Advanced Organic Chemistry Part A: Structure and Mechanisms

ADVANCED ORGANIC CHEMISTRY

PART A: Structure and Mechanisms PART B: Reactions and Synthesis

Advanced Organic Chemistry Part A: Structure and Mechanisms

Francis A. Carey and Richard 1. Sundberg University of Virginia, Charlottesville, Virginia

PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

Carey, Francis A 1937-Advanced organic chemistry.

Includes bibliographical references and indexes. CONTENTS: pt. A. Structure and mechanisms.-pt. B. Reactions and synthesis. 1. Chemistry, Organic. I. Sundberg, Richard J., 1938- joint author. II. Title.

[DNLM: 1. Chemistry, Organic. QD258 C273a) QD251.2.C36 547 76-26090

ISBN-13: 978-1-4615-8884-9 e-ISBN-13: 978-1-4615-8882-5 001: 10.1007/978-1-4615-8882-5

Softcover reprint of the hardcover 1 st edition 1977

© 1977 Plenum Press, New York A Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011

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

Preface to Part A

This volume is intended to serve as an advanced text in organic chemistry and is aimed at developing a deeper understanding of the structure of organic compounds and the mechanisms of organic reactions. The text assumes introductory courses in organic chemistry and in physical chemistry. The first three chapters consider three fundamental aspects of the structure of organic molecules: bondirfg, stereochemis­try, and conformation. Chapter 4 is an overview of the methods that have been used to probe details of organic reaction mechanisms. The remaining chapters are organized on the basis of fundamental mechanistic patterns, although we return to the topic of structure in Chapter 9, in which aromatic molecules are considered. At Virginia, we have used this material in a course that serves third- and fourth-year undergraduate chemistry majors and beginning graduate students.

By the use of extensive references and referenced problems from the literature, we hope to provide an opportunity for the student to delve into the research literature. Considerable numerical data are included with the intent that the student can supplement a qualitative understanding of the role that substituents and other structural features play in organic reactions with some grasp of the magnitude of such effects. A considerable amount of this material is presented with a minimum of commentary in schemes and tables. Much of organic chemistry, however, resists interpretation in terms of a single variable. Often, several factors may operate in different directions to influence rate or equilibria or both, and it may not be possible to make consistently correct interpretations by inspection. Caution also needs to be exercised in attempts at rationalizing small differences in rate or equilibria or both. We recommend that instructors and students use these schemes and tables as working outlines for further discussion.

We have tried to emphasize the teaching of concepts in our development and treatment of the material. This emphasis of concepts is often best done by referring the reader to review articles, and sometimes produces the unfortunate result of failing to credit important contributions to their original source. To our colleagues

v

VI

PREFACE TO PART A

whose work fell into this category, we extend our apologies and request their understanding of our attempts to produce a working text, rather than to review the historical development of various concepts and techniques.

This volume is a companion to Part B, Reactions and Synthesis. Part B emphasizes the synthetically important organic reactions. It adds some further mechanistic information, but is aimed primarily at introducing to students the available repertoire of organic reactions and providing an opportunity to develop a background in synthetic methodology.

We believe that Parts A and B used sequentially as texts in a one-year advanced course will prepare the student to turn to the extensive review and monograph literature and to the primary journals with a thorough exposure to both the mechanistic and synthetic areas of organic chemistry.

Francis A. Carey Richard J. Sundberg Charlottesville, Virginia

Contents of Part A

List of Figures

List of Tables

List of Schemes

Contents of Part B

Chapter 1. Chemical Bonding and Molecular Structure

Introduction . . . . . . . . . . . . . . . 1.1. Valence-Bond Approach to Chemical Bonding 1.2. Bond Energies, Lengths, and Dipoles 1.3. Molecular Orbital Theory 1.4. Hiickel Molecular Orbital Theory

General References Problems

Chapter 2. Stereochemical Principles

Introduction . . . . . . . 2.1. Enantiomeric Relationships 2.2. Diastereomeric Relationships 2.3. Dynamic Stereochemistry. 2.4. Prochiral Relationships

General References Problems ....

Chapter 3. Conformational and Other Steric Effects

Introduction . . . . . . . . . . . 3.1. Steric Strain and Molecular Mechanics 3.2. Conformations of Acyclic Molecules .

