 mixture of the (E)- and (Z)-dienes, respectively, at 79 °C [9]. The departure
from the NBO-predicted inward selectivity may be explained in much the same
manner as for 3-CF3 -cyclobutene above. As against the reversal (E)-diene → 3-
COMe-cyclobutene, (Z)-diene → 3-COMe-cyclobutene is easier by 2.5 kcal/mol
and, hence, a raise in the concentration of the (E)-diene may occur over the course
of the reaction. The (E)-diene is more stable than (Z)-diene and, further, both these
dienes are more stable than 3-COMe-cyclobutene by, respectively, 10 and 6 kcal/mol
[32]. The reaction profiles for openings in 3-acetylcyclobutene are collected in Fig. 2.
The prediction of outward opening of 3-CO2 Me-cyclobutene by the differen-
tial activation energy approach was considered vindicated by the experimentally
observed 1:10 mixture of the Diels–Alder (DA) cycloaddition products formed,
respectively, from (Z)-18 and (E)-19 on reaction of 7-CO2 Me-benzocyclobutene 17
Fig. 2 Reaction profiles for

the Inward (solid green line)
and outward (dashed red
line) openings in
3-COMe-cyclobutene at
MP2/cc-pVTZ//MP2/6-
31G* level of
theory
with N-phenylmaleimide (NPM) [33]. The activation energy for outward opening is
lower than inward opening by 2.3 kcal/mol. However, the NBO interactions support
inward opening, controlled exclusively by the σC3C4 → π*CO interaction.
H CO2Me
6 CO2Me
1 7
5 CO2Me H
o
+
4 140 C
2 8
3 11 d
17 18 19
H CONMe2
CONMe2
CONMe2 H
o
+
140 C
7d
20 21 22
On the basis of σC3C4 → π*CO and πCO → σ*C3C4 interactions for the control
of selectivity, one faces the challenge to explain 1:10 distribution of 18 and 19. The
ratio will hold only if each diene reacts in DA manner as soon as it is formed. In this
context, the following observations are significant:
(a) Energy of activation for inward opening 17 → (Z)-18 is 2.3 kcal/mol higher
than outward opening 17 → (E)-19.
(b) The transformation 17 → (E)-19 is endothermic by 18.0 kcal/mol against
21.0 kcal/mol for the transformation 17→ (Z)-18.
The activation energies of the reverse ring closing processes (E)-19 → 17 and (Z)-
18 → 17 are, respectively, 19.6 and 18.4 kcal/mol against 37.0 and 40.0 kcal/mol for
the corresponding ring opening reactions. The ring closing reactions will, therefore,
be lot faster than the corresponding ring opening reactions, allowing for a rapid
equilibration. Since (E)-19 → 17 is slower than (Z)-18 → 17 for the activation
energy difference of 1.2 kcal/mol, the more stable (E)-19 may accumulate and react
with NPM to form the predominantly observed DA product.
The intermolecular nature of DA reaction, with a consequent entropic penalty for
bringing the two reactants together, can not allow it to compete with the unimolecular
reverse reactions. The calculated profiles of these ring opening reactions are shown
in Fig. 3a.
On being heated at 140 °C in C6 D6 for 7 days, 7-CONMe2 -benzocyclobutene 20
is reported to generate 7:3 mixture of the DA adducts formed, respectively, from (Z)-
21 and (E)-22 on reaction with maleic anhydride [33]. Calculated reaction profiles
are given in Fig. 3b. The following analysis is in order:
(a) Both (Z)-21 and (E)-22 will be expected to be formed in nearly equal amounts
for the mere 0.2 kcal/mol difference in the activation energies of the two
transformations.
Fig. 3 a, b Reaction profiles for the transformations 17 → 18/19 and 20 → 21/22 (solid green line
for inward rotation and dashed red line for outward rotation)
(b) The Interactions πC1C2 → σ*C3C4 and σC3C4 → π*C1C2 support opening to
(Z)-21 as they are completely absent in the alternate TS leading to (E)-22.
(c) The transformations 20 → (Z)-21 and 20 → (E)-22 are endothermic by, respec-
tively, 19.0 and 20.0 kcal/mol. Thus, (Z)-21 is more stable than (E)-22 by
1.0 kcal/mol.
(d) The activation energies for the reverse transformations (Z)-21 → 20 and (E)-
22 → 20 are 22.0 and 21.0 kcal/mol, respectively. (E)-22 therefore reverts to
20 faster than (Z)-21.
(e) Unlike 7-CO2 Me-benzocyclobutene, (Z)-21 will accumulate and also lead to
formation of the predominant DA adduct.
3-Methyl-perfluorocyclobutene 23 has been reported by Dolbier to furnish only
24 from inward rotation of CF3 (i.e., outward rotation of F) on conducting the reaction
at 157 °C and only 25 from its outward rotation at 268 °C [34]. Activation energies
for inward and outward rotations of CF3 are, respectively, 38.9 and 48.1 kcal/mol
at M06-2X/6-31+G(d) level of theory, see Table 5. Thus, the inward rotation of
CF3 is favored over its outward rotation by 9.2 kcal/mol. Since both the reactions are
endothermic for the enthalpy changes of 7.5 and 7.9 kcal/mol, the activation energies
for the respective ring closing reactions are 31.4 and 40.3 kcal/mol, respectively.
Table 5 Gibbs free energies of activation (G‡ ), kcal/mol, for the opening of perfluoro-3-
methylperfluorocyclobutene 23 at M06-2X/6-31+G(d) level of theory. The rotations are in respect
of CF3 group. The enthalpy changes (Gproduct − Greactant ) are given in parentheses. G‡ =
G‡outward − G‡inward
Substrate G‡outward G‡inward G‡
23 48.1 (7.5) 38.9 (7.9) 9.2
F3C F CF3 F
F2C F F F F2C CF3
o 4 3 o
157 C 1 2
268 C
F F F F F F
24 23 25
The relevant NBO interactions are collected in Table 6. The absence of πC1C2 →
σ*C3C4 interaction, and also the presence of πC1C4 → π*C2C3 and πC2C3 → π*C1C4
interactions, clearly demonstrates that the TS is much advanced and product-like in
both the modes of ring opening. The σC3C4 bond is completely broken and, hence, its
interaction with σ*C-F (CF3 group) is absent. The fluorines directly bonded to C3 and
C4 play the key role and interactions of their lone pairs with the largely developed π
bonds between C1 and C4, and C2 and C3 control the torquoselectivity. The directly
bonded fluorines rotate outwards as usual, allowing CF3 to move inward. The profiles
for outward and inward opening reactions are shown in Fig. 4.
It is logically possible that at the lower end of the reaction temperature (157 °C),
only the lower energy pathway leading to 24 and the counter ring closing reaction
predominate and we obtain 24 as the sole product. At the higher end of the reac-
tion temperature (268 °C), the higher activation energy pathway leading to outward
Table 6 The NBO interactions (kcal/mol) in the TSs for the opening of perfluoro-3-
methylcyclobutene 23. The values in parentheses are for the inward rotation of CF3 group
πC1C2 → σ*C3C4 πC1C4 → π*C2C3 πC2C3 → π*C1C4 σC3C4 → σ*C-F lpF → π*C1C4/C2C3
0 (0) 65 (62) 60 (60) 0 (0)a 76 (77)b
a The σC-F in the interaction σC3C4 → σ*C-F refers to CF3 group. b lpF → π*C1C4/C2C3 refers to
interactions of lone pairs of electrons on fluorine directly attached to C3 and C4
Fig. 4 Reaction profile for

inward (solid red line) and
outward (solid blue line) ring
openings in perfluoro-3-
methylcyclobutene 23 at the
M06-2X/6-31+G(d) level of
theory
opening also becomes active and the consequent product 25 predominates for its
relatively lower reversibility. Double bond isomerization is yet another possibility.
However, this avenue has neither been investigated nor commented upon.
3 Restricted Conformational Effects on Torquoselectivity
The NBO interactions are essentially antiperiplanar interactions. The closer the
torsion angle between the two interacting bonds (or orbitals) to 180o , the larger is the
interaction [35]. The CHF2 and CH2 F substituents can adopt three distinct confor-
mations with respect to the cleaving cyclobutene bond. It is the torsion angle C4-C3-
C-H in 3-CHF2 -cyclobutene and C4-C3-C-F in 3-CH2 F-cyclobutene that changes
to give rise to three major conformers for each. For demonstration, the three major
conformers of 3-CHF2 -cyclobutene are shown in Fig. 5. These conformers are within
0.9 kcal/mol from each other and, hence, all of them (of course, those in between also)
will be available under the thermal conditions of the reaction. The three conformers
of 3-CH2 F-cyclobutene, all within 0.6 kcal/mol from each other, may be considered
likewise.
The activation energies of all the three conformers of 3-CHF2 - and 3-CH2 F-
cyclobutenes are given in Table 7 along with those of 3-CF3 -cyclobutene to facilitate
comparison. The energies of the conformers rise as one descends the Table. Among
the conformers of 3-CHF2 -cyclobutene, the most stable conformer is least selective
for the mere 0.4 kcal/mol activation energy difference in favor of outward opening.
Likewise, the conformer at entry 6 is relatively least selective among the conformers
of 3-CH2 F-cyclobutene. On the absolute scale, all the three conformers appear to
open outwards.
The instances of 2-CF3 -, 2-CHF2 -, and 2-CH2 F-oxetenes are similar to those of
the corresponding cyclobutene derivatives. The activation energies are collected in
Table 8. Here also, the energies of the conformers rise on descending the Table.
The most stable conformer of 3-CHF2 -oxetene is significantly less selective than
the other conformers, so much so that it will be predicted to generate almost 25%
Fig. 5 Three major conformers of 3-CHF2 -cyclobutene: a C4-C3-C-H = −47.0, b C4-C3-C-H =

70.7, c C4-C3-C-H = −169.0
Table 7 Gibbs free energies of activation (G‡ ), kcal/mol, for the opening of 3-
fluoromethylcyclobutenes. The enthalpy changes (Gproduct − Greactant ) are given in parentheses.
G‡ = G‡outward − G‡inward
Entry Substituent G‡outward G‡inward G‡
1 CF3 33.2 (−5.6) 36.3 (−1.8) −3.1
2 CHFa2 32.8 (−5.4) 33.2 (−5.0) −0.4
3 CHFb2 32.9 (−6.2) 36.1 (−2.8) −3.2
4 CHFc2 31.9 (−6.3) 35.4 (−2.0) −3.5
5 CH2 Fd 31.4 (−7.1) 34.5 (−5.7) −3.1
6 CH2 Fe 31.3 (−7.2) 32.9 (−6.3) −1.6
7 CH2 Ff 30.6 (−7.6) 36.5 (−3.5) −5.9
a Torsion angle C4-C3-C-H = −47.0. b Torsion angle C4-C3-C-H = 70.7. c Torsion angle C4-C3-C-H
= −169.0
d Torsion angle C4-C3-C-F = 72.6. e Torsion angle C4-C3-C-F = −167.6. f Torsion angle C4-C3-C-F
= −49.4
Table 8 Gibbs free energies of activation (G‡ ), kcal/mol, for openings of 2-fluoromethyloxetenes.
The enthalpy changes (Gproduct − Greactant ) are given in parentheses. G‡ = G‡outward −
G‡inward
Entry Substituent G‡outward G‡inward G‡
1 CF3 28.0 (−25.7) 30.8 (−20.1) −2.8
2 CHFa2 28.5 (−24.3) 29.2 (−23.1) −0.7
3 CHFb2 27.2 (−25.5) 29.9 (−24.3) −2.7
4 CHFc2 26.5 (−26.6) 30.8 (−19.5) −4.3
5 CH2 Fd 24.7 (−24.3) 31.0 (−24.9) −6.3
6 CH2 Fe 24.2 (−24.8) 28.5 (−25.5) −4.3
7 CH2 Ff 24.2 (−26.7) 30.7 (−26.0) −6.5
a Torsion angle O1-C2-C-H = −49.1. b Torsionangle O1-C2-C-H = 60.6. c Torsion
angle O1-C2-
C-H = −172.6
d Orsion angle O1-C2-C-F = 74.6. e Torsion angle O1-C2-C-F = −174.7. f Torsion angle O1-C2-C-F
= −61.9
of the inward product. The other conformers are predicted for exclusive outward
opening. Likewise, though all the conformers of 3-CH2 F-oxetene will be predicted
for exclusive outward opening from the differential activation energies, the conformer
with middle level stability is relatively less selective.
The NBO interactions in 3-fluoromethylcyclobutenes and the corresponding
oxetenes are shown in Tables 9 and 10, respectively. All the conformers in each
structural domain appear to favor inward opening on account of σC3C4 → σ*C-F/H
interaction alone as done previously by other researchers. However, on combining
this interaction with σC-F/H → σ*C3C4 interaction, both reinforcing each other, the
overall result remains unaltered. The differential interaction decreases down the Table
3 Restricted Conformational Effects on Torquoselectivity 173
Table 9 The NBO interactions (kcal/mol) in the TSs for opening of 3-fluoromethycyclobutenes.
The values in parentheses represent interactions in inward opening
S S H
H inward 4 3 outward S
opening 1 2 opening
S = CF3, CHF2, CH2F
Substrate πC1C2 → σ*C3C4 σC3C4 → π*C1C2 σC3C4 → σ*C-F/H σC-F/H → σ*C3C4

CF3 64 (71) 78 (84) 11 (21) 1.9 (1.7)
CHFa2 62 (64) 81 (83) 9 (25) 6.4 (2.8)
CHFb2 63 (73) 77 (84) 10 (18) 2.5 (2.1)
CHFc2 61 (69) 81 (85) 9 (16) 6.4 (4.7)
CH2 Fd 55 (62) 78 (85) 7 (19) 9.5 (4.0)
CH2 Fe 55 (64) 78 (81) 7 (23) 9.5 (3.2)
CH2 Ff 61 (68) 80 (86) 7 (12) 10 (7.3)
a Torsion angle C4-C3-C-H = −47.0. b Torsion angle C4-C3-C-H = 70.7. c Torsion angle C4-C3-C-H
= −169.0
d Torsion angle C4-C3-C-F = 72.6. e Torsion angle C4-C3-C-F = −167.6. f Torsion angle C4-C3-C-F
= −49.4
Table 10 The NBO interactions (kcal/mol) in the TSs for opening of 2-fluoromethyloxetenes. The
values in the parentheses represent interactions in inward opening TSs
S S H
O H inward 1O 2 outward O S
opening 4 3 opening
S = CF3, CHF2, CH2F
Substrate πC3C4 → σ*C-O σC-O → π*C3C4 σC-O → σ*C-F/H σC-F/H → σ*C-O

CF3 72 (80) 53 (61) 2.4 (10) 3.0 (2.6)
CHFa2 70 (76) 54 (63) 1.8 (12) 7.9 (3.0)
CHFb2 70 (79) 54 (60) 1.8 (10) 7.9 (4.6)
CHFc2 74 (78) 57 (63) 1.8 (8.0) 12.4 (8.2)
CH2 Fd 66 (76) 62 (72) 1.5 (7.7) 18 (10)
CH2 Fe 66 (71) 62 (59) 1.5 (12) 18 (4.9)
CH2 Ff 68 (73) 56 (64) 1.5 (6.6) 19 (14)
a Torsion angle O1-C2-C-H = −49.1. b Torsion angle O1-C2-C-H = 60.6. c Torsion angle O1-C2-
C-H = −172.6
d Torsion angle O1-C2-C-F = 74.6. e Torsion angle O1-C2-C-F = −174.7. f Torsion angle O1-C2-C-F
= −61.9
for the CHF2 -derivative. This is so for the CH2 F-derivative as well, but for the excep-
tion of the conformer in the middle. The conformational effects of substituents on
torquoselectivity requires to be studied in detail.
The NBO data for the conformers of CHF2 -substituted oxetene also suggests
decreasing inward ring opening. The conformers of CH2 F-substituted oxetene,
however, are different as the first two conformers favor outward selectivity and the
last one none.
It is not necessary that only the most stable conformer or, as above, only three
main conformers of a reactant be considered to study the stereochemical outcome.
This is so because chemical reactions are controlled by orbital interactions in the TSs
and the best orbital interaction arises from antiperiplanar bonds of complementary
nature [35]. The interaction is Lewis acid-Lewis base type, i.e., one of the two inter-
acting bonds is electron-rich and the other electron-poor. Under thermal conditions,
a molecule can adopt many rapidly equilibrating conformers and some or several
higher lying conformers may even react better than the most stable conformer for
being energetically closer to the TS due to better bond alignments.
4 Global Conformational Effects on Torquoselectivity
It was in the above spirit that a study was initiated to discern the effects of
global conformational changes in the substituent with respect to the cleaving ring
bond in 3-OMe-, 3-CHO-, and 3-COMe-cyclobutenes. Experimentally, 3-OMe-
cyclobutene opens exclusively outward, 3-CHO-cyclobutene opens >98% inward
and <2% outward at 25−70 °C and, in explicit contrast to 3-CHO-cyclobutene,
3-COMe-cyclobutene furnishes 3:2 mixture of the outward and inward opened prod-
ucts, respectively, at the reflux temperature of C6 D6 . It must be remembered that
while OMe is electron-rich for its lone pairs of electrons, both CHO and COMe are
electron-deficient, CHO more than COMe for its better resonance-acceptor strength
[36, 37].
The torsion angles of σO-Me in 3-OMe-cyclobutene and C=O in 3-CHO- and 3-
COMe-cyclobutenes with the σC3-C4 bond, as shown, were altered, 10o at a time,
beginning with the most stable ground-state conformer of each and the resultant
geometry optimized. This was followed by locating the TSs for inward and outward
openings of each conformer in each instance. The results for the three substrates are
graphically presented in Fig. 6.
H Me
3 O 3 3
2 2 O 2 O
1 4 1 4 1 4
All the conformers of 3-OMe-, 3-CHO-, and 3-COMe-cyclobutenes are, respec-

tively, within 5.6, 3.2, and 4.0 kcal/mol and, hence, abundantly available at room
4 Global Conformational Effects on Torquoselectivity 175
Fig. 6 The global conformational surfaces of 3-CHO-, 3-OMe-, and 3-COMe-cyclobutenes (left
column), and the inward and outward opening activation energy profiles (right column) at 1 atm
and 298 K
temperature. The concentrations of the higher lying conformers will rise on raise
in the temperature and, thus, they may exceedingly take part in the reaction. The
higher lying conformers may also react faster than the low-lying conformers for
being closer to the TS. The cumulative contribution of the higher lying conformers
to the overall outcome, torquoselectivity in the present instance, is therefore likely
to be significant.
From absolutely no cross-over of the activation energy profiles and substan-
tial difference between the outward and inward cleavage reactions, minimum
12 kcal/mol, 3-OMe-cyclobutene will overwhelmingly open outward to trans-1-
methoxy-1,3-butadiene. This is in accord with the experiments.
Except for a very tiny region on the far left and a reasonably significant region
on the right of the activation energy profiles, the reaction of 3-CHO-cyclobutene is
geared for inward opening for huge margins in activation energies. The reaction may
basically funnel through the conformers in the region, allowing little chance to the
conformers outside to participate. No doubt, the outward opened product is formed
<2%.
A good cross over and also significant activation energy differences indicate both
inward and outward openings of 3-COMe-cyclobutene. Almost half the conformers
appear to open inwards and the other half outwards. 3-COMe-cyclobutene is experi-
mentally known to furnish a 3:2 mixture of the outward and inward opened products
at 79 °C in C6 D6 . It will be interesting to investigate the conformational profile of
3-COMe-cyclobutene and the corresponding activation energy profiles at 79 °C in
C6 D6 to estimate the isomer distribution.
Houk predicted outward rotation of the NO group in the ring opening of 3-NO-
cyclobutene. However, from global conformational analysis of the reactant and acti-
vation energy profiles given in Fig. 7, it is clear that about half the conformers are
poised for inward rotation. All the substrate conformers are within 2.6 kcal/mol and,
hence, abundantly available for reaction even at room temperature.
It is amply clear from comparison of the ground-state conformer profile with the
activation energy profiles that the higher lying conformers react faster than lower
lying conformers for the reduced activation energies. Having taken the most stable
conformer alone for investigation, one would predict exclusive inward opening of 3-
CHO-cyclobutene and 3-NO-cyclobutene, outward opening of 3-OMe-cyclobutene,
Fig. 7 The global conformational surface of 3-NO-cyclobutenes (left column) and the inward and
outward opening activation energy profiles (right column) at 1 atm and 298 K
4 Global Conformational Effects on Torquoselectivity 177
and largely outward opening of 3-COMe-cyclobutene by factoring in the differential

activation energies.
Overall, the differential activation energy approach in its original form performs
poorly in predicting the torquoselectivities of cyclobutenes possessing electron-
deficient substituents. The NBO interaction approach predicts well the torquose-
lectivity of cyclobutenes substituted with both electron-rich and electron-deficient
substituents. The σC3C4 → π*CX interaction in cyclobutenes with resonance-
accepting groups such as CHO, COCH3 , CO2 R, CN, NO, and NO2 is an effective
control factor and supports inward opening. It is n → σ*C3C4 interaction that controls
outward opening of cyclobutenes bearing electron-rich heteroatom substituents. In
cyclobutenes bearing, σ-acceptor substituents such as CF3 , σC3C4 → σ*CF interaction
is significant. A σ-donor substituent such as CH3 causes σCH → σ*C3C4 interaction
and allows outward opening.
Global conformational change in the substituent and its effect on ring opening
profile must seriously be taken into consideration because the TSs are thoroughly
controlled by interactions of the cleaving bond orbital with the substituent orbital
and, also, some or many higher lying conformers may contribute significantly to
product distribution than lower lying conformers. The lowest lying conformer tells
only a small part of the entire story.
The product profile is undoubtedly also affected by reaction equilibration. The
relative enthalpy change controls the relative rates of equilibration of the (E)- and
(Z)-dienes with the same reactant. It allows accumulation of the slower equilibrating
diene during the course of the reaction. In an endothermic process, the (E)/(Z)-diene
cyclobutene equilibrium is expected to be significantly faster than intermolecular
Diels–Alder reaction of the same dienes with a given dienophile for the inherent
entropic penalty to the latter. Thus being the case, the ratio of the DA products does
not represent the ratio of the (E)/(Z)-dienes.
References
1. R.B. Woodward, R. Hoffmann, J. Am. Chem. Soc. 87, 395 (1965)

