Advanced Organic
`Ch m • t
`e
`IS ry
`
`SECOND
`EDITION
`
`Part A: Structure and Mechanisms
`
`Santen/Asahi Glass Exhibit 2048
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`
`

`

`Advanced Organic Chemistry
`
`PART A: Structure and Mechanisms
`PART B: Reactions and Synthesis
`
`IPR Page 2/79
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`

`

`Advanced Organic
`Chemistry
`
`SECOND
`EDITION
`
`Part A: Structure ,and Mechanisms
`
`FRANCIS A. CAREY
`and RICHARD J. SUNDBERG
`
`University of Virginia
`Charlottesville, Virginia
`
`SPRINGER SCIENCE+BUSINESS MEDIA, LLC
`
`IPR Page 3/79
`
`

`

`Library of Congress Cataloging in Publication Data
`
`Carey, Francis A., 1937-
`Advanced organic chemistry.
`
`Includes bibliographical references and index.
`Contents: pt. A. Structure and mechanisms-pt. B. Reactions and synthesis.
`I. Chemistry, Organic. I. Sundberg, Richard J., 1938-
`. II. Title.
`QD251.2.C36 1984
`547
`ISBN 978-1-4757-1145-5
`ISBN 978-1-4757-1143-1 (eBook)
`DOI 10.1007/978-1-4757-1143-1
`
`84-8229
`
`© 1984 Springer Science+ Business Media New York
`Originally published by Plenum Press, New York in 1984
`
`All rights reserved
`
`No part of this book may be reproduced, stored in a retrieval system, or transmitted,
`in any form or by any means, electronic, mechanical, photocopying, microfilming,
`recording, or otherwise, without written permission from the Publisher
`
`IPR Page 4/79
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`

`

`Preface to the Second Edition
`
`The purpose of this edition is the same as that of the first edition, that is, to provide
`a deeper understanding of the structures of organic compounds and the mechanisms
`of organic reactions. The level is aimed at advanced undergraduates and beginning
`graduate students. Our goal is to solidify the student's understanding of basic
`concepts provided in an introduction to organic chemistry and to fill in much more
`information and detail, including quantitative information, than can be presented
`in the first course in organic chemistry.
`The first three chapters consider the fundamental topics of bonding theory,
`stereochemistry, and conformation. Chapter 4 discusses the techniques that are used
`to study and characterize reaction mechanisms. The remaining chapters consider
`basic reaction types with a broad coverage of substituent effects and stereochemistry
`being provided so that each reaction can be described in good, if not entirely
`complete, detail.
`The organization is very similar to the first edition with only a relative shift in
`emphasis having been made. The major change is the more general application of
`qualitative molecular orbital theory in presenting the structural basis of substituent
`and stereoelectronic effects. The primary research literature now uses molecular
`orbital approaches very widely, while resonance theory serves as the primary tool
`for explanation of structural and substituent effects at the introductory level. Our
`intention is to illustrate the use of both types of interpretation, with the goal of
`facilitating the student's ability to understand and apply the molecular orbital
`concepts now widely in use.
`As in the first edition, the specific reactions discussed have been chosen to
`illustrate a point and no effort has been made to trace the origin of a particular
`explanation or observation. Thus references to a particular example do not imply
`any indication of priority. We have also tried to cite references to reviews which
`will give readers the opportunity to consider specific reactions from a much more
`comprehensive and detailed point of view than is possible in this text.
`
`v
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`Vl
`
`PREFACE
`
`Some of the problems are new. The general level is similar to that in the first
`edition and it is expected that most of the problems will present a considerable
`degree of challenge to the typical student, since most represent application of the
`ideas presented in the text to different systems and circumstances, rather than review
`or repetition of the material which was explicitly presented in the text. References
`to the literature material upon which the problems are based are given at the end
`of the book for nearly all the problems.
`The companion volume, Part B, has also been substantially revised to reflect
`the major developments in synthetic procedures that have taken place since the
`initial material was prepared. Part B extends the material of Part A with particular
`emphasis on the synthetic application of organic reactions. We believe that the
`material in Parts A and B can serve to prepare students to assimilate and apply the
`extensive primary and review literature of organic chemistry.
`We thank colleagues who have provided comments and encouragement regard(cid:173)
`ing the first edition. We hope that we will continue to receive suggestions concerning
`the organization and presentation of the material and also information concerning
`errors and omissions.
`
`F. A. Carey
`R. J. Sundberg
`Charlottesville, Virginia
`January 1983
`
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`