Xlll

xvii

xxi

xxiii

1

1 2

10 15 26 32 32

39

39 40 45 53 61 66 66

71

71 72 78

Vlll

CONTENTS OF PART A

3.3. Conformations of Cyclohexane Derivatives . 3.4. Carbocyclic Rings Other Than Six-Membered 3.5. Heterocyclic Conformational Analysis . . . 3.6. Molecular Orbital Methods Applied to Conformational Analysis 3.7. Conformational Effects on Reactivity 3.8. Other Steric Effects on Reactivity

General References Problems ....

83 94 98

103 107 111 119 119

Chapter 4. Study and Description of Organic Reaction Mechanisms 125

Introduction . . . . 4.1. Thermodynamic Data .............. . 4.2. Kinetic Data . . . . . . . . . . . . . . . . . . . 4.3. Substituent Effects and Linear Free-Energy Relationships 4.4. Isotope Effe<;ts . . . . . . . . . . . . 4.5. Characterization of Reaction Intermediates 4.6. Catalysis ............. . 4.7. Solvent Effects . . . . . . . . . . . . 4.8. Basic Mechanistic Concepts: Kinetic Versus Thermodynamic

125 125 127 139 149 152 154 158

Control, Hammond's Postulate, the Curtin-Hammett Principle 163 4.9. Isotopes in Labeling Experiments 170 4.10. Stereochemistry 171

General References 172 Problems .... 173

Chapter 5. Nucleophilic Substitution 183

Introduction . . . . . . . . . . . . . . . . . . . . 183 5.1. The Limiting Cases-Substitution by the Ionization (SN1)

Mechanism . . . . . . . . . . . . . . . . . . . . . 184 5.2. The Limiting Cases-Substitution by the Direct Displacement (SN2)

Mechanism .......... 187 5.3. Alternative Mechanistic Hypotheses 190 5.4. Carbonium Ions 195 5.5. Nucleophilicity . . . . . . . . . 206 5.6. Leaving-Group Effects ..... 212 5.7. Steric and Other Substituent Effects on Substitution and Ionization

Rates . . . . . . . . . . . . . . . . . . . . . . . . 215 5.8. Stereochemistry of Nucleophilic Substitution ....... 219 5.9. Secondary Kinetic Isotope Effects in Substitution Mechanisms 227 5.10. Neighboring-GroupParticipation . . . . . . . . . . . . 229 5.11. Carbonium Ion Rearrangements ............ 236 5.12. Nonclassical Carbonium Ions and the Norbornyl Cation Problem 242 5.13. Synthetic Applications of Nucleophilic Substitution Reactions 249

General References 257 Problems .... 257

Chapter 6. Polar Addition and Elimination Reactions

Introduction . . . . . . . . . . . . 6.1. Addition of Hydrogen Halides to Alkenes 6.2. Acid-Catalyzed Hydration of Alkenes 6.3. Addition of Halogens . . . . . . . 6.4. TheE2,El,andElcbMechanisms .. 6.5. Orientation Effects in Elimination Reactions 6.6. Stereochemistry of E2 Elimination Reactions 6.7. Dehydration of Alcohols . . . . . . 6.8. Eliminations Not Involving C-H Bonds

General References Problems ....

Chapter 7. Carbanions and Other Nucleophilic Carbon Species

Introduction . . . . . . . . . . . . . 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

Introduction . . . . . . . . . . . . . . . . . . . . . 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 and Related Reactions ..... . 8.5. Amide Hydrolysis .............. . 8.6. Acylation of Nucleophilic Oxygen and Nitrogen Groups 8.7. Intramolecular Catalysis

General References Problems

Chapter 9. Aromaticity and Electrophilic Aromatic Substitution

9.1. Aromaticity . . . . . . . . . . 9.1.1. The Concept of Aromaticity 9.1.2. TheAnnulenes ..... . 9.1.3. Aromaticity in Charged Rings 9.1.4. Fused-RingSystems 9.1.5. Homoaromaticity . . . . .

