Writing Reaction Mechanisms in Organic Chemistry by Audrey Miller, Philippa H. Solomon • ISBN: 0124967124 • Publisher: Elsevier Science & Technology Books • Pub. Date: November 1999 PREFACE TO THE SECOND EDITION In revising this text for the second edition, a major goal was to make the book more user-friendly for both graduate and undergraduate students. Introductory material has been fleshed out. Headings have been added to make it easier to locate topics. The structures have been redrawn throughout, with added emphasis on the stereochemical aspects of reaction mechanisms. Coverage of some topics such as solvent effects and neighboring group effects has been expanded, and Chapter 6 has been completely reorganized and extensively rewritten. As in the previous edition, the focus of this book is on the how of writing organic mechanisms. For this reason and to keep the book compact and portable, the number of additional examples and problems has been mini mized, and no attempt has been made to cover additional topics such as oxidation-reduction and organotransition metal reactions. The skills devel oped while working through the material in this book should equip the reader to deal with reactions whose mechanisms have been explored less thoroughly. I am most grateful to the reviewers, who gave so generously of their time and experience in making suggestions for improving this book. Particular thanks go to series editor Jim Whitesell, who cast his eagle eye over the numerous structures and contributed to many stimulating discussions. Thanks also to John DiCesare and Hilton Weiss, and to John Murdzek, who meticu lously annotated the entire manuscript both before and after revisions. Any comments regarding errors or suggestions for improvements in future edi tions will be most welcome. XI xii Preface to the Second Edition Finally, my warmest thanks go to my husband, Dan, and to my children, Michael, Sarah, and Jeremy. Their loyal support, unflagging patience, and bizarre sense of humor bolster my spirits daily and shortened the long hours involved in preparing the manuscript. Philippa Solomon P R E F A CE TO T HE FIRST EDITION The ability to write feasible reaction mechanisms in organic chemistry depends on the extent of the individual's preparation. This book assumes the knowledge obtained in a one-year undergraduate course. A course based on this book is suitable for advanced undergraduates or beginning graduate students in chemistry. It can also be used as a supplementary text for a first-year course in organic chemistry. Because detailed answers are given to all problems, the book also can be used as a tutorial and a review of many important organic reaction mecha nisms and concepts. The answers are located conveniently at the end of each chapter. Examples of unlikely mechanistic steps have been drawn from my experience in teaching a course for beginning graduate students. As a result, the book clears up many aspects that are confusing to students. The most benefit will be obtained from the book if an intense effort is made to solve the problem before looking at the answer. It is often helpful to work on a problem in several different blocks of time. The first chapter, a review of fundamental principles, reflects some of the deficiencies in knowledge often noted in students with the background cited above. The second chapter discusses some helpful techniques that can be utilized in considering possible mechanisms for reactions that may be found in the literature or during the course of laboratory research. The remaining chapters describe several of the common types of organic reactions and their mechanisms and propose mechanisms for a variety of reactions reported in the literature. The book does not cover all types of reactions. Nonetheless, XIII xiv Preface to the First Edition anyone who works all the problems will gain insights that should facilitate the writing of reasonable mechanisms for many organic reactions. Literature sources for most of the problems are provided. The papers cited do not always supply an answer to the problem but put the problem into a larger context. The answers to problems and examples often consider more than one possible mechanism. Pros and cons for each mechanism are pro vided. In order to emphasize the fact that frequently more than one reason able pathway to a product may be written, in some cases experimental evidence supporting a particular mechanism is introduced only at the end of consideration of the problem. It is hoped that this approach will encourage users of this book to consider more than one mechanistic pathway. I acknowledge with deep gratitude the help of all the students who have taken the course upon which this book is based. Special thanks to Drs. David Kronenthal, Tae-Woo Kwon, and John Freilich and Professor Hilton Weiss for reading the manuscript and making extremely helpful suggestions. Many thanks to Dr. James Holden for his editing of the entire manuscript and to my editor, Nancy Olsen, for her constant encouragement. Audrey Miller Table of Contents Preface to the Second Edition xi Preface to First Edition xiii 1 Introduction: Molecular Structure and Reactivity How to Write Lewis Structures and Calculate Formal 1. 