`

`Contents of Part A
`
`Chapter 1. Chemical Bonding and Molecular Structure
`
`1.1. Valence Bond Approach to Chemical Bonding
`1.2. Bond Energies, Lengths, and Dipoles
`. . . .
`1.3. Molecular Orbital Methods
`. . . . . . . .
`1.4. Qualitative Application of Molecular Orbital Theory
`1.5. Hiickel Molecular Orbital Theory
`. . . . . . . .
`1.6. PMO Theory
`. . . . . . . .
`. . . . . . . .
`1. 7.
`Interaction between 1T and u Systems-Hyperconjugation
`General References
`Problems . . . .
`
`Chapter 2. Stereochemical Principles
`
`2.1. Enantiomeric Relationships
`2.2. Diastereomeric Relationships
`2.3. Dynamic Stereochemistry
`2.4. Prochiral Relationships
`General References
`Problems . . . .
`
`Chapter 3. Conformational, Steric, and Stereoelectronic Effects
`
`3.1. Steric Strain and Molecular Mechanics
`3.2. Conformations of Acyclic Molecules
`3.3. Conformations of Cyclohexane Derivatives
`3.4. Carbocyclic Rings Other Than Six Membered
`3.5. Conformational Analysis of Heterocyclic Molecules
`3.6. Molecular Orbital Methods Applied to Conformational Analysis
`
`Vll
`
`1
`
`2
`11
`17
`23
`37
`44
`51
`55
`55
`
`61
`
`62
`69
`76
`85
`91
`92
`
`99
`
`100
`107
`111
`123
`128
`133
`
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`vm
`
`CONTENTS OF
`PART A
`
`.
`. . .
`. .. . . . .
`3. 7. Conformational Effects on Reactivity
`.
`. . .
`3.8. Angle Strain and Its Effect on Reactivity
`.
`. . .
`3.9. Relationships between Ring Size and Facility of Ring Closure
`3.1 0. Torsional Strain and Related Stereoelectronic Effects
`General References
`Problems
`. .
`. .
`
`Chapter 4. Study and Description of Organic Reaction Mechanisms
`
`4.1. Thermodynamic Data
`. . .
`. . . .
`. . .
`. . .
`4.2. Kinetic Data
`.
`. .
`. . . .
`4.3. Substituent Effects and Linear Free-Energy Relationships
`4.4.
`Isotope Effects
`4.5. Characterization of Reaction Intermediates
`4.6. Catalysis
`.
`. .
`. . . .
`. . . .
`4. 7. Solvent Effects
`. . .
`. . . . .
`.
`4.8. Structural Effects in the Gas Phase
`4.9. Basic Mechanistic Concepts: Kinetic Versus Thermodynamic Control,
`Hammond's Postulate, the Curtin-Hammett Principle
`4.10. Isotopes in Labeling Experiments
`4.11. Stereochemistry
`General References
`Problems
`.
`. .
`.
`
`Chapter 5. Nucleophilic Substitution
`
`5.1. The Limiting Cases-Substitution by the Ionization (SN 1) Mechanism
`5.2. The Limiting Cases-Substitution by the Direct Displacement (SN2)
`Mechanism
`5.3. Detailed Mechanistic Descriptions and Borderline Mechanisms
`5.4. Carbonium Ions
`. .
`. . . .
`. .
`5.5. Nucleophilicity and Solvent Effects
`5.6. Leaving-Group Effects
`. .
`. . .
`5. 7. Steric and Other Substituent Effects on Substitution and Ionization
`Rates
`.
`. . . .
`. .
`. . . .
`. . .
`. .
`. . .
`. . . .
`. .
`5.8. Stereochemistry of Nucleophilic Substitution
`. . . .
`. . .
`.
`5.9. Secondary Kinetic Isotope Effects in Substitution Mechanisms
`5.10. Neighboring-Group Participation
`5.11. Carbonium Ion Rearrangements
`5.12. The Norbornyl Cation
`General References
`Problems
`.
`. . .
`
`137
`141
`147
`150
`154
`154
`
`161
`
`161
`165
`179
`190
`194
`197
`202
`209
`
`212
`220
`221
`223
`224
`
`235
`
`238
`
`240
`243
`248
`263
`271
`
`274
`278
`287
`289
`298
`304
`312
`313
`
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`lX
`
`CONTENTS OF
`PART A
`
`Chapter 6. Polar Addition and Elimination Reactions
`
`6.1. Addition of Hydrogen Halides to Alkenes . . . . . . .
`6.2. Acid-Catalyzed Hydration and Related Addition Reactions
`6.3. Addition of Halogens
`. . . .
`. .
`6.4. Additions Involving Metal Ions
`6.5. Additions to Acetylenes
`. . . . .
`6.6. The E2, E1, and E1cb Mechanisms
`6. 7. Orientation Effects in Elimination Reactions
`6.8. Stereochemistry of E2 Elimination Reactions
`6.9. Dehydration of Alcohols
`. . . . . .
`6.10. Eliminations Not Involving C-H Bonds
`General References
`Problems . . . .
`
`Chapter 7. Carbanions and Other Nucleophilic Carbon Species
`
`0 • • 0
`
`. . . . . . . .
`7 .1. Acidity of Hydrocarbons
`7.2. Carbanions Stabilized by Functional Groups
`7.3. Enols and Enamines
`General References
`Problems . . . .
`
`Chapter 8. Reactions of Carbonyl Compounds
`
`. . . . . . . . . .
`
`8.1. Hydration and Addition of Alcohols to Aldehydes and Ketones
`8.2. Addition-Elimination Reactions of Ketones and Aldehydes
`8.3. Reactivity of Carbonyl Compounds toward Addition
`8.4. Ester Hydrolysis
`8.5. Aminolysis of Esters
`8.6. Amide Hydrolysis
`8. 7. Acylation of Nucleophilic Oxygen and Nitrogen Groups
`8.8.
`Intramolecular Catalysis
`General References
`Problems
`. . . .
`
`323
`
`324
`330
`333
`339
`341
`345
`351
`356
`361
`362
`365
`366
`
`373
`
`373
`382
`390
`395
`396
`
`403
`
`404
`411
`417
`421
`426
`431
`433
`437
`444
`444
`
`Chapter 9. Aromaticity and Electrophilic Aromatic Substitution
`
`0 • • • 455
`
`. . . . . . . . . .
`9.1. Aromaticity
`9 .1.1. The Concept of Aromaticity
`9.1.2. The Annulenes . . . . .
`9.1.3. Aromaticity in Charged Rings
`9.1.4. Homoaromaticity
`9.1.5. Fused-Ring Systems
`
`455
`455
`460
`468
`472
`475
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`