9.2. Electrophilic Aromatic Substitution Reactions 9.3. Structure-Reactivity Relationships 9.4. Specific Substitution Mechanisms

9.4.1. Nitration ...... .

265 IX

265 CONTENTS OF

266 PART A

271 272 278 282 286 290 291 294 294

299

299 299 307 315 319 319

325

325 326 329 334 335 341 343 347 352 352

361

361 361 365 372 376 383 385 391 400 400

x CONTENTS OF PART A

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 .

9.5. Theoretical Treatments of Aromatic Substitution Reactions General References Problems ....

Chapter 10. Concerted Reactions

Introduction . . . . . . 10.1. Electrocyc1ic Reactions 10.2. SigmatropicRearrangements 10.3. Cyc1oaddition and Cyc1oelimination Reactions

General References Problems ....

Chapter 11. Photochemistry

404 408 410 412 414 415 417 419 419

425

425 426 439 449 457 458

465

11.1. General Principles ................. 465 11.2. Orbital Symmetry Considerations Related to Photochemical

Reactions . . . . . . . . . . . . 470 11. 3. Photochemistry of Carbonyl Groups . . 474 11.4. Photochemistry of Alkenes and Dienes . 483 11.5. Photochemistry of Aromatic Compounds 492

General References 494 Problems

Chapter 12. Free-Radical Reactions

12.1. Generation and Characterization of Free Radicals 12.1.1. Background ........... . 12.1.2. Stable 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

Intermediates . . . . . . . . . . . . . . . . 12.1.6. ChargedRadicalSpecies .......... .

12.2. Characteristics of Reaction Mechanisms Involving Radical Intermediates . . . . . . . . . . . . . . . . 12.2.1. Kinetic Characteristics of Chain Reactions 12.2.2. Structure-Reactivity Relationships

12.3. Free-Radical Substitution Reactions 12.3.1. Halogenation 12.3.2. Oxidation

494

501

501 501 502 504 510

512 516

519 519 522 527 527 531

12.3.3. Substitutions Involving Aryl Radicals 12.4. Free-Radical Addition Reactions

12.4.1. Addition of Hydrogen Halides . . 12.4.2. Addition of Halomethanes 12.4.3. Addition of Other Carbon Radicals 12.4.4. Addition of S-H Compounds

12.5. Intramolecular Free-Radical Reactions 12.6. Rearrangement and Fragmentation Reactions of Free Radicals

12.6.1. Rearrangement . . 12.6.2. Fragmentation

12.7. Electron-Transfer Reactions General References Problems ....

References for Problems

Subject Index . . . . .

532 Xl

534 CONTENTS OF 534 PART A

537 538 540 540 545 545 547 548 555 556

561

571

List of Figures

1.1. Idealized view of a-bond formation by overlap of an s- and a p-orbital and two p-orbitals . . . . . . . . . . . . . 3

1.2. Cross section of angular dependence of orbitals 4 1.3. The 'IT-bond in ethylene 4 1.4. 'IT-Bonding in acetylene 5 1.5. Bent bonds in cyclopropane 7 1.6. Graphic description of combination of two Is-orbitals to give two

molecular orbitals ............ 19 1. 7. Energy-level diagram for HHe + . . . . . . . . . . . . 20 1.8. Energy levels in the carbon monoxide molecule ..... 20 1.9. Representation of the molecular orbitals of carbon monoxide 21 1.10. Molecular orbital energies in atomic units for methane 23 1.11. Atomic orbital combinations giving rise to bonding molecular orbitals

for methane ........................ 23 1.12. ESCA spectrum of methane ................. 25 1.13. Graphic representation of 'IT-molecular orbitals of 1,3,5-hexatriene as

combinations of 2p-AO's .................. 29 1.14. Energy-level diagrams for cyclobutadiene and benzene . . . . .. 30 1.15. Energy-level diagrams for cyclobutadiene and benzene, illustrating

the application of Frost's circle .......... 31 1.16. Energy-level diagrams for C3H3 and C5H5 systems 31 2.1. Stereoisomeric relationships in 2,3,4-trihydroxybutanal 47 3.1. Potential energy as a function of torsion angle for ethane 73 3.2. Energy as a function of internuclear distance for nonbonded atoms 74 3.3. Potential energy diagram for rotation about C(2)-C(3) bond of

n-butane ................ 75 3.4. Energy diagram for ring inversion of cyclohexane 85