2. R.B. Woodward, R. Hoffmann, Angew. Chem. Int. Ed. 8, 781 (1969)
3. W. Kirmse, N.G. Rondan, K.N. Houk, J. Am. Chem. Soc. 106, 7989 (1984)
4. N.G. Rondan, K.N. Houk, J. Am. Chem. Soc. 107, 2099 (1985)
5. K.N. Houk, D.C. Spellmeyer, C.W. Jefford, C.G. Rimbault, Y. Wang, R.D. Miller, J. Org.
Chem. 53, 2125 (1988)
6. K. Rudolf, D.C. Spellmeyer, K.N. Houk, J. Org. Chem. 52, 3708 (1987)
7. S. Niwayama, E.A. Kallel, D.C. Spellmeyer, C. Sheu, K.N. Houk, J. Org. Chem. 61, 2813
(1996)
8. S. Niwayama, Y. Wang, K.N. Houk, Tetrahedron Lett. 36, 6201 (1995)
9. S. Niwayama, K.N. Houk, Tetrahedron Lett. 34, 1251 (1993)
10. P.S. Lee, X. Zhang, K.N. Houk, J. Am. Chem. Soc. 125, 5072 (2003)
11. The acetyl, carbomethoxy, cyano, nitro and nitroso groups are all resonance acceptors to varying
degree. A comparison of the resonance accepting ability comes from the LUMO energies of
ethylene substituted with these groups. The lower the LUMO energy, the larger will be the
resonance-accepting ability. The LUMO energy at MP2/cc-pVTZ level rises as the substituent
changes from NO2 (27.6 kcal/mol) to NO (33.3 kcal/mol) to CN (49.0 kcal/mol) to CHO
(49.6 kcal/mol) to COCH3 (54.0 kcal/mol) to CO2 Me (59.0 kcal/mol). Clearly, among these
select functional groups, NO2 is the most resonance-accepting, CO2 Me the least, and CHO in
between and at par with CN
12. For a somewhat contentious discussion on NO and NO2 acceptor strengths, see: F. Gerson, W.
Huber, Electron Spin Resonance Spectroscopy of Organic Radicals (Wiley, 2003), p. 331
13. For another contentious discussion on NO and NO2 acceptor strengths, see: H. Vančik, Aromatic
C-nitroso Compounds (Springer Science & Business Media, 2013), p. 41
14. A.E. Reed, L.A. Curtiss, F. Weinhold, Chem. Rev. 88, 899 (1988). Note: The NBO perturbation
terms are somewhat exaggerated as it lacks the repulsive interactions
15. M. Murakami, T. Miyamoto, Y. Ito, Angew. Chem. Int. Ed. 40, 189 (2001)
16. J.E. Barquera-Lozada, J. Phys. Chem. A 120, 8450 (2016)
17. W.R. Dolbier Jr., T.A. Gray, J.J. Keaffaber, L. Celewicz, H. Koroniak, J. Am. Chem. Soc. 112,
363 (1990)
18. W.R. Dolbier Jr., H. Koroniak, K.N. Houk, C. Sheu, Acc. Chem. Res. 29, 471 (1996)
19. K. Aikawa, Y. Hioki, N. Shimizu, K. Mikami, J. Am. Chem. Soc. 133, 20092 (2011)
20. K. Aikawa, N. Shimizu, K. Honda, Y. Hioki, K. Mikami, Chem. Sci. 5, 410 (2014)
21. K. Honda, S.A. Lopez, K.N. Houk, K. Mikami, J. Org. Chem. 80, 11768 (2015). The
publication concludes, “The torquoselectivities are thus controlled by a competition of
σCO →σCF * effect and unfavorable closed-shell repulsions. Our calculations suggest that 2-
difluoromethyloxetenes prefer inward rotation because the favorable σCO → σCF * orbital effect
outweighs closed-shell repulsions in the transition state.”
22. L. Akilandeswari, C. Prathipa, J. Chem. Sci. 127, 1505 (2015)
23. A. Saal, L. Merzoud, J. Comput. Methods Sci. Eng. 16, 437 (2016)
24. A. Yadav, D.L.V.K. Prasad, V.K. Yadav, ChemRxiv. Preprint (2017). https://doi.org/10.26434/
chemrxiv.5743305.v1
25. E. Gil-Av, J. Shabtai, J. Org. Chem. 29, 258 (1964)
26. H.M. Frey, D.C. Marshall, Trans. Faraday Soc. 61, 1715 (1965)
27. W.R. Dolbier Jr., H. Koroniak, D.J. Burton, P.L. Heinze, A.R. Bailey, G.S. Shaw, S.W. Hansen,
J. Am. Chem. Soc. 109, 219 (1987)
28. The G#cis-trans data shown in Table 1 for several of the reactions suggest that the cis-trans
isomerization is a difficult process under the ring opening conditions as the activation energies
are anywhere between 40–80 kcal/mol
29. R.E.K. Winter, Tetrahedron Lett. 6, 1207 (1965)
30. R. Criegee, D. Seebach, R.E.K. Winter, B. Borretzen, H. A. Brune, Chem. Ber. 98, 23 (1965)
31. I. Fleming, Molecular Orbitals and Organic Reactions (Wiley 2010), p. 363
32. The small difference in the two activation barriers (1.6 kcal/mol) may also be considered to
explain the formation of both the products, more from outward and less from inward opening
33. C.W. Jefford, G. Bernardinelli, Y. Wang, D.C. Spellmeyer, A. Buda, K.N. Houk, J. Am. Chem.
Soc. 114, 1157 (1992)
34. W.R. Dolbier, H. Koroniak, D.J. Burton, P. Heinze, Tetrahedron Lett. 27, 4387 (1986)
35. P. Deslongchamps, Stereoelectronic Effects in Organic Chemistry (Pergamon Press, 1983)
36. V.K. Yadav, A. Yadav, ChemRxiv. Preprint (2019). https://doi.org/10.26434/chemrxiv.808194
5.v1
37. V.K. Yadav, A. Yadav, ChemRxiv. Preprint (2019). https://doi.org/10.26434/chemrxiv.823915
7.v1
Chapter 8
Hammett Substituent Constants
Abstract Benzoic acid ionizes into C6 H5 CO2 − and H+ only partially in water.
However, this ionization is rendered facile by electron-withdrawing substituents and
more difficult by electron-rich substituents on the aromatic ring. The effect on ioniza-
tion is also dependent on the position of the substituent on the ring in respect of the
carboxylic acid group. While substituents on the meta and para positions exert only
electronic effects on ionization, substituents on the ortho position cause steric effects
as well. The Hammett constant σR for a given substituent R is given by the equation:
σR = log (K R /K H ), where KR and K H are the dissociation constants of the substituted
and unsubstituted acids, respectively. Obviously, the constant σ for a given substituent
is accurate only for the molecular structure from which it has been derived and also
its position with respect to the ionizing group. An electron-withdrawing substituent
will have a positive σ value and an electron-donating substituent a negative σ value.
The σ constant for substituents on meta and para positions of the aromatic ring are
designated as σm and σp , respectively. The constant σ is derived from the ionization
of benzoic acids wherein the negative charge of the carboxylate ion is not in conju-
gation with the ring and/or the substituent through the ring. The Hammett equation,
therefore, need not apply to instances in which the substituent comes into direct reso-
nance interaction with the reaction site. When there is resonance between a reaction
site that becomes electron-rich and an electron-withdrawing substituent, σ− constant
is used. The standard reactions for the evaluation of σ− constants are the ionization
of p-substituted phenols and p-substituted anilinium ions. Likewise, when there is
resonance between a reaction site that becomes electron-deficient and an electron-
donating substituent, σ+ constant is used. The standard reaction for the evaluation of
σ+ constant is the solvolysis of p-substituted tert-cumyl chlorides. The application
of σ constants is primarily in the study of reaction pathways.
https://doi.org/10.1007/978-3-030-75622-2_8
180 8 Hammett Substituent Constants
1 Hammett Substituent Constants for Benzoic Acids (σm

and σp )
The electronic property of an aromatic substituent is expressed by the Hammett

substituent constant σ. This constant for a given substituent is arrived at by measuring
its effect on the dissociation of benzoic acid. Benzoic acid itself is a weak acid and it
ionizes into C6 H5 CO2 − and H+ only partially in water. The ratio of the ionized and
non-ionized species at equilibrium is known as equilibrium or dissociation constant
K H , the subscript H indicates that there is a hydrogen as substituent on the aromatic
ring.

[PhCO]2 − H3 O+
KH =
[PhCO2 H]
A substituent on the aromatic ring will affect the above ionization equilibrium.
An electron-withdrawing substituent stabilizes the carboxylate ion and shifts the
equilibrium to the ionized form to lead to a larger equilibrium constant, i.e. K R >
K H . In contrast, an electron-donating substituent destabilizes the carboxylate ion
and shifts the equilibrium to the non-ionized form to lead to a smaller equilibrium
constant, i.e. K R < K H . The Hammett constant σR for the given substituent R is given
by the following equation:
KR
σR = log = log K R − log K H = (pK a )H − (pK a )R
KH
(pK a )H = pK a of the unsubstituted acid, (pK a )R = pK a of the R-substituted acid.

The pKa is the pH value at which a chemical species will accept or donate a
proton. The lower the pKa, the stronger the acid and the greater the ability to donate
a proton in aqueous solution. The Henderson-Hasselbalch equation relates pKa and
pH in the manner: pKa = −log K a
The following conclusions emerge from the above discussion:
(a) The constant σ for a given substituent is accurate only for the molecular
structure from which it is derived.
(b) An electron-withdrawing substituent will have a positive σ value and an
electron-donating substituent a negative σ value.
The Hammett constant is based on benzoic acid and it takes into consideration both
the inductive and resonance effects of the substituent and, thus, the value depends on
whether the substituent is positioned meta (σm ) or para (σp ) to the ionizing group. A
meta-substituent will exert inductive effect and a para-substituent resonance effect
largely. Let us consider phenol as an example. The property of the substituent R is
influenced by the inductive effect of OH in 1 and resonance effect in 2, as shown.
1 Hammett Substituent Constants for Benzoic Acids (σm and σp ) 181
R OH
1
R OH R OH R OH R OH
2 2a 2b 2c
The constants σm and σp for a host of substituents are collected in Table 1. The
following observations must be noted:
(a) Both σm and σp for alkyl substituents such as methyl, ethyl, isopropyl, tert-
butyl, and CH2 SiMe3 are negative as they exert only positive inductive effect
and, thus, destabilize the carboxylate ion.
(b) Both σm and σp are negative also for the nitrogen-based substituents such as
NH2 , NHMe, and NMe2 . These substituents exert their effect largely through
strong resonance with the π electrons of the ring such that, irrespective of the
Table 1 Hammett constants, σ, based on the ionization of benzoic acids*

Substituent σm σp σ+ σ− Substituent σm σp σ+ σ-
CH3 −0.07 −0.17 −0.31 – N2 + +1.76 +1.91
CH2 CH3 −0.07 −0.15 NMe3 + +0.88 +0.82
CHMe2 − −0.15 NO2 + 0.71 +0.78 +0.79 +1.24
CMe3 −0.10 −0.20 CN + 0.56 +0.66 +0.66 +0.90
CH2 SiMe3 −0.16 −0.21 CF3 +0.43 +0.54
SiMe3 −0.04 −0.07 COMe +0.38 +0.50 – +0.87
NH2 −0.16 −0.66 −1.30 – CO2 H +0.37 +0.45 +0.42 –
NHMe – −0.84 SH + 0.25 +0.15
NMe2 – −0.83 SCN – +0.52
NHCOMe +0.21 +0.00 SCOMe +0.39 +0.44
OH + 0.12 −0.37 −0.92 – SMe +0.15 +0.00
OMe +0.12 −0.27 −0.78 −0.20 SMe2 + +1.00 +0.90
OCOMe +0.39 +0.31 SOMe +0.52 +0.49
F +0.34 +0.06 −0.07 −0.02 SO2 Me +0.60 +0.72
Cl +0.37 +0.23 +0.11 – SO2 NH2 +0.46 +0.57
Br +0.39 +0.23 +0.15 – SO3 − +0.05 +0.09
I +0.35 +0.18 +0.13 –
*The values in the table are taken from J E Leffler and E Grunwald, Rates and Equilibria of Organic
Reactions, Wiley, 1963
*The σ+ and σ− values are given for the para substituents only. The σ+ values for select meta-
substituents have been measured, but they don’t differ appreciably from the σm values
meta or para positioning of the substituent, there is enough negative charge

residence on the ring carbon bearing the carboxylic acid group. This reduces
ionization.
(c) Unlike the nitrogen substituents above, OH and OMe exert largely inductive
effect when located at the meta-position to turn σ positive, and resonance
effect when at the para-position to turn σ negative. It is not that the lone pair
on oxygen in OH or OMe at the meta-position is not in resonance with the π
electrons of the ring, but just that the accumulation of negative charge on the
carboxy-bearing carbon through this exercise is negligible.
(d) The substituent SH is unique as it exerts only electron-withdrawing inductive
effect from both meta and para positions. This is largely because of mismatch
of the lone pair orbital coefficient on sulfur with the p orbital coefficient on the
adjacent ring carbon to result in poor or no overlap.
The equilibrium ionization constants K a for selected para-substituted benzoic
acids including benzoic acid, their pK a values and Hammett’s constants are collected
in Table 2. The plots of K a × 105 and also pK a against σ for these acids are shown in
Fig. 1. The data in Table 2 and the plots in Fig. 1 demonstrate their linear relationships.
As K a increases, pK a decreases and σ increases.
Table 2 Equilibrium ionization constant K a , pK a values, and Hammett constants σ of a group of

acids
------------------------------------------------------------------------------------------
R Ka pKa
------------------------------------------------------------------------------------------
NO2 3.55 x 10-4 3.45 0.78
CN 2.75 x 10-4 3.56 0.66
Cl 1.00 x 10-4 4.00 0.23
H 6.31 x 10-5 4.20 0.00
Me 4.27 x 10-5 4.37 -0.17
OMe 3.39 x 10-5 4.47 -0.27
------------------------------------------------------------------------------------------
The values are taken from L P Hamme Chem Rev 1935, 17, 125
2 Hammett Substituent Constants for Phenylacetic and 3-Arylpropionic Acids 183
Fig. 1 Plots of σ versus K a

× 105 and pK a for the
substrates in Table 2
2 Hammett Substituent Constants for Phenylacetic

and 3-Arylpropionic Acids
Note that the σ values are so designed that a plot of log10 (K R /K H ) versus the σ
constant gives a straight line with the slope of unity. The substituent effects found
from the ionizations of substituted benzoic acids are applicable to other similar acid
ionizations. For instance, a plot of log10 (K R /K H ) for a number of ring-substituted
phenylacetic acids (RC6 H4 CH2 CO2 H) vis-à-vis the unsubstituted phenylacetic acid
(PhCH2 CO2 H) against the σ values obtained for those substituents from the ionization
of substituted benzoic acids (RC6 H4 CO2 H) is a straight line but with a slope of less
than unity (0.489) [1, 2].
A similar exercise with the ring-substituted 3-arylpropionic acids gives a value
of 0.212 to ρ [1, 2]. The observed diminution in the substituent effect relative to the
effect in benzoic acid is due to the greater separation between the substituent and the
acid group. This differential feature is accommodated in Eq. (1) by incorporating ρ
as the slope of the line. This relationship is applicable to a large number of equilibria
of other substituted acids also. The closely related Eq. (2) applies to the reaction
rates of a large number of substituted aromatic compounds. Both Eqs. (1) and (2) are
known as Hammett equations.
ρσ R = log10 ( K R/K H ) (1)
ρσ R = log10 ( K R/K H ) (2)
The σ values are always those determined from the ionization of substituted
benzoic acids, but the ρ values are different for each substrate and reaction type
because they reflect the sensitivity of the substrate to the electronic effects of the
substituent.
With ρ > 1, the ionization or reaction rate is more sensitive to the substituent’s elec-
tronic effects than the ionization of benzoic acid. With ρ < 1, the electron-withdrawing
groups will increase the equilibrium constant or rate, but less than in benzoic acid
dissociation. A negative ρ indicates that the electron-donating groups increase the
reaction constant. In consideration of reaction rates, a small ρ often indicates that the
reaction involves either radical intermediates or some other pathway that requires
little charge separation.
3 Hammett Substituent Constants and Free Energy

Assessment
Hammett equation is a linear free energy relationship and we will now see how it is
so. The equilibrium constant K is related to free energy by the equation Go = −RT
lnK = −2.303RT log10 K, where R is the gas constant and T is the temperature in
Kelvin. This translates into log10 K = −(Go /2.303RT ). If the free energy change

for the ionization of a R-substituted acid is (Go )R and that of the unsubstituted

acid is is (Go )H , Eq. (1) may be modified as follows:
ρσ R = log10 K R − log10 K H

i.e., ρσ R = − G o /2.303RT − − G o /2.303RT
R H
o o
i.e., 2.303RTρσ R = − G + G

R H
i.e., G o − G o = −2.303RTρσ R
R H
If the free energy changes in the ionizations of substituted and unsubstituted

benzoic acids are represented by (Go )R and (Go )H , respectively, we obtain the
relationship (G o )R − (G o )H = −2.303RTσ R on account of the above derivation.
Substituting this into the above equation, we arrive at the relationship given in Eq. (3).

G o − G o = p G o R − G o H (3)
R H
This equation states that the extent to which the free energy change of a particular
equilibrium is alerted by adding a substituent R is linearly related to the extent to
which the free energy change of ionization of benzoic acid is alerted by putting the
same substituent on the benzene ring.
(a) A linear correlation of log10 (K R /K H ) or log10 (k R /k H ) with σ implies that the
position of transition state does not change on changing the substituent.
(b) A curved line implies constant change in the position of the transition state.
(c) Two intersecting straight lines imply a sharp change from one distinct transi-
tion state to another distinct transition state. However, neither transition state
changes its position on minor changes in the nature of the substituent.
4 Hammett Substituent Constants and Reaction Pathway Relationship 185
4 Hammett Substituent Constants and Reaction Pathway

Relationship
The rate of hydrolysis of ethyl benzoate 3 in 99.9% H2 SO4 first decreases as the
substituents are made more electron-withdrawing. Then, a break occurs and the
rate increases [2]. It is apparent that the mechanism with electron-donating and
weakly electron-withdrawing substituents is the one as shown in Eq. (4). However,
it changes to the one shown in Eq. (5) when the substituents are strongly electron
withdrawing. Electron-donating substituents stabilize the acyl cation 6 and weakly
electron-withdrawing substituents are not likely to change the prospects of such acyl
cation formation and, hence, the pathway in Eq. (4). Highly electron-withdrawing
substituents do not allow the formation of the acyl cation due to its high instability
and, thus, the pathway shown in Eq. (5) sets in rapidly.
H
O OEt HO OEt O OEt O
(4)
R R R R + EtOH
3 4 5 6
H
O OEt O OH
(5)
3 R R + Et
5 7
5 Hammett Substituent Constants σ+ and σ−
The constant σ is derived from the ionization of benzoic acids wherein the negative
charge of the carboxylate ion is not in conjugation with the ring and/or the substituent
through the ring. The Hammett equation, therefore, need not apply to equilibria or
reaction rates in which the substituent comes into direct resonance interaction with
the reaction site. For instance:
(a) The p-nitro group increases the ionization constant of phenol much more than
what would normally be predicted from the σp-NO2 constant obtained from the
ionization of p-nitrobenzoic acid. The product p-nitrophenoxide ion 8 has a
resonance structure in which the nitro group participates with the oxide ion
through resonance, as shown. The resultant extra stabilization of the oxy anion
is not included in the σp-NO2 constant.
(b) In yet another example, a p-methoxy group is much more effective at increasing
the ionization rate of triphenylmethyl chloride 9 than what would be predicted
from the σp-OMe constant obtained from the ionization of benzoic acids.
O O
N O N O
O O
8
Cl Ph Ph
Ph
MeO MeO MeO
Ph Ph Ph
9 10
It was therefore felt that the rate and equilibria constants could be correlated better
by the Hammett equation if two new types of σ constants were introduced.
(a) When there is resonance between a reaction site that becomes electron-rich
and an electron-withdrawing substituent, σ− constant is used. The standard
reactions for the evaluation of σ− constants are the ionization of p-substituted
phenols and p-substituted anilinium ions [3].
(b) When there is resonance between a reaction site that becomes electron-deficient
and an electron-donating substituent, σ+ constant is used. The standard reaction
for the evaluation of σ+ constant is the solvolysis of p-substituted tert-cumyl
chlorides 11 using 90% aqueous acetone [4]. Selected σ+ and σ− values are
included in Table 1.
Cl Me OH
Me Me
R R R
Me Me Me
11 12 13
The utility of the σ+ and σ− values in comparison to the σ values could be under-
stood from the plots of log10 (k R /k H ) for the bromination of monosubstituted benzenes
versus σ and σ+ . While the plot log10 (k R /k H ) versus σ is a scatter of points, the plot
log10 (k R /k H ) versus σ+ is a straight line [4]. Bromination of anisole, at both ortho
and para positions, demonstrates how a substituent, electron-donating by resonance,
can stabilize the positive charge in the intermediate cations 14 and 15 and, therefore,
the respective transition states.
5 Hammett Substituent Constants σ+ and σ− 187
OMe OMe
H H
Br Br
14
H H
MeO MeO
Br Br
15
6 Hammett Substituent Constants and Ester Hydrolysis