`X
`
`CONTENTS OF
`PART A
`
`9.2. Electrophilic Aromatic Substitution Reactions
`9.3. Structure-Reactivity Relationships
`9.4. Specific Substitution Mechanisms
`9.4.1. Nitration
`9.4.2. Halogenation
`9.4.3. Protonation and Hydrogen Exchange
`9.4.4. Friedel-Crafts Alkylation and Related Reactions
`9.4.5. Friedel-Crafts Acylation and Related Reactions
`9.4.6. Coupling with Diazonium Compounds
`9.4.7. Substitution of Groups Other Than Hydrogen
`General References
`Problems
`
`Chapter 10. Concerted Reactions
`
`1 0.1. Electrocyclic Reactions
`1 0.2. Sigma tropic Rearrangements
`10.3. Cycloaddition Reactions
`General References
`Problems . . . .
`
`Chapter 11. Photochemistry
`
`to Photochemical
`
`11.1. General Principles
`11.2. Orbital Symmetry Considerations Related
`Reactions
`11.3. Photochemistry of Carbonyl Groups
`11.4. Photochemistry of Alkenes and Dienes
`11.5. Photochemistry of Aromatic Compounds
`General References
`Problems
`
`Chapter 12. Free-Radical Reactions
`
`12.1. Generation and Characterization of Free Radicals
`12.1.1. Background
`. .
`. .
`. . .
`. .
`. . .
`12.1.2. Stable and Persistent Free Radicals
`12.1.3. Direct Detection of Radical Intermediates
`12.1.4. Sources of Free Radicals
`12.1.5. Structural and Stereochemical Properties of Radical Inter-
`. . .
`. .
`. . .
`. ·.
`mediates
`. .
`. . .
`. . .
`. .
`. .
`12.1.6. Charged Radical Species
`. .
`.
`. . . .
`. .
`. .
`. . .
`12.2. Characteristics of Reaction Mechanisms Involving Radical Inter-
`mediates
`.
`. . .
`. . .
`. .
`. .
`. .
`. . . .
`. .
`. . .
`
`481
`489
`503
`503
`505
`511
`512
`515
`517
`518
`520
`521
`
`529
`
`530
`544
`557
`572
`572
`
`583
`
`583
`
`588
`592
`604
`614
`616
`616
`
`625
`
`625
`625
`626
`628
`634
`
`637
`641
`
`644
`
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`

`xi
`
`CONTENTS OF
`PART A
`
`120201. Kinetic Characteristics of Chain Reactions
`1202020 Structure-Reactivity Relationships
`12030 Free Radical Substitution Reactions
`0 0 0 0 0
`120301. Halogenation
`0 0 0 0 o
`1203020 Oxidation
`1203030 Substitutions Involving Aryl Radicals
`12.40 Free Radical Addition Reactions
`12.401. Addition of Hydrogen Halides
`12.4020 Addition of Halomethanes 0 0
`12.4030 Addition of Other Carbon Radicals
`12.4.40 Addition of S-H Compounds
`Intramolecular Free-Radical Reactions
`12050
`12060 Rearrangement and Fragmentation Reactions of Free Radicals
`120601. Rearrangement 0 0 0 o 0 0 0 0 0 0 0 0 0 0 0 0
`0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
`1206020 Fragmentation
`12070 Electron Transfer Reactions Involving Transition Metal Ions
`12080 SRN1 Substitution Processes
`General References
`0 0 0 0
`Problems
`
`References for Problems
`
`Index
`
`644
`647
`655
`655
`660
`662
`664
`664
`666
`669
`670
`671
`676
`676
`678
`679
`683
`690
`691
`
`699
`
`711
`
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`