xiii

XIV

LIST OF FIGURES

3.5. Appearance of NMR spectra for system undergoing two~site

exchange .................... 86 3.6. NMR spectrum of cyclohexyl iodide at -80aC . . . . . 88 3.7. Equivalent diamond~lattice conformations of cyclodecane 98 3.8. Approximate energy diagram for acetylation of cis~ and trans~4~t-

butyIcyclohexanol ..................... 108 3.9. Approximate energy diagram for oxidation of cis- and trans-4~t-

butyIcyclohexanol ..................... 109 3.10. Approximate energy diagram for saponification of ethyl esters of cis-

and trans-4-t~butyIcyclohexanecarboxyIic acid ......... 11 0 4.1. Potential energy diagrams .................. 136 4.2. Correlation of acid dissociation constants of benzoic acids with rates

of alkaline hydrolysis of ethyl benzoates 140 4.3. Resonance effects 142 4.4. Field effects 142 4.5. Inductive effects 143 4.6. Differing zero-point energies of protium- and deuterium-substituted

molecules as the cause of primary kinetic isotope effects . . . . 149 4.7. BrS1lnsted relation for the hydrolysis of methyl cyclohexenyl ether .. 157 4.8. Specific solvation effects . . . . . . . . . . . . . . . . . .. 160 4.9. Reactant and transition-state solvation in the hydrolysis of ethyl

acetate .......................... 162 4.10. Kinetic versus thermodynamic control ............. 163 4.11. Some typical potential energy diagrams that illustrate the application

of Hammond's postulate . . . . . . . 165 4.12. Electrophilicaromaticsubstitution .... 166 4.13. Transition-state energies in bromination 167 4.14. Effect of conformation on product distribution 169 5.1. Potential energy diagram for nucleophilic substitution by the ioniza-

tion(SN1)mechanism ., . . . . . . . . . . . . . . . . .. 186 5.2. Potential energy diagram for nucleophilic substitution by the direct

displacement (SN2) mechanism ................ 188 5.3. Structure of macrocyclic polyether 18-crown-6 ......... 209 6.1. Enthalpy differences of starting alkenes and transition states in

bromination . . . . . . . . . . . . . . . . . . . 275 6.2. Variable-transition-state theory of elimination reactions 279 6.3. Product-determiningstepforEI elimination .... 283 8.1. Logarithm of the first-order rate constants for the hydrolysis of

substituted benzylidene-I, I-dimethylethylamines as a function of pH . . . . . . . . . . . . . . . . . . . . . . . . . . .. 331

8.2. pH-Rate profile for release of salicylic acid from benzaldehyde disalicyl acetal ..................... 348

9.1. Orbital energies for conjugated ring systems of 3-9 carbon atoms 362 9.2. Somefully conjugated monocylic organic ions . . . . . . . . 373

9.3. Transition states for highly reactive and less reactive electro-philes ......................... .

904. Various potential energy profiles for electrophilic aromatic substitu-tion ...................... .

10.1. Symmetry properties for the 7T-system of a conjugated diene . . . . 10.2. Symmetry properties of hexatriene molecular orbitals ..... . 10.3. Symmetry properties of cyclobutene and butadiene orbitals with

respect to the disrotatory opening of cyclobutene to butadiene lOA. Correlation diagram for cyclobutene and butadiene orbitals

(symmetry-forbidden reaction) . . . . . . . . . . . . . . . .

397

400 429 429

430

430 10.5. Symmetry properties of cyclobutene and butadiene orbitals with

respect to the conrotatory opening of cyclobutene or closure of butadiene . . . . . . . . . . . . . . . . . . . . . . . .. 431

10.6. Correlation diagram for cyclobutene and butadiene orbitals (symmetry-allowed reaction) . . . . . . . . . . . . . . . .. 431

10.7. Classification of sigmatropic hydrogen shifts with respect to basis set orbitals ............ . . . . . . . . . . . . .. 440

10.8. Classification of sigmatropic shifts of alkyl groups with respect to basis set orbitals . . . . . . . . . . . . . . . . . . . . . . . .. 441

10.9. Symmetry properties of ethylene, butadiene, and cyclohexene orbitals with respect to cycloaddition ................. 452

10.10. Correlation diagram for ethylene, butadiene, and cyclohexene orbi-tals . . . . . . . . . . . . . . . . . . . . . . . . . . .. 453