Mechanism
The σ value alone can, of course, be used to understand the mechanism of those
reactions which do not come under the ambit of the σ+ and σ− values. For instance,
the base hydrolysis of a benzoic acid ester may take two different pathways:
(a) Nucleophilic attack of hydroxide ion on the carbonyl carbon to result in a
tetrahedral intermediate, in a rate determining step, followed by its collapse
into carboxylic acid.
(b) Nucleophilic attack of hydroxide ion on the alkyl carbon of the ester function,
leading to the formation of the carboxylate ion directly.
Since the carbonyl carbon is closest to the ring, the effect of a substituent felt by
it must be much larger than the effect felt by the alkyl carbon. Hence, the rate of
hydrolysis will be expected to increase much more in the former instance than in the
latter with the increase in substituent’s σ value. This is indeed the case as evident
from the σ versus rate constant k given in Table 3. The large increase in the rate of
hydrolysis with the increase in σ could be justified only if the tetrahedral pathway is
involved. The correlation of σ with log k is linear as seen from the plot in Fig. 2.
Likewise, the substituent constants in the aliphatic series have also been measured
from the rates of hydrolysis of a series of aliphatic esters (RCH2 CO2 CH3 ) where
methyl acetate (CH3 CO2 CH3 ) is the parent ester. The effect of the substituent R
arises purely from the inductive effect. An electron-withdrawing group increases the
rate of hydrolysis by (a) making the carbonyl carbon more electrophilic and (b) better
stabilization of the resultant carboxylate ion. The Hammett constant therefore has a
positive value. For reasons opposite to the above, an electron-donating group makes
the constant negative. A bulky substituent is likely to exert steric effect as well as on
the rate of hydrolysis by shielding the carbonyl group from attack. A compilation of
Hammett constants for the aliphatic series of substrates is also available [5].
Table 3 Hammett constant σ versus the rate of base hydrolysis of a benzoic acid ester
----------------------------------------------------------------------------------
R k(M-1s-1)
----------------------------------------------------------------------------------
NO2 0.78 032.9
CN 0.66 015.7
Cl 0.23 02.10
H 0.00 0.289
Me -0.17 0.172
OMe -0.27 0.143
----------------------------------------------------------------------------------
L P Hamme Chem Rev 1935, 17, 125
Fig. 2 Plot σ versus log k for the substrates given in Table 3

References 189
References
1. J.F. Dippy, J.E. Page, J. Chem. Soc. 357 (1938)

2. H.H. Jaffe, J. Chem. Phys. 21, 415 (1953)
3. J.E. Leffler, E. Greenwald, Rates and Equilibria of Organic Reactions (Wiley, New York, 1963)
4. H.C. Brown, Y. Okamoto, J. Am. Chem. Soc. 80, 4979 (1958)
5. C. Hansch, A. Leo, R.W. Taft, Chem. Rev. 91, 165 (1991)
Chapter 9
Relative Aromaticity of Pyrrole, Furan,
Thiophene and Selenophene, and Their
Diels–Alder Stereoselectivity
Abstract Thiophene has been suggested to have better aromatic character than
pyrrole and furan for its poorest reactivity under Diels–Alder cycloadditions condi-
tions. Many theories have been developed around this notion over a period of
time, prominent among them being aromaticity index based on interaction coor-
dinates (AIBIC), nucleus-independent chemical shift (NICS), topological resonance
energy (TRE), magnetic resonance energy (MRE), ring current (RC), and ring
current diamagnetic susceptibility. However, they are not consistent because different
aromaticity values derived from different indices lead to different aromaticity orders.
The suitability of the NICS and some other approaches for the prediction of
aromaticity has also been questioned. Aromaticity follows Hückel’s 4n + 2 (n =
0, 1, 2, 3, etc.) rule. The electron count, however, is not enough. Along with the
number of requisite electrons, all the bond lengths in the ring must be the same or
very similar, as in benzene. In five-membered heterocylces such as pyrrole, furan,
and thiophene, the size of the heteroatom lone pair orbital must be similar to that of
the p orbital on ring π bonds. Both the requirements are not fulfilled in thiophene
because σC–S bond is significantly longer than σC–C bond and, in comparison to the p
orbital on carbon, the size of lone pair orbital on sulfur is too large to allow effective
overlap. It is demonstrated with enough experimental data available in the literature
and new data from computations that the separation between the termini of 1,3-diene
is a significant control factor as the p orbitals on these carbons must coaxially interact
with the p orbitals on dienophile to result in σ bonds. This control factor has been
named R-factor.
1 Introduction
Aromaticity is an important concept in chemistry [1]. It is neither observable nor

a directly measurable quantity and, hence, many indices of aromaticity have been
introduced over a period of time. Manogaran and Schaefer recently published an
‘Aromaticity Index Based on Interaction Coordinates (AIBIC)’ and observed that
the relative aromaticity of five-membered heterocycles followed the order thiophene
https://doi.org/10.1007/978-3-030-75622-2_9
192 9 Relative Aromaticity of Pyrrole, Furan, Thiophene and Selenophene …
Fig. 1 The conjugative

interaction of heteroatom
lone pair with ring π system
X X X
X = N, O, S, Se
> pyrrole > furan [2]. This order was previously also observed by the nucleus-
independent chemical shift (NICS) studies carried out by Horner and Karadakov
[3–5]. The topological resonance energy (TRE) [6–7], magnetic resonance energy
(MRE) [8], ring current (RC), and ring current diamagnetic susceptibility (χG ) [9]
are the other approaches used to determine the degree of aromaticity. Not all indices
of aromaticity give consistent results among themselves and sometimes different
aromaticity values derived from different indices lead to different aromaticity orders
[10–15]. The suitability of the NICS and some other approaches has even been
questioned [16–18]. The aromaticity, in fact, is a challenge to theoretical and exper-
imental chemists and, hence, numerous approaches have been developed to improve
our understanding [19].
The largely accepted superior aromaticity of thiophene over pyrrole and furan
appears doubtful from the following observations.
1. The aromaticity accrued is necessarily due to the conjugative interaction, as
shown in Fig. 1, of the heteroatom lone pair with the π system of the ring to
cause a six-electron system following Hückel’s 4n + 2 electrons rule [20, 21].
2. The conjugative interaction must decrease in about the same order as the increase
in carbon-heteroatom σ bond length. This is so because of the increased size-
mismatch of the interacting 3p orbital of S and 2p orbitals of the ring π system
in thiophene. It is the 4p orbital of Se in selenophene.
3. The uniformity of bonds [22, 23], required for uniform distribution of elec-
trons to cause ring current and magnetic susceptibility [24–28], decreases
dramatically for the relatively long C–S bond in thiophene and C–Se bond
in selenophene in comparison to C-N/C-O bonds in, respectively, pyrrole and
furan.
4. The relative rate of piperidinodenitration of 1-methyl-2,5-dinitropyrrole at 25 °C
is markedly lower than those of 2,5-dinitrofuran and 2,5-dinitrothiophene, the
k rel being 1.0, 2.4 × 106 and 4.4 × 103 , respectively [29]. A less significant
difference is found with the rate of 1,4-dinitrobenzene (k rel = 9.6). The rate-
reducing effect may derive from the conjugative interaction of the heteroatom
lone pair with the leaving NO2 group in the ground state. The low reactivity
of pyrrole in nucleophilic substitution may, therefore, be mainly interpreted in
terms of the stability of the ground state, since a significant conjugative interac-
tion between the lone pair on ring nitrogen and the nitro group, as occurring in
the ground state, must be lost in the transition state. This interaction is expected
to be stronger than that of the ring oxygen or sulfur for the stronger tendency
1 Introduction 193
Fig. 2 Relative pKa values 4 3

of C2-hydrogen in five-ring 5 2 n-BuLi
heterocycles
X H
THF X
1
X = NR, pKa = 39.5
X = O, pKa = 35.6
X = S, pKa = 33.0
of nitrogen to share its electrons, and may well be responsible for the position
of the pyrrole system in rate sequence [30].
5. The relative rates of bromination of pyrrole, furan, thiophene, and benzene are
3 × 1018 , 6 × 1011 , 5 × 109 , and 1.0, respectively [31]. Delocalization of lone
pair into the ring decreases in the same order.
6. The reactivity profiles of pyrrole, furan, and thiophene in electrophilic substi-
tution reactions suggest significant differences. The reactivity falls by approxi-
mately 10 orders of magnitude in the series pyrrole furan > thiophene. This
may be explained by the different conditions for delocalization of ring atom
electron density, wherein overlap of π orbitals of carbon atoms and lone pairs
of the heteroatoms takes place [32]. Delocalization of lone pair of nitrogen in
pyrrole with the ring π system is clearly far greater than those of oxygen in
furan and sulfur in thiophene.
7. The pKa of C2–H (Fig. 2) in solvent tetrahydrofuran decreases in the order
39.5 > 35.6 > 33.0 in pyrrole, furan, and thiophene, respectively [33]. Measured
pKa values indicate higher electron density on C2 in pyrrole than in furan and
thiophene. In other words, electron donation, through resonance, by N in pyrrole
is larger than by O in furan and S in thiophene, in that order.
8. The C3–H and C4–H appear at δ 6.20 in pyrrole, 6.25 in furan, and 6.92 in thio-
phene in 1 H NMR spectrum [34]. These chemical shifts demonstrate decreasing
resonance donor ability of the heteroatoms. One may be tempted to consider
this a consequence of increasing ring current and, thus, increasing deshielding
and aromaticity. The following discussions will make it clear that it is due to the
relative resonance donor ability of the heteroatom and not deshielding effect of
the increased ring current.
The above observations point to the order pyrrole furan > thiophene for the
overall ring electron density and, thus, the relative aromaticity which we wish to
address herein. The intensely debated notion of superior aromaticity of thiophene
over pyrrole and furan stemmed essentially from the failure of thiophene to react
with maleic anhydride (MA) in Diels–Alder (DA) manner under the typical thermal
conditions [35], coupled with the solid understanding that more aromatic a system, the
larger the activation barrier as it must overcome the aromatic stabilization. Thiophene,
however, does react under high-pressure conditions [36–38].
Other than the resonance interaction of heteroatom lone pair with ring π bonds to
contribute to different reactivity features, including the facility for DA reaction, one
may also proceed with the simple premise that as the distance R between the termini
O O O
Se + O Se O O
-Se
O O O
Scheme 1 DA reaction of selenophene with MA followed by Se extrusion
of the cyclic diene increased with increased σC–X (X = heteroatom) bond length, the
difficulty in attaining the alignment of the terminal p orbitals of the diene with those
of the dienophile will increase, and so will the energy of activation. Though choosing
such dienes to test this premise is difficult because parameters other than R must not
change, one can still design and investigate some systems. From here onward, we
shall also include selenophene (X = Se) in the discussion. Like thiophene (X = S),
selenophene is also known to react in DA manner under high-pressure conditions. The
product, however, extrudes selenium in situ to deliver a diene as shown in Scheme 1
[39].
In an effort to resolve the aromaticity issue in a manner that a less serious theory
expert would appreciate, the author has carried out extensive quantum chemical
calculations in the gas phase at MP2/6-31+G(d) level of theory using Gaussian 16.
The use of any other level has been specifically mentioned in the discussions that
follow. Optimized structures were verified as minima or first-order saddle points
by harmonic vibrational frequency analysis. The effects of solvents on the potential
energy profiles of DA reactions of pyrrole, furan, thiophene, and selenophene with
MA were estimated using the Conductor Polarized Continuum Model (CPCM) [40,
41]. The orbital interactions were estimated by natural bond orbital (NBO) analysis
[42].
2 Heteroatom Lone Pair Interaction with Ring π Bonds

in the Ground State
The interaction of heteroatom lone pair (lp) with π system of the ring, lp → π*C=C ,
in the ground state was estimated to be 61.9 kcal/mol in pyrrole, 42.9 kcal/mol in
furan, 41.9 kcal/mol in thiophene, and 33.0 kcal/mol in selenophene. Since it is this
very interaction that confers aromatic character to the ring by making up for six-
electron system, the aromaticity order requires to be pyrrole furan > thiophene
> selenophene. The interaction intensity decreases from pyrrole to selenophene,
the difference between furan and thiophene is rather small. The relative interaction
intensities may be gleaned from the molecular orbitals shown in Fig. 3.
The activation energy of DA reaction of any 1,3-diene system with a given
dienophile is expected to rise with the rise in its aromatic character because the
path to transition state (TS) structure must negotiate with resonance stabilization
2 Heteroatom Lone Pair Interaction … 195
Fig. 3 Molecular orbitals showing interaction of heteroatom lone pair with ring π bonds in pyrrole,
furan, thiophene, and selenophene, all at the same isovalue
as well. Another important parameter that has generally been overlooked from the
general description of relative aromaticity is the separation R of the termini of 1,3-
diene in relation to the unsaturated bond in dienophile [43–46]. R controls the efficacy
of orbital overlap in TS structure for new σCC bond formation. Larger the R from
the unsaturated bond in dienophile, poorer will be the collinearity for interaction,
leading to higher activation energy.
3 DA Reactions of Pyrrole, Furan, Thiophene,

and Selenophene with MA
The separation, enthalpy changes, and activation energies of the endo- and exo-DA
reactions of pyrrole, furan, thiophene, and selenophene with MA are collected in
Table 1. R rises in the order furan < pyrrole < thiophene < selenophene in both TS
structures. The variation in π bond length of MA is relatively very small except in
reaction with pyrrole, where it is the largest. The reason for the largest π bond in
reaction with pyrrole alone is probably due to pyrrole’s reduced ability to deform in
its migration to the TS structure and, hence, enhanced force on dienophile to allow
it negotiate with the diene for the reaction. The reduced ability of pyrrole to deform
also translates into its highest aromaticity among the heterocycles. The activation free
energy, G‡ , is seen to rise with R. The relatively reduced R and also MA’s πbond
in the TS structure for reaction of furan lower the activation energy in comparison
Table 1 R and π bond distances (Å), activation energies (G‡ , kcal/mol), and enthalpy
changes (G, kcal/mol) in endo- and exo-DA reactions of pyrrole–selenophene with MA at
MP2/6-311++G(d, p) level
Diene endo-TS exo-TS
R π G‡ G R π G‡ G
X=NH 2.1984 1.4250 22.7 7.3 2.1944 1.4300 21.1 5.6
X=O 2.1492 1.4123 18.5 −0.0 2.1512 1.4117 19.1 −1.7
X=S 2.3940 1.4148 24.6 0.9 2.3930 1.4149 26.0 0.3
X=Se 2.4836 1.4120 24.8 −2.9 2.4805 1.4124 26.9 −0.3
to pyrrole. The reduced R in furan in comparison to pyrrole is likely due to poorer

resonance on account of larger electronegativity of oxygen over nitrogen [47].
It is significant to note that R always contracted in the TS structure from that in
the ground state. The distances in the ground-state structures are 2.1862 Å in furan,
2.2538 Å in pyrrole, 2.4673 Å in thiophene, and 2.5746 Å in selenophene. The
contraction in R by 0.0370 Å in furan, 0.0554 Å in pyrrole, 0.0733 Å in thiophene,
and 0.0910 Å in selenophene in the TS structure is probably in efforts to ensure the
best possible collinearity of the interacting terminal orbitals.
The activation energy is not expected to rise linearly with R because the facility to
push the heteroatom out of the plane of the ring carbons in the TS structure must also
rise as the overlap of heteroatom lone pair with ring π bonds weakens. This could be
readily seen from the marginal differences in activation energies of the reactions of
thiophene and selenophene. By taking activation energy alone, the aromaticity order
from both the endo and exo modes of reaction is selenophene > thiophene > pyrrole
> furan.
DA reactions of the heterocycles with weaker-than-MA dienophiles such
acetylene-1,2-bisnitrile (NCC≡CCN) and acetylene (HC≡CH) avoid (a) charge- and
electron-transfer considerations [48–52] to deal with the concerted processes alone,
(b) secondary orbital interactions, if any, and (c) the stereochemical endo/exo issues.
The charge- and electron-transfer mechanisms are more likely between significantly
electron-rich and electron-deficient reactants. The results are collected in Table 2.
These results are at slight variance from those in Table 1 From the activation ener-
gies, while the aromaticity order is thiophene > pyrrole > furan > selenophene from
reactions with acetylene-1,2-bisnitrileis, it is thiophene > pyrrole > selenophene >
furan from reactions with acetylene. The aromaticity order therefore cannot be fixed.
Described below are DA reactions of some cyclic dienes to demonstrate the effect
of R on activation energies.
Table 2 R and C≡C bond distances (Å), activation energies (G‡ , kcal/mol), and enthalpy changes
(G, kcal/mol) in the DA reactions of five-ring heterocycles with acetylene-1,2-bisnitrile and
acetylene
Diene NCC≡CCN HC≡CH
R C≡C G‡ G R C≡C G‡ G
X=NH 2.1937 1.2898 25.1 2.5 2.1959 1.2715 41.0 12.2
X=O 2.1528 1.2816 23.9 −4.0 2.1530 1.2645 36.7 3.6
X=S 2.3876 1.2837 30.7 −4.1 2.3924 1.2647 44.6 5.3
X=Se 2.4802 1.2803 23.1 −17.7 2.4784 1.2621 40.1 −4.9
4 DA Reactions of Cyclopentadiene, Silole … 197
Table 3 R and π bond distances (Å), activation energies (G‡ , kcal/mol), and enthalpy changes
(G, kcal/mol) in endo- and exo-TS structures for DA reactions of cyclopentadiene, silole, and
germole with MA at MP2/6-311++G(d, p) level
Y
O O
4 Y
3 O
5Y + O + O
2
O
1
O O O
endo-adduct exo-adduct

Y=CH2 2.3267 1.3870 9.8 −20.4 2.3269 1.3890 12.3 −20.4
Y=SiH2 2.6370 1.3878 9.6 −23.9 2.6356 1.3906 15.7 −21.2
Y=GeH2 2.6725 1.3898 10.5 −24.7 2.6704 1.3913 16.4 −21.1

with MA
Cyclopentadiene, silole, and germole are grossly expected to behave like normal
1,3-dienes because there is no delocalization of the double bond character within
the rings like in pyrrole, furan, thiophene, and selenophene [53, 54]. A raise in R is
therefore expected to raise the DA activation energy.
The relevant distances and activation energies are collected in Table 3. Analysis of
numbers reveals that the activation energy has indeed increased with R. The increase
in activation energy for the exo-addition is significantly larger than the endo-addition.
This is likely due to the interplay of interactions such as maximum accumulation of
unsaturation [55], secondary orbital interactions [56, 57], and dispersion forces [58–
61] in the endo-TS structure that are known to significantly influence the activation
energy. It may also be that due to these additional interactions, the activation energy
of the endo-addition of silole is slightly lower than cyclopentadiene. However, the
actual reason for the small discrepancy with silole only is not clear.

with Acetylene-1,2-Bisnitrile and Acetylene
As with the heterocycles, DA reactions of cyclopentadiene, silole and germole with

acetylene-1,2-bisnitrile and acetylene have also been investigated to assess how
the reaction profiles obeyed the R-premise. The results are collected in Table 4.
The results predict consistent fall in the activation energy from cyclopentadiene
(G, kcal/mol) in the DA reactions of cyclopentadiene, silole and germole with acetylene-1,2-
bisnitrile and acetylene
Y=CH2 2.3175 1.2685 15.3 −29.1 2.3131 1.2540 28.4 −18.2
Y=SiH2 2.6353 1.2659 14.8 −40.0 2.6253 1.2529 25.5 −29.7
Y=GeH2 2.6670 1.2647 8.0 −49.5 2.6448 1.2537 22.6 −34.2
to germole, indicating reduced aromaticity. The sudden significant fall in the acti-
vation energy for the endo-addition of germole to acetylene-1,2-bisnitrile is not
understood at the present.
It is not that the R-premise failed because the discrepancy can be explained.
The hydrogen allylic to ring π bond in each instance is in hyperconjugative inter-
action with the ring π bonds in the TS [62–64]. In reaction with acetylene-1,2-
bisnitrile, the interactions σC/Si/Ge–H → π*ring and πring → σ*C/Si/Ge–H measure 16.9
and 8.9 kcal/mol in cyclopentadiene, 4.7 and 10.1 kcal/mol in silole, and 5.0 and
10.1 kcal/mol in germole. The combined effect of the two interactions in cyclopen-
tadiene, 8.0 kcal/mol, is that of net electron donation from σC5–H to the ring to
impart aromatic character. In contrast, the rings are electron-depleted in silole and
germole to render them antiaromatic. Consequently, cyclopentadiene reacts with
higher activation energy in comparison to silole and germole. This argument holds
for reactions with acetylene also as the interactions σC/Si/Ge–H → π*ring and πring →
σ*C/Si/Ge–H measure, respectively, 17.8 and 15.0 kcal/mol in cyclopentadiene, 4.8 and
15.5 kcal/mol in silole, and 5.4 and 15.2 kcal/mol in germole. The hyperconjugative
interactions are collected in Table 5.
The switch over in the intensities of the σC/Si/Ge–H → π*ring and πring → σ*C/Si/Ge–H
interactions from cyclopentadiene to silole and germole is interesting as it has impli-
cations on reaction kinetics. In the falling activation energy regime under control
of the above hyperconjugative interactions, it is difficult to assign any definitive
role to R. Also, the results with acetylenes are not the same as with MA. In partic-
ular, the activation energies of the reactions of silole and germole decreased, rather
Table 5 The σC–H → π*ring and πring → σ*C–H interactions (kcal/mol) in the DA reactions of
cyclopentadiene, silole and germole with acetylene-1,2-bisnitrile and acetylene
σC/Si/Ge–H → π*ring πring → σ*C/Si/Ge–H σC/Si/Ge–H → πring → σ*C/Si/Ge–H
π*ring
Y=CH2 16.9 8.9 17.8 15.0
Y=SiH2 4.7 10.1 4.8 15.5
Y=GeH2 5.0 10.1 5.4 15.2
5 DA Reactions of Cyclopentadiene, Silole … 199
than increased, from that of cyclopentadiene. The clean R-compliant result from the
exo-addition to MA appears fortuitous.
Having had the effect of changing R on the activation energies of DA reactions
complicated for the presence of other forces in the dienes, the search for more dienes
was continued.
and 1,3-Cycloheptadiene with MA
These dienes were considered because the separation of the termini varied from
2.8429 Å in 1,3-cyclohexadiene to 3.1757 Å in 1,3-cycloheptadiene in the ground-
state structures and they were anticipated to follow the same order in the TS structures
for reactions with dienophiles as well. The activation energy was, therefore, expected
to rise from 1,3-cyclohexadiene to 1,3-cycloheptadiene. The relevant parameters for
reactions with MA are collected in Table 6. The activation energies, as expected, rose
for both the endo and exo modes of addition. The R-premise holds.
Scrutiny of orbital interactions in the endo-TS structures reveals the σC–H → π*ring
and πring → σ*C–H interactions to be 18.9 and 9.0 kcal/mol in 1,3-cyclohexadiene,
and 18.9 and 4.2 kcal/mol in 1,3-cycloheptadiene. The differential interaction
(σC–H → π*ring )–(πring → σ*C–H ) rose from 9.9 kcal/mol in 1,3-cyclohexadiene to
14.7 kcal/mol in 1,3-cycloheptadiene. Likewise, the σC–H → π*ring and πring → σ*C–H
interactions in the exo-TS structures are 20.3 and 8.4 kcal/mol in 1,3-cyclohexadiene,
and 21.2 and 5.4 kcal/mol in 1,3-cycloheptadiene. The difference here too has risen
from 11.9 kcal/mol in 1,3-cyclohexadiene to 15.8 kcal/mol in 1,3-cycloheptadiene.
changes (G, kcal/mol) in endo- and exo-DA reactions of 1,3-cyclohexadiene (CHXDN) and 1,3-
cycloheptadiene (CHPTDN) with MA
4 4
5
3 5 3
6
2 6 2
7
1 1
1,3-cyclohexadiene 1,3-cycloheptadiene