2 Charges A. Determining the Number of Bonds 2 Determining the Number of Rings and/or [pi] Bonds B. 2 (Degree of Unsaturation C. Drawing the Lewis Structure 3 D. Formal Charge 6 2. Representations of Organic Compounds 12 3. Geometry and Hybridization 14 4. Electronegativities and Dipoles 16 5. Resonance Structures 18 A. Drawing Resonance Structures 18 B. Rules for Resonance Structures 23 6. Aromaticity and Antiaromaticity 26 A. Aromatic Carbocycles 26 B. Aromatic Heterocycles 27 C. Antiaromaticity 28 7. Tautomers and Equilibrium 29 8. Acidity and Basicity 32 9. Nucleophiles and Electrophiles 37 A. Nucleophilicity 37 B. Substrate 38 C. Solvent 39 2 General Principles for Writing Reaction Mechanisms 1. Balancing Equations 64 2. Using Arrows to Show Moving Electrons 66 3. Mechanisms in Acidic and Basic Media 69 4. Electron-Rich Species: Bases or Nucleophiles? 76 5. Trimolecular Steps 78 6. Stability of Intermediates 79 7. Driving Forces for Reactions 82 A. Leaving Groups 83 B. Formation of a Small Stable Molecule 84 Structural Relationships between Starting Materials and 8. 85 Products 9. Solvent Effects 86 10. A Last Word 88 3 Reactions of Nucleophiles and Bases 1. Nucleophilic Substitution 106 A. The S[subscript N]2 Reaction 106 Nucleophilic Substitution at Aliphatic sp[superscript 2] B. 112 Carbon (Carbonyl Groups) C. Nucleophilic Substitution at Aromatic Carbons 116 2. Eliminations at Saturated Carbon 120 A. E2 Elimination 120 B. Ei Elimination 122 3. Nucleophilic Addition to Carbonyl Compounds 123 A. Addition of Organometallic Reagents 123 Reaction of Nitrogen-Containing Nucleophiles with B. 128 Aldehydes and Ketones Reactions of Carbon Nucleophiles with Carbonyl C. 130 Compounds 4. Base-Promoted Rearrangements 141 A. The Favorskii Rearrangement 141 B. The Benzilic Acid Rearrangement 142 5. Additional Mechanisms in Basic Media 144 4 Reactions Involving Acids and Other Electrophiles 1. Stability of Carbocations 195 2. Formation of Carbocations 196 A. Ionization 196 B. Addition of an Electrophile to a [pi] Bond 197 C. Reaction of an Alkyl Halide with a Lewis Acid 199 3. The Fate of Carbocations 199 4. Rearrangement of Carbocations 200 A. The Dienone-Phenol Rearrangement 204 B. The Pinacol Rearrangement 206 5. Electrophilic Addition 208 A. Regiospecificity 208 B. Stereochemistry 209 6. Acid-Catalyzed Reactions of Carbonyl Compounds 213 A. Hydrolysis of Carboxylic Acid Derivatives 213 B. Hydrolysis and Formation of Acetals and Orthoesters 216 C. 1,4-Addition 218 7. Electrophilic Aromatic Substitution 220 8. Carbenes 224 A. Singlet and Triplet Carbenes 225 B. Formation of Carbenes 226 C. Reactions of Carbenes 227 9. Electrophilic Heteroatoms 231 A. Electron-Deficient Nitrogen 232 B. Rearrangements Involving Electrophilic Nitrogen 233 C. Rearrangement Involving Electron-Deficient Oxygen 238 5 Radicals and Radical Anions 1. Introduction 283 2. Formation of Radicals 284 A. Homolytic Bond Cleavage 284 B. Hydrogen Abstraction from Organic Molecules 285 C. Organic Radicals Derived from Functional Groups 286 3. Radical Chain Processes 287 4. Radical Inhibitors 290 Determining the Thermodynamic Feasibility of Radical 5. 292 Reactions 6. Addition of Radicals 294 A. Intermolecular Radical Addition 294 Intramolecular Radical Addition: Radical Cyclization B. 296 Reactions 7. Fragmentation Reactions 299 A. Loss of CO[subscript 2] 299 B. Loss of a Ketone 300 C. Loss of N[subscript 2] 300 D. Loss of CO 300 8. Rearrangement of Radicals 303 9. The S[subscript RN] 1 Reaction 307 10. The Birch Reduction 310 A Radical Mechanism for the Rearrangement of Some 11. 312 Anions 6 Pericyclic Reactions 1. Introduction 343 A. Types of Pericyclic Reactions 343 B. Theories of Pericyclic Reactions 344 2. Electrocyclic Reactions 346 A. Selection Rules for Electrocyclic Reactions 346 Stereochemistry of Electrocyclic Reactions (Conrotatory B. 347 and Disrotatory Processes) Electrocyclic Reactions of Charged Species (Cyclopropyl C. 353 Cations) 3. Cycloadditions 355 A. Terminology of Cycloadditions 355 B. Selection Rules for Cycloadditions 358 C. Secondary Interactions 361 D. Cycloadditions of Charged Species 362 4. Sigmatropic Rearrangements 366 A. Terminology 366 B. Selection Rules for Sigmatropic Rearrangements 368