Organic Mechanisms Reactions, Stereochemistry and Synthesis Reinhard Bruckner Organic Mechanisms Reactions, Stereochemistry and Synthesis Edited by Michael Harmata With a foreword by Paul A. Wender Prof. Dr.Reinhard Bruckner Albert-Ludwigs-Universität Freiburg Institut für Organische Chemie und Biochemie Albertstr. 21 79104 Freiburg [email protected] Prof. Dr. Michael Harmata Norman Rabjohn Distinguished Professor of Chemistry Department of Chemistry University of Missouri-Columbia 601 S. College Avenue Columbia, Missouri 65211 [email protected] Translation: Karin Beifuss ISBN: 978-3-642-03650-7 e-ISBN: 978-3-642-03651-4 DOI: 10.1007/978-3-642-03651-4 Library of Congress Control Number: 2009938642 © Springer-Verlag Berlin Heidelberg 2010 Translation of Brückner, R Reaktionsmechanismen, 3rd edition, published by Spektrum Akademi- scher Verlag, © 2007 Spektrum Akademischer Verlag, ISBN 987-3-8274-1579-0 This work is subject to copyright. 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Cover design: KuenkelLopka GmbH Printed on acid-free paper 987654321 springer.com Biographies Reinhard Bruckner (born 1955) studied chemistry at the Lud- wig-Maximilians-Universität München, acquiring his doctoral degree under the supervision of Rolf Huisgen. After postdoctoral studies with Paul A. Wender (Stanford University), he completed his habilitation in collaboration with Reinhard Hoffmann (Philipps-Universität Marburg). He was appointed associate pro- fessor at the Julius-Maximilians-Universität Würzburg and full professor at the Georg-August-Universität Göttingen before he moved to his current position in 1998 (Albert-Ludwigs- Universität Freiburg). Professor Bruckner´s research interests are the total synthesis of natural products and the development of synthetic methodology. Besides being the author of 150 publications he has written 4 textbooks, for one of which he was awarded the Literature Prize of the Foundation of the German Chemical Industry. He has been a Visiting Professor in the US, Spain, and Japan, and served as an elected peer reviewer of the German Research Foundation and as the Vice-President of the Division of Organic Chemistry of the German Chemical Society. Michael Harmatawas born in Chicago on September 22, 1959. He obtained his A.B. in chemistry from the University of Illinois- Chicago in 1980. He received a Ph.D. from the University of Illi- nois-Champaign/Urbana working with Scott E. Denmark on the carbanion-accelerated Claisen rearrangement. He was an NIH postdoctoral fellow in the labs of Paul A. Wender at Stanford Uni- versity, where he focused on synthetic work involving the neo- carzinostatin chromophore. He joined the faculty at the Univer- sity of Missouri-Columbia in 1986 and is now the Norman Rabjohn Distinguished Professor of Chemistry at that institution. Professor Harmata’s research interests span a large range of chemistry and include molecular tweezers, [4+3]-cycloadditions, pericyclic reactions of cyclopentadienones and benzothia zine chemistry. He enjoys cooking, reading, stamp collecting, and recently earned his black belt in Taekwondo. I dedicate this book to my family, who serve to support me in my pursuit of science and provide the love that so enriches my life. Judy L. Snyder Gail Harmata Diana Harmata Alexander Harmata Foreword “Much of life can be understood in rational terms if expressed in the language of chemistry. It is an international language, a language without dialects, a language for all time, a language that explains where we came from, what we are, and where the physical world will allow us to go. Chemical Language has great esthetic beauty and links the physical sciences to the bio- logical sciences.” from The Two Cultures: Chemistry and Biology by Arthur Kornberg (Nobel Prize in Physiology and Medicine, 1959) Over the past two centuries, chemistry has evolved from a relatively pure disciplinary pursuit to a position of central importance in the physical and life sciences. More generally, it has pro- vided the language and methodology that has unified, integrated and, indeed, molecularized the sciences, shaping our understanding of the molecular world and in so doing the direction, development and destiny of scientific research. The “language of chemistry” referred to by my former Stanford colleague is made up of atoms and bonds and their interactions. It is a sys- tem of knowledge that allows us to understand structure and events at a molecular level and increasingly to use that understanding to create new knowledge and beneficial change. The words on this page, for example, are detected by the eye in a series of events, now generally understood at the molecular level. This knowledge of molecular mechanism (photons in, elec- trons out) in turn enables us to design and synthesize functional mimetics, providing for the development of remarkable retinal prosthetics for those with impaired vision and, without a great leap in imagination, solar energy conversion devices. Similarly, the arrangement of atoms in natural antibiotics provides the basis for understanding how they function, which in turn has enabled the design and synthesis of new antibiotics that have saved the lives of count- less individuals. We are even starting to learn about the chemistry of cognition, knowledge that defines not only “what we are” but how we think. We have entered the age of molecular- ization, a time of grand opportunities as we try to understand the molecular basis of all science from medicine to computers, from our ancient past (molecular paleontology) to our molecu- lar future. From our environment and climate to new energy sources and nanotechnology, chemistry is the key to future understanding and innovation. This book is a continuation of a highly significant educational endeavor started by Rein- hard Bruckner and joined by Michael Harmata. It is directed at understanding the “language of chemistry”: more specifically, the structures of organic compounds; how structure