CHXDN 2.7570 1.3846 16.0 −29.2 2.7570 1.3894 20.2 −27.2
CHPTDN 3.0121 1.3906 20.1 −31.0 3.0093 1.3970 27.3 −27.3
The consequence of σC–H → π*ring > πring → σ*C–H will be expected to raise
the HOMO of the diene and make it more reactive toward a dienophile. The activa-
tion energy will, therefore, be lowered. However, it is substantially raised from 1,3-
cyclohexadiene to 1,3-cycloheptadiene due probably to strong R-effect. R changed
from 2.7570 Å in the endo-TS structure for reaction of 1,3-cyclohexadiene to
3.0121 Å for 1,3-cycloheptatriene.
and 1,3-Cycloheptadiene with Acetylene-1,2-Bisnitrile
and Acetylene
The reactions of 1,3-cyclohexadiene and 1,3-cycloheptadiene with acetylene-1,2-

bisnitrile and acetylene bypass the endo/exo issue. The results are collected in Table
7. Here also, the activation energy for reaction of 1,3-cycloheptadiene with both the
dienes is substantially more than that of 1,3-cyclohexadiene.
The σC–H → π*ring and πring → σ*C–H interactions in the TS structures for reac-
tions with acetylene-1,2-bisnitrile are 19.7 and 8.7 kcal/mol in 1,3-cyclohexadiene
and 20.3 and 4.1 kcal/mol in 1,3-cycloheptadiene. The difference (σC–H → π*ring )–
(πring → σ*C–H ) has increased from 11.0 kcal/mol in 1,3-cyclohexadiene to
16.2 kcal/mol in 1,3-cycloheptadiene. Likewise, the σC–H → π*ring and πring →
σ*C–H interactions in the TS structures for reactions with acetylene are 16.7 and
9.4 kcal/mol in 1,3-cyclohexadiene and 18.1 and 5.6 kcal/mol in 1,3-cycloheptadiene.
The difference of the two interactions therefore increased from 7.3 kcal/mol in
1,3-cyclohexadiene to 12.5 kcal/mol in 1,3-cycloheptadiene. In spite of net acti-
vation energy-lowering σC–H → π*ring interaction substantially raised from 1,3-
cyclohexadiene to 1,3-cycloheptadiene, the larger activation energy for reaction of
1,3-cycloheptadiene strongly favors the R-premise. In other words, when we expected
decrease in activation energy for favorable σC–H → π*ring interaction, we observed
rather increase, and this could solely be due to R-effect. The σC–H → π*ring and πring
→ σ*C–H interactions are collected in Table 8.
(G, kcal/mol) in the DA reactions of 1,3-cyclohexadiene (CHXDN) and 1,3-cycloheptadiene
(CHPTDN) with acetylene-1,2-bisnitrile and acetylene
CHXDN 2.7591 1.2661 18.5 −44.6 2.7374 1.2509 31.2 −33.7
CHPTDN 3.0114 1.2705 22.5 −47.7 2.9851 1.2538 36.0 −36.4
8 DA Reactions of 1,3-Cyclohexadiene and 1,3-Cyclooctadiene-6-Yne … 201
Table 8 The σC–H → π*ring and πring → σ*C–H interactions (kcal/mol) in the DA reactions of
1,3-cyclohexadiene (CHXDN) and 1,3-cycloheptadiene (CHPTDN) with acetylene-1,2-bisnitrile
and acetylene
σC/Si/Ge–H → π*ring πring → σ*C/Si/Ge–H σC/Si/Ge–H → π*ring πring → σ*C/Si/Ge–H
CHXDN 19.7 8.7 16.7 9.4
CHPTDN 20.3 4.1 18.1 5.6
and 1,3-Cyclooctadiene-6-Yne
Introduction of an alkyne bond between C5 and C6 of 1,3-cyclooctadiene must

increase the separation of the termini of the diene due to linear alkyne geom-
etry. Indeed, the distance between the termini is 2.8429 Å in 1,3-cyclohexadiene
and 3.6348 Å in 1,3-cyclooctadiene-6-yne. Accordingly, the activation energy was
expected to rise in DA reactions with acetylene-1,2-bisnitrile and acetylene. The
activation energy for the reactions of 1,3-cyclooctadiene-6-yne with both acetylene-
1,2-bisnitrile and acetylene is significantly more than that of 1,3-cyclohexadiene.
The TS results are collected in Table 9.
The σC–H → π*ring and πring → σ*C–H interactions in TS structures for reactions of
acetylene-1,2-bisnitrile are 19.7 and 8.7 kcal/mol with 1,3-cyclohexadiene and 21.8
and 7.3 kcal/mol in 1,3-cyclooctadiene-6-yne. The difference (σC–H → π*ring )–(πring
→ σ*C–H ) has altered from 11.0 kcal/mol in 1,3-cyclohexadiene to 14.5 kcal/mol in
1,3-cyclooctadiene-6-yne. Likewise, the σC–H → π*ring and πring → σ*C–H interac-
tions in the TS structures for reactions with acetylene are 16.7 and 9.4 kcal/mol in
1,3-cyclohexadiene and 19.4 and 8.8 kcal/mol in 1,3-cycloheptadiene. The differ-
ence here too has altered from 7.3 kcal/mol in 1,3-cyclohexadiene to 10.6 kcal/mol
(G, kcal/mol) in the DA reactions of 1,3-cyclohexadiene (CHXDN) and 1,3-cycloctadiene-6-yne
(COCTDNYN) with acetylene-1,2-bisnitrile and acetylene
4 5
3 6
2 7
1 8
1,3-cyclooctadiene-6-yne

CHXDN 2.7591 1.2661 18.5 −44.6 2.7374 1.2509 31.2 −33.7
COCTDNYN 3.3822 1.2734 22.4 −59.7 3.3510 1.2546 35.3 −50.1
in 1,3-cyclooctadiene-6-yne. In spite of the increased activation energy-lowering

σC–H → π*ring interaction, the raise in the activation energy for the reaction of
1,3-cyclooctadiene-6-yne over 1,3-cyclohexadiene could be attributed to the R-effect.
9 Evaluation of Allylic Interaction in DA Reactions

of Acyclic Dienes
Whether indeed the allylic σC–H → π*ring interaction in dienes other than cyclopen-
tadiene lowers the activation energy of its DA reaction requires to be established.
An electron-withdrawing substituent, on the contrary, is expected to raise the acti-
vation energy through the πring → σ*C–X (X = allylic substituent) interaction.
Unlike cyclopentadiene, butadienes do not acquire aromatic or antiaromatic character
because they are not cyclic. The separation of the reacting termini also does not alter
to attract attention. The TS data for the reactions of butadiene, 1-methylbutadiene,
1,4-bis-Me-butadiene, 1-CF3 -butadiene, and 1,4-bis-CF3 -butadiene with MA are
collected in Table 10.
The activation energy has decreased from 16.6 kcal/mol for butadiene to
14.5 kcal/mol for 1-Me-butadiene, and 12.4 kcal/mol for 1,4-bis-Me-butadiene as the
difference of the electron density enhancing interaction σC–H → π*ring exceeds the
electron-depleting interaction πring → σ*C–H by 5.2 and 9.6 kcal/mol, respectively,
in respect of butadiene. In contrast, the activation energy rises from 16.6 kcal/mol
for butadiene to 19.5 kcal/mol for 1-CF3 -butadiene and 22.3 kcal/mol for 1,4-bis-
CF3 -butadiene as the electron density depleting interaction πring → σ*C-F exceeds
the electron density enhancing interaction σC-F → π*ring by 10.7 and 18.7 kcal/mol,
respectively.
The above discussions support R-premise, i.e., an increased R increases the acti-
vation energy of DA reaction of a diene with a given dienophile. The R-premise was
suggested long ago [43–46], but thrown into the dustbin in search for more lucrative
avenues and never used in connection with the relative aromaticity of five-membered
heterocycles. The R-effect and overlap intensity of the heteroatom lone pair with ring
Table 10 Activation energies (G‡ , kcal/mol), enthalpy changes (G, kcal/mol), σC–X → π*ring
and πring → σ*C–X interactions (kcal/mol) in endo-DA reactions of butadiene, 1-Me-butadiene,
1,4-bis-Me-butadiene, 1-CF3 -butadiene, and 1,4-bis-CF3 -butadiene with MA
Diene endo-TS
G G‡ σC–X → π*ring πring → σ*C–X
Butadiene −33.3 16.6 – –
1-Me-butadiene −31.2 14.5 9.8 4.6
1,4-bis-Me-butadiene −28.9 12.4 18.8 9.2
1-CF3 -butadiene −28.4 19.5 1.8 12.5
1,4-bis-CF3 -butadiene −23.7 22.3 3.8 22.5
9 Evaluation of Allylic Interaction in DA Reactions … 203
π bonds together determine the activation energy of DA reaction and the aromaticity
order is pyrrole > furan > thiophene > selenophene.
10 DA Reactions of 6-Oxa-, 6-Aza-, 6-Thia-,

and 6-Selena-1,3-Cycloheptadienes with MA
The idea behind studying these molecules was that the changing σC–X bond length
will also change R as in the heterocycles. Indeed, R in the ground-state structure
changed from 3.1098 Å in 6-oxa- to 3.1422 Å in 6-aza- to 3.2312 Å in 6-selena- to
3.2351 Å in 6-thia-1,3-cycloheptadiene. The R changed, respectively, to 2.9673 Å,
2.9868 Å, 3.0933 Å, and 3.0554 Å in the endo-TS structure for DA reaction with
MA. It must be noted that the distance in the Se-analog is larger than S-analog by
0.0379 Å. The distance R and different energy parameters are collected in Table 11.
The net of the interactions σC–H → π*ring and πring → σ*CH in the TS structures
measures 10.2, 11.9, 12.9, and 12.6 kcal/mol in the reactions of 6-oxa-, 6-aza-, 6-thia-,
and 6-selena-1,3-cycloheptadienes, respectively. This interaction raises the reactivity
of the respective diene. Must this interaction be the sole control, the reactivity order
will be 6-thia- > 6-selena- > 6-aza- > 6-oxa-1,3-cycloheptadiene. Likewise, if R alone
were the control factor, the reactivity order will be 6-oxa- > 6-aza- > 6-thia- > 6-
selena-1,3-cycloheptadiene. Since the reactivity order from the activation energies is
6-aza- > 6-oxa- > 6-selena- > 6-thia-1,3-cycloheptadiene, R and allylic interactions
collectively control the reaction.
changes (G, kcal/mol) in the endo-DA reactions of 6-oxa-, 6-aza-, 6-thia-, and 6-selena-1,3-
cycloheptadienes with MA
4
5
3
Y6
2
7
1
Diene endo-TS
R π G‡ G
Y=O 2.9673 1.3878 17.1 −33.6
Y=NH 2.9868 1.3864 16.1 −35.4
Y=S 3.0554 1.3892 20.4 −33.1
Y=Se 3.0933 1.3893 18.1 −36.3
11 DA Reactions of 2,3-Cyclopropano-, 2,3-Cyclobutano-,

and 2,3-Cyclopentano-6-Oxa-1,3-Cycloheptadienes
with MA
These molecules take advantage of different geometrical constraints of three-, four-,

and five-membered rings on account of inherent angle strain to manipulate R, which
was expected to decrease in that order. Indeed, R varied from 3.3516 Å to 3.2652 Å
to 3.1376 Å in the ground-state structures of cyclopropano-, cyclobutano-, and
cyclopentano-6-oxa-1,3-cycloheptadienes, respectively. As above, R was expected
to maintain a similar decreasing trend in the TS structures for DA reaction with MA.
The relevant structural and energy parameters are collected in Table 12.
The activation energy decreased with R. The net allylic interaction (including
interactions arising from the allylic hydrogens of the smaller ring) increased from
5.9 kcal/mol in the cyclopropano-derivative to 12.6 kcal/mol in the cyclobutano-
derivative to 12.8 kcal/mol in cyclopentano-derivative. The increasing interaction
will lower energy of activation. There is hardly any difference between the net allylic
interactions in the last two reactions. This leaves R to primarily control the reaction.
Overall, we can safely assume that the fall in activation energy is due to a combined
effect of decreasing R and the increasing diene-activating allylic interactions.
Having thoroughly established the roles of R and the diene-activating or deacti-
vating orbital interactions above, we can now go to aromatic substrates wherein R
varies little and yet there are known differences in aromaticity to estimate changes in
activation energies of DA reactions. The following combinations appeared attractive
from comparison purposes: (a) benzene; pyridine, and 1,4-diazine; (b) naphthalene,
1-azanaphthalene and 1,4-diazanaphthalene; (c) anthracene, 9-azaanthracene and
Table 12 Enthalpy changes (G, kcal/mol), activation energies (G‡ , kcal/mol), σC–H → π*ring
and πring → σ*C–H interactions (kcal/mol) in endo-DA reactions of 2,3-cyclopropano-, 2,3-
cyclobutano-, and 2,3-cyclopentano-6-oxa-1,3-cycloheptadienes with MA
4
3 5
(CH2)n O6
2 7
1
n = 1; 2,3-cyclopropano-6-oxa-1,3-cycloheptadiene
n = 2; 2,3-cyclobutano-6-oxa-1,3-cycloheptadiene
n = 3; 2,3-cyclopentano-6-oxa-1,3-cycloheptadiene
Diene endo-TS
R G G‡ σC–H → π*ring πring → σ*C–H
n=1 3.1107 −33.3 16.6 18.1 12.2
n=2 3.0587 −28.0 13.8 26.3 13.7
n=3 2.9895 −35.8 11.8 27.7 14.9
11 DA Reactions of 2,3-Cyclopropano-, 2,3-Cyclobutano- … 205
9,10-diazaanthracene; and (d) benzene, naphthalene and anthracene. The results are
described hereunder.
12 DA Reactions of Benzene, Pyridine, and 1,4-Diazine

The uniformity of ring bonds is a major requirement for the ring current and, hence,
the aromaticity. Any disruption in bond-uniformity reduces aromaticity and such is
the case with pyridine and 1,4-diazine. Pyridine is known to possess slightly lower
resonance energy than benzene [65, 66]. An extension of this argument would make
1,4-diazine further less aromatic than pyridine. For the reactions of pyridine and 1,4-
diazine, we chose 1,4-positions for DA reaction [67] because nitrogen is the source
of the said non-uniformity of bonds. The relevant structural and energy parameters
are collected in Table 13.
The activation energy is surprisingly noticed to have increased in the order the
resonance energy decreased. It is also surprising to note the activation energy decrease
for the reactions across 2,4-positions of pyridine and 1,4-diazine, see footnotes to
Table 13. Though the noted positional dependence of activation energy may be used
as a tool to assess bond-uniformity, it is not prudent to draw any other conclusion for
now.
Table 13 R and C≡C bond distances (Å), activation energies (G‡ , kcal/mol), and enthalpy
changes (G, kcal/mol) in TS structures for DA reactions of benzene, pyridine and 1,4-diazine
with acetylene-1,2-bisnitrile and acetylene
4
4
N
3 5 3 5
2 6 2 6
N N
1 1
benzene pyridine 1,4-diazine

Benzene 2.6587 1.2848 35.7 1.6 2.6547 1.2655 48.5 12.0
Pyridinea 2.6529 1.2895 49.2 19.5 2.6529 1.2674 57.7 24.2
1,4-diazineb 2.6477 1.2912 64.3 37.4 2.6511 1.2716 69.0 41.6
a G‡ = 32.8 kcal/mol for DA reaction across positions 2 and 4 with NCC≡CCN
b G‡ = 29.6 kcal/mol for DA reaction across positions 2 and 4 with NCC≡CCN
Scheme 2 DA reactions of Y
naphthalene, Y
1-azanaphthalene, and +
X
1,4-diazanaphthalene X
naphthalene, X = Y = CH
1-azanaphthalene, X = N, Y = CH
1,4-diazanaphthalene, X = Y = N
(G, kcal/mol) in the DA reactions of naphthalene, 1-azanaphthalene, and 1,4-diazanaphthalene
with cyclopropene
Diene Cyclopropene
R π G‡ G
Naphthalene 2.7315 1.3562 23.0 −19.3
1-azanaphthalene 2.7370 1.3663 28.5 −5.0
1,4-diazanaphthalene 2.7339 1.3787 37.5 10.4
13 DA Reactions of Naphthalene, 1-Azanaphthalene,

and 1,4-Diazanaphthalene with Cyclopropene
Naphthalene, 1-azanaphthalene and 1,4-diazanaphthalene are the benzo-derivatives

of benzene, pyridine and 1,4-diazine, respectively, and, hence, they will also have
decreasing resonance energy. DA reactions of these aromatics with cyclopropene
were studied. The reaction was kept exo to the benzene ring in each instance as
shown in Scheme 2 [68–71]. Relevant structural and energy parameters are collected
in Table 14.
Here also, the activation energy is noted to rise from naphthalene to 1-
azanaphthalene to 1,4-diazanaphthalene concurrent with the decline in resonance
energy.
14 DA Reactions of Anthracene, 9-Azaanthracene,

and 9,10-Diazaanthracene with Cyclopropene
The DA reactions of anthracene, 9-azaanthracene, and 9,10-diazaanthracene with

cyclopropene were studied next for further confirmation of the above results.
Anthracene has 24 kcal/mol less resonance energy than 3×benzene ring. 9-
Azaanthracene and 9,10-diazaanthracene will have less resonance energy than
anthracene for the same reason as pyridine and 1,4-diazabenzene over benzene. The
relevant estimated parameters are collected in Table 15.
14 DA Reactions of Anthracene, 9-Azaanthracene … 207
(G, kcal/mol) in the DA reactions of naphthalene, 1-azanaphthalene, and 1,4-diazanaphthalene
with cyclopropane
10
4 10 5 4 10 5 4 5
N
3 6 3 6 3 6
2 7 2 7 2 7
N 8
N N
1 9 1 9 8 1 9 8
anthracene 9-azaanthracene 9,10-diazaanthracene
Diene Cyclopropene
R π G‡ G
Anthracene 2.7595 1.3443 11.9 −43.2
1-azaanthracene 2.7680 1.3550 19.1 −25.5
9,10-diazaanthracene 2.8712 1.3674 27.0 −9.2
The activation energy rises significantly as the resonance energy of the system
decreases. We will not draw conclusions for now and proceed with more discussion
to thoroughly convince ourselves with the eventual finding.
15 DA Reactions of Benzene, Naphthalene, and Anthracene

with Acetylene-1,2-Bisnitrile
The study of all carbon systems benzene, naphthalene, and anthracene for DA reac-
tion with acetylene-1,2-bisnitrile is sensible proposition. Anthracene has 24 kcal/mol
less resonance energy than 3×benzene ring. Likewise, naphthalene has 11 kcal/mol
less resonance energy than 2×benzene rings. The drop in resonance energy must
result in drop in the activation energy. The data is collected in Table 16.
The activation energy is now indeed seen to drop with resonance energy from
35.7 kcal/mol for benzene to 26.4 kcal/mol for naphthalene and 12.3 kcal/mol for
anthracene. The drop in activation energy is significantly large. It is to be remembered
that the separation of the termini of the diene remained practically unchanged. One
Table 16 R and C≡C bond distances (Å), activation energies (G‡ , kcal/mol), and enthalpy
changes (G, kcal/mol) in TS structures for DA reactions of benzene, naphthalene, and anthracene
with acetylene-1,2-bisnitrile
Diene NCC≡CCN
R C≡C G‡ G
Benzene 2.6587 1.2848 35.7 1.6
Naphthalene 2.6858 1.2812 26.4 −13.8
Anthracene 2.7124 1.2752 12.3 −37.4
Table 17 The deformation free energy (GD , kcal/mol) and stabilization free energy (GS ,
kcal/mol) for the DA reactions of benzene, naphthalene, and anthracene with acetylene-1,2-bisnitrile
(ABN)
Reactants NCC≡CCN (ABN)
GD(diene) GD(ABN) G‡ GS
Benzene + ABN 25.1 20.9 35.7 10.3
Naphthalene + ABN 20.2 18.4 26.4 12.2
Anthracene + ABN 12.2 14.8 12.3 14.7
GS = GD(diene) + GD(ABN) − G‡
may therefore infer that more the resonance energy, more is the energy required to
deform it for DA reaction.
The relationship between resonance and deformation free energy was verified by
studying the DA reactions of benzene, naphthalene, and anthracene with acetylene-
1,2-bisnitrile. The difference of the free energies of a reactant in the TS and ground-
state structures constitutes its deformation free energy (GD ). We treat the difference
of the sum of deformation free energies of the reactants and the actual activation
free energy as the stabilization free energy (GS ) arising from orbital-orbital and
other interactions. The deformation free energy of each reactant and the activation
free eneergy in each instance are collected in Table 17.
The relationship between the deformation and resonance energies of the aromatic
system is crystal clear from the data. The deformation energy of the aromatic unit
decreased with the resonance energy just as the deformation energy of the dienophile
decreased with the deformation energy of the aromatic unit. In other words, more
the aromatic character, more is the deformation energy of each reactant in the effort
to perturb each other to cause an effective orbital interaction for the formation of
new bonds. This is in line with the broadly accepted notion and also genesis of the
controversy in regard to relative aromaticity of pyrrole, furan, and thiophene.
16 Deformation Energy Considerations in DA Reactions