10.11. Classification of cycloaddition reactions with respect to basis set orbitals ........................ 454

10.12. Concerted cycloaddition of a ketene and an olefin ........ 457 11.1. Energy-level diagram and summary of photochemical processes .. 468 11.2. Orbital correlation diagram for two ground-state ethylenes and

cyclobutane ........................ 470 11.3. Orbital correlation diagram for one ground-state alkene and one

excited alkene ....................... 470 1104. Correlation of energy states involved in the photochemical butadiene­

to-cyclobutene conversion . . . . . . . . . . . . . . . . .. 472 11.5. Energy diagram illustrating the relationship between thermal and

photochemical reactions . . . . . . . . . . . . . . . . . .. 473 11.6. Symmetry properties for 1,4-sigmatropic shifts with inversion and

11.7. 11.8.

12.1. 12.2. 12.3.

retention Absorption spectra of a cis-trans isomer pair ... . . . . . . . . Energy of excited states involved in cis-trans isomerization of stil-bene ................. . Hyperfine splitting in EPR spectra . . . . . . . . . . . . . . . Some EPR spectra of small organic free radicals ........ . NMR spectra recorded during thermal decomposition of dibenzoyl peroxide ........................ .

482 484

485 505 506

508

xv

LIST OF FIGURES

List of Tables

1.1. Dependence of structure on hybridization of carbon 5 1.2. Bond lengths . . . . . . . . . . . . . . . . 10 1.3. Bond energies ............... 11 1.4. Standard heats of formation of some hydrocarbons 12 1.5. Heats of hydrogenation of some alkenes .... 13 1.6. Atomic and group electronegativities .... 13 1.7. Bond and group dipoles for some organic functional groups 14 1.8. pKa Values for some substituted acetic acids . . . . . . 15 1.9. Coefficients of wave functions calculated for methyl cation by

CNDO/2 approximation . . . . . . . . . . . . . . . 18 1.10. Energy levels and coefficients for HMO's of 1,3,5-hexatriene 28 3.1. Van der Waals radii of several atoms and groups . . . . . 74 3.2. Composition-equilibrium-free-energy relationships 77 3.3. Rotational energy barriers of compounds of the type CH3-X 79 3.4. Half-life of equatorial cyclohexyl chloride at various temperatures 87 3.5. Conformationalfree energies for substituent groups ...... 89 3.6. Relative strain energies of cycloalkanes ........... 95 3.7. Conformational free energies for substituents in 1,3-dioxanes and

1,3-dithianes . . . . . . . . . . . . . . . . . . . . . . .. 100 3.8. Energy-component changes for ethane and ethyl fluoride: Conversion

of staggered conformation to eclipsed .... 105 3.9. Strainenergiesinsomealicycliccompounds . . . . 112 3.10. Relative stabilities of cis- and trans-cycloalkenes . . 115 3.11. Comparison of the stereochemistry of reactions with

bicyclo[2.2.1 ]heptene and 7,7 -dimethylbicyclo[2.2.1 ]heptene 118 4.1. Substituent constants 145 4.2. Reaction constants 145

xvii

XVlll 4.3. Classification of substituent groups 148

LIST OF 4.4. Dielectric constants of some common solvents 158

TABLES 4.5. Y values for some solvent systems 159 5.1. Values of HR for sulfuric acid-water mixtures 197 5.2. Values of pKR+ for some carbonium ions 198 5.3. Nucleophilic constants of various nucleophiles 208 5.4. Values of N+ for nucleophiles 210 5.5. Solvent nucleophilicity values 211 5.6. Relative solvolysis rates of I-phenylethyl esters and halides 212 5.7. Relative solvolysis rates of ethyl sulfonates and halides 213 5.8. Tosylate/bromide rate ratios for solvolysis of RX in 80% ethanol 214 5.9. Rate constants for nucleophilic substitution in primary alkyl sub-

strates 215 5.10. Relative hydrolysis rates of 2-alkyl-2-adamantyl p-nitrobenzoates 217 5.11. a -Substituent effects 218 5.12. Stereochemical course of nucleophilic substitution reactions 221 5.13. Stereochemical course of deamination reactions in acetic acid 226 5.14. Solvolysis rates of w-chloroalcohols 232 5.15. Solvolysis of some w-methoxyalkyl p-bromobenzenesulfonates in