`Contents of Part B
`
`List of Figures
`
`List of Tables
`
`List of Schemes
`
`Chapter 1. Alkylation of Nucleophilic Carbon.
`Enolates and Enamines
`
`1.1. Generation of Carbon Nucleophiles by Deprotonation
`1.2. Regioselectivity and Stereoselectivity in Enolate Formation
`1.3. Other Means of Generating Enolates
`.
`1.4. Alkylation of Enolates
`. . . . . . .
`1.5. Generation and Alkylation of Dianions
`1.6. Medium Effects in the Alkylation of Enolates
`1. 7. Oxygen versus Carbon as the Site of Alkylation
`.
`1.8. Alkylations of Aldehydes, Esters, and Nitriles
`1.9. The Nitrogen Analogs of Enols and Enolates-Enamines and
`Metalloenamines
`. . . . . . . . . . . .
`1.10. Alkylation of Carbon by Conjugate Addition
`General References
`Problems . . . . . . . . . . . . . . . .
`
`Chapter 2. Reactions of Carbon Nucleophiles
`with Carbonyl Groups
`
`2.1. Aldol Condensation
`2.2. Amine-Catalyzed Aldol Condensation Reactions
`
`xiii
`
`xiii
`
`XV
`
`XVll
`
`1
`
`1
`5
`10
`10
`17
`18
`21
`24
`
`26
`31
`34
`35
`
`43
`
`43
`57
`
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`

`XlV
`
`CONTENTS OF
`PART B
`
`2030 The Mannich Reaction 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
`2.40 Acylation of Carbanionso The Claisen, Dieckmann, and Related Con(cid:173)
`densation Reactions
`0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
`2050 The Wittig and Related Carbonyl Olefination Reactions
`0 0 0 0 0
`2060 Carbonyl Olefination Using a-Trimethylsilyl-Substituted Organa-
`lithium Reagents
`0 o 0 o o o 0 0 0 0 0 0 0 0
`2070 Sulfur Ylides and Related Species as Nucleophiles
`2080 Nucleophilic Addition-Cyclization
`General References
`Problems 0 0 0 0 0 0 0 0 0 0 0
`
`Chapter 3. Functional Group Interconversion by
`Nucleophilic Substitution
`
`3ol. Conversion of Alcohols to Alkylating Agents
`3o1.1. Sulfonate Esters 0 0 0 0 0 0 0 0 0 0
`301.20 Halides
`0 0 0 0 0 0 0 0 0 0 0 0 0
`3o2o Introduction of Functional Groups by Nucleophilic Substitution at
`Saturated Carbon
`0 0 0 o 0
`30201. General Solvent Effects
`302020 Nitriles 0 0 0 0 0 0 0
`302030 Azides 0 0 0 0 0 0 0
`3o2.4o Alkylation of Amines and Amides
`302050 Oxygen Nucleophiles
`302060 Sulfur Nucleophiles
`302070 Phosphorus Nucleophiles
`302080 Summary of Nucleophilic Substitution at Saturated Carbon
`303 0 Nucleophilic Cleavage of Carbon-Oxygen Bonds in Ethers and Esters
`3.40 Synthetic Interconversion of Carboxylic Acid Derivatives
`3.401. Preparation of Reactive Reagents for Acylation
`3.4020 Preparation of Esters
`3.4030 Preparation of Amides
`Problems 0 0 0 0 0 0 o 0 0
`
`Chapter 4. Electrophilic Additions to Carbon-Carbon
`Multiple Bonds
`
`0 o o 0 o o o
`401. Addition of Hydrogen Halides
`4020 Hydration and Other Acid-Catalyzed Additions
`4030 Oxymercuration 0 0 0 0 0 0 0 0 o o 0 0
`4.40 Addition of Halogens to Alkenes
`0 0 0 0
`4o5o Electrophilic Sulfur and Selenium Reagents
`4o6o Addition of Other Electrophilic Reagents 0
`
`58
`
`62
`69
`
`77
`78
`83
`85
`86
`
`95
`
`95
`95
`96
`
`101
`103
`105
`106
`106
`108
`113
`114
`115
`115
`118
`118
`126
`127
`129
`
`139
`
`139
`143
`144
`147
`154
`157
`
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`

