Microscale Organic

Laboratory
with Multistep and Multiscale Syntheses
THIRD EDITION

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Dana W. Mayo Charles Weston Pickard

Research Professor of Chemistry
Bowdoin College

Ronald M. Pike Professor of Chemistry, Emeritus

Merrimack College

Peter K. Trumper Professor of Chemistry

University of Southern Maine

John Wiley *L Sons, Inc.

New York Chichester Brisbane Toronto Singapore
Contents

General Ruies for the Microscaie Laboratory 3 CHAPTER 1

The Organic Chemistry Laboratory 4 INTRODUCTION
l

Making the Laboratory a Safer Place 5 CHAPTER 2

Nature of Hazards 6 SAFETY
Reduction of Risks 6 5
Precautionary Measures 7
Thinking about the Risks in Using Chemicals 7
Storage of Chemicals 8
Disposal of Chemicals 8
Material Safety Data Sheets 8
Estimating the Risks from Vapors 11
Hood Use 13
Concluding Thoughts 13

XXV
XXVi Contents

CHAPTER 3 Microglassware Equipment 17

INTRODUCTION TO Standard Experimental Apparatus 19
MICROSCALE ORGANIC Heating and Stirring Arrangements 19
LABORATORY EQUIPMENT Reflux Apparatus 24
AND TECHNIQUES Distillation Apparatus 26
15 Moisture-Protected Reaction Apparatus 29
Specialized Pieces of Equipment 32
Microscale Laws 34
Rules of the Trade for Handling Organic Materials at the
Microscale Level 34
Rules for Working with Liquids at the Microscale Level 34
Rules for Working with Solids at the Microscale Level 37
The Laboratory Notebook 38
Example of a Laboratory Notebook Entry 39
Calculation of Yields 41

CHAPTER 4 LIQUIDS 44
DETERMINATION OF Ultramicro-Boiling Point 44
PHYSICAL PROPERTIES Density 47
43 Refractive Index 48
SOLIDS 50
Melting Points 50
Mixture Melting Points 53

CHAPTER 5 TECHNIQUE 1 Microscale Separation of Liquid Mixtures by

DEVELOPMENT OF Preparative Gas Chromatography 56
MICROSCALE TECHNIQUES Introduction 56
55 Procedure for Preparative Collection 60
TECHNIQUE 2 Semimicroscale Distillation 61
Introduction 61
Distillation Theory 61
Technique 2A Simple Distillation at the Microscale Level 65
Technique 2B Fractional Distillation at the Semimicroscale
Level 68
TECHNIQUE 3 Steam Distillation 71
Theory 71
TECHNIQUE 4 Solvent Extraction 73
Solubility 73
Partition Coefficient 76
Extraction 78
Solid-Liquid Extraction 78
Liquid—Liquid Extraction 80
 Contents xxvii

Separatory Funnel Extraction 82

Continuous Liquid-Liquid Extraction 83
Drying of the Wet Organic Layer 86
Separation of Acids and Bases 87
Salting Out 88
Solid-Phase Extraction 88
TECHNIQUE 5 Crystallization 90
Procedure 91
Simple Crystallization 92
Filtration Techniques 93
Use of the Hirsch Funnel 93
Craig Tube Crystallizations 95
Recrystallization Pipet 96
TECHNIQUE 6 Chromatography 97
Technique 6A Column, High-Performance Liquid, and
Thin-Layer Chromatography 97
Column Chromatography 98
Packing the Column 99
Sample Application 100
Elution of the Column 100
Fraction Collection 100
Flash Chromatography 101
Thin-Layer Chromatography 103
High-Performance Liquid Chromatography 105
Technique 6B Concentration of Solutions 106
Distillation 106
Evaporation with Nitrogen Gas 107
Removal of Solvent Under Reduced Pressure 107
TECHNIQUE 7 Collection and Control of Gaseous Products 109
TECHNIQUE 8 Measurement Of Specific Rotation 111
Optical Rotation Theory 111
The Polarimeter 113
TECHNIQUE 9 Sublimation 116
Sublimation Theory 116

