ELECTRON FLOW IN ORGANIC CHEMISTRY

ELECTRON FLOW IN ORGANIC CHEMISTRY

ELECTRON FLOW IN ORGANIC CHEMISTRY A Decision-Based Guide to Organic Mechanisms Second Edition Paul H. Scudder New College of Florida WILEY A JOHN WILEY & SONS, INC., PUBLICATION

Copyright 2013 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317)572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data Scudder, Paul H. Electron flow in organic chemistry : a decision-based guide to organic mechanisms / Paul H. Scudder, New College of Florida. Second edition. pages cm Includes index. Summary: "The revised 2nd edition builds on and improves this legacy, continuing the rigorous mechanistic approach to organic chemistry. Each mechanistic process is divided into its basic units, the dozen common electron flow pathways that become the building blocks of all the common mechanistic processes" Provided by publisher. ISBN 978-0-470-63804-0 (pbk.) 1. Chemistry, Organic. 2. Chemical bonds. 3. Charge exchange. I. Title. QD251.3.S38 2013 547.128 dc23 2012025745 Printed in the United States of America. 10 987654321

Contents in Brief 1 BONDING AND ELECTRON DISTRIBUTION 1 2 THE PROCESS OF BOND FORMATION 34 3 PROTON TRANSFER AND THE PRINCIPLES OF STABILITY 61 4 IMPORTANT REACTION ARCHETYPES 88 5 CLASSIFICATION OF ELECTRON SOURCES 151 6 CLASSIFICATION OF ELECTRON SINKS 166 7 THE ELECTRON FLOW PATHWAYS 179 8 INTERACTION OF ELECTRON SOURCES AND SINKS 213 9 DECISIONS, DECISIONS 251 10 CHOOSING THE MOST PROBABLE PATH 269 11 ONE-ELECTRON PROCESSES 326 12 QUALITATIVE MOLECULAR ORBITAL THEORY AND 343 PERICYCLIC REACTIONS APPENDIX 364 INDEX 407

Contents 1 BONDING AND ELECTRON DISTRIBUTION 1 1.1 The Decision-Based Approach to Organic Chemistry 2 1.2 Ionic and Covalent Bonding 6 1.3 Lewis Structures and Resonance Forms 8 1.4 Curved-Arrow Notation 11 1.5 Nomenclature and Abbreviations 16 1.6 An Orbital View of Bonding 18 1.7 The Shapes of Molecules 21 1.8 Molecular Repulsions, Attractions, and Hydrogen Bonding 25 1.9 Conjugation, Vinylogy, Aromaticity 27 1.10 Summary 30 2 THE PROCESS OF BOND FORMATION 34 2.1 Energetics Control Knowledge 35 2.2 Orbital Overlap in Covalent Bond Formation 35 2.3 Orbital Interaction Diagrams 38 2.4 Polarizability and Hard and Soft Acid-Base Theory 41 2.5 Thermodynamics, Position of Equilibrium 43 2.6 Kinetics, Rate of Reaction 47 2.7 Solvent Stabilization of Ions 53 2.8 Enzymatic Catalysis Lessons from Biochemistry 55 2.9 Summary 57 3 PROTON TRANSFER AND THE PRINCIPLES OF STABILITY 3.1 Introduction to Proton Transfer 62 3.2 Ranking of Acids and Bases, the pk a Chart 63 3.3 Structural Factors That Influence Acid Strength 66 3.4 Structural Factors That Influence Base Strength 70 3.5 Carbon Acids and Ranking of Electron-Withdrawing Groups 3.6 Calculation of K e(, for Proton Transfer 76 3.7 Proton Transfer Mechanisms 77 3.8 Common Errors 81 3.9 Proton Transfer Product Predictions 82 3.10 Proton Transfer Summary 83 71 61 4 IMPORTANT REACTION ARCHETYPES 88 4.1 Introduction to Reaction Archetypes 89 4.2 Nucleophilic Substitution at a Tetrahedral Center 89 4.3 Elimination Reactions Create Pi Bonds 110 4.4 Addition Reactions to Polarized Multiple Bonds 124 4.5 Nucleophilic Substitution at a Trigonal Planar Center 133 4.6 Electrophilic Substitution at a Trigonal Planar Center 140 4.7 Rearrangements to an Electrophilic Carbon 144 4.8 Reaction Archetype Summary 146 5 CLASSIFICATION OF ELECTRON SOURCES 151 5.1 Generalized Ranking of Electron Sources 151 5.2 Nonbonding Electrons 152 5.3 Electron-Rich Sigma Bonds 154 5.4 Electron-Rich Pi Bonds 155 5.5 Simple Pi Bonds 156

