The Art of Writing Reasonable Organic Reaction Mechanisms, Second Edition Robert B. Grossman Springer 3879_efm1_pi-xvi 10/22/02 9:57 AM Page i The Art of Writing Reasonable Organic Reaction Mechanisms Second Edition 3879_efm1_pi-xvi 10/22/02 9:57 AM Page ii Springer New York Berlin Heidelberg Hong Kong London Milan Paris Tokyo 3879_efm1_pi-xvi 10/22/02 9:57 AM Page iii Robert B. Grossman University of Kentucky The Art of Writing Reasonable Organic Reaction Mechanisms Second Edition 13 3879_efm1_pi-xvi 10/22/02 9:57 AM Page iv Robert B. Grossman Department of Chemistry University of Kentucky Lexington, KY 40506-0055 USA rbgros1@uky.edu Library of Congress Cataloging-in-Publication Data Grossman, Robert B., 1964– The art of writing reasonable organic reaction mechanisms / Robert B.
Grossman—2nd ed. Includes bibliographical references and index. ISBN 0-387-95468-6 (hc : alk. Organic reaction mechanisms.139—dc21 2002024189 ISBN 0-387-95468-6 Printed on acid-free paper.
This material is based on work supported by the National Science Foundation under Grant 9733201. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author and do not necessarily reflect the views of the National Science Foundation. © 2003, 1999 Springer-Verlag New York, Inc. All rights reserved.
This work may not be translated or copied in whole or in part without the writ- ten permission of the publisher (Springer-Verlag New York, Inc., 175 Fifth Avenue, New York, NY 10010, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in con- nection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed in the United States of America.com Springer-Verlag New York Berlin Heidelberg A member of BertelsmannSpringer ScienceBusiness Media GmbH 3879_efm1_pi-xvi 10/22/02 9:57 AM Page v Preface to the Student The purpose of this book is to help you learn how to draw reasonable mecha- nisms for organic reactions.
A mechanism is a story that we tell to explain how compound A is transformed into compound B under given reaction conditions. Imagine being asked to describe how you travelled from New York to Los Angeles (an overall reaction). You might tell how you traveled through New Jersey to Pennsylvania, across to St. Louis, over to Denver, then through the Southwest to the West Coast (the mechanism).
You might include details about the mode of transportation you used (reaction conditions), cities where you stopped for a few days (intermediates), detours you took (side reactions), and your speed at various points along the route (rates). To carry the analogy further, there is more than one way to get from New York to Los Angeles; at the same time, not every story about how you traveled from New York to Los Angeles is believable. Likewise, more than one reasonable mechanism can often be drawn for a reaction, and one of the purposes of this book is to teach you how to dis- tinguish a reasonable mechanism from a whopper. It is important to learn how to draw reasonable mechanisms for organic reac- tions because mechanisms are the framework that makes organic chemistry make sense.
Understanding and remembering the bewildering array of reactions known to organic chemists would be completely impossible were it not possible to or- ganize them into just a few basic mechanistic types. The ability to formulate mechanistic hypotheses about how organic reactions proceed is also required for the discovery and optimization of new reactions. The general approach of this book is to familiarize you with the classes and types of reaction mechanisms that are known and to give you the tools to learn how to draw mechanisms for reactions that you have never seen before. The body of each chapter discusses the more common mechanistic pathways and suggests practical tips for drawing them.
The discussion of each type of mechanism con- tains both worked and unworked problems. You are urged to work the unsolved problems yourself. Common error alerts are scattered throughout the text to warn you about common pitfalls and misconceptions that bedevil students. Pay attention to these alerts, as failure to observe their strictures has caused many, many exam points to be lost over the years.
v 3879_efm1_pi-xvi 10/22/02 9:57 AM Page vi vi Preface to the Student Occasionally, you will see indented, tightly spaced paragraphs such as this one. The in- formation in these paragraphs is usually of a parenthetical nature, either because it deals with formalisms, minor points, or exceptions to general rules, or because it deals with topics that extend beyond the scope of the textbook. Extensive problem sets are found at the end of all chapters. The only way you will learn to draw reaction mechanisms is to work the problems! If you do not work problems, you will not learn the material.
The problems vary in difficulty from relatively easy to very difficult. Many of the reactions covered in the prob- lem sets are classical organic reactions, including many “name reactions.” All examples are taken from the literature. Additional problems may be found in other textbooks. Ask your librarian, or consult some of the books discussed be- low.
Detailed answer keys are provided in a separate volume that is available for download from the Springer–Verlag web site (http://www.tpl?isbn=0387985409) at no additional cost. The answer keys are format- ted in PDF. You can view or print the document on any platform with Adobe’s Acrobat Reader®, a program that is available for free from Adobe’s web site (http://www. It is important for you to be able to work the problems without looking at the answers.
Understanding what makes Pride and Prejudice a great novel is not the same as being able to write a great novel yourself. The same can be said of mechanisms. If you find you have to look at the answer to solve a problem, be sure that you work the problem again a few days later. Remember, you will have to work problems like these on exams.
