Strategies and solutions to advanced organic reaction mechanisms

STRATEGIES AND SOLUTIONS TO ADVANCED ORGANIC REACTION MECHANISMS STRATEGIES AND SOLUTIONS TO ADVANCED ORGANIC REACTION MECHANISMS A New Perspective on McKillop’s Problems ANDREI HENT University of Toronto, Toronto, ON, Canada JOHN ANDRAOS CareerChem, Toronto, ON, Canada Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom © 2019 Elsevier Inc All rights reserved No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein) Notices Knowledge and best practice in this field are constantly changing As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN 978-0-12-812823-7 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals Publisher: Susan Dennis Acquisition Editor: Emily McCloskey Editorial Project Manager: Peter Llewellyn Production Project Manager: Paul Prasad Chandramohan Cover Designer: Mark Rogers Typeset by SPi Global, India Dedication To Paul, and to my parents—AH To Mom, Ed, Riley, and Josh—JA Preface THE PURPOSE OF WRITING THIS BOOK Upon reading the title of this book one may wonder, “why write another book about reaction mechanism” among a sea of already published books on this mature subject? We offer several reasons in the categories of pedagogy and research With respect to pedagogy we point out the following issues Pedagogical books on the subject of organic chemistry not contain references to the original literature Disappointingly, authors not take the time to explain how to draw chemical structures and reaction schemes before introducing the plethora of chemistries according to functional group characteristics This is so vital and fundamental that the current osmotic “monkey-see-monkey-do” pedagogical approach of copying an instructor’s motions without understanding is, we believe, the source of all frustrations encountered by students, regardless of ability, in their study of organic chemistry Instructors have forgotten that the idea of learning the language of organic chemistry follows the same sense as how a child learns how to draw the letters of the alphabet before learning how to pronounce them, read words, and then to construct sentences from those words according to grammatical logic In organic chemistry, two-dimension pictures of three-dimensional chemical structures replace the function of words in sentences The skill of reading and writing in organic chemistry is based entirely on visual representation, communication, and understanding Other missing aspects of pedagogy include: how to problem solve, how to connect mechanisms with actual experimental evidence, and showing the evolution of various proposed mechanisms for a given transformation and how each proposal is tested against experimental evidence Instead, in current pedagogical practice there is a strong emphasis on osmotic learning and rote memorization coupled with a poor and nonchalant attitude to using curly arrow notation without regarding the arrow notation as a mathematical directed graph that follows strict rules This is in sharp contrast to Henry E Armstrong’s (the father of the concept of valence) derisive comment that “a bent arrow never hit anything” when he described what he thought of the concept of electron-pair displacement along conjugated systems.1 Some of these educational laments were nicely summarized in a recent article in Chemical & Engineering News in 2016 based on a symposium entitled “Is There a Crisis in Organic Chemistry Education” held at an ACS National Meeting in San Diego.2 With respect to research published in the literature there are the following issues Modern scientific publications show that scientists, particularly synthetic organic chemists, have a foggy understanding of reaction mechanism They are rather surprised, even shocked, to learn that the sum of elementary steps in a reaction mechanism must add up to the overall stoichiometric balanced chemical equation for a given transformation One of us (JA) recalls an amusing situation at a conference of industrial process chemists when such a statement was made and the number of double takes, unsettled frowns, and other facial contortions observed in the audience Such reactions soon disappeared when they saw illustrative examples from elementary organic chemistry learned in the undergraduate curriculum Authors of publications, particularly in communications, often represent mechanisms as a customary after-thought when concluding their papers They are left as a conjecture without any supporting experimental evidence They are given as a best educated guess with no serious follow-up to test hypotheses It is perfectly acceptable for a synthetic chemist to relinquish the task of supplying experimental verification for a reaction mechanism if they are not skilled in the kind of techniques and instrumentation required to so However, it is not acceptable to put forward a conjectured mechanism without at least offering well-thought out suggestions as to how it can be tested given the fact that there exists more than a century of well-established knowledge in the literature on mechanism elucidation techniques that form the standard lexicon of the study of organic chemistry This is consistent with the finding that more than two-thirds of posed problems investigated in this work are based on conjectured mechanisms Furthermore, we were surprised to find some publications containing curly arrow notations that were sloppy and in some cases completely wrong, which we believe is more telling of the peer review process than authors’ faux pas We also point out that the modern fad of depicting mechanisms as catalytic cycles, though it serves as convenient shorthand, obscures the visual ix x PREFACE communication of mechanism because curly arrow notation for tracking electron flow cannot be used due to the already used curly reaction arrows Furthermore, authors not always specify the oxidation states of metals in organometallic catalysts in these depictions We suggest that authors who not specify oxidation