`XV
`
`CONTENTS OF
`PART B
`
`4. 7. Electrophilic Substitution Alpha to Carbonyl Groups
`4.8. Additions to Allenes and Alkynes
`4.9. Hydroboration . . . . . . . .
`4.9.1. Synthesis of Organoboranes
`4.9.2. Reactions of Organoboranes
`4.9.3. Formation of Carbon-Carbon Bonds via Organoboranes
`4.9.4. Hydroboration of Acetylenes
`4.10. Hydroalumination
`.
`General References
`Problems . . . . .
`
`Chapter 5. Reduction of Carbonyl and
`Other Functional Groups
`
`5.1. Addition of Hydrogen . . . . . . . . .
`5 .1.1. Catalytic Hydrogenation
`. . . . .
`5.2.1. Other Hydrogen-Transfer Reagents
`5.2. Group III Hydride-Transfer Reagents
`5.2.1. Reduction of Carbonyl Compounds
`5.2.2. Reduction of Other Functional Groups
`5.3. Group IV Hydride Donors
`5.4. Hydrogen Atom Donors
`5.5. Dissolving-Metal Reductions
`5.5.1. Addition of Hydrogen
`5.5.2. Reductive Removal of Functional Groups
`5.5.3. Reductive Carbon-Carbon Bond Formation
`5 .6. Reductive Deoxygenation of Carbonyl Groups
`General References
`Problems . . . . . . . . . . . . . . . .
`
`Chapter 6. Organometallic Reagents
`
`6.1. Organic Derivatives of Group I and II Metals
`6.1.1. Preparation and Properties
`6.1.2. Reactions
`. . . . . . .
`6.2. Organic Derivatives of Group lib Metals
`6.3. Organocopper Intermediates . . . . .
`6.4. Synthetic Applications of Other Transition Metals
`6.4.1. Reactions Involving Organonickel Compounds
`6.4.2. Reactions Involving Palladium
`. . . . . .
`6.4.3. Reactions Involving Rhodium, Iron, and Cobalt
`6.5. Organometallic Compounds with 1r-Bonding
`General References-
`Problems . . . . . . . . . . . . . . . .
`
`159
`162
`167
`167
`171
`174
`183
`184
`185
`186
`
`193
`
`193
`193
`199
`199
`199
`213
`217
`220
`223
`223
`226
`230
`233
`239
`239
`
`249
`
`249
`249
`257
`268
`270
`281
`281
`285
`292
`294
`298
`299
`
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`

`

`XVI
`
`CONTENTS OF
`PART B
`
`Chapter 7. Cycloadditions and Unimolecular Rearrangements
`and Eliminations
`
`307
`
`307
`308
`313
`318
`321
`322
`
`. . . . . . . . . . . .
`7 .1. Cycloaddition Reactions
`7 .1.1. The Diels-Alder Reaction: General Features
`7 .1.2. The Diels-Alder Reaction: Dienophiles
`7.1.3. The Diels-Alder Reaction: Dienes ..
`7 .1.4. Intramolecular Diels-Alder Reactions
`7.1.5. Dipolar Cycloaddition Reactions
`7.1.6. 2 + 2 Cycloadditions and Other Reactions Leading to Cyclo-
`329
`. . . . . . . . . . . . . . . . . . . . . . .
`butanes
`. . . . . . . . . . . . 332
`7.2. Photochemical Cycloaddition Reactions
`7.3. [3,3]-Sigmatropic Rearrangements: Cope and Claisen Rearrange-
`. . . . . . . . . . . .
`ments
`. . . . .
`7.4. [2,3]-Sigmatropic Rearrangements
`. . . . . . . . . . . . .
`7.5. Ene Reactions
`7 .6. Unimolecular Thermal Elimination Reactions
`. . . . . .
`7.6.1. Cheletropic Eliminations
`7.6.2. Decomposition of Cyclic Azo Compounds
`7 .6.3. {3 -Eliminations Involving Cyclic Transition States
`General References
`. . . . . . . . . . . . . . . . . . . . .
`Problems
`
`337
`347
`349
`350
`351
`354
`356
`365
`365
`
`Chapter 8. Aromatic Substitution Reactions
`
`8.1. Electrophilic Aromatic Substitution
`. . . . . . . .
`8.1.1. Nitration
`. . . . . .
`8.1.2. Halogenation
`8.1.3. Friedel-Crafts Alkylations and Acylations
`8.1.4. Electrophilic Metalation
`8.2. Nucleophilic Aromatic Substitution
`8.2.1. Diazonium Ion Intermediates
`8.2.2. Addition-Elimination Mechanism
`8.2.3. Elimination-Addition Mechanism
`8.2.4. Copper-Catalyzed Reactions
`8.3. Free-Radical and Electron-Transfer Processes
`8.4. Reactivity of Polycyclic Aromatic Compounds
`General References
`. . . . . . . . . . . . . . . .
`Problems
`
`Chapter 9. Reactions of Electron-Deficient Intermediates
`
`9.1. Carbenes . . . . . . . . . . . . . . . . . . .
`
`375
`
`375
`375
`3 77
`380
`389
`391
`391
`400
`402
`407
`409
`410
`415
`415
`
`423
`
`424
`
`IPR Page 15/79
`
`