of Five-Membered Heterocycles
with Acetylene-1,2-Bisnitrile
In view of the above findings, it is prudent to explore whether a similar relationship of

the deformation energies existed in the DA reactions of five-membered heterocycles.
The relevant data for DA reactions with acetylene-1,2-bisnitrile is collected in Table
18.
Following the deformation energy of five-membered heterocycle alone, the reso-
nance energy follows the order thiophene ≥ selenophene ≥ pyrrole > furan. However,
following the deformation energy of the dienophile which perturbs the diene in the TS
structure, the resonance energy follows the order pyrrole > thiophene > selenophene
16 Deformation Energy Considerations in DA Reactions … 209
Table 18 Deformation free energy (GD , kcal/mol) and stabilization free energy (GS , kcal/mol)
in theDA reactions of five-membered heterocycles with acetylene-1,2-bisnitrile (ABN)
Heterocycle NCC≡CCN (ABN)
GD(heterocycle) GD(ABN) G‡ GS
Pyrrole 22.2 21.0 25.1 18.1
Furan 17.9 17.5 23.9 11.5
Thiophene 22.40 18.9 30.7 22.4
Selenophene 22.36 17.9 23.1 17.2
GS = GD(heterocycle) + GD(ABN) − G‡
≥ furan. The discrepancy is obvious because the orders are not the same as for
benzene, naphthalene, and anthracene. The deformation energy approach, therefore,
is not applicable to five-membered heterocycles because different heteroatoms allow
different flexibility to the molecule and, hence, different deformity traits enroute the
reaction.
The above deformation energy-based results were subjected to further scrutiny
by studying the endo-DA reactions of five-membered heterocycles with MA. The
heteroatom affects the reaction in the endo-TS by impacting the electronics of the
diene system but not directly as it may possibly do in the exo-TS. The deformation
and activation free energy data are collected in Table 19. The aromaticity order
is pyrrole > selenophene > thiophene > furan from the deformation energies of
the heterocycles and pyrrole > thiophene > furan > selenophene from deformation
energies of the dienophile. Other than pyrrole being on the top of the aromaticity
order, nothing else is certain. For sure, the deformation energy approach cannot be
used with confidence to assess reactivity order and, thus, the relative aromaticity of
five-membered heterocycles.
Table 19 Deformation free energy (GD , kcal/mol) and stabilization free energy (GS , kcal/mol)
in the endo-DA reactions of pyrrole, furan, thiophene, and selenophene with MA
Reactants MA
GD(heterocycle) GD(MA) G‡ GS
Pyrrole 25.2 17.0 24.2 18.0
Furan 19.6 12.9 20.4 12.1
Thiophene 23.8 13.7 27.1 10.4
Selenophene 24.7 12.2 21.1 15.8
GS = GD(heterocycle) + GD(MA) − G‡
17 DA Reactions of Thiophene 1,1-Dioxide with MA
Unlike thiophene, thiophene 1,1-dioxide reacts with MA in DA fashion under usual

thermal conditions. The perceived resonance stabilization due to the mixing of sulfur
lone pair with ring π bonds is lost on oxidation of sulfur and the molecule begins to
behave more like a normal cyclic 1,3-diene. The difference in the reactivity of this
molecule and cyclopentadiene must, therefore, emanate from two primary sources:
(a) R and (b) allylic interactions.
The relevant parameters for DA reactions of cyclopentadiene, thiophene, and
thiophene 1,1-dioxide are collected in Table 20. The larger R in the TS structure for
reaction of thiophene 1,1-dioxide must ensure higher activation energy in keeping
with the findings above.
The σC5–H → π*ring and πring → σ*C5–H interactions in the TS for reaction of
cyclopentadiene with MA are, respectively, 15.9 and 9.3 kcal/mol in the endo-TS.
The net σC5–H → π*ring interaction, therefore, is 6.6 kcal/mol and its role is to impart
aromatic character to the ring to raise energy of activation. In comparison, the σS–O
→ π*ring and πring → σ*S–O interactions in the reaction of thiophene 1,1-dioxide
with MA are, respectively, 1.9 and 12.9 kcal/mol. The net πring → σ*S–O interaction,
therefore, is 11.0 kcal/mol and its role would be to impart antiaromatic character to the
ring and, thus, lower the energy of activation. If R-effect is ignored for the time being,
the activation energy for reaction of thiophene 1,1-dioxide will be expected to be
lower than that for cyclopentadiene. However, it is not! The activation energy for the
reaction of thiophene 1,1-dioxide is 2.7 kcal/mol higher than that of cyclopentadiene.
More than 2.7 kcal/mol energy is required to offset the R-effect in allowing thiophene
1,1-dioxide to react.
Likewise, the σC5–H → π*ring and πring → σ*C5–H interactions in the exo-TS struc-
ture for reaction of cyclopentadiene with MA are, respectively, 17.8 and 8.4 kcal/mol.
The net σC5–H → π*ring interaction, therefore, is 9.4 kcal/mol to impart aromatic char-
acter to the ring and raise the activation energy. Likewise, the σS–O → π*ring and πring
→ σ*S–O interactions are, respectively, 1.9 and 13.0 kcal/mol. The net πring → σ*S–O
interaction is 11.1 kcal/mol to impart antiaromatic character to the ring and lower
Table 20 R and π bond distances (Å), activation energies (G‡ , kcal/mol) and enthalpy changes
(G, kcal/mol) in endo- and exo-DA reactions of cyclopentadiene, thiophene and thiophene 1,1-
dioxide with MA

Y=CH2 2.3213 1.3890 12.0 −18.6 2.3221 1.3905 14.7 −18.5
Y=S 2.3979 1.4150 27.1 +2.3 2.3958 1.4152 28.7 +2.1
Y=SO2 2.5343 1.3816 14.7 −30.7 2.5338 1.3849 24.4 −27.1
17 DA Reactions of Thiophene 1,1-Dioxide with MA 211
the activation energy. However, the activation energy for the reaction of thiophene
1,1-dioxide is 9.7 kcal/mol higher than that of cyclopentadiene. Other than the steric
interactions, R-effect must also contribute to the higher energy demand.
One will expect the lpS → π*ring and πring → lp*S (lpS = lone pair on S) interac-
tions in the TS structures for reaction of thiophene with MA. However, these inter-
actions are absent in both endo- and exo-TS structures. In such a situation, R will be
a significant control factor and raise the activation energy above that of cyclopenta-
diene. Indeed, the activation energy for the reaction of thiophene is 14–15 kcal/mol
higher than cyclopentadiene.
It is important to note that interactions of the sorts lpX → π*ring and πring → lp*X
(lpX = heteroatom lone pair) are completely absent in the endo- and exo-TSs for
reactions of pyrrole, furan, thiophene, and selenophene with MA. The interaction
σN–H → π*ring is also absent in the reaction of pyrrole. The absence of lpX →
π*ring interaction clearly suggests that their aromatic characters are fully lifted in
the TS structures. On account of ground state aromaticity ensuring planar structures,
sufficient energy is required for deformation to assume the TS structure.
The activation energy drops from 27.1 kcal/mol for the endo-addition of thiophene
to 14.7 kcal/mol for thiophene 1,1-dioxide, which is only 2.7 kcal/mol more than the
activation energy for reaction of cyclopentadiene. The drop in activation energy for
the reaction of thiophene 1,1-dioxide from that of thiophene arises largely from the
antiaromatic character introduced by the net of σS–O → π*ring and πring → σ*S–O
interactions.
18 Reaction Profile and Solvent Effects

on Diastereoselectivity of DA Reactions
of Five-Membered Heterocycles with MA
Having dealt with so many TS structures, it is desirable to comment on the stere-

oselectivity of DA reactions of five-membered heterocycles with maleic anhydride.
For all but pyrrole, the endo-addition is kinetically favored over the exo-addition.
However, on including the enthalpy change of the reaction and also allowing for
reaction equilibration, all the heterocycles except selenophene are predicted for exo
selectivity. Using the results in Table 1a and the results of solvent study collected in
Table 21, the reaction profiles are depicted in Fig. 4.
The analysis of data in detail is as follows:
(a) Both the endo- and exo-additions of pyrrole are endergonic and, hence, the
reversal is eminent. The differential activation energy (G‡ ) of the reverse
reactions is, therefore, more important than those of the forward reactions.
Since the reverse reactions are very similar in their activation energies for
differing merely by 0.1 kcal/mol from each other, a mixture of products
is predicted. The G‡ for the reverse processes, however, is raised to
2.0 kcal/mol in chloroform as solvent. The reversal of the exo-adduct is slower
Table 21 Study of the effects of solvents on activation free energies (G‡ ) of the endo- and exo-
DA reactions of pyrrole, furan, thiophene and selenophene with MA and enthalpy changes (G,
kcal/mol) at MP2/6-311++G(d, p) level
Diene-Solvent endo-TS exo-TS
G‡ G G‡ G
Pyrrole-CH3 CN 22.04 9.66 22.14 7.04
Pyrrole-Et2 O 22.32 9.05 21.90 6.73
Pyrrole-CHCl3 22.30 9.12 21.93 6.77
Furan-CH3 CN 18.33 0.37 18.16 −2.13
Furan-Et2 O 18.40 0.25 18.49 −1.98
Furan-CHCl3 18.39 0.26 18.46 −1.99
Thiophene-CH3 CN 24.56 1.57 25.31 0.31
Thiophene-Et2 O 24.60 1.37 25.56 0.36
Thiophene-CHCl3 24.60 1.40 25.54 0.36
Selenophene-CH3 CN 24.91 −2.07 26.29 −2.69
Selenophene-Et2 O 24.91 −2.30 26.52 −2.69
Selenophene-CHCl3 24.91 −2.27 26.50 −2.69
Fig. 4 The reaction profiles

(a) (b)
for the endo (red line) and
exo (blue line) DA reactions
of maleic anhydride with
a pyrrole, b furan,
c thiophene, and
d selenophene at
MP2/6-311++G(d, p) level
(c) (d)
18 Reaction Profile and Solvent Effects on Diastereoselectivity … 213
than endo-adduct. The exo-adduct will, therefore, accumulate and constitute

the major product. The situation remains much the same in solvents ether and
acetonitrile. Specifically, the G‡ for the reverse processes are 1.9 kcal/mol
in ether and 2.7 kcal/mol in acetonitrile. The largest G‡ in acetonitrile is
expected to best promote exo-adduct formation among the solvents investigated
herein.
(b) The energy requirement for the endo-addition of furan is the same as for the
reverse reaction. The exo-addition is 0.5 kcal/mol higher than the endo-addition
and also the reversal of the exo-adduct is 2.2 kcal/mol more difficult than that
of the endo-adduct. Consequently, under thermal conditions allowing the exo-
addition, it is predicted to constitute the major pathway. In acetonitrile, kinetics
favors exo- over endo-addition by 0.2 kcal/mol. Reversal of the endo-adduct is
faster than its formation by 0.4 kcal/mol and, hence, it must not accumulate.
In contrast, reversal of the exo-adduct is 2.1 kcal/mol more difficult than its
formation, allowing it to accumulate and constitute the predominant product.
The overall scenario remains unchanged in solvents ether and chloroform [72].
(c) The exo-addition of thiophene is less endergonic than endo-addition by
0.5 kcal/mol. Further, since the reversal of the endo-process is faster than
forward process by 0.9 kcal/mol, the endo-product will not accumulate. The
reversal of the exo-process is also faster than the forward process, but only by
0.3 kcal/mol. Thus, under the reaction conditions that both the endo (G‡ =
24.6 kcal/mol) and exo (G‡ = 26.0 kcal/mol) processes could take place, the
exo-process may predominate. Except for small changes in kinetics, overall
scenario remains unchanged in ether, acetonitrile, and chloroform.
(d) The exo-addition of thiophene is less endergonic than the endo-addition by
0.5 kcal/mol. Further, since the reversal of the endo-process is faster than
forward process by 0.9 kcal/mol, the endo-product will not accumulate. The
reversal of the exo-process is also faster than the forward process but by only
0.3 kcal/mol. Thus, under the reaction conditions that both the endo (G‡ =
24.6 kcal/mol) and exo (G‡ = 26.0 kcal/mol) processes could take place,
the exo-process will predominate. Except for small changes in kinetics, overall
scenario remains unchanged in ether, acetonitrile, and chloroform.
(e) Both the endo (G‡ = 24.8 kcal/mol) and exo (G‡ = 26.9 kcal/mol) additions
of selenophene are exergonic by 2.9 and 0.3 kcal/mol, respectively. Since G‡
for the reverse processes (G‡ endo-adduct = 27.7 kcal/mol and G‡ exo-adduct =
27.2 kcal/mol) are larger than the corresponding forward processes, the reaction
is expected to proceed under kinetic control (under mild reaction conditions) to
allow the endo-adduct predominate. The scenario remains unchanged in ether,
acetonitrile, and chloroform.
Experimentally, pyrrole is reported to undergo DA reaction with maleic anhydride
to furnish a mixture (composition not determined) of the adducts [73, 74], and both
furan [75] and thiophene [36, 37] the exo-adducts largely. Since the DA adduct
formed from selenophene undergoes rapid extrusion of selenium, it prevents us from
commenting on endo/exo selectivity [39].
Overall, the following significant points emerge from the above discussions.
(a) The order of aromaticity predicted on account of the difficulty of DA reaction
and also on account of AIBIC is selenophene > thiophene > pyrrole > furan.
This order, however, is pyrrole furan > thiophene > selenophene on account
of the lp − πC=C interaction in the ground-state structures. The use of relative
DA reactivity as the marker of aromaticity is not always appropriate because
the reactivity changes substantially with the change in the separation of the
termini of the diene for reaction with a given dienophile. A distance larger than
the unsaturated bond of the dienophile lifts the collinearity of the requisite p
orbitals required for σ bond formation and the activation energy is raised.
(b) Having considered aromaticity as the sole factor for the control of reactivity,
one will predict very similar reactivity profiles for both furan and thiophene (lp
→ π*C=C = 42.9 kcal/mol in furan and 41.9 kcal/mol in thiophene). However,
thiophene reacts only under forcing conditions. This is due to the difference in
the distances between the reacting termini of the diene; the significantly large
separation in thiophene results in significantly poor collinearity of the terminal
p orbitals.
(c) The endo/exo-selectivities predicted from the combination of differential TS
energies for forward and reverse reactions and also the enthalpy changes are in
excellent agreement with experiments. Among the five-ring heterocycles under
consideration, while furan and thiophene furnish exo-adducts, selenophene
is predicted for endo- and pyrrole for the exo-addition, depending upon the
reaction conditions. Solvents are likely to change the kinetics and also the
course of the reaction.
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Chapter 10
Miscellaneous
Abstract The control elements that did not find mention in the earlier chapters are
dealt with in this chapter. The prominent among these elements are spiroconjuga-
tion, periselectivity, ambident nucleophiles and electrophiles, α-effect, carbene addi-
tion to 1,3-dienes, Hammond postulate, Curtin–Hammett principle, diastereotopic
substituents, homotopic substituents, enantiotopic substituents, and captodative
effect.
1 Spiroconjugation
When one conjugated system is held orthogonal to another conjugated system, as in

spirostructures, the p orbitals of one conjugated system can overlap with those of the
other conjugated system, as indicated by the red curved lines on the front lobes and
green curved lines on the rear lobes in structure 1, with a small overlap integral. In the
situation when the symmetries match, the interaction leads to two new orbitals, one
raised and the other lowered in energy, in the usual fashion that we have previously
learnt elsewhere. However, when the symmetry elements do not match, the overlap
is considered to have no effect.
1 2 3
Let us consider spiroheptatriene 2 with the unperturbed orbitals of cyclopenta-

diene component shown on the left and that of cyclopropene shown on the right in
Fig. 1. It is easy to see that only the orbitals ψ 2 and π* can interact for having the
right symmetry as all other orbitals possess wrong symmetry. For example, the top
lobes of ψ 1 and the upper p orbital of π (one lobe on the front and the other on the
back) have one interaction in phase and the other out of phase, exactly canceling
each other. A similar situation exists between the lower lobes of ψ 1 and the lobes of
the lower p orbitals of π on the right.
https://doi.org/10.1007/978-3-030-75622-2_10
218 10 Miscellaneous
ψ4
π*
ψ3
ψ2
E
ψ1
Fig. 1 Molecular orbitals of spiroheptatriene leading to spiroaromaticity
The interaction ψ 2 → π* creates two new orbitals, one raised and the other
lowered in energy. Since there are only two electrons to go into one of these orbitals
and, also, since these two electrons will occupy the lower orbital, the overall energy of
the system stands lowered. This lowering in energy, ΔE, is small because of the poor
overlap, and the poor overlap is necessarily on account of having the two interacting
p orbitals significantly apart. Nevertheless, it is generally concluded that if the total
number of π electrons is 4n + 2 (n = 0), the spirosystem is stabilized and this leads
to the concept of spiroaromaticity.
Spiroantiaromaticity arises when the total number of π electrons is 4n (n = 0), as
in spirononatetraene 3. Ignoring the interactions of the unfilled ψ 4 with ψ 4 because
they have no effect on energy for having no electrons in them, the only Mos with the
right symmetry to interact constructively are ψ 2 on each side, Fig. 2. The ψ 2 → ψ 2
interaction leads to two new orbitals, each occupied by two electrons. The net effect
is a rise in the overall energy of the system because, according to perturbation theory,
the bonding combination is lowered less than the rise in the antibonding combination,
i.e., ΔE 1 < ΔE 2 . The energy levels ΔE 1 and ΔE 2 have been measured to be 1.2 eV
(1 eV = 23.061 kcal/mol) apart from each other. This energy difference is expected
to impart exceptional reactivity to the molecule [1]. Indeed, this is in agreement with
the increase in the overall energy of the molecule and, in particular, the energy of
HOMO to raise the reactivity of the substrate.
2 Periselectivity 219
ψ4 ψ4
ψ3 ψ3
ΔE 2
ψ2 ψ2
ΔE 1
ψ1 ψ1
Fig. 2 Molecular orbitals of spirononatetraene leading to spiroantiaromaticity
2 Periselectivity
In the cycloaddition of a conjugated system, there are three different situations to

consider:
(a) The entire conjugated array of electrons is involved.
(b) A large part of the conjugated array of electrons is involved.
(c) Only a small part of the conjugated array of electrons is involved.
The conservation of orbital symmetry rules restrict the total number of electrons
to 6, 10, 14, 18, etc., in suprafacial reactions, but it is silent on which of these
electrons would be preferred if they were all geometrically feasible. For instance,
the cycloaddition of tropone 4 with cyclopentadiene 5 may be expected to give a
mixture of the [6 + 4] adduct 6 and [4 + 2] adduct 7 as shown in Fig. 3. However,
the adduct 6 is formed in preference to 7 in a process called periselectivity. Let us
understand the origin of this selectivity.
2 3 4
LUMO 1
5 O
O 7 6
4
[6 + 4] approach
HOMO
5 6
HOMO
O
5 O [4 + 2] approach
LUMO
7
4
Fig. 3 The FMOs of tropone and cyclopentadiene placed together for [6 + 4] and [4 + 2]
cycloadditions
From the frontier molecular orbital (FMO) approach, the longer conjugated system
in tropone is more reactive than any shorter conjugated system because the largest
LUMO coefficients are concentrated at C2 and C7. This allows bonding to these
sites more energy-lowering as in the [6 + 4] addition, leading to 6, than bonding to
C2 and C3 sites as in the [4 + 2] addition, leading to 7. In general, the termini of
a conjugated system carry the largest frontier orbital coefficients to allow pericyclic
reactions to occur with the longest conjugated system.
The cycloaddition of 8 with dimethyl acetylene dicarboxylate 9 to generate 10
[2, 3], the electrocyclic ring closures 11 → 12 and 14 → 15 (8 electron conrotatory
ring closures) [4, 5] under thermal conditions, and the sigmatropic rearrangements
18 → 19 [6] and 20 → 21 [7, 8] are some among many examples to support the
argument that the largest possible number of electrons are mobilized when smaller,
but equally allowed, numbers could have been used instead. The transformations 18
→ 19 and 20 → 21 are examples of [4,5]- and [1,7] sigmatropic shifts, respectively.
CO2Me
CO2Me
+
CO2Me CO2Me
8 9 10
13 11 12
16 14 15
4 1
Ph NMe2
Ph NMe2 Ph 3
2 NMe2
5
1
4 3 2
17 18 19
H H
Ac R HO R
20 21
Note that 18 could also have undergone [2,3]- and [2,5] sigmatropic shifts to
generate 22 and 23, respectively. However, neither of these products was formed.
Likewise, 24, which could have formed from 20 via a suprafacial [1,5] sigmatropic
shift, was also not formed.
Ph NMe2 Ph NMe2
X
18 22
Ph NMe2
Ph NMe2 X
18 23
H
H
X
HO R HO R
20 24
The 2,4-pentadienyl phenyl ether 25 makes an interesting case [9]. The indicated
products 26, 27, and 28 arise from [3]-, [5]-, and [3,5] sigmatropic shifts, respectively.
When the reaction was conducted, only the products 26 and 27 were formed. Thus,
unlike all the above examples, the [3] sigmatropic shift, which involved only a small
part of the conjugated array of electrons, competed reasonably well with the product
26 formed from [5] sigmatropic shift that involved the entire conjugated array of
electrons. The product 28, which involved a large part of the conjugated array of
electrons, was not observed.
OH
O OH OH
+ +
25 26 (27%) 27 (50%) 28 (0%)
The exclusive acid-catalyzed transformations 29 → 30, 31 → 32, and 33 → 34