5.6 Aromatic Rings 159 5.7 Summary of Generic Electron Sources 160 6 CLASSIFICATION OF ELECTRON SINKS 166 6.1 Generalized Ranking of Electron Sinks 166 6.2 Electron-Deficient Species 167 6.3 Weak Single Bonds 168 6.4 Polarized Multiple Bonds Without Leaving Groups 170 6.5 Polarized Multiple Bonds with Leaving Groups 172 6.6 Summary of Generic Electron Sinks 173 7 THE ELECTRON FLOW PATHWAYS 179 7.1 The Dozen Most Common Pathways 180 7.2 Six Minor Pathways 191 7.3 Common Path Combinations 197 7.4 Variations on a Theme 201 7.5 Twelve Major Paths Summary and Crosschecks 208 7.6 Six Minor Paths Summary 209 8 INTERACTION OF ELECTRON SOURCES AND SINKS 213 8.1 Source and Sink Correlation Matrix 214 8.2 H-A Sinks Reacting with Common Sources 214 8.3 Y-L Sinks Reacting with Common Sources 218 8.4 sp 3 C-L Sinks Reacting with Common Sources 222 8.5 C=Y Sinks Reacting with Common Sources 227 8.6 R-C=Y Sinks Reacting with Common Sources 233 8.7 C=C-Ewg Sinks Reacting with Common Sources 235 8.8 L-C=Y Sinks Reacting with Common Sources 237 8.9 Miscellaneous Reactions 240 8.10 Metal Ions as Electron Sinks 242 8.11 Rearrangements to an Electrophilic Center 243 8.12 Nu-L Reactions 244 8.13 Product Matrix Summary 248 9 DECISIONS, DECISIONS 251 9.1 Decision Point Recognition 252 9.2 Multiple Additions 252 9.3 Regiochemistry and Stereochemistry of Enolate Formation 254 9.4 Ambident Nucleophiles 255 9.5 Substitution vs. Elimination 258 9.6 Ambident Electrophiles 262 9.7 Intermolecular vs. Intramolecular 263 9.8 To Migrate or Not to an Electrophilic Center 264 9.8 Summary 266 10 CHOOSING THE MOST PROBABLE PATH 269 10.1 Problem Solving in General 270 10.2 General Mechanistic Crosschecks 274 10.3 The Path Selection Process 276 10.4 Reaction Mechanism Strategies 278 10.5 Worked Mechanism Examples 279

10.6 Product Prediction Strategies 297 10.7 Worked Product Prediction Examples 297 10.8 Methods for Testing Mechanisms 313 10.9 Lessons from Biochemical Mechanisms 319 10.10 Summary 321 ONE-ELECTRON PROCESSES 326 11.1 Radical Structure and Stability 326 11.2 Radical Path Initiation 329 11.3 Major Paths for Radicals Reacting with Neutrals 330 11.4 Unimolecular Radical Paths 332 11.5 Termination Radical Paths 333 11.6 Radical Path Combinations 333 11.7 Approaches to Radical Mechanisms 336 11.8 Single-Electron Transfer, S.E.T., and Charged Radicals 338 11.9 Dissolving Metal Reductions 339 11.10 Electron Transfer-Initiated Processes 340 11.11 One-Electron Path Summary 340 QUALITATIVE MOLECULAR ORBITAL THEORY AND PERICYCLIC REACTIONS 343 12.1 Review of Orbitals as Standing Waves 344 12.2 Molecular Orbital Theory for Linear Pi Systems 344 12.3 Molecular Orbital Theory for Cyclic Conjugated PI Systems 348 12.4 Perturbation of the HOMO And LUMO 351 12.5 Delocalization of Sigma Electrons 352 12.6 Concerted Pericyclic Cycloaddition Reactions 353 12.7 Concerted Pericyclic Electrocyclic Reactions 357 12.8 Concerted Pericyclic Sigmatropic Rearrangements 359 12.9 Pericyclic Reactions Summary 361 APPENDIX (A COLLECTION OF IMPORTANT TOOLS) Bibliography 364 Abbreviations Used in This Text 365 Functional Group Glossary 366 Composite pk a Chart 369 Bond Strength Table 372 Generic Classification Guide 373 Flowcharts for the Classification of Electron Sources and Sinks Pathway Summary 375 Trends Guide 380 Major Routes Summary 384 Major Decisions Guide 388 Thermodynamics and Kinetics 390 Generation of Alternate Paths, Reaction Cubes 390 Organic Structure Elucidation Strategies 393 Notes on Nomenclature 399 Hints to Selected Problems from Chapters 8, 9, and 10 404 INDEX 407 375 364