`

`XVll
`
`CONTENTS OF
`PART B
`
`9 .1.1. Structure and Reactivity
`9.1.2. Generation of Carbenes
`9.1.3. Addition Reactions
`9 .1.4. Insertion Reactions
`9 .1.5. Rearrangement Reactions
`9.1.6. Related Reactions
`. . .
`9.2. Nitrenes
`. . . . . . . . . .
`9.3. Rearrangement to Electron-Deficient Nitrogen
`9.4. Rearrangement of Carbonium Ion Intermediates
`9.5. Other Rearrangements . . . . . . . . . . .
`9.6. Carbon-Carbon Bond Formation Involving Carbonium Ions
`9. 7. Fragmentation Reactions
`General References
`Problems . . . . . . .
`
`Chapter 10. Oxidations
`
`1 0.1. Oxidation of Alcohols to Aldehydes, Ketones, or Carboxylic Acids
`10.1.1. Transition Metal Oxidants
`. . . . . . . . .
`10.1.2. Other Oxidants
`. . . . . . . . . . . . .
`10.2. Addition of Oxygen at Carbon-Carbon Double Bonds
`10.2.1. Transition Metal Oxidants
`. . . . . . . . .
`10.2.2. Epoxides from Olefins and Peroxidic Reagents
`10.2.3. Subsequent Transformations of Epoxides
`10.2.4. Reactions of Alkenes with Singlet Oxygen
`10.3. Cleavage of Carbon-Carbon Double Bonds
`10.3.1. Transition Metal Oxidants
`. . . . . . .
`10.3.2. Ozonolysis
`. . . . . . . . . . . . .
`10.4. Selective Oxidative Cleavages at Other Functional Groups
`10.4.1. Cleavage of Glycols
`. . . . .
`10.4.2. Oxidative Decarboxylation
`10.5. Oxidations of Ketones and Aldehydes
`10.5.1. Transition Metal Oxidants
`. .
`10.5.2. Oxidation of Ketones and Aldehydes by Peroxidic
`Compounds and Oxygen
`10.5.3. Oxidation with Other Reagents
`10.6. Allylic Oxidation
`. . . . . . .
`. .
`10.6.1. Transition Metal Oxidants
`10.6.2. Other Oxidants
`. . . . . .
`10.7. Oxidations at Unfunctionalized Carbon
`General References
`Problems
`. . . . . . . . . . . . .
`
`424
`427
`435
`440
`441
`443
`446
`449
`454
`459
`461
`469
`473
`473
`
`481
`
`481
`481
`487
`491
`491
`494
`498
`506
`509
`509
`510
`513
`513
`515
`517
`517
`
`520
`523
`524
`524
`525
`527
`531
`531
`
`IPR Page 16/79
`
`

`

`XV Ill
`
`Chapter 11. Multistep Syntheses
`
`CONTENTS OF
`PART B
`
`. . . . . . . .
`11.1. Protective Groups
`11.1.1. Hydroxyl-Protecting Groups
`11.1.2. Amino-Protecting Groups
`.
`11.1.3. Carbonyl-Protecting Groups
`11.1.4. Carboxylic Acid-Protecting Groups
`11.2. Synthetic Equivalent Groups
`11.3. Asymmetric Synthesis
`11.4. Synthetic Strategy
`11.5. Juvabione
`. .
`11.6. Longifolene
`. .
`11.7. Aphidicolin
`11.8. Thromboxane B2
`General References
`Problems . . . .
`
`References for Problems
`
`Index
`
`539
`
`539
`540
`546
`549
`551
`552
`558
`569
`572
`583
`590
`602
`604
`605
`
`619
`
`633
`
`IPR Page 17/79
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`

`

`3
`
`Conformational, Steric, and
`Stereoelectronic Effects
`
`The total energy of a molecule is directly related to its geometry. Several aspects
`of molecular geometry can be recognized, and, to some extent, the energetic
`consequences can be dissected and attributed to specific structural features. Among
`the factors which contribute to total energy and have a recognizable connection
`with molecular geometry are nonbonded repulsions, ring strain in cyclic systems,
`and destabilization resulting from distortion of bond lengths or bond angles from
`optimal values. Conversely, there are stabilizing interactions which have geometric
`constraints. Most of these can be classed as stereoelectronic effects; that is, a
`particular geometric relationship is required to maximize the stabilizing interaction.
`In addition there are other molecular interactions, such as hydrogen bonds and
`dipole-dipole interactions, where the strength of the interaction will be strongly
`dependent on geometric factors. A molecule will adopt the minimum energy
`geometry that is available by rotations about single bonds. The various shapes that
`a given molecule can attain by these rotations are called conformations. The principles
`on which analysis of conformational equilibria and rotational processes are based
`have been developed using a classical mechanical framework, for the most part.
`More recently, the problem of detailed interpretation of molecular geometry has
`also been attacked from the molecular orbital viewpoint.
`Many molecules exhibit strain caused by nonideal geometry. The molecule will
`minimize the energetic consequences by whatever changes of bond angle or length
`are available to it. These structural adjustments, however, cannot compensate
`entirely for the unfavorable consequences of nonideal bonding arrangements, and
`such molecules will be less stable than one would calculate by simply summing the
`energies of all the bonds in the molecule. This decreased stability is called strain
`energy. This chapter will focus on these interrelated topics: the sources of strain in
`molecules and the response of molecular geometry to various types of strain.
`
`99
`
`F. A. Carey et al., Advanced Organic Chemistry
`© Springer Science+Business Media New York 1984
`
`IPR Page 18/79
`
`