are some other examples of [5] sigmatropic shifts involving the entire conjugated
array of electrons. The products from [3]- and [3,5] sigmatropic shifts (not shown)
were not observed in either instance [10].
HN NH
H2N NH2
29 30
HN NH R
N
N
S R H2N
S NH2
31 32
RN NR R' R'
S S R'
R' S S NHR
RHN
33 34
It is important to understand whether the above predominant selectivity arises

solely on account of the FMO coefficients or the thermodynamic stability of the
product has any role in it. The species 6 and 15 were calculated to be more stable
than 7 and 16 by 9.2 and 24.1 kcal/mol, respectively, at the HF/6-31G(d) level of
theory [11]. Further, 19 is more stable than 22 and 23 by 13.8 and 2.53 kcal/mol,
respectively. From the observation that only the most stable products 6, 15, and 19 are
formed, one tends to infer that the thermodynamic factor may also have contributed
to the observed selectivity.
On the contrary, the species 12 is less stable than 13 by 6.2 kcal/mol and yet 12
is formed predominantly. Likewise, 26 is less stable than 27 by 4.1 kcal/mol and
yet the reaction leading to 26 competes reasonably well with the reaction leading
to 27, so much so that both 26 and 27 are formed in approximately a 1:2 ratio. It
is also noteworthy that though 28 is more stable than both 26 and 27 by 4.6 and
0.5 kcal/mol, respectively, none of 28 is formed.
Taking into consideration the observed selectivity and product stability together,
it can be argued that the latter per se is not a significant factor to have a controlling
effect on the selectivity of the reaction. In an instance where the selectivity based
on FMO coefficients is matched by the product stability, the reaction may at best be
predicted to be relatively faster than when the match is absent. It is also expected that
the energy of the TS structure which involves the entire conjugated array of electrons
is lower than the TS structure which involves a shorter array of conjugated electrons,
and it is this feature that contributes the most to the selectivity.
In contrast, carbenes react with 1,3-dienes such as 35 to give vinylcyclopropanes
36. The symmetry-allowed [4 + 2] cycloaddition leading to cyclopentenes such
as 37 does not occur. An exception to this general observation is the reaction of
difluorocarbene with norbornadiene 38, where [2 + 2 + 2] reaction, leading to 39,
competes with the [2 + 2] reaction that results in the formation of 40 [12].
:CCl2 Cl
Cl :CCl2
X Cl
Cl
37 s-cis-35 s-trans-35 36
F
:CF2
+ F
F F
38 39 40
Cl Cl Cl
Cl Cl Cl
41 42 43
Cyclopropanation reaction requires a nonlinear approach of a carbene to the π

bond as shown in 41. As the reaction progresses, both the substituents tilt upwards
to occupy positions where they will be in the product 42. In the corresponding linear
approach, as shown in 43, the carbene comes straight down to the middle of the π
bond with its substituents already lined up where they will be in the product. There
is experimental evidence for the nonlinear approach based on isotope effects [13].
Calculations also support the nonlinear approach even though they suggest two steps
through a short-lived diradical for the reaction [14, 15]. One needs to understand why
a nonlinear approach giving vinyl cyclopropane is preferred over the linear approach
giving cyclopentene, even when the cyclopentene formation is likely to benefit from
the overlap of the atomic orbitals of carbene with the two large coefficients at the
ends of the diene.
In considering the reaction of a carbene with 1,3-diene, three different situations
are likely to emerge:
(a) Overlap of HOMO of the carbene with the lowest occupied MO (LOMO) of
1,3-diene, as shown in 44, must be repulsive because both the orbitals are filled
(note that the phases of the orbitals appear to match and this could be mistaken
for a constructive overlap).
(b) Overlap of LUMO of the carbene and HOMO of 1,3-diene, as shown in 45, is
constructive.
(c) Overlap of HOMO of the carbene with LUMO of 1,3-diene, as shown in 46,
is also constructive.
Calculations show that the repulsive forces in 44 are much stronger than the
attractive forces in either 45 or 46, which prevents the [1 + 4] addition. On the
contrary, the nonlinear approach of LUMO of the carbene to the HOMO of an alkene
as in 41 is virtually barrierless and, hence, cyclopropanation takes place rapidly and
predominantly [16].
HOMO LUMO HOMO
LOMO HOMO LUMO
44 45 46
Additional factors that may be responsible for the cyclopropanation reaction are
as follows:
(a) The probability of s-cis conformation of the diene necessary to develop simul-
taneous overlap at both the ends is low. Since cyclopropanation can take place
in any conformation, it goes ahead without waiting for the diene to change
from the predominant s-trans conformation to the s-cis conformation.
(b) The cyclic dienes such as cyclopentadiene are fixed in the s-cis conforma-
tion and yet they react to give cyclopropanes predominantly. This is probably
because the alternative would create a strained bicyclo[2.1.1]hexene system.
(c) Cyclic dienes in larger rings also form cyclopropanes, probably because they
have the two ends of the diene held so far apart that both cannot easily be
reached by the single carbon atom of the carbene.
Ketenes avoid higher FMO coefficients in their reactions with 1,3-dienes and
undergo exclusive [2 + 2] cycloaddition in a suprafacial manner to form adducts
such as 47 from cyclopentadiene [17]. Neither 48 nor 49, both products of the [4 +
2] cycloaddition, is formed. The orthogonal disposition of the p orbitals of πC=C and
πC=O does not allow πC=C to have a low-lying LUMO. The energy of this LUMO is
raised even further from its mixing with the lone pair orbitals on the oxygen atom.
The πC=C of ketene is, therefore, not a good dienophile and, hence, the [4 + 2]
cycloaddition giving 48 does not occur. The [4 + 2] addition in which the carbonyl
group acts as dienophile to generate 49 is unfavorable just like any other [4 + 2]
cycloaddition with a normal carbonyl group. In the [2 + 2] cycloaddition giving 47,
it is the LUMO of πC=O which is involved in the formation of the leading σC–C bond
for being low-lying on account of its conjugation with the two σC–Cl bonds [18].
O H O
C
+
Cl
Cl Cl
H Cl
47
O
or O
X Cl
Cl Cl
48 49 Cl
However, the equivalent of 49 is known from the reaction of diphenyl ketene with
cyclopentadiene. The adduct 50, formed at low temperature, rearranges through [3]
sigmatropic shift to form 51, which appears to be [2 + 2] adduct. The reaction of
1-methoxybutadiene with diphenyl ketene to form 52 at low temperature is akin to [2
+ 2] reaction involving πC=C of the ketene. However, this species rearranges further
by [3] sigmatropic shift to form 53, which is akin to the [4 + 2] cycloaddition of the
butadiene with πC=O of the ketene, just as in 49 [19].
O O
[4 + 2] O [3,3]
+ C
-20 oC 0 oC Ph
Ph Ph Ph Ph
Ph
50 51
Ph Ph
O Ph Ph
C [2 + 2] [3,3]
+ O O
MeO 0 oC 0 oC
Ph Ph MeO
OMe
52 53
In conclusion, reactions generally take the path that uses the longest array of the
conjugated system in compliance with orbital symmetry control. However, several
other factors such as spatial separation of the ends of the conjugated system, entropy
changes required to attain the requisite geometrical disposition on the way to the
transition state, and steric factors that operate during this progression must also be
taken into consideration [20].
3 Ambident Nucleophiles
Nucleophiles that could react with electrophiles with two sites are called ambident
nucleophiles. The Hard and Soft Acids and Bases (HSAB) principle applies because
a hard electrophile reacts at the harder nucleophilic site and a soft electrophile at the
softer nucleophilic site. For instance, the sulfenate ion 54 is an ambident nucleophile
because it reacts (a) with methyl fluorosulfonate, a hard electrophile, at the oxygen
atom, where most of the negative charge is concentrated, to give the sulfenate ester
55 and (b) with methyl iodide, a soft electrophile, through the sulfur atom to give
the sulfoxide 56 Sulfur atom is the softer of the two nucleophilic sites available in
the sulfenate ion and, furthermore, it is rendered more nucleophilic by the α-effect
arising from the adjacent oxygen atom.
3 Ambident Nucleophiles 227
Me OSO2F S Me
S Ar O
Ar O
54 55
Me I Me
S S
Ar O Ar O
54 56
The thiocyanate, cyanide, and nitrite ions are also ambident nucleophiles. The
thiocyanate ion is softer on sulfur and harder on nitrogen. Likewise, the cyanide ion
is softer on carbon and harder on nitrogen, and the nitrite ion is harder on oxygen
and softer on nitrogen. Depending on the nature of the electrophile R+ and also the
reaction conditions, each of these ions can react to give either of the two possible
products: the thiocyanate 58 or the isothiocyanate 59 from the thiocyanate ion 57,
the nitrile 61 or the isonitrile 62 from the cyanide ion 60, and the nitroalkane 64 or
the alkyl nitrite 65 from the nitrite ion 63.
R+ R+
R S C N S C N S C NR
58 57 59
R+ R+
R C N C N C N R
61 60 62
R
R+ R+
N O N O R O N O
O O
64 63 65
We tend to expect that a harder electrophile will form isothiocyanate, isonitrile,

and nitrite. However, other factors also play significant roles. For instance, the thio-
cyanate 58 is the kinetically preferred product in alkylation by alkyl halides and
carbocation species even when the carbocation constitutes a hard electrophile by
virtue of being charged. This is partly explained by the relatively small changes in
the bond lengths and also the electronic reorganization required in the transition
from thiocyanate ion to thiocyanate product. However, the thiocyanate isomerizes
rapidly to the corresponding isothiocyanate which is thermodynamically more stable.
A tertiary alkyl thiocyanate rearranges by the SN 1 pathway (ionization followed by
recombination) [21], and a primary alkyl thiocyanate by SN 2 pathway (the nitrogen
of one thiocynate attacks the alkyl group of another thiocyanate) [22].
Just as with the thiocyanate ion 57, the cyanide ion 60 reacts with soft alkyl halides
in a SN 2 fashion and with hard carbocations in the SN 1 fashion to give, almost always,
the nitrile 61, which is thermodynamically more stable than the corresponding isoni-
trile 62. The isonitrile is formed along with nitrile when (a) the cation is so very
reactive that the rate of reaction reaches the diffusion-controlled limit and (b) the
reversible reaction, which equilibrates the isonitrile and nitrile, is very slow. Since
the reaction of cyanide ion with a carbocation falls in the domain of ion–ion reaction,
it is indeed very fast. For such a barrierless combination of ions, the kinetic factors
associated with the HSAB principle are not applicable.
The isonitrile product is formed under special conditions. For example, silver
cyanide reacts with the bromide 66 to form the isonitrile 68, whereas potassium
cyanide gives only the nitrile 69 [23]. Both reactions proceed through the episul-
fonium ion 67 to allow overall retention of configuration. These observations are
explained as follows:
(a) The relatively soft silver is attached to the carbon end of the cyanide ion, leaving
the nitrogen end free to participate as a nucleophile, whereas potassium is not
so attached.
(b) Likewise, trimethylsilyl cyanide sometimes gives isonitrile on reaction with a
carbocation that is stabilized only by alkyl groups. It happens perhaps because
the silyl group is attached to the carbon end of the cyanide at the time of the reac-
tion and/or the formed isonitrile rearranges very slowly to the corresponding
nitrile.
H Ag C N: H
H
Br H C
SMe N
SMe
S
H Me H
66 67 68
H K N C H
H N
Br H C
SMe SMe
S
H Me H
66 67 69
Nitrite ion generally gives nitroalkane 64 as the major product. Since nitroalkane is
thermodynamically more stable than the corresponding alkyl nitrite, the alkyl nitrite
isomerizes to the corresponding nitroalkane in a manner as shown below.
3 Ambident Nucleophiles 229
R O N O R
R
O N O N + R O N O
O N O R O N O R O O
65 63 64 65
As with the cyanide ion, when the reaction of nitrite ion with a carbocation reaches
the diffusion-controlled limit, the alkyl nitrite may be detected and it may even be
the predominant product. Nitrite ion gives a mixture of nitroalkane and alkyl nitrite
in SN 2 reactions even when the alkyl electrophile is relatively soft. For instance, the
SN 2 reaction of nitrite ion with methyl iodide, trimethyloxonium ion (Me3 O+ ), and
methyl triflate gives, respectively, 30:70, 50:50, and 60:40 mixtures of methyl nitrite
and nitromethane. The gradual increase in the methyl nitrite component is in keeping
with the gradual increase in the hardness of the electrophile [24].
The nitrite to nitroalkane ratio also increases from 16:84 to 30:70 to 61:39 in
the reactions of silver nitrite with primary benzyl bromides as the p-substituent on
the benzene ring is changed from NO2 → H → OMe, respectively [25–27]. Silver,
being soft, is bound largely to the nitrogen of the nitrite ion, leaving the oxygen as
the more available nucleophilic species. As the hardness of the electrophile rises in
the order that the substituent on the benzene ring is changed, more of the alkyl nitrite
is formed. The OMe substituent imparts a more cationic character to the benzyl
bromide through the conjugation effect.
4 Ambident Electrophiles
These are molecules that have two electron-deficient centers, each capable to react
with nucleophiles. The reactivity profile is susceptible to the same kind of analysis as
above for ambident nucleophiles with electrophiles. In the reaction of an electrophile
with a nuclephile, it is the LUMO of the electrophile that interacts with the HOMO of
the nucleophile. Thus, the higher the HOMO and/or the lower the LUMO to reduce
the energy gap between the two, the faster will be the reaction. Alternatively, the
better the match of the HOMO and LUMO coefficients, the more effective will be
the reaction.
α,β-Unsaturated Carbonyl Compounds
Most nucleophiles attack α,β-unsaturated ketones faster at the carbonyl carbon than
the β-carbon. The attack at β-carbon is generally the result of a slower, but thermo-
dynamically more favorable, reaction. For the β mode of attack to predominate, it is
necessary that the attack at the carbonyl carbon is reversible. Well-stabilized anions
and higher temperatures assist this reversibility. For example, reaction with cyanide
ion at a temperature below 15 °C leads to reaction largely at the carbonyl carbon and
a cyanohydrin (70 → 71) is formed. However, the same reaction, when conducted
at temperatures above 15 °C, turns largely in favor of conjugate addition to result in
a β-cyanoketone (70 → 72) [28].
HO CN O O
KCN, K2CO3, <15 oC β KCN, K2CO3, >15 oC
NC
α
71 70 72
Likewise, the lithium enolate 73 reacts with cyclohexenone 74 at −78 °C to give

75, the product of direct attack at the carbonyl carbon. However, warming the reaction
mixture to room temperature allows this step to revert to the starting materials and they
react again to form the thermodynamically more stable conjugate addition product
76 [29]. The enolate formed from a β-dicarbonyl compound does not allow isolation
of any product from direct attack at the carbonyl group because the diketone →
enolate step is even more easily reversible in this instance.
O
O LiO OMe OLi
CO2Me -78 oC MeO2C
+
> -78 oC
75 74 73 76
In the simplest α,β-unsaturated carbonyl compound acrolein (CH2 = CHCHO),

the LUMO coefficient is largest at the β-carbon [30]. Thus, if any nucleophile is
to attack at this carbon, it must be soft in response to the frontier molecular orbital
(FMO) theory. This is borne out well from the observation that radicals, which are
inherently soft, add to the β-carbon exclusively. Further, the relatively soft Grig-
nard reagents react more in conjugate fashion than the relatively hard organolithium
reagents [31].
Many additions to α,β-unsaturated carbonyl compounds take advantage of coor-
dination to the oxygen by a metal ion or a proton or even a hydrogen bond. In such
a situation, the LUMO coefficient is largest at the carbonyl carbon. Thus, even soft
nucleophiles are expected to attack directly at the carbonyl carbon under catalysis by
a Lewis or protic acid. For instance, the ratio of direct to conjugate attack to cyclo-
hexenone by LiAlH4 in ether is 98:2, and it changes to 23:77 on sequestering the
lithium ion by a cryptand [32]. The proportion of the conjugate attack is obviously
enhanced on engaging the lithium ion with the cryptand.
Hydroxide and alkoxide ions, both hard nucleophiles, react with ethyl acrylate 77
by the direct attack at the carbonyl carbon to bring about ester hydrolysis and ester
exchange, respectively. However, the enolate 78, a soft carbon nucleophile derived
from ethyl acetoacetate, reacts in a conjugate manner to form 79 predominantly. In
an alternate pathway, it is also likely that the enolate 78 reacts through the oxy anion
(hard nucleophile) directly at the carbonyl carbon (hard electrophile) to generate
4 Ambident Electrophiles 231
the species 80, which rearranges in an oxy anion-accelerated [3.3] sigmatropic shift
manner to form 81 and, finally, 79.
RO O O
R = H, alkyl
OEt OR
77
O O O O
H3O
OEt OEt
CO2Et CO2Et
78 77 79
EtO2C EtO2C EtO2C

O O OO
O O- 79
78 OEt OEt
OEt
77 80 81
The thiolate ion (RS− /ArS− ) does not react with α,β-unsaturated esters to give
α,β-unsaturated thioesters 82 because the equilibrium favors the carboxylic acid ester.
It rather gives the product of conjugate addition 83 exclusively. The relative rate of
attack at both the sites can, therefore, not be measured. It is likely that the conjugate
attack is kinetically controlled.
O O O
EtO ArS
SAr OEt ArS OEt
ArS
82 77 83
Ammonia, a soft nucleophile for being neutral, reacts with methyl acrylate 84 in
methanol in a conjugate manner to give the primary amine 85. The reaction continues
in the same vein and the secondary amine 86 and tertiary amine 87 are formed
successively [33]. It is to be noted that ammonia, and other primary and secondary
amines, do not react with simple esters to form amides. Combining this with the
established observation that an attack at the carbonyl group is irreversible and also
rate-determining [34], the above conjugate addition must necessarily be a product of
kinetic control, supported by the HOMO–LUMO interaction.
O O O O
NH3
OMe H2N OMe MeO N OMe
H
84 85 86
O O
MeO N OMe
CO2Me
87
Making the carbonyl group more electrophilic by protonation or coordination

with a metal cation increases the possibility of direct attack at the carbonyl carbon.
Contrary to this, reduction in electrophilicity, which indeed happens in the corre-
sponding cyclohexyl imine, increases the chances of conjugate addition. For instance,
acryloyl chloride, which is like protonated acrolein on account of the high electroneg-
ativity of chlorine, reacts with ammonia directly at the carbonyl group to result in
acrylamide exclusively. Contrary to this, the cyclohexyl imine derivative exclusively
reacts with organolithium reagents in a conjugate manner.
The ratio of the products from conjugate and direct reductions increases with an
increase in the softness of the hydride reagent. This softness follows the order: carbon
hydrides > boron hydrides > aluminum hydrides. It is this difference that brings
about exclusive conjugate addition when an α,β-unsaturated ketone is allowed for
reduction using lithium aluminum hydride in pyridine [35]. In the process, pyridine
is first reduced by lithium aluminum hydride to 88, which then delivers hydride ion
to the substrate in the manner shown to form the saturated ketone 90. The reduction
using Hantzsch ester (diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate)
is similar to this [36–45]. Contrast this with Meerwein–Ponndorf–Verley reduction
wherein the hydride delivery is constrained by the six-membered transition structure
91 to furnish the product of direct reduction 92 [46]. The conjugate addition is avoided
because it would involve an eight-membered transition state structure.
H
Al N O O
H
88 89 90
R R
Al H OH
O O
91 92
CN CN
Nu Nu
O O
OEt OEt
93 94
Olefins with two activating substituents, as in ester 93, undergo fast conjugate
addition of carbon nucleophiles. The stability of the conjugated enolate species 94
and frontier orbital factors, i.e., the largest LUMO coefficient at the β-carbon explain
this selectivity.
Aromatic Electrophiles
Considering the LUMO of the conjugated system and the HOMO of the nucleophile
as the two important Frontier Molecular Orbitals for a reaction, the electrophilic sites
of a select group of aromatic compounds 95–100 are indicated by the arrows. In each
instance, there is a high LUMO coefficient at the site of attack, each such site also
has a high total electron deficiency, with the possible exception of pyridine 100. The
tetrahedral intermediate formed from such an attack is lower in energy than an attack
at an alternate site.
0.43 0.44 -0.31 0.47

0.10 -0.06
-0.26 0.22
-0.51 -0.29 0.31
95 96 97
0.45
0.75 -0.23 -0.13
0.52
-0.19 -0.42
O -0.38
-0.35
N
0.28 0.68
98 99 100
The pyridinium ion 101 is even more readily attacked by nucleophiles at C2 and
C4 than pyridine itself. On the product side, the linearly conjugated intermediate 102,
which also benefits from an anomeric effect should the nucleophile be an electroneg-
ative heteroatom, will be the product of thermodynamic control. Since this step is
not always reversible, the frontier orbitals and the charge distribution in the starting
material are likely to be important when the reaction is kinetically controlled. Charge
control, taken together with the high π electron deficiency at C2, will favor reaction
with hard nucleophiles at this site. This is indeed the case with hard nucleophiles
such as hydroxide ion, amide ion, borohydride, and Grignard reagents [47, 48]. In
contrast, soft nucleophiles such as cyanide ion, enolates, and hydride ion derived
from the Hantzsch ester attack faster at C4 than C2 to form 103 [49, 50].
0.16
Nu
Nu
0.24
N N H
101 102
Nu H
Nu
N N
101 103
The ortho- and para-halo-nitrobenzenes are readily attacked by nucleophiles. The

first step is generally rate-determining. The product development control favors faster
attack at the ortho than para position because the intermediate 105 is lower in energy
with its linear conjugation than 108 that has cross conjugation. The electrostatic factor
also favors attack at the ortho position because of greater π electron deficiency at
this position than the para position. However, since the LUMO coefficient is larger
at the para than the ortho position, attack by a soft nucleophile at the para position
must be faster than that at the ortho position. Indeed, DABCO (neutral and, hence,
a soft nucleophile) attacks at the para position in p-chloronitrobenzene 2.5 × 102
times faster than the ortho position in o-chloronitrobenzene.
Nu
Nu Nu
Cl
Cl
O O O
N N N
O O O
104 105 106