Preface TO THE STUDENT Critical Thinking Approach Organic chemistry courses have a well-deserved reputation for being highly memorization based. But it does not have to be so. An organic chemistry course is a great place to learn critical thinking. My students kept asking me, "Why didn't it do this instead of that?" Soon I was mapping out alternatives and getting them to decide the answers to those questions. My course had evolved from "know the answer" to "explain the answer," and also "predict what would happen here." As the course progressed, my students developed a good chemical intuition and felt they understood why reactions occurred. They could write reasonable mechanisms for unfamiliar reactions and predict what might happen for reactions they had never seen. How to learn organic chemistry by using this critical thinking approach is the essence of this book. Dealing with Informational Overload Ideally, college is where you learn to think, but there is often so much factual material to cover in an organic chemistry course that memorization can take over. In the face of the sheer mass of content to be learned, the development of the necessary skills critical to becoming a scientist logic and analysis can be lost. This "tyranny of content" in an ever-growing field means that the "why" of the field may get swamped under a flood of facts. The mystery of a good puzzle, the draw of the sciences, can also be lost. You might approach organic chemistry with the idea that only memorization can get you through it; this may have been true many years ago, but it is not the case now. With memorization, if you have not seen it before, you are usually in trouble. Information learned through memorization is also the first to be forgotten, and the volumes of information required in organic chemistry seem to be lost particularly rapidly. This loss can even occur before the cumulative second semester final. An Expert Systems Approach to Organic Chemistry To "explain the answer," you need to know what the alternatives are, and why one of them succeeds and others fail. You need to "generate and select" alternatives, which is the essence of a good critical thinking process. The map of all alternatives from the start point can be represented as a tree, and is our "problem space." You need an efficient way to navigate this problem space to the correct answer. For that, you need a small set of essential principles, or "control knowledge," to guide the route selection decisions toward the correct answer. Good intuition arises from the automatic use of control knowledge to guide the decision process. The impressive advantage that a decision-based approach to organic chemistry has over memorization is that it engages you in critical thinking, a skill everyone can benefit from improving. This approach allows for extrapolation into the unknown and provides room for the joy of discovery. If you are going to learn how to think in organic chemistry, you need to know what the alternative paths are and how to decide between them. xi

Xll Preface The development of decision-making algorithms for artificial intelligence systems has led to a new way of thinking about the decision process. Computers have to make use of decision trees and problem spaces, where all possible choices are examined and weighed and the best of the options selected. This same methodology can be applied to organic chemistry. You will have to learn about problem spaces, search trees, and methods to decide the best path. This text extracts the essence of the field: the conceptual tools, the general rules, the trends, the modes of analysis, and everything that one would use to construct an expert system. It explains and makes use of analysis tools more common to expert systems, but rare in undergraduate organic chemistry texts. If you can internalize this expert-system decision process, you will develop a chemical intuition and are well on your way to becoming an expert yourself. Unique to This Text This book organizes reactions by similar processes, as you would in an expert system. Reactants are grouped into generic groups that behave similarly. By being able to classify hundreds of different structural types into a small number of electron sources and sinks, you take control of the information overload and make it manageable. You will be able to make a good guess at how new reaction partners might behave. All mechanisms are viewed as composed of simple elemental processes, the electron flow paths. Even the most complex reactions can be simplified into a sequence of basic electron flow paths. These elemental processes are limited in number and are repeated, again and again, making them easier to both learn and retain. In this way, a mere dozen electron flow paths can explain nearly all of the common reactions found in an undergraduate organic course. This decision-based book shows how to choose which of the dozen common electron flow paths are reasonable to use, and in what order. New reactions become puzzles to solve, not just another item to be memorized. Reactions are much easier to remember if you can understand how they work. Motivation and Relevance The most important question that you as a student have to answer is, "Why am I in this course?" Organic chemistry is a lot of work no matter what approach is used, and you will need to see the personal relevance in order to have the motivation to succeed. Premedical students need the ability to reason through complex problems; this is the essence of diagnosis. Biology majors need to have a good chemical intuition, so that they can understand the chemistry of life, what makes it work or malfunction. A good organic chemistry course will give you precisely these skills: good chemical intuition and the ability to approach and solve complex problems. Rote memorization will provide neither. The critical thinking skills and methods of analysis learned in a decision-based organic course are highly valuable and easily transportable to other areas.