acetic acid 233 5.16. Extent of aryl rearrangement in 2-phenylethyl tosylate solvolysis 235 5.17. Extent of solvolysis with aryl participation as a function of substituent

and solvent for l-aryl-2-propyl tosylates 236 6.1. Stereochemistry of halogenation 273 6.2. Relative reactivity of alkenes toward halogenation 277 6.3. Product ratios for some E2 eliminations 284 6.4. Orientation in E2 elimination as a function of base strength 285 6.5. Orientation of elimination in the 2-butyl system under various E2

conditions 286 6.6. Stereochemistry of E2 eliminations for some acyclic substrates 288 7.1. Values of H- for some representative solvent-base systems 301 7.2. Acidities of some hydrocarbons 303 7.3. Equilibrium acidities of substituted methanes in dimethyl sulfoxide 308 7.4. Relative rates of base-catalyzed deuteration of some ketones 310 7.5. Acidities of some cyano compounds 312 7.6. Acidities of some compounds with sulfur and phosphorus sub-

stituents 313 7.7. Relative rates of acid-catalyzed enolization for some ketones 317 7.8. Mole fraction of enol in some organic compounds 318 8.1. Equilibrium constants for hydration of carbonyl compounds 327 8.2. Rates of reduction of aldehydes and ketones by sodium borohy-

dride 335 9.1. Stabilization energies of some conjugated hydrocarbons 378 9.2. Resonance-energy calculations 381

9.3. Percent meta nitration for some alkyl groups with electron-withdrawing substituents . . . . . . . . . . . . . . . . .

9.4. Isomer proportions in the nitration of some substituted benzenes 9.5. Selectivity in some electrophilic aromatic substitution reactions 9.6. Values of p for some electrophilic aromatic substitution reactions 9.7. Kinetic isotope effects in some electrophilic aromatic substitution

reactions ........................ . 9.8. Relative reactivity and position selectivity for nitration of some

aromatic compounds .................. . 9.9. Partial rate factors for hydrogen exchange in some substituted

aromatic compounds ................... . 9.10. Toluene-benzene reactivity ratios in Friedel-Crafts alkylation reac-

tions .......................... . 9.11. Substrate and position selectivity in Friedel-Crafts acylation reac-

tions .......................... . 11.1. General wavelength ranges for lowest energy-absorption band of

some classes of photochemical substrates . . . . . . . . . . . 12.1. Bond-dissociation energies . . . . . . . . . . . . . . . . . 12.2. Relative reactivities of some aromatic hydrocarbons toward oxygen

XIX 394

LIST OF 395 TABLES

396 399

399

403

409

411

413

466 525 532

List of Schemes

2.1. Planar and axially dissymmetric molecules of established configura-tion ........................... 46

2.2. Resolution of 2-phenyl-3-methylbutanoic acid ......... 51 2.3. Stereoisomeric alkenes and related molecules with the double-bond

geometry named according to the sequence rule 52 2.4. Stereospecific reactions .......... 54 2.5. Stereoselectivereactions . . . . . . . . . . 56 3.1. Equilibria in compounds that exhibit the anomeric effect 101 3.2. Effects of functional-group orientation on rates and equilibria 108 3.3. Some data correlated by the I -strain concept 114 3.4. Bridgehead olefins .......... 117 4.1. Some representative rate laws ..... 129 4.2. Some representative kinetic isotope effects 151 4.3. Effect ofsolvent polarity on reactions of various charge types 160 5.1. Representative nucleophilic substitution reactions . . . . 184 5.2. Protonation and ionization of organic substrates in superacid media 202 5.3. Conversion ofalcohols to halides ............. 252 5.4. Some synthetically important nucleophilic substitution reactions 254 6.1. Some examples of /3-elimination reactions ......... 280 8.1. Acetals and ketals that exhibit general acid catalysis in hydrolysis 329 8.2. Some addition-elimination reactions of aldehydes and ketones 330 9.1. Electrophilic species active in aromatic substitution .... 386 9.2. Generalized mechanism for electrophilic aromatic substitution 388