Introduction 119 CHAPTER 6

EXPERIMENT [1] Measurement of Physical Properties 121 MICROSCALE ORGANIC
EXPERIMENT [2] The Separation of a 25 ^L Mixture of Heptanol LABORATORY EXPERIMENTS
(bp 153 °C) and Cydohexanol (bp 160 °C) by Gas 119
Chromatography 126
EXPERIMENT [3] Distillation 132
Experiment [3A] Simple Distillation at the Semimicroscale
Level: Separation of Ethyl Acetate from
trans-i,2-Dibenzoylethylene 133
Experiment [3B] Fractional Semimicroscale Distillation:
Separation of Hexane and Toluene 136
XXVÜi Contents

Experiment [3C] Fractional Semimicroscale Distillation:

Separation of 2-Methylpentane and Cyclohexane Using a
Spinning Band Column 139
Experiment [3D] Fractional Semimicroscale Distillation: The
Separation of 2-Methylpentane and Cyclohexane Using a
Spinning Band in a Hickman-Hinkle Still 142
EXPERIMENT [4] Solvent Extraction 144
Experiment [4A] Determination of a Partition Coefficient for
the System Benzoic Acid, Methylene Chloride, and Water 144
Experiment [4B] Solvent Extraction I: The System; Benzoic
Acid, Methylene Chloride, and 10% Sodium Bicarbonate
Solution; An Example of Acid-Base Extraction Techniques 150
Experiment [4C] Solvent Extraction II: A Three Component
Mixture; An Example of the Separation of an Acid, a Base,
and a Neutral Substance 151
EXPERIMENT [5] Reduction of Ketones Using a Metal Hydride
Reagent: Cyclohexanol and eis- and
frans-4-tert-Butylcyclohexanol 155
Experiment [5A] Cyclohexanol 158
Experiment [5B] eis- and trans-4-tert-Butylcyclohexanol 163
EXPERIMENT [6] Photochemical Isomerization of an Alkene:
c/s-1,2-Dibenzoylethylene 169
Experiment [6A] Purification of frans-1,2-Dibenzoylethylene 172
Experiment [6B] Isomerization of an Alkene: Thin-Layer
Chromatographie Analysis 173
Experiment [6C] Isomerization of an Alkene: Nuclear
Magnetic Resonance Analysis 177
EXPERIMENT [7] The Cannizzaro Reaction with
4-Chlorobenzaldehyde: 4-Chlorobenzoic Acid and
4-ChlorobenzyI Alcohol 180
EXPERIMENT [8] The Esterification Reaction: Ethyl Laurate,
Isopentyl Acetate, and the Ilse of Acidic Resins 190
Experiment [8A] Ethyl Laurate 202
Experiment [8B] Isopentyl Acetate 203
Semimicroscale Preparation
Experiment [8C] Esterification by Acidic Resins 207
Semimicroscale Preparations
EXPERIMENT [9] The EI Elimination Reaction: Dehydration of
2-Butanol to Yieid 1-Butene, frans-2-Butene, and
c/s-2-Butene 210
EXPERIMENT [10] The E2 Elimination Reaction:
Dehydrohaiogenation of 2-Bromobutane to Yield
1-Butene, frans-2-Butene, and c/s-2-Butene 219
EXPERIMENT [11] The Isolation of Natural Products 226
Experiment [IIA] Isolation and Characterization of an
Optically Active Natural Product: Usnic Acid 226
Experiment [IIB] Isolation and Characterization of a Natural
Product: Caffeine and Caffeine 5-Nitrosalicylate 232
Experiment [ 11C] Isolation of a Natural Product by Steam
Distillation: Cinnamaldehyde from Cinnamon 241
EXPERIMENT [12] Reductive Catalytic Hydrogenation of an
Alkene: Octane 246
EXPERIMENT [13] Hydroboration-Oxidation of an Alkene:
Octanol 252
EXPERIMENT [ 14] Diels-Alder Reaction:
4-Cyclohexene-c/s-l,2-dicarboxyIic Acid Anhydride 260
Optional Semimicroscale Preparation
EXPERIMENT [15] Diels-Alder Reaction:
9,10-Dihydroanthracene-9,10-a,/3-sucdnic Acid
Anhydride 272
Optional Semimicroscale and Macroseale Preparations
EXPERIMENT [16] Grignard Reaction with a Ketone:
Triphenylmethanol 277
EXPERIMENT [ 17] Grignard Reaction with an Aldehyde:
4-Methyl-3-heptanol 286
EXPERIMENT [18] The Perkin Reaction: Condensation of
Rhodanine with an Aromatic Aldehyde to Yield
o-Chlorobenzylidene Rhodanine 292
Optional Semimicroscale Preparation
EXPERIMENT [19] Alkene Preparation by the Wittig Reaction:
(f)-Stilbene; 1 -MethyIene-4-ferf-butylcyclohexane; and
fr«uis-9-(2-Phenylethenyl)anthracene 297
Experiment [ 19A] (£)-Stilbene by the "Instant Ylide" Method 302
Experiment [19B] (£)-Stilbene by the Homer-Wadsworth-
Emmons Reaction 305
Experiment [ 19C] Methylene-4-rerf-butylcyclohexane 307
Experiment [ 19D] frans-9-(2-Phenylethenyl)anthracene 309
EXPERIMENT [20] Aldo! Reaction: Dibenzalacetone 313
Optional Semimicroscale Preparation
EXPERIMENT [21 ] Quantitative Analysis of Grignard Reagents:
1 -Methylbutylmagnesium Bromide and Phenylmagnesium
Bromide 321
Part 1 1 -Methylbutylmagnesium Bromide 323
Part 2 Phenylmagnesium Bromide 324
EXPERIMENT [22] Williamson Synthesis of Ethers: Propyl p-Tolyl
Ether and Methyl p-Ethylphenyl Ether 325
Experiment [22A] Propyl p-Tolyl Ether 327
Optional Macroseale Preparation
Experiment [22B] Methyl p-Ethylphenyl Ether 331
Optional Semimicroscale and Macroseale Preparations
EXPERIMENT [23] Amide Synthesis: Acetanilide and
JV,iV'-Diacetyl-1,4-phenylenediamine 339
Experiment [23A] Acetanilide 342
Optional Semimicroscale Preparation
Experiment [23B] N,N'-Diacetyl-1,4-phenylenediamine 344
EXPERIMENT [24] Imide Synthesis: N-Phenylmaleimide 347
Experiment [24A] Maleanilic Acid 349
Experiment [24B] N-Phenylmaleimide 351
EXPERIMENT [25] Synthesis of Cyclic Carboxylic Acid
Anhydrides: Succinic Anhydride and Phthalic Anhydride 353
Experiment [25A] Succinic Anhydride 355
Experiment [25B] Phthalic Anhydride 356
EXPERIMENT [26] Diazonium Coupling Reaction: Methyl Red 358
 Contents