Preface хш TO THE INSTRUCTOR Critical Thinking Approach Critical thinking has become a major emphasis in undergraduate education. Science students respond well to being given puzzles to solve rather than content to memorize. Organic reaction mechanisms can provide the hook to interest students in analyzing and thinking like a scientist. "How does this reaction work?" We need to prepare our students to enter a world where content is easily accessible on the web, but critical analysis of all this content is not easy at all. We want our future scientists and physicians to be good at critical thinking, for the web will be at their fingertips to aid their recall. Adding this text as a critical thinking supplement to your organic chemistry course can make the course more important to students and should help them succeed. This second edition provides students with something that they cannot get anywhere else: a chemical intuition based on learning and internalizing a cross-checked decision process. An important part of the scientific method (or diagnosis) is the ability to postulate a reasonable hypothesis, fitting the data. This text teaches students how to write reasonable reaction mechanisms, and assumes only a general chemistry background. Unique Decision-Based Approach To be able to teach students to make good decisions, we need to teach "control knowledge," which is the essence of a good intuition. These are checks of reasonability that include, among other things: stability trends, compatibility with the media ph, evaluation of energetics, and similarity to known processes. The second edition uses flowcharts and energy surfaces as problem space maps to help with illustration of these concepts, while continuing the rigorous mechanistic approach to organic chemistry. Unique to this text is the concept of mechanisms being built from a limited number of elementary electron flow pathways, and the concept that learning to assemble these pathways in a reasonable manner is all that is necessary to master mechanisms in organic chemistry. The impressive advantage that a decision-based approach has over memorization is that it engages the student. The instructor can ask questions like, "Why did it go this way and not that way?" New reactions become puzzles to solve, not simply more items to memorize. This text uses several concepts and tools not present in most undergraduate organic chemistry texts to aid in understanding the most difficult sections of the course. Hardsoft acid-base theory is used to guide decisions and to explain and predict the dual reactivity of many species. Energy diagrams and surfaces are presented so that students have a physical model to help with the more complex decisions. An optional level of explanation is included that makes use of frontier molecular orbital theory to explain reactivity. A beginner who has difficulty with molecular orbital concepts can skip these sections without penalty. Changes From the First Edition Besides the usual clarifications and modifications necessary to bring the text up to date, the text has been expanded to reinforce a decision-based approach. There are more flowcharts, correlation matrices, and algorithms that illustrate decision processes. Energy surfaces, normally the domain of graduate texts, serve as concept maps and allow

XIV Preface students to visualize alternatives. The text has been made more accessible to beginning students and meshes better with standard texts. A new Chapter 3, "Proton Transfer and the Principles of Stability," has been added to thoroughly develop how structure determines reactivity using a reaction from general chemistry. Proton transfer mechanisms and product predictions are introduced, setting up the discussion of organic reactions. A new Chapter 4, "Important Reaction Archetypes," was added so that the main mechanistic reaction types that form the core of an organic course are emphasized first. This chapter shows the problem space for each archetype and how reactant structure influences the favored route. Electron flow paths are introduced gradually with these reaction archetypes. The ДрЛГ а rule is used for deciding reasonable reaction energetics. The later chapters develop a general approach to all organic reactions by showing how to focus on the most reactive centers and choose the best route. This book provides tools for handling large amounts of information. It emphasizes the "why" of organic chemistry in order to help make sense of all the material. Common errors are now placed within the appropriate sections. A new Chapter 12, "Qualitative Molecular Orbital Theory and Pericyclic Reactions," collects most of the more difficult orbital control related topics into a final chapter. A larger collection of important tools is gathered together in the Appendix, including a new section on structure elucidation strategies. More Biochemical Examples Biochemical examples give added relevance for the biology majors and premedical students who make up a significant portion of undergraduate organic chemistry students. The elegance of biochemical processes in optimizing a low-energy route can be appreciated and understood by looking at mechanisms. These examples also provide a bridge if this text is to be used for review of organic chemistry before a biochemistry or enzymology course. Online Aids No matter what you hand out on the first day of class, your exams are your syllabus. Unfortunately, the students' universal test of importance of any material is, "Is this going to be on the exam?" Therefore, if you do not alter the way you test on the material, you have not significantly changed your course. In addition to the answers to the exercises, material is online at the Wiley instructor's website for this text to aid in implementing a decision-based approach to organic chemistry. Applications This textbook is designed to be flexible in its instructive role. It can be used in the major's sophomore undergraduate organic chemistry course as a short, highly mechanistic supplemental text. It can be used as the primary text in an advanced undergraduate or beginning graduate course in organic reaction mechanisms, or as a supplemental review text for graduate courses in physical organic chemistry, enzymatic reaction mechanisms, or biochemistry. This text is the product of over thirty years of teaching organic chemistry at New College, the Honors College of the State of Florida.