`

`100
`
`CHAPTER 3
`CONFORMATIONAL.
`STERIC, AND
`STEREO ELECTRONIC
`EFFECTS
`
`From a molecular orbital viewpoint, the energy of a molecule is the sum of the
`energy of the occupied molecular orbitals. Calculations of molecules in different
`spatial arrangements reveals that the energy can vary greatly as a function of
`geometry. The physical picture of this is given in terms of the effectiveness of orbital
`overlap. Maximum overlap between orbitals which have a bonding interaction lowers
`the total molecular energy while overlap of antibonding orbitals raises the energy
`of the molecule. The term stereoelectronic effect can be used to encompass these
`relationships between molecular structure and energy which can be traced to the
`contributions of specific orbital interactions.
`
`3.1. Steric Strain and Molecular Mechanics
`
`A system of analyzing the energy differences among molecules and among
`various geometries of a particular molecule has been developed, based on some
`fundamental concepts formalized by Westheimer. 1 The method is now known by the
`term molecular mechanics, although the expressions empirical force field calculations
`or the Westheimer method are sometimes applied . 2
`A molecule will adopt the geometry that minimizes its total energy. The
`minimum-energy geometry will be strained to a degree dependent on the extent to
`which its structural parameters deviate from their ideal values. The energy for a
`particular kind of distortion is given by the product of the amount of distortion and
`the restoring force acting on it. The total steric energy (Esteric) can be formulated as
`the sum of several contributors:
`Esteric = E(r) + E(fJ) + E(c/>) + E(d)
`
`where E(r) is the energy increment associated with stretching or compression of
`single bonds, E(fJ) is the strain energy of bond-angle distortion, E(¢>) is the torsional
`strain, and E(d) are the energy increments that result from nonbonded interactions
`between atoms or groups.
`The mathematical expressions for the force fields are derived from classical
`mechanical potential energy functions. The energy required to stretch bonds or to
`bend bond angles increases as the square of the distortion.
`
`Bond stretching:
`
`1. F. H. Westheimer, in Steric Effects in Organic Chemistry, M.S. Newman (ed.), Wiley, New York,
`1956, Chap. 12.
`2. For reviews, see J. E. Williams, P. J. Stang, and P. v. R. Schleyer, Annu. Rev. Phys. Chern. 19,
`531 (1968); D. B. Boyd and K. B. Lipkowitz, J. Chern. Educ. 59, 269 (1982); P. J. Cox, J. Chern.
`Educ. 59, 275 (1982); N. L. Allinger, Adv. Phys. Org. Chern. 13, I (1976); E. Osawa and H.
`Musso, Top. Stereochem. 13, 117 (1982); U. Burkert and N. L. Allinger, Molecular Mechanics, ACS
`Monograph 177, American Chemical Society, Washington D.C., 1982.
`
`IPR Page 19/79
`
`

`

`101
`SECTION 3.1.
`STERIC STRAIN
`AND MOLECULAR
`MECHANICS
`
`0
`E
`
`0
`u
`.>(_
`
`>.
`Ol
`L
`Q)
`
`1: w
`Ci
`+'
`1:
`Q)
`
`0
`0..
`
`3
`
`2
`
`0
`
`~
`
`2.9 kcol
`mol
`
`~ 0
`~
`
`0
`
`60
`
`120
`Torsion angle (degrees)
`
`180
`
`240
`
`300
`
`360
`
`H
`
`H~HH
`
`Eclipsed conformations correspond to torsion
`angles of 0', 120', 240'.
`
`HH
`H
`
`H
`
`"1$:"
`
`Staggered conformations correspond to torsion
`angles of 60', 180', and 300'.
`
`H
`
`H
`
`Fig. 3.1. Potential energy as a function of torsion angle for ethane.
`
`where k, is the stretching force constant, r the bond length, and r0 the normal bond
`length.
`
`Bond-angle bending:
`
`E(O) = 0.5k0 (d8) 2
`
`where k0 is the bending force constant and d(} is the deviation of the bond angle from
`its normal value.
`The torsional strain is a sinusoidal function of the torsion angle. (In the context of
`its use in structural organic chemistry, torsion angle is synonymous with the more
`familiar, but less precise, dihedral angle. 3) For molecules with a threefold barrier
`such as ethane, the form of the torsional barrier is
`
`E(¢) = 0.5 V0(1 +cos 3¢)
`
`where V 0 is the rotational energy barrier and ¢ is the torsion angle. For hydrocarbons
`
`3. For applications of the concept of torsion angle to conformational descriptions, see R. Bucourt,
`Top. Stereochem. 8, 159 (1974).
`
`IPR Page 20/79
`
`