EXPERIMENT [27] Friedel-Crafts Acylation: Acetylferrocene and

Diacetylferrocene 364
EXPERIMENT [28] Halogenation: Electrophilic Aromatic
Substitution to Yield 4-Bromoacetaniiide 370
EXPERIMENT [29] Nitration: 2,5-Dichloronitrobenzene;
N,N' -Diacety!-2,3-dinitro-1,4-phenylenediamine;
5-Nitrosalicylic Acid; and 2- and 4-Nitrophenol 376
Semimicroscale Preparation of Anhydrous Nitric Acid 378
Experiment [29A] 2,5-Dichloronitrobenzene 379
Experiment [29B] A/,N'-Diacetyl-2,3-dinitro-1,4-
phenylenediamine 380
Experiment [29C] 5-Nitrosalicylic Acid 382
Experiment [29D] 2- and 4-Nitrophenol 384
EXPERIMENT [30] Nucleophilic Aromatic Substitution:
2,4-Dinitrophenyithiocyanate 388
EXPERIMENT [31 ] Halogenation Using JV-Bromosucdnimide:
9-Bromoanthracene 392
EXPERIMENT [32] Hypochlorite Oxidation of an Alcohol:
Cyclohexanone 396
EXPERIMENT [33] Chromium Trioxide-Resin Oxidation of an
Alcohol: 9-Fluorenone; Conversion to the
2,4-Dinitrophenylhydrazone 400
Experiment [33A] 9-Fluorenone 402
Experiment [33B] 9-Fluorenone 2,4-Dinitrophenylhydrazone 403
EXPERIMENT [34] Hypochlorite Oxidation of Methyl Ketones by
the Haloform Reaction: Benzoic Acid and
p-Methoxybenzoic Acid 405
Experiment [34A] Benzoic Acid 407
Experiment [34B] p-Methoxybenzoic Acid 408
Optional Semimicroscale Preparation
EXPERIMENT [35] Photochemical Isomerization: c/s-Azobenzene 411