If you can’t solve them at home without looking at the answers, how do you expect to solve them on exams when the answers are no longer available? This book assumes you have studied (and retained) the material covered in two semesters of introductory organic chemistry. You should have a working fa- miliarity with hybridization, stereochemistry, and ways of representing organic structures. You do not need to remember specific reactions from introductory or- ganic chemistry, although it will certainly help. If you find that you are weak in certain aspects of introductory organic chemistry or that you don’t remember some important concepts, you should go back and review that material.
There is no shame in needing to refresh your memory occasionally. Pine’s Organic Chemistry, 5th ed. (McGraw-Hill, 1987) and Scudder’s Electron Flow in Organic Chemistry (John Wiley & Sons, 1992) provide basic information supplemental to the topics covered in this book. This book definitely does not attempt to teach specific synthetic procedures, reactions, or strategies.
Only rarely will you be asked to predict the products of a particular reaction. This book also does not attempt to teach physical organic chemistry (i., how mechanisms are proven or disproven in the laboratory). Before you can learn how to determine reaction mechanisms experimentally, you must learn what qualifies as a reasonable mechanism in the first place. Isotope effects, Hammett plots, kinetic analysis, and the like are all left to be learned from other textbooks.
3879_efm1_pi-xvi 10/22/02 9:57 AM Page vii Preface to the Student vii Errors occasionally creep into any textbook, and this one is no exception. I have posted a page of errata at this book’s Web site (http://www.edu/re- search/grossman/textbook. If you find an error that is not listed there, please contact me (rbgros1@uky. In gratitude and as a reward, you will be im- mortalized on the Web page as an alert and critical reader.
Graduate students and advanced undergraduates in organic, biological, and medicinal chemistry will find the knowledge gained from a study of this book invaluable for both their graduate careers, especially cumulative exams, and their professional work. Chemists at the bachelor’s or master’s level who are work- ing in industry will also find this book very useful. Lexington, Kentucky Robert B. Grossman January 2002 This page intentionally left blank 3879_efm1_pi-xvi 10/22/02 9:57 AM Page ix Preface to the Instructor Intermediate organic chemistry textbooks generally fall into two categories.
Some textbooks survey organic chemistry rather broadly, providing some information on synthesis, some on drawing mechanisms, some on physical organic chem- istry, and some on the literature. Other textbooks cover either physical organic chemistry or organic synthesis in great detail. There are many excellent textbooks in both of these categories, but as far as I am aware, there are only a handful of textbooks that teach students how to write a reasonable mechanism for an or- ganic reaction. Carey and Sundberg, Advanced Organic Chemistry, Part A, 4th ed.
(New York: Kluwer Academic/Plenum Publishers, 2000), Lowry and Richardson’s Mechanism and Theory in Organic Chemistry, 3rd ed. (New York: Addison Wesley, 1987), and Carroll’s Perspectives on Structure and Mechanism in Organic Chemistry (Monterey CA: Brooks/Cole Publishing Co., 1998), are all physical organic chemistry textbooks. They teach students the experimental ba- sis for elucidating reaction mechanisms, not how to draw reasonable ones in the first place. Smith and March, March’s Advanced Organic Chemistry, 5th ed.
(John Wiley & Sons, 2001) provides a great deal of information on mechanism, but its emphasis is synthesis, and it is more a reference book than a textbook. Scudder’s Electron Flow in Organic Chemistry (John Wiley & Sons, 1992) is an excellent textbook on mechanism, but it is suited more for introductory or- ganic chemistry than for an intermediate course. Edenborough’s Writing Organic Reaction Mechanisms: A Practical Guide, 2nd ed. (Bristol, PA: Taylor & Francis, 1997) is a good self-help book, but it does not lend itself to use in an American context.
Miller and Solomon’s Writing Reaction Mechanisms in Organic Chemistry, 2nd ed. (New York: Academic Press, 1999) is the textbook most closely allied in purpose and method to the present one. This book provides an alternative to Miller & Solomon and to Edenborough. Existing textbooks usually fail to show how common mechanistic steps link seemingly disparate reactions, or how seemingly similar transformations often have wildly disparate mechanisms.
For example, substitutions at carbonyls and nucleophilic aromatic substitutions are usually dealt with in separate chapters in other textbooks, despite the fact that the mechanisms are essentially identical. This textbook, by contrast, is organized according to mechanistic types, not ac- ix 3879_efm1_pi-xvi 10/22/02 9:57 AM Page x x Preface to the Instructor cording to overall transformations. This rather unusual organizational structure, borrowed from Miller and Solomon, is better suited to teaching students how to draw reasonable mechanisms than the more traditional structures, perhaps be- cause the all-important first steps of mechanisms are usually more closely related to the conditions under which the reaction is executed than they are to the over- all transformation. The first chapter of the book provides general information on such basic concepts as Lewis structures, resonance structures, aromaticity, hy- bridization, and acidity.
It also shows how nucleophiles, electrophiles, and leav- ing groups can be recognized, and it provides practical techniques for determin- ing the general mechanistic type of a reaction and the specific chemical transformations that need to be explained. The following five chapters examine polar mechanisms taking place under basic conditions, polar mechanisms taking place under acidic conditions, pericyclic reactions, free-radical reactions, and transition-metal-mediated and -catalyzed reactions, giving typical examples and general mechanistic patterns for each class of reaction along with practical ad- vice for solving mechanism problems. This textbook is not a physical organic chemistry textbook!