`

`102
`CHAPTER 3
`CONFORMATIONAL,
`STERIC, AND
`STEREO ELECTRONIC
`EFFECTS
`
`Potential
`energy
`
`Internuclear separation
`
`Fig. 3.2. Energy as a function of internuclear distance for non bonded atoms.
`
`V0 can be taken as being equal to the ethane barrier (2.8-2.9 kcal/mol). The
`potential energy diagram for rotation a~out the C-C bond of ethane is given in Fig.
`3.1. The ethane barrier may be taken as a standard rotational barrier for acyclic
`hydrocarbons when analyzing the contribution of torsional strain to the total steric
`strain. The stereoelectronic origin of the ethane barrier was discussed in Chapter
`1. Any steric interactions which are present in more highly substituted systems will
`make an additional contribution to the barrier. 4
`Nonbonded interaction energies are the most difficult contribution to evaluate,
`and may be attractive or repulsive. When two uncharged spherical atoms approach
`each other, the interaction between them is very small at large distances, becomes
`increasingly attractive as the separation approaches the sum of their van der Waals
`radii, then becomes strongly repulsive as the atoms approach each other with a
`separation less than the sum of their van der Waals radii. This behavior is represented
`graphically by the familiar Morse potential diagram in Fig. 3.2. The attractive
`interaction results from a mutual polarization of the electrons of each atom by the
`other. Such attractive forces are called London forces or dispersion forces, and are
`normally weak interactions. London forces vary inversely with the sixth power of
`internuclear distance, and therefore become unimportant at large distances. At
`
`4. L. S. Bartell, J. Am. Chern. Soc. 99, 3279 (1977); N. L. Allinger, D. Hindman, and H. Honig, J.
`Am. Chern. Soc. 99, 3282 (1977).
`
`IPR Page 21/79
`
`

`

`Table 3.1. Vander Waals Radii of Several
`Atoms and Groups (A)a
`
`H
`N
`0
`F
`
`1.20
`p
`1.55
`1.52 s
`1.47 Cl
`
`1.80
`1.80
`1.75
`
`CH3
`
`2.0
`
`Br
`
`1.85
`
`I
`
`1.98
`
`a. From A. Bondi, 1. Phys. Chern. 68,441 (1964).
`
`103
`SECTION 3.1.
`STERIC STRAIN
`AND MOLECULAR
`MECHANICS
`
`distances smaller than the sum of the van der Waals radii, the attractive forces are
`overwhelmed by repulsion between the atoms. Table 3.1 lists van der Waals radii of
`atoms commonly encountered in organic molecules.
`The interplay between torsional strain and nonbonded interactions can be
`illustrated by examining conformational isomerism inn-butane. The diagram relat(cid:173)
`ing potential energy to torsion angle for rotation about the C(2)-C(3) bond is
`presented in Fig. 3.3.
`The potential energy diagram of n-butane resembles that of ethane in having
`three energy maxima and three minima, but differs from it in that one of the minima
`is of lower energy than the other two, and one of the maxima is of higher energy than
`the other two. The minima correspond to staggered conformations, of which the anti
`is lower in energy than the two gauche conformations. The energy difference
`between the anti and gauche conformations inn-butane is about 0.8 kcal/mol. 5 The
`maxima correspond to eclipsed conformations, with the highest-energy conforma(cid:173)
`tion being the one with the two methyl groups eclipsed with each other. The
`methyl-methyl eclipsed conformation is about 2.6 kcal/mol higher in energy than
`the methyl-hydrogen eclipsed conformations and 6 kcal/mol higher in energy than
`the staggered anti conformation.
`The rotational profile of n -butane can be understood as a superimposition of
`van der Waals forces on the ethane potential energy diagram. The two gauche
`conformations are raised in energy relative to the anti 'by an energy increment
`resulting from a van der Waals repulsion between the two methyl groups of
`0.8 kcal/mol. The eclipsed conformations all incorporate 2.8 kcal/mol of torsional
`strain relative to the staggered conformations. The methyl-methyl eclipsed confor(cid:173)
`mation is further strained by van der Waals repulsion between methyl groups. The
`van der Waals repulsions between methyl and hydrogen are smaller in the other
`eclipsed conformations. If we subtract the
`torsional-strain contribution of
`2.8 kcal/mol we conclude that the methyl-methyl eclipsing interaction destabilizes
`the 0° conforma