Nu
Cl Cl Nu Nu
Cl
O O O
N N N
O O O
107 108 109
Unsymmetrical Anhydrides
Unsymmetrical Maleic Anhydrides
The selectivities demonstrated by unsymmetrical maleic and phthalic anhydrides for

the attack of a nucleophile on one of the two carbonyl groups are large enough to
warrant an explanation. In principle, maleic anhydride 110 can undergo attack by
a nucleophile at either of the two carbonyl carbons Cα and Cβ . However, there is
an exclusive attack at Cα by lithium aluminum hydride with methoxy group as a
substituent. The ratio of attack at Cα and Cβ reduces only slightly to 88:12 when the
substituent is a methyl group.
Being electron-rich and/or electron-releasing, both these groups are in conjuga-
tion with the carbonyl group at Cβ . This results in a reduction of the LUMO coeffi-
cient at Cβ . Consequently, Cα is more electrophilic than Cβ and, hence, the observed
preferential attack in spite of the greater steric demand imposed by the substituent.
Calculations show that the LUMO coefficient at Cα is slightly smaller in the methyl
derivative than the methoxy species and, hence, the difference in the observed selec-
tivities [51]. The difference in the LUMO coefficients at Cα is in line with the known
fact that methoxy is a more powerful electron donor than the methyl group.
MeO MeO
α β
O O O O O O
110 (R = OMe)
LUMO coefficients at Cα versus Cβ in maleic anhydride derivatives
R Cα Cβ
MeO 0.39 −0.34
Me 0.36 −0.35
Ph 0.22 −0.25
The selectivity changes in favor of the attack at Cβ in the reaction with a phosphorus
ylide when the substituent is methyl (Cα :Cβ = 6:94) and phenyl (Cα :Cβ = 0:100),
although still in favor of exclusive attack at Cα when the substituent is a methoxy
group (Cα :Cβ = 100:0). It appears that the inherent LUMO controlled reactivity
at Cα is preserved with better electron-donating groups, but steric effects override
with other substituents. The methoxy group may additionally help by coordination
to deliver the nucleophile to the nearer carbonyl group.
Unsymmetrical Phthalic Anhydrides
The above analysis, however, is not applicable to phthalic anhydride 111. The
electron-donating and electron-withdrawing substituents should make the reaction
selective for the attack at Cβ and Cα , respectively, due to the relatively larger LUMO
coefficients on these positions. Except for R = Me, when the values are hardly
different, the LUMO coefficients match this expectation. However, in spite of being
sterically disfavored, the attack by NaBH4 takes place preferably at Cα of all the three
substrates: Cα : Cβ = 87:13 for R = OMe, 57:43 for R = Me, and 83:17 for R = NO2 .
The overall situation, therefore, remains unclear and no suitable rationale could be
offered to explain the observed selectivity.
R O
α
O
β
O
111
LUMO coefficients at Cα and Cβ

R Cα Cβ
MeO −0.26 0.30
Me −0.33 0.33
NO2 −0.21 0.08
Unsymmetrical Succinic Anhydrides
The selectivity observed from the reaction of unsymmetrical succinic anhydride

112 is remarkably in favor of Cα -attack. The electronic difference between the two
carbonyl groups is that while Cα is under a hyperconjugative interaction with the
CMe2 group, Cβ is under a hyperconjugative interaction with the CH2 group. Since
σC-H is more electron-donating than σC–C , Cα must have a larger LUMO coefficient
than Cβ . Calculations indeed place a larger LUMO coefficient at Cα than Cβ and,
hence, the observed selectivity. The composition 113:114 is 95:5. Grignard reagents,
with whom the steric effects are more important, attack at the less-hindered Cβ .
However, having had the two methyl substituents exchanged for chlorine, the attack
becomes completely selective for Cα . Due to the negative hyperconjugation caused
by the electronegative chlorine atoms, the LUMO at Cα turns fairly large and, hence,
the observed selectivity.
LUMO coefficient
α β NaBH4 or LiAlH4
Cα Cβ +
0.60 -0.59 O O O O O O O
112 113 114
Arynes
Ortho-substituted benzynes show synthetically useful regioselectivity in reactions

with nucleophiles and, therefore, it is desirable to reflect upon its origin. The two
in-plane p orbitals are bent apart, making their interaction considerably less than the
interaction of the two p orbitals orthogonal to the plane and forming the π bond.
Consequently, the HOMO is raised and LUMO lowered in respect of alkenes and
linear alkynes. The nucleophilic addition to benzyne is, therefore, rendered favorable
by the low energy of the LUMO.
Even though the HOMO is raised in energy, benzynes do not normally react with
electrophiles. A likely rationale for this discrepancy is found from the analysis of the
product. The product of the attack of a nucleophile on an aryne is aryl anion, which is
stable relative to a tetrahedral anion. This is one of the reasons why acetylenes react
more readily than alkenes with nucleophiles. In contrast, the product of the attack of
an electrophile on an aryne is aryl cation which is high in energy. The high energy of
this aryl cation is possibly the main reason why arynes and acetylenes are generally
less reactive toward electrophiles than alkenes.
Et2N O Et2N O
Li
PhSLi
F
SPh 1 2
115 116
F F 3
Li 119 120
PhLi
Ph
117 118
The regioselectivity of ortho-benzyne is controlled by the electronic as well as

steric effects of the substituent. A major factor is the relative stability of the regioi-
someric products, with the benzyne 115 giving the lithium intermediate 116 and the
benzyne 117 giving the lithium intermediate 118. These two substituents are excel-
lent at stabilizing the neighboring σC-Li bond, the former by coordination of oxygen
to lithium, as shown, and the latter by conjugation between σC-F and σC-Li bonds.
An alternate argument also holds in the instance of 117. Being highly electron-
withdrawing, the σC-F bond in 117 has some characteristics of a cation on the carbon
as shown in 119, allowing the empty p orbital to be conjugated to the bent p orbital
on the adjacent carbon. The LUMO will, therefore, resemble that of an allyl cation
with its largest coefficient on C3, as indicated in 120. Additionally, C3 is also the site
with less steric hindrance, but it is clear from additions discussed above that steric
hindrance at C2 is not the reason why nucleophiles attack at C3.
With an alkyl substituent, neither the two regioisomeric product anions nor the
LUMO coefficients on C2 and C3 are substantially different. Such systems are there-
fore expected to show poor selectivity. Indeed, the benzyne 121 is attacked equally
at C2 and C3 to form, respectively, 122 and 123, except when the nucleophile is
substantially large.
Li NH2
KNH2
+
NH2 Li
121 122 123

Pyridynes are inherently unsymmetrical. Nucleophiles attack 4-methyl-2,3-

pyridyne 124 exclusively at C2. The larger LUMO coefficient is on C2 than C3, as
shown in 126 [52]. Also, the total charge distribution, as shown in 127, is such that C2
bears a partial positive charge. The overall result is that nucleophiles attack preferably
at C2 because both electrostatic and frontier orbital forces favor attack at this site.
Additionally, in terms of product analysis, the product 3-pyridyl anion is more stable
than the 2-pyridyl anion due to the hyperconjugative interaction between the electron
pair orbital on C3 and the electronegative σC-N bond, both being antiperiplanar to
each other across the σC2-C3 bond.
4
3
5 NH3
6
N 2
N NH2
1
124 125
-0.25
N +0.23
N
127
126
5 α-Effect
The pKa of the conjugate acid of a given nucleophile is a good measure of the rate at
which it attacks electrophiles. A plot, known as the Brønsted plot, of the log of the rate
constant for nucleophilic attack on a carbonyl group against the pKa of the conjugate
acid of the nucleophile is a good straight line, but only when the nucleophilic atom
is the same. In other words, there is a straight line for every nucleophilic atom.
However, species such HO2 – , ClO– , HONH2 , N2 H4, and R2 S2 are unique because
they are more nucleophilic than one would normally expect from the pKa values of
their conjugate acids. Consequently, these nucleophiles do not fit on the Brønsted
plots. The nucleophilic site in each of HO2 – , ClO– , HONH2 , N2 H4, and R2 S2 is
attached to a heteroatom bearing an electron pair orbital. The electron pair orbital
on the nucleophilic atom overlaps with the electron pair orbital on the adjacent
atom. This interaction raises the energy of the HOMO relative to its position in the
unsubstituted nucleophile and, thus, results in an increase of nucleophilicity, called
α-effect, which could be dramatic at times. The α-effect becomes more noticeable
when the reactions are carried out in dipolar aprotic solvents because such solvents
do not stabilize anions by solvation [53].
The LUMO of the triple bond in a nitrile group is lower than that of the double
bond in a carbonyl group. Further, the LUMO of the double bond in a carbonyl group
is lower than that of the σC–Br bond. In other words, the LUMO energy changes in
the order CN < C = O < σC–Br bond. Thus, the relative rate of reaction of HO2 – vs
HO– (k HOO -/k HO -) decreases when the substrate is changed from PhCN (k HOO -/k HO -
= 105 ) to p-NO2 -C6H4-CO2 Me (k HOO -/k HO - = 103 ) to PhCH2 Br (k HOO -/k HO - = 50)
[54].
The raised HOMO also provides an explanation for a single electron transfer
(SET) mechanism as it allows an electron to be easily transferred to the LUMO
of an electrophile to generate a radical pair to further couple to the product. Since
the removal of a single electron from one of the two electron pair orbitals on the
nucleophilic atom leaves behind a stabilized radical, the rate constant for the reaction
of a nucleophile with α-effect is likely to be more sensitive to the LUMO energy
of the electrophile than for a nucleophile with a normal electron pair [55]. This is
indeed the case in the rates of N-methylation of a series of N-phenylhydroxylamines
(ArNHOH), which are higher than the rates of comparable anilines [56].
The α-effect influences the thermodynamic stability of the species as well. For
instance, the overlap of the lone pair on nitrogen with π*C=O is responsible, in large
part, for the higher stability of amides such as 128 relative to the corresponding
ketones. In the hydroxamic acid 129, the effect of lone pair on oxygen is to raise the
HOMO on nitrogen which, in turn, makes its overlap with π*C=O more efficient and,
thus, more energy-lowering. Consequently, hydroxamic acids are more stable than
the corresponding amides.
O O
OH
N N
128 129
6 Carbenes
Carbenes can act both as nucleophilic and electrophilic species. The HOMO is a
filled p orbital, high in energy because of its closeness to an isolated p orbital. The
LUMO is an unfilled p orbital, orthogonal to HOMO. The high energy of HOMO
makes carbenes very reactive as nucleophiles. Likewise, the low energy of the LUMO
makes carbenes very reactive as electrophiles.
A donor substituent lowers the energy of the LUMO, if they are conjugated as
shown in 130. Likewise, an electron-withdrawing substituent lowers the energy of
the HOMO, if they are conjugated as shown in 131. Since these interactions leave the
other orbital more or less unchanged for its orthogonal disposition, the situation in 130
6 Carbenes 241
leaves us with a high-energy HOMO and, likewise, 131 with a low-energy LUMO.
The species 130 and 131 are, therefore, nucleophilic and electrophilic, respectively
[57].
H
p LUMO
H
H
n HOMO
H
filled
filled empty
X empty Z filled
X empty Z
130 131
The electron-donor substituents have a more remarkable effect on carbenes than

electron-withdrawing substituents. This is so because the electron-donor substituent
makes it possible to isolate a good range of carbenes such as 132 [58–60]. The
carbene 133 is the key intermediate in the metabolic pathways catalyzed by thiamine
coenzymes. These reactions proceed by the nucleophilic addition of the carbene to
the substrates such as aldehydes [61].
S
HO O
HO O N
HO O P N
R N N R
HO P P
O N
O
O
H2N
132 133
Dimethoxycarbene 134 is known to react with dimethyl maleate and benzoyl chlo-
ride to give the intermediates 135 and 137 and, then, the products 136 and 138, respec-
tively. While the transformation 135 → 136 involves an intramolecular SN 2 reaction,
leading to the formation of the cyclopropane ring, the transformation 137 → 138
involves an intermolecular SN 2 reaction. Thus, for all practical purposes, dimethoxy-
carbene behaves primarily like the ionic species 134a. Note that dimethoxycarbene
does not directly insert isolated alkenes to form cyclopropanes.
OMe OMe CO2Me

OMe CO2Me O
MeO MeO
(MeO)2C: +
MeO OMe
CO2Me MeO O MeO O
134 134a 135 136
Me O O O O
(MeO)2C: + PhCOCl Cl + MeCl
MeO Ph MeO Ph
137 138
The insertion of a carbene into an alkene is a result of simultaneous interaction

of the HOMO of the alkene with the LUMO of carbene or the LUMO of the alkene
with HOMO of the carbene. It is the HOMO of a nucleophilic carbene that interacts
predominantly with the LUMO of the alkene and, likewise, the LUMO of an elec-
trophilic carbene that interacts predominantly with the HOMO of the alkene. In the
case of the highly nucleophilic dimethoxycarbene, the interaction of its HOMO with
the LUMO of the alkene is so very strong that it gives zwitterionic intermediates such
as 135, which results in the loss of stereochemistry of the alkene in transition from
cis-alkene to trans-cyclopropane. With less nucleophilic carbenes, the geometrical
integrity of the alkene is retained in the product. Note that nucleophilic carbenes do
not insert σC-H bonds.
In contrast to nucleophilic carbenes, the electrophilic carbenes with low-energy
LUMO react with alkenes of high-energy HOMO stereospecifically to form cyclo-
propanes, wherein the geometrical integrity of the latter is retained. The electrophilic
carbenes also insert σC-H bonds, tertiary σC-H bonds in particular. For example, the
bis(methoxycarbonyl)carbene 139 reacts with 2,3-dimethylbutane 140 to form the
malonate 141 selectively (141:142 = 97:3) even though there are only two tertiary
σC-H bonds competing against 12 such primary bonds. The selectivity for the tertiary
σC-H bond is taken to presume a substantial cationic charge on the carbene carbon in
the transition state structure which results in an electrophilic attack on the hydrogen
atom [62, 63].
CO2Me MeO2C
MeO2C MeO2C
+ + MeO2C
MeO2C
139 140 141 142
The cyclopropenylidene carbene 143 has the empty p orbital conjugated with the
π bond, making it a two-electron three-center cyclic system and, hence, aromatic like
the cyclopropenyl cation. Likewise, the cycloheptatrienylidene carbene 144 has the
empty p orbital conjugated with three π bonds, making it a six-electron seven-center
cyclic system and, hence, aromatic like tropylium cation. In both these instances,
6 Carbenes 243
the filled HOMO orbital of the carbene remains unaltered to impart sufficient nucle-
ophilic character. Both these carbenes, therefore, must possess a highly nucleophilic
character and react readily with electrophilic alkenes but not with simple alkenes.
Indeed, 144 reacts faster with styrenes having electron-attracting substituents and
slower with those having no such substituents or donor substituents.
empty empty
Ph
filled filled
Ph
143 144
Cyclopentadienylidene carbene is different from 143 and 144. This is so because

the configuration of the carbene may change from 145a to 145b. In configuration
145a, the empty p orbital of the carbene is in conjugation with the two π bonds,
leaving the filled p orbital to act as a nucleophile. However, in configuration 145b,
the filled p orbital of the carbene is conjugated with the two π bonds, making it
like a cyclopentadienyl anion and, hence, aromatic in character. The configuration
145b can act only as an electrophile. Overall, the carbene 145 is only somewhat
electrophilic as it reacts with more substituted alkenes at, more or less, the same rate
as with the less-substituted alkenes. The predominant 145b character is evident in
the reaction with dimethyl sulfide when the zwitterion 146 is smoothly formed [64].
empty
empty S
145a 145b 146
Two distinct scenarios arise for dichlorocarbene. First, the inductive withdrawal
along the σC—Cl bond lowers the electron density on the carbon to such an extent that
the carbene is rendered largely electrophilic in nature. Second, a situation similar
to that shown in 130 emerges and the electron pairs on chlorine atoms conjugate
with the unfilled LUMO, leaving the filled HOMO to act as a nucleophile. It has
been discovered from calculations that the former situation prevails over the latter,
allowing dichlorocarbene to exhibit the electrophilic character largely [65].
The carbene 147 is stable enough to be isolated [66]. Carbenes such as 147 are
employed as reagents to achieve many transformations and also as preferred ligands
for catalyst design. With the six electrons, two from the π bond and two each from
the two nitrogen lone pairs, forming an aromatic sextet through the carbene LUMO,
the HOMO remains available to be employed as a nucleophile. For instance, 147
combines with an aldehyde to form the enol species 148, which is in resonance
with the zwitterion species 149. The species 149 is capable of reacting through the
carbanion [67].
N N OH N OH
+ RCH2CHO
N N N
R R
147
148 149
N N H N O N OH
O 148
N N N N
R R R
147 147a 150 151
The carbene 147 exists in resonance with 147a. The nucleophilic reaction of 147a
with an aldehyde forms the 1,4-zwitterion 150. Now, proton transfer from carbon
to oxygen generates the 1,3-zwitterion 151, which collapses to 148 after electron
reorganization.
7 Hammond Postulate
The transition state of a reaction cannot be characterized directly by experimental

means because it is only transient in nature. Therefore, any guiding principle that
can provide some guess of the chemical structure of the transition state is useful.
Hammond postulated, “If two states, such as a transition state and an unstable inter-
mediate, occur consecutively during the course of a reaction and have nearly the same
energy, their inter-conversion will require a small reorganization of the molecular
structures”. In other words, the transition state most resembles the adjacent reactant,
intermediate, or product that is closest to it in energy.
Accordingly, the transition state must resemble, respectively, the reactants and
the products in highly exothermic and endothermic processes. For a thermoneutral
process, the transition state is in between the reactants and the products. This allows
us to, more or less, accurately predict the shape of a reaction coordinate, and also an
insight into the structure of the transition state. We generally place the transition state
higher than the reactant and product on the energy scale. Note that the Hammond
postulate predicts only the relative position of the transition state as the reaction
progresses but not the height of the energy barrier compared to the reactant and
product.
In the most well-known example of the application of the Hammond postulate,
we compare the structures of various carbocations in the SN 1 reaction. The relative
stabilities of the carbocations decrease in the order 3° > 2° > 1° > Me+ . According
7 Hammond Postulate 245
Fig. 4 Plot demonstrating

Hammond’s postulate
to the Hammond postulate, as shown in Fig. 4, the transition state shifts toward the
product cation as the stability of the cation decreases. Also, coupled with this, the
transition state energy is lowered with the increase in the stability of the resultant
cation [68–71].
8 Curtin–Hammett Principle
The Curtin–Hammett principle deals with the product ratio when there are
two or more competing pathways originating from fast inter-converting isomers,
conformers, or intermediates. Of course, each product is derived from a different
transition state. According to this principle, the ratio of the products is ascertained
by the relative heights of the transition states leading to different products, and is
not significantly influenced by the relative energies of the isomers, conformers, or
intermediates. Let us understand this principle by examining the reaction coordinate
versus potential energy diagram given in Fig. 5. Here, the intermediates I1 and I2
equilibrate readily because the energy barrier between them is much smaller than
the exit barriers I1 → P1 and I2 → P2 . The intermediate I2 is lower in energy than
I1 . So being the case, the predominant product arises from the less-stable structure
I1 because the barrier for I1 → P1 conversion is less than the barrier for I2 → P2
conversion [72, 73].
Let us consider the nucleophilic addition to a carbonyl group adjacent to a stere-
ogenic center. Following the Anh–Felkin modification of Crams’s model for asym-
metric induction, the reaction can follow either of the pathways shown in Eqs. (1)
and (2). The pathway shown in Eq. (1) involves attack syn to the smallest size group
Fig. 5 Plot demonstrating

Curtin–Hammett principle
whereby I1 → P1
predominates over I2 → P2
and, thus, proceeds through a lower energy TS than the pathway shown in Eq. (2),
which involves attack syn to the medium size group, due to the steric interactions
between the nucleophile and the medium-size substituent in the latter. Since the
barrier between the two reactant conformers is much too small compared to the
8–15 kcal/mol TS energies for the addition of hydride ion to the carbonyl group,
they equilibrate much more rapidly with each other than pass on to the respective
products on reaction with nucleophiles. We analyzed the product distribution only on
account of the relative TS structure energies; the Curtin–Hammett principle applies
to reactions taking place solely under kinetic control.
O M HO S
L L Nu (1)
Nu R M
R S
O M OH
S
L Nu L (2)
Nu
M R S R
S = small group, M = medium group, L = large group
9 Diastereotopic, Homotopic, and Enantiotopic