influ- ences function, reactivity and change; and how this knowledge can be used to design and syn- thesize new structures. The book provides a cornerstone for understanding basic reactions in chemistry and by extension the chemical basis for structure, function and change in the whole of science. It is a gateway to the future of the field and all fields dependent on a molecular view for innovative advancement. In an age of instant access to information, Bruckner and Harmata provide special value in their scholarly treatment by “connecting the dots” in a way that converts a vast body of chemical information into understanding and understanding into knowledge. The logical and rigorous exposition of many of the core reactions and concepts of chemistry and the addition of new ones, integration of theory with experiment, the infusion of x Foreword “thought” experiments, the in -depth attention to mechanism, and the emphasis on fundamen- tal principles rather than collections of facts are some of the many highlights that elevate this new text. As one who has been associated with the education of both the author and the edi- tor, I find this book to be an impressively broad, deep and clear treatment of a subject of great importance. Students who seek to understand organic chemistry and to use that understand- ing to create transformative change will be well served in reading, studying and assimilating the conceptual content of this book. It truly offers passage to an exciting career and expertise of critical importance to our global future. Whether one seeks to understand Nature or to create new medicines and materials, Bruckner and Harmata provide a wonderfully rich and exciting analysis that students at all levels will find beneficial. Congratulations to them on this achievement and to those embarking upon this journey through the molecular world! October, 2009 Paul A. Wender Stanford University Preface to the English Edition This book is an attempt to amalgamate physical, mechanistic and synthetic organic chemistry. It is written by a synthetic organic chemist who happens to also think deeply about mecha- nism and understands the importance of knowing structure and reactivity to synthetic organic chemistry. I helped get the 1st German edition of this book translated into English, for two reasons. First, Reinhard Bruckner has been a friend of mine for over twenty years, ever since we were postdocs in the Wender group in the mid-80s. He was a study in Teutonic determina- tion and efficiency, and I, and a few other Americans, and one Frenchman in particular, have been trying to cure him of that, with some success, I might add, though he remains an extremely dedicated and hard-working educator and scientist. That’s a good thing. Second, I especially liked the project because I liked the book, and I thought Reinhard’s way of dealing with synthesis and mechanism together was an approach sufficiently different that it might be the “whack on the side of the head” that could be useful in generating new thought patterns in students of organic chemistry. Well, I was actually a bit surprised to be invited to work on the English translation of the 3rd German edition of the book. I was even more surprised when the publisher gave me edi- torial license, meaning I could actually remove and add things to the work. This potentially gives the English edition a life of its own. So besides removing as many “alreadys” (schon, in German) as humanly possible and shortening sentences to two lines from the typical German length of ten or so, I was able to add things, including, among others, a word of caution about the reactivity/selectivity principle. Speaking of long sentences… Will the English-speaking world find the book useful? Time will tell. I see this book as being most appropriate as an organic capstone course text, preparing those who want to go to graduate school or are just starting graduate school, as it makes use not only of strictly organic chemistry knowledge, but of physical and inorganic chemistry as well. I could dream of this becoming the Sykes of the 21stcentury, but to make that a reality will require a great deal of work. To that end, constructive criticism is necessary. As you read this book, can you tell me what should be added or omitted, mindful of the fact that it should not get any longer and will likely present concepts with the same general format? Most importantly, is it easy and inter- esting to read? I did not do all I could have done to “spice up” the text, but I was very tempted. I could easily do more. In any case, if you have suggestions, please send them to me at h [email protected]; and put the phrase Bruckner Bookin the subject line. I can’t say I will answer, but feedback given in the spirit of the best that our community has to offer will do nothing but good. One omission that might be considered flagrant is the lack of problems. Time precluded our constructing a problem set with answers. (However, if you are inclined to do one, contact the publisher!) In the meantime, the web is bulging with organic chemistry problems, and it may be redundant to construct a book when so much is out there waiting to be harvested. One website in particular is noteworthy with regard to the variety and quality of advanced organic chemistry problems and that is the one by Dave Evans at Harvard. With the help of students and colleagues, Dave put together a site called Challenging Problems in Chemistry and Chem- xii Preface to the English edition ical Biology (http://www2.lsdiv.harvard.edu/labs/evans/problems/index.cgi) and it is a good place to start practicing advanced organic chemistry. Students! There are a number of things I want to say to you. Don’t just read this book, study it. Read novels, study chemistry. This book is typeset with fairly wide margins. Use those mar- gins! Draw structures there. Write down questions. Write down answers, theories, conjectures. We did not supply you with problem sets. Create them. Ask