CHAFTER 7 Introduction 415

ADVANCED MICROSCALE EXPERIMENT [l a d v ] Diborane Reductions: Thioxanthene and
ORGANIC LABORATORY Xanthene 416
EXPERIMENTS Experiment [ 1 Aadv] Thioxanthene 419
415 Experiment [ 1 Badv] Xanthene 420
EXPERIMENT [2 adv ] Heterocyclic Ring Synthesis: Benzimidazole 425
EXPERIMENT [3 adv ] Heterocyclic Ring Synthesis:
4-Hydroxycoumarin and Dicoumarol 428
Experiment [3Aadv] 4-Hydroxycoumarin 431
Experiment [3Badv] Dicoumarol 433
EXPERIMENT [4adv] Grignard and Aryl Halide Cross-Coupling
Reaction: l-Methyl-2-(methyl-d3)-benzene 435
EXPERIMENT [5adv] Oxidative Coupling of 2-Naphthol:
l,i'-BI-2 Naphthol 442
EXPERIMENT [6 adv ] Beckmann Rearrangement: Benzanilide 446
 Contents XXXI

EXPERIMENT [7 adv ] Preparation of an Enol Acetate:

ChoIesta~3,5-dien-3-ol Acetate 453

Introduction 459 CHAPTER 8

SEQUENCE A The Synthesis of Hexaphenylbenzene 462 S E Q U E N T I A L SYNTHESES:
Experiment [Al a ] The Benzoin Condensation of THE TRANSITION FROM
Benzaldehyde: Benzoin 468 MACRO TO MICRO
Semimicroscale Preparation and Optional Microscale
Preparations
Experiment [A2a] Copper(II) Ion Oxidation of Benzoin: Benzil 473
Semimicroscale Preparation and Optional Microscale
Preparation
Experiment [A3a] Tetraphenylcyclopentadienone 478
Optional Microscale Preparation
Experiment [AI b ] (£)-Stilbene 482
Semimicroscale Preparation
Experiment [A2b] Bromination of (E)-Stilbene: meso-Stilbene
Dibromide 485
Semimicroscale Preparation and Optional Macroseale and
Microscale Preparations
Experiment [A3b] Dehydrohalogenation of meso-Stilbene
Dibromide: Diphenylacetylene 490
Semimicroscale Preparation and Optional Macroseale and
Microscale Preparations
Experiment [A4ab] Hexaphenylbenzene 494
SEQUENCE B The Stepwise Synthesis of Nylon-6,6 497
Experiment [B1 ] Oxidation of Cyclohexanol: Adipic Acid 499
Macroseale Preparation
Experiment [B2] Preparation of an Acid Chloride: Adipoyl
Chloride 502
Semimicroscale Preparation
Experiment [B3] Preparation of a Polyamide: Nylon-6,6 505
SEQUENCE C The Synthesis of Sulfanilamide 507
Experiment [C1 ] Acetylation of Aniline:
2,2,2-Trifluoroacetanilide 508
Semimicroscale Preparation
Experiment [C2] Chlorosulfonation of
2,2,2-Trifluoroacetanilide:
p-(Trifluoroacetamido)benzenesulfonyl Chloride 512
Semimicroscale Preparation
Experiment [C3] Preparation of an Arene Sulfonamide:
Sulfanilamide 515
Semimicroscale Preparation
SEQUENCE D The Synthesis of 2 -Bromostyrene 518
Experiment [DI ] The Verley-Doebner Modifcation of the
Knoevenagel Reaction: frans-Cinnamic Acid 521
Semimicroscale Preparation
Experiment [D2] Bromination of frans-Cinnamic Acid:
e/yf/7ro-2,3-Dibromo-3-phenylpropanoic Acid 525
Semimicroscale Preparation
XXXII Contents