Preface xv Acknowledgments I would like to thank all that have helped to bring the first and second editions of this book to fruition, especially my father, Prof. Harvey I. Scudder, who helped me refine an algorithm-based teaching approach, and my Ph.D. mentor, Prof. Barry M. Trost. I am indebted to my students, who helped me work through the many versions of this text, to my colleagues at New College, and to the reviewers of this manuscript. I will maintain an errata list and encourage anyone to send me errors not on the list. I gratefully acknowledge the encouragement of my parents and my wife, son, and daughter, who inspired me to keep writing in the face of an ever-growing project. Finally, I would like to thank all those at John Wiley & Sons who made the publication of this book possible. This book is dedicated to my students, who have taught me to question everything.

1 BONDING AND ELECTRON DISTRIBUTION 1.1 THE DECISION-BASED APPROACH TO ORGANIC CHEMISTRY Approach of Text; Problem Spaces; Tree Searches; Control Knowledge; Overview; the Principle of Electron Flow; Nucleophiles; Electrophiles 1.2 IONIC AND COVALENT BONDING Valence Electrons; Covalent and Ionic Bonds; Electronegativity; Polar Covalent 1.3 LEWIS STRUCTURES AND RESONANCE FORMS Number of Valence Electrons; General Bonding Trends; Formal Charges; Only Electrons Move, Not Atoms; Major and Minor Resonance Forms 1.4 CURVED-ARROW NOTATION Full-Headed Curved Arrow Moves Two Electrons; Half-Headed Curved Arrow Moves One Electron; Electron Source; Electron Sink; Charge Is Conserved; Direction of Electron Flow; Good Arrow Pushing Habits; Common Errors 1.5 NOMENCLATURE AND ABBREVIATIONS Line Structure; First Ten Alkanes; Common Functional Groups; Abbreviations 1.6 AN ORBITAL VIEW OF BONDING (A Supplementary, More Advanced Explanation) Electrons Behave as Waves; Standing Waves in One and Two Dimensions; Standing Waves in Three Dimensions; Atomic Orbitals; Mixing Atomic Orbitals into Molecular Orbitals; Bonding and Antibonding MOs of Hydrogen 1.7 THE SHAPES OF MOLECULES Valence Shell Electron Pair Repulsion (VSEPR) Theory; Hybridization of Atomic Orbitals, sp, sp 2, sp 3 ; Single Bonds; Conformational Isomers; Pi Bonds; Pi Barrier to Rotation; Cis and Trans; 2p-3p; Triple Bonds; Cumulenes 1.8 MOLECULAR REPULSIONS, ATTRACTIONS, AND HYDROGEN BONDING Nonbonded Repulsion; van der Waals Radii; Common Groups Ordered by Size; Dipole Attractions; Hydrogen Bonding; Cation Pi-Complexes; Donor-Acceptor 1.9 CONJUGATION, VINYLOGY, AROMATICITY Overlapping p Orbitals Behave as One System, Have Greater Stability; Vinylogy Is the Extension of the Properties of a System by the Insertion of a Double Bond; Unbroken Loop of p Orbitals with 4n + 2 Pi Electrons Has Aromatic Stabilization 1.10 SUMMARY Structure Determines Reactivity; Lewis Structures and Electron Flow Arrows Allow Us to Keep Track of Electrons and Explain Reactions Electron Flow In Organic Chemistry: A Decision-Based Guide To Organic Mechanisms, Second Edition. By Paul H. Scudder Copyright 2013 John Wiley & Sons, Inc. 1