states in such representations likely not know them, and therefore are not convincing readers of their papers that they know what they are talking about WHAT THIS BOOK OFFERS The main highlights of our contribution not mentioned by other books include the following: • connecting the elementary steps in a reaction mechanism to the overall balanced chemical equation; • depicting reaction mechanisms using the principle of conservation of structural aspect throughout the visual display; • balancing each elementary step in a mechanism according to number of elements and charges, and showing reaction by-products along the way; • showing care and rigor in using the curly arrow notation for one- and two-electron transfers; • strongly connecting the experimental and theoretical evidences found that support a proposed mechanism for a given reaction; • showing how to problem solve when one is faced with the same question that is repeated 300 times in our book; namely, given the following reaction with substrate structure A undergoing a reaction under conditions B that yields product structure C, write out a mechanism that best satisfies the given evidence Our emphasis is on problem solving to showcase how to integrate all of the earlier ideas The focus is on the how aspect of problem solving Problem solving is an active exercise that is a highly effective pedagogical tool to absorb, assimilate, integrate, and implement tools learned, in contrast to the passive exercise of reading descriptive information as is customary in the delivery of physical organic chemistry and reaction mechanism subjects in the current university curriculum A key insight to contemplate is that a chemical drawing of a structure or mechanism is a representation of our understanding of it This statement is true for any kind of drawing beyond drawings of chemical structures In our experience over the course of this work we have found that the principle of conservation of structural aspect applied to the drawing of structures in a mechanism scheme was the most powerful in directing our thought processes in writing out sensible and probable mechanisms Time and time again the degree of clarity of presentation revealed a path to a solution Yet, amazingly this simple technique is never mentioned in all the books and pedagogical literature we have found on the subject of organic chemistry Well-displayed mechanistic schemes in truth not need accompanying text to explain what is going on in a chemical transformation They can be read and understood readily without need for redundant exposition With respect to balancing chemical equations, we point out that the equal sign notation was used in the 19th century chemistry literature to keep track of atoms on the reactant and product sides without depicting chemical structures In those representations only molecular formulas were used for reactants and products There was an obvious and strong connection between the meaning of a balanced chemical equation and a mathematical one The reaction arrow sign was later adopted when equations were written out using chemical structures instead of molecular formulas Borrowing from van’t Hoff’s notation where arrows depicted the direction of a reaction from reactants to products, and therefore the kinetics and dynamics of reactions, the currently used representation of chemical equations resulted in significant loss of information with respect to not specifying by-products and hence loss of information in deducing reaction mechanism In modern literature chemical equations are no longer balanced as before atom-by-atom Synthetic chemists adopted the reaction arrow notation since their focus was only on the substrate and product of interest in a chemical reaction, and comparing their structures to see “what happened.” Why would a research chemist investigate a reaction mechanism in the first place? Some possible reasons include: (1) the product of the reaction they were carrying out yielded an unexpected product—this could be a surprise or the result of a “failed” experiment toward an intended target product; (2) the reaction has synthetic utility and knowledge of the mechanism can elucidate how to further optimize the reaction conditions to a desired product outcome; (3) a reaction produces at least two desirable product outcomes depending on reaction conditions and knowledge of the mechanism can exploit shunting the reaction in favor of each of these products in high yield; or (4) the reaction is unusual and has no precedent in the database of known organic reactions Rearrangement and redox reactions are by far the two classes of reactions that generate the most interest and challenges in terms PREFACE xi of reaction mechanism elucidation Modern synthetic chemists are particularly keen on ring construction reactions that can form more than one ring in a single step, and on reactions that are able to functionalize unactivated CH groups Regio- and stereoselectivity in reaction performance is also of very high interest and goes back a long way What constitutes “proof” or “evidence” in support of a proposed mechanism? What does it mean to say that you understand how a reaction proceeds? There are some key philosophical aspects of providing evidence for a given mechanism proposal that is thought to be operative for a given reaction that need mentioning Experimental methods used to study mechanisms are never 100% conclusive Evidence is obtained from a consensus of experimental observations that are self-consistent and point in the same direction Mechanisms can be disproved but not proved This statement needs some time to digest From a set of mechanistic proposals for a given chemical transformation, rather than proving directly which one is the mechanism, the approach is to devise a series of experiments to disprove them until one is left standing that is most consistent with the available experimental evidence This becomes the “accepted” prevailing mechanism for the given transformation—for