Experiment [D3] An Elimination Reacton with

e/yf/iro-2,3-Dibromo-3-phenylpropanoic Acid:
2'-Bromostyrene 530
Semimicroscale Preparation
SEQUENCE E The Synthesis of Piperonylonitrile from Piperonyl
Alcohol 536
Experiment [El] Piperonal 538
Macroseale Preparation and Optional Microscale
Preparations
Experiment [E2] Piperonal 0-(2,4-Dinitrophenyl)oxime 543
Semimicroscale Preparation and Optional Microscale
Preparation
Experiment [E3] Piperonylonitrile 548
SEQUENCE F Introduction of Photochromism: The Synthesis of a
Photochromic Imine 553
Experiment [Fl] An Aldol Reaction: frar?s-4-Nitrochalcone 557
Semimicroscale Preparation
Experiment [F2] e/yf/7ro-2,3-Dibromo-3-
(4-nitrophenyl)propiophenone 562
Semimicroscale Preparation
Experiment [F3] rrans-2-(4-Nitrophenyl)-3-benzoylaziridine 568
Semimicroscale Preparation
Experiment [F4] A Photochromic lmine: 2-exo-6-exo-2,4-
Diphenyl-6-(4-nitrophenyl)-1,3-diazabicyclo[3.1.0]hex-3-ene 576

CHAPTER 9 INTRODUCTION TO INFRARED SPECTROSCOPY 585

SPECTROSCOPIC Molecular Energy 587
IDENTIFICATION OF Molecular Vibrations 587
ORGANIC COMPOUNDS Quantized Vibrational Energy 589
585 Selection Rules 590
The Case of Water 591
The Case of Carbon Dioxide 591
Vibrational Coupling 592
Coupled Oscillators 592
Second-Order Coupling 593
INTRODUCTION TO GROUP FREQUENCIES: Interpretation of
Infrared Spectra 594
Group Frequencies of the Hydrocarbons 594
Characteristic Group Frequencies of Alkanes 594
Characteristic Group Frequencies of Alkenes 599
Characteristic Group Frequencies of Alkynes 602
Characteristic Group Frequencies of Arenes 603
Group Frequencies of the Phenyl Group 603
Factors Affecting Carbonyl Group Frequencies 606
Mass Effects 606
Geometrie Effects 607
Electronic Effects (Resonance and Inductive) 607
Interaction Effects 609
 Contents XXXIII

Characteristic Frequencies of Functional Groups 613

Strategies for Interpreting lnfrared Spectra 629
INFRARED SPECTROSCOPY: Instrumentation and Sample Handling 630
Instrumentation 631
Sample Handling in the lnfrared 634
Liquid Samples 634
Solution Spectra and Spectra of Materials Boiling Below 100°C 635
Solid Samples 635
NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY:
Introduction to Nuclear Magnetic Resonance 644
Nuclear Spin 644
Instrumentation 645
Chemical Shift 647
Spin-Spin Coupling 648
Intensities 652
Second-Order Effects 652
INTERPRETATION OF 'H NMR SPECTRA 653
'H Chemical Shifts 655
Spin-Spin Coupling 656
Geminal Coupling 657
Vicinal Coupling 657
Long-Range Coupling 658
Examples of Complex, Yet First-Order, Coupling 658
Ethyl Vinyl Ether 658
Allyl Acetate 660
,3
C NMR SPECTROSCOPY 663
TWO-DIMENSIONAL NUCLEAR MAGNETIC RESONANCE
SPECTROSCOPY 669
NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY SAMPLING 671
ULTRAVIOLET-VISIBLE SPECTROSCOPY: Introduction to
Absorption Spectroscopy 676
UV-VS Spectroscopy 678
Applications to Organic Molecules 679
Instrumentation 688
Sample Preparation 690

ORGANIC QUALITATIVE ANALYSIS 693 CHAPTER 1 0

Preliminary Tests 695 QUALITATIVE
Separation of Impurites 698 IDENTIFICATION OF
Detection of Elements Other Than Carbon, Hydrogen, and Oxygen 698 ORGANIC C O M P O U N D S
Solubility Characteristics 702 693
The Classification Tests 704
PREPARATION OF DERIVATIVES 718
Carboxylic Acids 718
Alcohols 720
Aldehydes and Ketones 721
xxxiv Contents

Amines 722
Acid Chlorides and Anhydrides 723
Aromatic Hydrocarbons 724
Nitriles 724
Phenols 724
Aliphatic Hydrocarbons, Halogenated Hydrocarbons, Amides, Nitro
Compounds, Ethers, and Esters 725

APPENDIX A
TABLES OF DERIVATIVES
729

APPENDIX B
CHAFTERS 6, 7 AND 8:
EXPERIMENTS CLASSIFIED
BY MECHANISM
743

GLOSSARY
751

INDEX
755