Substituents
When two identical groups or atoms on the same carbon are in a nonequivalent envi-
ronment, they are termed diastereotopic. For instance, the hydrogen atoms labeled
Ha and Hb in (S)-2-butanol 152 are diastereotopic. There is no symmetry operation
that can inter-convert these two hydrogens so that one assumes the characteristics
9 Diastereotopic, Homotopic, and Enantiotopic Substituents 247
of the other. These hydrogen atoms are different from each other in all meaningful
ways, such as NMR shifts, σC-H bond lengths, and, hence, bond dissociation energies.
Ha Hb
Ha Hb
H OH
152 153
Unlike the above, the two hydrogen atoms labeled Ha and Hb in propane 153
are homotopic because a C2 operation converts one into the other, so that they are
considered to be equivalent in all possible ways. Even if one of these hydrogen atoms
is replaced by a substituent other than methyl and hydrogen, the resultant molecule
is not chiral. Homotopic groups remain indistinguishable under the chiral influence,
i.e., in the presence of chiral ligands.
Ha Hb D H H D H3C CH3 Cl Cl
Cl CH3
Cl Cl Cl
154 155 156 157 158
Unlike the case of propane above, replacement of one of the two hydrogen atoms
labeled Ha and Hb in chloroethane 154 by a substituent different from methyl and
chlorine leads to one enantiomer and, likewise, replacement of the other hydrogen
atom leads to the other enantiomer. For instance, while the replacement of Ha by
deuterium (D) forms (R)-155, a similar replacement of Hb by D forms (S)-2–156.
Such hydrogens are called enantiotopic hydrogens. The enantiotopic groups need
not be hydrogen atoms alone. For instance, the two methyl groups in 2-chloro-2,3-
dimethylbutane 157 and the two chloro groups in 2,2-dichloro-3-methylbutane 158
are also enantiotopic. The enantiotopic hydrogens are distinguishable under the chiral
influence, i.e., in the presence of chiral ligands.
O H OH HO H
H
+
159 160 161
O H OH HO H
H
+
H Cl H Cl H Cl
162 163 164
The topicity concept is also important in the reactions of trigonal centers, such as
carbonyls and alkenes. In consideration of carbonyls, for example, the two faces are
homotopic in a symmetrically substituted ketone, such as acetone or 2-pentanone,
because the molecule has C2 symmetry. However, the faces are enantiotopic in an
unsymmetrically substituted ketone, such as 2-butanone 159. While the reaction
with hydride ion on the top face of the carbonyl group forms (R)-2-butanol 160,
the reaction on the bottom face forms (S)-2-butanol 161. Extending this argument
further, the two faces are diastereotopic in an unsymmetrical ketone bearing a chiral
center elsewhere in it, e.g., (R)-3-chloro-2-butanone 162. The delivery of hydride ion
to the top face of the carbonyl group forms 2(R),3(R)-3-chloro-2-butanol 163 and the
delivery to the bottom face forms 2(S),3(R)-3-chloro-2-butanol 164. The molecules
163 and 164 are diastereoisomers.
Mea Meb D3C CH3 CD3
Cl Cl Cl
157 165 166
Mea Meb H3C CD3 Cl
Cl Cl CD3
157 166 167
Cla Clb *Cl Cl Cl
CH3 CH3 Cl*
158 168 169
Cla Clb Cl Cl* Cl*
CH3 CH3 Cl
158 170 171
The topicity is described in yet another way also. Here, we use something similar
to the R/S notation in an attempt to connect it to the topicity. For the CH2 group,
we take the hydrogen that is to be assigned a descriptor and mentally replace it with
deuterium. Now, we assign the configuration in the normal way. If the result is that
the newly formed stereogenic center is R, the hydrogen that we mentally replaced by
deuterium is denoted as pro-R, and if the new stereogenic center is S, the hydrogen is
denoted as pro-S. For instance, in chloroethane 154, Ha is pro-R (as in structure 155)
and Hb is pro-S (as in structure 156). Likewise, in 157 and 158, we replace CH3 with
CD3 and Cl with its higher isotope, say Cl*, to distinguish the CH3 and Cl groups.
Since CD3 takes precedence over CH3 , the Mea and Meb in 157 are pro-R and pro-S,
9 Diastereotopic, Homotopic, and Enantiotopic Substituents 249
as shown in 197 and 198, respectively. Likewise, the Cla and Clb in 158 are pro-S
and pro-R, as shown in 169 and 171, respectively.
O O
Re face Si face
The other descriptors that are sometimes used in describing the enantiotopic faces
of a carbonyl group are Re and Si faces. In arriving at these descriptors, we simply
place the molecule in the plane of the paper and assign priorities to the three groups
as we normally assign the R/S or E/Z configurations. If the result is a clockwise
rotation, the face we are looking at is referred to as the Re face. However, if it is
anticlockwise rotation, the face is Si face. An example using 2-butanone is given
below.
10 Captodative Effect
The captodative effect is the stabilization of radicals by a synergistic effect of an

electron-withdrawing and an electron-donating substituent. The name originates as
the electron-withdrawing group is sometimes called the ‘captor’ group, while the
electron-donating group is the ‘dative’ substituent [74–76]. The resultant stabiliza-
tion has mechanistic consequences for homolytic reactions and its applications in
selective organic synthesis and, hence, there has been a considerable amount of work
on the subject. Being steric or electronic in nature, the substituents influence both
the kinetic and thermodynamic radical stabilizations [77].
Substituents play a significant role in the kinetic stabilization of radicals through
their steric effects. It is understood that by preventing other radicals from approaching
the radical center, steric effects isolate it from its environment and grant it some
persistence (life). This is so for di- and tri-tert-butylmethyl radicals, for example.
Thermodynamic stabilization, on the other hand, corresponds to the lowering of the
radical energy ground state. It is, therefore, an intrinsic property that is principally
influenced by the ability of the substituent to delocalize the unpaired electron. This
can reduce the reactivity by reducing the spin density on the radical center. In general,
however, thermodynamically stabilized radicals are not persistent (less life).
A captodative effect of a few kcal/mol may be helpful in the selection of a lower
energy pathway in instances where a radical can react by several paths, discriminated
by activation barriers of closely similar energies.
The theory supports that captodative radicals have charge-separated resonance
structures, which should be stabilized by polar solvents. Chemists have indeed
found a strong solvent effect that is convincing evidence for the captodative effect.
In non-polar toluene, a captodative radical with two nitrile acceptor groups and a
Fig. 6 Effect of polar solvents on captodative effect leading to polar species (JACS 2019, 141,
12,901)
dimethylamino donor is mostly present in the form of a dimer. But polar dimethyl-
formamide stabilizes the free radical such that there is an order of magnitude more
of it than in toluene. This can be seen with the naked eye as the DMF solution is dark
blue—color of the free radical—while the toluene mix is only faintly blue, as shown
in Fig. 6 [78].
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Questions
The questions given below are designed to test the comprehension of the contents of
this book. It is likely that in answering these questions, the reader may need to read
through the relevant chapter again to find the correct solution.
1. If the energy of trans-decalin is equated to zero kcal/mol, calculate the energy

of cis-decalin.
2. Benzaldehyde reacts with an excess of methanol in the presence of a small
amount of concentrated sulfuric acid under azeotropic removal of the water
formed to form dimethyl acetal. Write the chemical events that take place
during the course of the transformation in such a way that the prevailing
stereoelectronic effects are clearly expressed through the structures.
3. Express, by structures only, the more plausible mode of protic cleavage of
each of the following acetal conformers. By considering the oxygen atom
tetrahedral, write the electron pair orbitals on the oxygen atoms as well.
O O O
R O R O R O
H H H
4. Both the acetals A and B undergo hydrolysis under acidic aqueous condition but
with great difficulty. However, the difficulty experienced by A is significantly
more severe than that experienced by B, so much so that A is practically
non-reacting. Provide a rationale for this observation.
O
R O
O
O H
A B
© The Editor(s) (if applicable) and The Author(s), under exclusive license 253
to Springer Nature Switzerland AG 2021
https://doi.org/10.1007/978-3-030-75622-2
254 Questions
5. Write an account of all possible arguments to demonstrate that it is fairly

unlikely for a γ-lactone to undergo carbonyl oxygen exchange when subjected
to hydrolysis using aqueous NaO*H [O* denotes labeled oxygen]. The
stereochemical relationship, if any, may be shown meticulously.
6. How will you chemically separate one isomer from the other from the mixture
of the following? You are allowed to destruct or chemically change one of the
two.
H H
O O O O
OR OR
7. The following compound is allowed to stand with very dilute aqueous sulfuric
acid for long enough to leave none of this. What products(s) will you expect
to form? The rationale could be revealed through stereostructures alone.
OEt
O OH
8. The following compound is taken in dry toluene along with a catalytic amount
of pyridinium p-toluenesulfonate and heated to reflux under azeotropic removal
of water to obtain a mixture of two products. Write the stereostructures of the
products, calculate the relative energy difference of the two, and predict which
one of the two is more likely to constitute the major product.
H
OH
O
H
OH
9. Comment, with rationale, on the relative distribution of products formed from

the following compound when it is heated with a trace of p-toluenesulfonic
acid in toluene under dehydrating conditions. The conformational profile of
the products must also be taken into account.
O H
OH
OH
10. In reference to Q9 above, comment on the scenario that is likely to emerge

when the configuration at the methyl-bearing carbon is reversed.
Questions 255
11. The compound A is treated with NaBH4 and B with NaOH, both in aqueous
MeOH, when each one is transformed into a monocyclic product. Show the
sequence of reactions and the operating stereoelectronic effects by arrows.
O Cl OCOPh
H
TsO
A B
12. Recognize the elements of orbital–orbital interaction in the most appropriate

antiperiplanar setup and write the product of each of the following reactions.
O
Me
O
MeONa MeONa
(a) ? (b) ?
MeOH MeOH
TsO N
H
O
O O
H
MeONa H MeONa
(c) ? (d) ?
MeOH MeOH
13. Take a look at the following reaction and note the formation of two isomeric
products. Predict, on account of relative energy calculation, the ratio of the
isomers. Consider the anomeric stabilization arising from sulfur to be the same
as that arising from oxygen.
H S
SH
O O S O
OH +
H
14. The monocyclic material in the following reaction is transformed efficiently

into the bicyclic material on exposure to light. Interestingly, the latter reverts to
the former on heating at an elevated temperature as shown. How do you account
for this observation within the purview of conservation of orbital symmetry
rules?
O
O Ph
Ph hν
N N
N NH H
256 Questions
15. Which of the following two enolates is likely to be more easily generated from
the corresponding ketone? Explain with rationale.
O O
H H
H H H H
KO KO
a b
16. Double-bond isomerization to achieve higher conjugation takes place when the
following compound is allowed to react with dilute solution of caustic soda in
aqueous alcohol at 25 °C for an extended duration. Write the structure of the
product with absolute stereochemical clarity.
AcN
H
O
HO
HO
H
17. Consider the following reactions and offer a brief rationale for the decline in
the observed diastereoselectivity (ds).
CH2Li H
O
OLi
H ds = 100%
a b
CH2Li
O
OLi
H ds = 50% H
c d
18. A δ-lactone is reacted with trimethyloxonium tetrafluoroborate (Me3 O+ BF4 − ).

The product formed is next refluxed with sodium iodide in acetone until the
reaction is complete. By taking entropy effects, stereoelectronic effects, and
the relative ease of SN 2 reactions on primary, secondary, and tertiary carbons
into consideration, comment on the possible product(s) profile.
Questions 257
19. The following enone is subjected to dissolving metal reduction in the pres-
ence of an appropriate protonating species such tert-butanol. Write the struc-
tures of all the possible products and calculate their relative energies. Which
product will you predict to predominate if allowed to consider the product’s
thermodynamic stability as the sole control factor?
Me
20. The substrate given in Q19 is subjected to a reaction with lithium dimethyl-
cuprate. Write the structures of all the possible products and calculate their
relative energies by taking 0.9 kcal/mol for 1,3-diaxial interaction between
Me and H. Which product will you predict to predominate in view of the
product’s thermodynamic stability as the primary control factor?
21. On being subjected to Baeyer–Villiger oxidation using m-chloroperoxybenzoic
acid in chloroform, 2-norbornanone generates a mixture of two products.
One of these products is reluctant to further reaction with aqueous ethanolic
caustic soda while the other reacts easily to form a product which cannot
be extracted out from the alkaline solution by organic solvents such as Et2 O
and CH2 Cl2 . The said solvent extraction, however, removes the non-reacting
species conveniently. Present an elaborate account of the events with structures
and arguments.
22. Write the transition state structure for the following transformation. The role
of HMPT is only that of a high boiling neutral solvent as it does not take part
in the reaction.
NaI, HMPT
CH2OTs
CH2OTs
23. The following substrate is subjected to reaction with an equimolar amount

of dicyclohexylborane to generate a single boron-containing entity in quan-
titative yield. Without isolation, it is mixed with an equimolar amount of
aqueous caustic soda to isolate trans,trans-1-methyl-1,6-cyclodecadiene as the
sole product. Present the events in a schematic fashion with due care of the
stereochemical features.
OMs
Me
258 Questions
24. The following cis-2,6-disubstituted piperidine derivative is expected to exist

largely as a single conformer. Speculate on account of allylic strain and write
the conformer.
O O
Ph O
25. Consider the reaction of Me2 CuLi with the oxirane A. Steer through the reac-
tion pathways with appropriate stereostructures to the products B and C. Which
product will you expect as the major product and why?
OH
O
OH
A B C
26. Write the 3D geometrical orientation of the reactant which is suitable for the
following transformation.
H
H
27. Comment on the hydrolysis of the “stable but devoid of any anomeric effect”
conformer of benzaldehyde dimethyl acetal. Write the Newman projection of
the cation formed from the first σC-O bond cleavage.
28. Write the entire schematic pathway for the change of α-D-glucose into β-D-
glucose under mild acidic conditions.
29. Write the chair structures of each of the following substrates and also the major
product formed from each on single decarboxylation on reaction with LiCl in
DMSO-H2 O.
MeO2C CO2Me MeO2C CO2Me MeO2C CO2Me MeO2C CO2Me
O O O2S SO2 ON NO S S
Ph Ph Ph Ph
Questions 259
30. Write the major product formed from each of the following substrates
on heating. Consider torquoselectivity which supports electron-donating
substituents moving outwards and electron-attracting substituents inwards for
reasons of greater stabilization of the respective TS structures.
OMe F
CHO COMe
CF3
F
CF3
Ph Ph
Ph Ph
31. The CO2 Me group is an electron-deficient group and yet 3-CO2 Me-
1,2-benzocyclobutene is experimentally observed to predominantly open
outwards. In contrast, the closely related 3-CONMe2 -1,2-benzocyclobutene
opens largely inward. Provide plausible rationales for these observations.
32. Orbital–orbital interactions are essentially the antiperiplanar interactions
considered for stereoelectronic effects. In view of this interaction, confor-
mational changes in the substituent resident on C3 of cyclobutene can have
consequences on the overall torquoselectivity of the system. Speculate on the
consequences of such conformational changes in 3-NO-cyclobutene.
33. The substrate A reacts with ozone to form the hydroxy ester B. Write the
structure of the transition state that leads to the breakdown of the intermediate
hydrotrioxide species into the product in a single step.
H O
O O
O OH
A B
34. Which of the following substrates is not likely to react with ozone? Provide
rationale also.
H
O O O
O O O O O
H H H H
35. (S)-2-Dimethylphenylsilyl-3(E)-pentene and (S)-2-dimethylphenylsilyl-3(Z)-

pentene display 50% and >95% diastereoselectivity, respectively, on hydrob-
oration followed by oxidative cleavage of the so-formed carbon–boron bond.
Write these transformations and explain the observed difference in the level
of selectivity.
260 Questions
36. The following substrates are separately subjected to solvolysis in aqueous

alcohol and the resultant oxidized with IBX. Write the product from each with
a complete stereostructure.
H H
TsO
TsO
H
N N
H
H
37. Indicate which of the products from each of the following reactions is expected
to predominate. Also, comment on the trans relationships of the methyl
substituents in both the products in reaction (2).
CO2Me
CO2Me
CO2Me MeO2C
+ + (1)
CO2Me
CO2Me
+ (2)
+ (3)
Ac HO R Ac
Ph NMe2 Ph NMe2 Ph NMe2

Ph NMe2
+ + (4)
38. The following compounds are treated with alcoholic aqueous caustic soda.
Write the product(s) from each with suitable relative stereochemistry as and
where applicable.
O Ph
Br O
C6H5 Br Ph
Ph
O O
39. Write the 3D structures of cis- and trans-2,10-dioxabicyclo[4.4.0]decalins and

calculate the relative energy difference between the two.
40. 1,9-Dihydroxy-5-nonanone is refluxed in C6 H6 with a catalytic amount of p-
toluenesulfonic acid monohydrate under azeotropic removal of water formed,
if any. Write the stereostructures of all the possible products and calculate the
energy of each on a relative scale.
Questions 261
41. Show the progress of acetolysis of the tosylates derived from optically active
erythro- and threo-3-phenyl-2-butanol and also comment on the overall optical
activity of the product(s) in each instance.
42. Write the molecular orbitals of allyl anion, allyl radical, and allyl cation with
the number of electrons in each. Indicate the symmetry characteristics of each
orbital in respect of (a) mirror plane and (b) C 2 axis.
43. The [2 + 2] combination of one olefin with another forms a cyclobutane deriva-
tive. Show the molecular orbitals along with the symmetry characteristics in
respect of the mirror plane on both sides of the reaction. Comment on whether
the reaction is thermal or photochemical.
44. Comment on the relative nucleophilicity of t-BuOO- versus t-BuO- with
reason(s) for the difference.
45. Define Hammett’s constant for aromatic carboxylic acids and comment on the
relationship of this constant with both ionization constant (K) and acid strength
(pKa) value.
46. By taking an example of spiro[2.4]heptatriene, explain the concept of
spiroaromaticity.
47. An excellent example of spiroantiaromaticity is spiro[4.4]nonatetraene.
Explain how the antiaromaticity comes into the picture.
48. Apply Houk’s electrostatic and Cieplak’s σ-σ*# model to predict
the diastereoselectivity of LiAlH4 reduction of endo,endo-2,3-
dimethylybicyclo[2.2.1]norbornan-7-one.
49. How does the cation coordination model explain the experimental
anti-selectivity of endo,endo-2,3-dimethylbicyclo[2.2.1]norbornan-7-
one and also the relatively higher anti-selectivity of endo,endo-2,3-
diethylybicyclo[2.2.1]norbornan-7-one?
50. Write the more stable orbital structures of cyclopropylidene and cyclohepta-
trienylidene carbenes and explain, in words, what actually contributes to the
stability.
51. What are the fundamental differences between the more stable structures of
dimethoxycarbene and bis-carbomethoxycarbene? What bearings do they have
on the nucleophilic and electrophilic characters?
52. Unsymmetrical maleic and succinic anhydrides substituted by a single
methoxy group react selectively at one of the two carbonyl groups. Explain
the origin of observed selectivity.
53. The uniform overlap of p orbital on each carbon in benzene is taken as a measure
of aromaticity following the six-electron rule. What is different about pyrrole,
furan, and thiophene that the same rule cannot be applied with confidence?
54. Allylic interaction is greatly used to describe the electrophilic and nucleophilic
characters of allylic species. How confident do you feel about using this concept
262 Questions
in judging the reactivity of a cyclic 1,3-diene toward the Diels–Alder reaction

with a dienophile?
55. It is the collinear interaction of two π-orbitals that leads to the formation of
σ bond. In view of this phenomenon, the separation between termini of 1,3-
dienes in reactions with a given dienophile must also be a control factor. How
convinced do you feel that this factor may be decisively used to explain the
low Diels–Alder reactivity of thiophene over furan and pyrrole?

Veejendra K. Yadav - Steric and Stereoelectronic Effects in Organic Chemistry

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Veejendra

Steric and Stereoelectronic

ISBN 978-3-030-75621-5 ISBN 978-3-030-75622-2 (eBook)

1st edition: © Springer Science+Business Media Singapore 2016

Kanpur, India Veejendra K. Yadav

1 Steric and Stereoelectronic Control of Molecular Structures

13 Application of 5-Exo-Trig Cyclization Rule . . . . . . . . . . . . . . . . . . . . 70

1,3-Butadiene → Cyclobutene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142

5 DA Reactions of Cyclopentadiene, Silole, and Germole

8 Curtin–Hammett Principle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245

Veejendra K. Yadav earned his Ph.D.

1 Influence of Steric Effects on Structures

1, ethane staggered eclipsed 2, propane staggered eclipsed

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 1

Consider trans-1,2-dimethylcyclohexane 6. In conformer 6a, the two equatorial

In either of the two conformations 7a and 7b of cis-1,2-dimethylcyclohexane 7,

Trans-1,3-dimethylcyclohexane can adopt the conformations 8a and 8b. In both,

Cis-1,3-dimethylcyclohexane can adopt two conformations. In conformer 9a, both

The two conformers of trans-1,4-dimethylcyclohexane are 10a and 10b. In view

Each conformer of cis-1,4-dimethylcyclohexane, 11a or 11b, has one methyl

Three different representations of trans-decalin are 12a–c. The bonds in both

12a 12b 12c

2 Influence of Stereoelectronic Effects on Reactions

RCHO + MeOH H+ RCH(OMe)2 (7)

(b) An axial oxygen atom on the cyclohexane ring contributes 2 × 0.4 =

47 48a 48b 48c

E48a: -(2 × 1.4) + (2 × 0.4) + (2 × 0.4) = -1.2 kcal/mol

An argument similar to the one for the hydrolysis of D-gluconolactone leads us to

Having understood the consequences of stereoelectronic effects and also the

Ozone may be considered as either 1,3-dipolar or 1,3-diradical species. The

Orthoesters such as 79 are protected forms of esters. The hydrolysis of orthoesters

R'C(OR)3 + H2 O + H + R'CO2R + 2ROH + H+ (23)

The importance of the stereoelectronic effect in orthoester hydrolysis could be

OH2 OR1 OR1

CH3 CH3 CH3

CH3 CH3 CH3

are predicted to be energetically more favorable than the transformation 92a

(h) Stereoelectronically controlled hydration of the E,Z-lactonium ion 95b will

We will now consider the cleavage of each of the above hemi-orthoester

100 101 102

105, R1 = CD3, R2 = CH3 109, R2 = CH3

106a 111 112a 112b

The reaction of ozone with tetrahydropyranyl ethers is similar to the reaction

128 129 130

The reaction of ozone with simple tetrahydropyranyl ethers and conformationally

O OMe OAc CO2Me

Hemiorthothiol esters, formed from the combination of hydrosulfide ion [HS− ]

137 138 139

OMe OMe OMe

143 144 145

146 147 148

146 147 149

3 Evaluation of the Numerical Value of Anomeric Effect

4 Influence of Anomeric Effect on Conformational

The spiroacetal 157 can exist as an equilibrium mixture of three conformers

157 157a 157b 157c

E157a = 2 (-1.4) kcal/mol + (2 × 0.4) kcal/mol + (2 × 0.4) kcal/mol = -1.2 kcal/mol

(a) Two anomeric effects to contribute 2 × (−1.4) kcal/mol.

E160a: 2 × (−1.4) + (2 × 0.4) + (2 × 0.4) = −1.2 kcal/mol

E162a: 2 × (−1.4) + (2 × 0.4) + (1 × 0.4) + 3.0 = 1.4 kcal/mol

165a 165b 166a 166b

We have discussed above the conformational profile of 1,7-

5 Influence of Anomeric Effect on Conformational

190 191 192