10.1. Some 1,3-dipoles . . . . . . . . . . . . . . . . . . . 455 11.1. Some examples of photochemical cycloaddition and electrocyclic

reactions .................... 474 12.1. Stability of some free radicals . . . . . . . . . . . . 503 12.2. Stereochemistry ofradical reactions at chiral carbon atoms 514

XXI

XXll 12.3. Radical halogenation ....... 529

LIST OF 12.4. Free-radical chain additions to olefins 536

SCHEMES 12.5. Free-radical rearrangements . . . . 546 12.6. Carbon alkylation via nitroalkane radical anions generated by elec-

tron transfer . . . . . . . . . . . . . . . . . . . . . . .. 554

Contents of Part B

List of Figures

List of Tables

List of Schemes

Contents of Part A

Chapter 1. Alkylation of Carbon via Enolates and Enamines

xi

xiii

xv

xix

1

1.1. Generation of Carbon Nudeophiles by Proton Abstraction 1 1.2. Kinetic Versus Thermodynamic Control in Formation of Enolates 3 1.3. Other Means of Generating Enolates 7 1.4. Alkylations of Enolates . . . . . . . 8 1.5. Generation and Alkylation of Dianions 12 1.6. Solvent Effects in Enolate Alkylations . 12 1.7. Oxygen Versus Carbon as the Site of Alkylation 15 1.8. Alkylations of Aldehydes, Esters, Nitriles, and Nitro Compounds. 19 1.9. The Nitrogen Analogs of Enols and Enolates-Enamine Alkylations 21

1.10. Alkylation of Carbon by Conjugate Addition 24 General References 28 Problems . . . . . . . . . . . . . . . 28

Chapter 2. Reactions of Nucleophilic Carbon Species with Carbonyl Groups 33

2.1. Aldol Condensation. . . . . . 33 2.2. Related Condensation Reactions 42 2.3. The Mannich Reaction .... 44 2.4. AcylationofNudeophilicCarbon 47 2.5. The Wittig Reaction .... 53

xxiii

XXIV

CONTENTS OF PART B

2.6. Sulfur Ylides as Nucleophiles 2.7. Nucleophilic Addition-Cyclization

General References . Problems .......... .

Chapter 3. Addition Reactions of Carbon-Carbon Multiple Bonds

3.1. Addition of Hydrogen .......... . 3.2. Addition of Hydrogen Halides . . . . . . . 3.3. Hydration and Other Acid-Catalyzed Additions 3.4. Oxymercuration .......... . 3.5. Addition of Halogens to Ole fins . . . . . . . 3.6. Addition of Other Electrophilic Reagents 3.7. Electrophilic Substitution Alpha to Carbonyl Groups 3.8. Hydroboration ...... . 3.9. Additions to Allenes and Alkynes

General References Problems ......... .

Chapter 4. Reduction of Carbonyl and Other Functional Groups

4.1. Hydride-Transfer Reagents 4.2. Hydrogen-Atom Donors 4.3. Dissolving-Metal Reductions

General References Problems ........ .

Chapter 5. Organometallic Compounds

5.1. Organic Derivatives of Group I and II Metals 5.1.1. Preparation and Properties 5.1.2. Reactions ...... .

5.2. Organic Derivatives of Group IIb Metals 5.3. Organic Derivatives of Transition Metals 5.4. Catalysis of Rearrangements by Metal Ions and Complexes 5.5. Organometallic Compounds with 1T-Bonding

General References Problems .............. .

Chapter 6. Cycloadditions and Unimolecular Rearrangements and Eliminations

6.1. Cycloaddition Reactions ..... . 6.1.1. Diels-Alder Reaction ... . 6.1.2. Dipolar Cycloaddition Reactions 6.1.3. 2+2 Cycloadditions and Other Reactions Leading to

Cyclobutanes 6.2. Photochemical Cycloadditions . . . . . . . . . . . . .

59 63 64 65

73

73 81 85 87 90 95 98

100 112 121 122

129

129 143 145 152 152

163

163 163 170 180 182 191 193 197 198

205

205 206 212

219 222

6.3. Sigmatropic Rearrangements ....... . 6.4. Unimolecular Thermal Elimination Reactions

6.4.1. Cycloreversions and Related Eliminations 6.4.2. f3-Eliminations Involving Cyclic Transition States General References Problems ............ .