your instructors for help. Or go off on your own. Hone your skills by using resources to search out answers to questions. Searching the literature is not any easier than it used to be, in spite of the space age databases that exist. Developing the skills to find answers to chemical questions can save time and money, always a good thing, especially to those whose money you are spending. You will learn this soon enough if you haven’t already done so. Although this book is being published by Springer, it was initially taken on by Spektrum. I want to thank Ms. Bettina Saglio and Ms. Merlet Behncke-Braunbeck of Spektrum for all of their efforts. I was able to visit with them in Heidelberg and found working with these two lovely people to be a real joy. They gave me a very long leash and I appreciate it! My experi- ence with Springer has just begun. May it be as pleasant and productive. My work on this book began in earnest in Germany in the spring and summer of 2008. The Alexander von Humboldt Foundation saw fit to “reinvite” me back to Germany for a three month stay. I am grateful for the opportunity and would like to thank Ms. Caecilia Nauderer, who was my liaison at the Humboldt Foundation, for her assistance. It is an honor to serve as a part of the “Atlantik-Brücke”, helping, if in only a small way, to build and maintain strong and positive relations between the United States and Germany. I was hosted by my friend and colleague Peter R. Schreiner at the University of Giessen. Thank you, Peter, for your hospi- tality. But beware: I will return! Of course, my family must tolerate or endure, as the case may be, my “projects”! Thank you Judy, Gail, Diana and Alexander for your support! Finally, I must note that ventures of this type are very time consuming. They represent “synergistic activities” and “broader impacts” that would not be possible without my having some funding for a research program of my own. The Petroleum Research Fund and the National Institutes of Health deserve some recognition in this context, but it is by far the National Science Foundation that has allowed me the greatest opportunity to build a research program of which I can be proud. To them and the anonymous reviewers who have supported me, I offer my most sincere thanks. Learning and creating organic chemistry are joys that only a few are privileged to experi- ence. May your travels into this delightful world be blessed with the thrills of discovery and creativity. August, 2009 Michael Harmata University of Missouri–Columbia Preface to the 1st German Edition To really understand organic chemistry requires three stages. First, one must familiarize one- self with the physical and chemical properties of organic chemical compounds. Then one needs to understand their reactivities and their options for reactions. Finally, one must develop the ability to design syntheses. A typical curriculum for chemistry students incorporates these three components. Introductory courses focus on compounds, a course on reaction mecha- nisms follows, and a course on advanced organic chemistry provides more specialized k nowledge and an introduction to retrosynthesis. Experience shows that the secondstage, the presentation of the material organized accord- ing to reaction mechanisms, is of central significance to students of organic chemistry. This systematic presentation reassures students not only that they can master the subject but also that they might enjoy studying organic chemistry. I taught the reaction mechanisms course at the University of Göttingen in the winter semester of 1994, and by the end of the semester the students had acquired a competence in organic chemistry that was gratifying to all concerned. Later, I taught the same course again— I still liked its outline—and I began to wonder whether I should write a textbook based on this course. A text of this kindwas not then available, so I presented the idea to Björn Gondesen, the editor of Spektrum.Björn Gondesen enthusiastically welcomed the book proposal and asked me to write the “little booklet” as soon as possible. I gave up my private life and wrote for just about two years. I am grateful to my wife that we are still married; thank you, Jutta! To this day, it remains unclear whether Björn Gondesen used the term “little booklet” in earnest or merely to indicate that he expected onebook rather than a series of volumes. In any case, I am grateful to him for having endured patiently the mutations of the “little booklet” first to a “book” and then to a “mature textbook.” In fact, the editor demonstrated an indes- tructible enthusiasm, and he remained supportive when I repeatedly presented him increases in the manuscript of yet another 50 pages. Moreover, the reader must thank Björn Gondesen for the two-color production of this book. All “curved arrows” that indicate electron shifts are shown in red so that the student can easily grasp the reaction. Definitions and important state- ments also are graphically highlighted. In comparison to the preceding generation, students of today study chemistry with a big handicap: an explosive growth of knowledge in all the sciences has been accompanied in par- ticular for students of organic chemistry by the need to learn a greater number of reactions than was required previously. The omission of older knowledge is possible only if that know- ledge has become less relevant and, for this reason, the following reactions were omitted: Darzens glycidic ester synthesis, Cope elimination, S i reaction, iodoform reaction, Reimer- N Tiemann reaction, Stobbe condensation, Perkin synthesis, benzoin condensation, Favorskii rearrangement, benzil-benzilic acid rearrangement, Hofmann and Lossen degradation, Meer- wein-Ponndorf reduction and Cannizarro reaction. A few other reactions were omitted because they did not fit into the current presentation (nitrile and alkyne chemistry, cyanohydrin formation, reductive amination, Mannich reaction, enol and enamine reactions).