Chapter 7. Aromatic Substitution Reactions

7.1. Electrophilic Aromatic Substitution 7.1.1. Nitration . . . . . . . . 7.1.2. Halogenation . . . . . . 7.1.3. Friedel-Crafts Alkylations and Acylations 7.1.4. Electrophilic Metalation ...... .

7.2. Nucleophilic Aromatic Substitution . . . . . . 7.2.1. Nucleophilic Aromatic Substitution via Diazonium Ions 7.2.2. Nucleophilic Aromatic Substitution by Addition-Elimination 7.2.3. Nucleophilic Aromatic Substitution by Eliminationc..Addition 7.2.4. Copper-Catalyzed Nucleophilic Aromatic Substitution

7.3. Substitutions Involving Aryl Free Radicals 7.4. Reactivity of Polycyclic Aromatics

General References Problems .......... .

Chapter 8. Reactions Involving Carbenes, Nitrenes, and Other

226 234 235 242 247 248

257

257 257 260 261 272 275 275 280 282 288 288 292 294 295

Electron-Deficient Intermediates 301

8.1. Carbenes . . . . . . . . . 302 8.1.1. Structure . . . . . . 302 8.1.2. Generation of Carbenes 304 8.1.3. Reactions ..... 311

8.2. Nitrenes . . . . . 320 8.3. Rearrangements of Electron-Deficient Intermediates 322

8.3.1. Migration to Carbon 322 8.3.2. Migration to Nitrogen 328

8.4. Fragmentation Reactions 333 8.5. Some Synthetically Useful Carbonium-Ion Reactions 336

General References 343 Problems . . . . . . . . . . . . . . . . . . . 343

Chapter 9. Oxidations 351

9.1. Oxidation of Alcohols to Aldehydes, Ketones, or Carboxylic Acids 351 9.1.1. Transition-Metal Oxidants 351 9.1.2. Oxygen, Ozone, and Peroxides . . . . . . . 356 9.1.3. Other Oxidants ............. 356

9.2. Addition of Oxygen at Carbon-Carbon Double Bonds 359

xxv CONTENTS OF

PART B

XXVI

CONTENTS OF PART B

9.2.1. Transition-Metal Oxidants 9.2.2. Epoxides from Olefins and Peroxidic Reagents

9.3. Qeavage of Carbon-Carbon Double Bonds 9.3.1. Transition-Metal Oxidants ....... . 9.3.2. Ozonolysis ...... . ...... .

9.4. Selective Oxidative Qeavages at Other Functional Groups 9.4.1. QeavageofGlycols .... 9.4.2. Oxidative Decarboxylation

9.5. Oxidations of Ketones and Aldehydes 9.5.1. Transition-Metal Oxidants 9.5.2. Oxidation of Ketones and Aldehydes by Peroxidic Compounds

andOxygen ........ . 9.5.3. Oxidations with Other Reagents

9.6. Allylic Oxidation of Olefins .... 9.6.1. Transition-MetalOxidants . . 9.6.2. Oxygen, Ozone, and Peroxides 9.6.3. Other Oxidants ..... .

9.7. Oxidations at Unfunctionalized Carbon Atoms General References Problems ....... .

Chapter 10. Multistep Syntheses

10.1. Protective Groups ....... . 10.1.1. Hydroxyl-ProtectingGroups 10.1.2. Amino-ProtectingGroups . 10.1.3. Carbonyl-Protecting Groups 10.1.4. Carboxylic Acid Protecting Groups

10.2. Synthetic Equivalent Groups 10.3. AsymmetricSyntheses 10.4. Synthetic Strategy

General References Problems .....

Chapter 11. Synthesis of Macromolecules

11.1. Polymerization ........ . 11.1.1. Chain-Addition Polymerization 11.1.2. Step-Growth Polymerization .

11.2. Peptide and Protein Synthesis .... 11.3. Nucleosides, Nucleotides, and Polynucleotides

General References Problems ............... .

References for Problems

Subject Index . . . . .

359 362 371 371 373 377 377 379 381 381

383 386 387 387 388 390 393 396 396

407

407 408 414 416 417 418 423 429 449 450

459

460 460 467 472 482 491 491

497

509

Advanced Organic Chemistry Part A: Structure and Mechanisms