now However, there is always the possibility of revision of thinking based on new findings or extra verification pending the utilization of new, more efficient techniques or more sensitive and accurate instrumentation or better computational methods that can become available in the future Mechanisms are therefore regarded as tested models rather than ironclad theorems that are true for all time as is the case in mathematics This is a different line of thinking compared to mathematical proofs which can be constructed as deductive, inductive, or contradictive The best evidence is to have a synergy between experimental and theoretical (computational) support Although our efforts may not achieve true certainty, they will undoubtedly produce much opportunity Publications that demonstrate how mechanism informs organic synthesis, and vice versa, also demonstrate a complementary and strengthened understanding of how reactions proceed We point out that this key insight is often not practiced and hence such papers are scarce in the literature This may be a result of the personal rift between two giants in the development of organic chemistry: Sir Robert Robinson (synthesis) versus Sir Christopher K Ingold (mechanism).3–6 Unfortunately, the two schools of thought that each man created had more of an antagonistic relationship between them than a cooperative one that survives to the present day Their differing nomenclatures for the same ideas including opposing sign conventions attached to substituent effects were a direct result of their mutual ego bashing and created in the early days much unnecessary confusion for the rest of the chemistry community, hence delaying adoption of mechanistic understanding and delaying advancement in science Hard core mechanistic chemists are largely engaged in exploring the minutia of mechanism details, such as the number of water molecules involved in the transition state of a hydration reaction, which synthetic chemists would find no use for On the other hand, hard core synthetic chemists have poor to nonexistent mathematics skills which means they are unable to carry out and understand kinetics experiments and are strained beyond their comfort zone in interpreting energy reaction coordinate diagrams Mechanistic chemists, in turn, not routinely read the synthesis literature on natural products because they perceive their complex structures to be outside the scope of their investigations Yet, experimental problems often encountered in organic synthesis practice, such as failed attempts to carry out intended reactions or the obtainment of unexpected products, can all be explained and resolved by understanding the underlying reaction mechanism A good example is the difficulty in trying to carry out esterifications of salicylic acids due to the internal hydrogen bond that exists between the ortho juxtaposed carboxylic acid and phenolic groups A well-known synthetic chemist at Queen’s University in Canada “discovered” this problem in his own research about a decade ago and thought that this was a “new” finding without knowing that this problem was well described and investigated in the literature by mechanistic chemists several decades earlier The ideological tensions between synthetic and mechanistic chemists resulted in an identity crisis of Hamletian proportions in the late 1990s when several heavyweights in physical organic chemistry convened a symposium to address perceived declines in the field with respect to recruitment, scientific advancement, and funding This crisis of relevance to modern chemistry research led some to remind the community of its triumphs over many years in advancing basic science and its connection to other emerging fields in chemistry Others advocated for a complete rebranding of the perceived “dead subject” to make it more palatable and ultimately marketable to chemists working in the well-funded applied areas of biological chemistry and material science The reader is referred to the second issue of Pure and Applied Chemistry (1997) and the first issue of Israel Journal of Chemistry (2016) which are special issues containing several papers discussing this ongoing debate albeit largely written by old-guard members of a bygone era Another more recent account traces historical highlights of the field.7 The main take-home message that we hope comes across to the reader in this book is that the intellectual exercise of elucidating reaction mechanisms works hand-in-hand in the service, understanding, and ultimately improvement of organic synthesis design and thinking Putting problem solving as the main focus of human effort over base human needs of recognition and attribution is more convincing to aspiring young scientists to join the enterprise to increase xii PREFACE human knowledge in the chemical sciences and ultimately to make serious contributions to addressing pressing problems that actually matter to the wider world ORGANIZATION OF BOOK AND LAYOUT OF SOLUTIONS We present a brief synopsis of the topics covered in each chapter Chapter 1: Logic of Organic Reaction Mechanisms • • • • • • What constitutes a chemical reaction? The importance and meaning of a chemically balanced chemical equation and its connection to reaction mechanism What constitutes a reaction scheme? The principle of conservation of structural aspect Curly arrow notation convention and correct implementation for two- and one-electron transfer steps Illustration of the fundamental ideas of reaction mechanism using the Baeyer-Villiger oxidation reaction as a worked example • Survey of textbooks of physical organic chemistry • Special topics: base strength and pKa, autoxidation Chapter 2: Evidence for Organic Reaction Mechanisms • • • • What constitutes physical organic chemistry? Energy reaction coordinate diagrams—how to construct, read, interpret, and use them Summary of direct and indirect experimental evidences to support reaction mechanisms Illustration of the evolution of supporting experimental evidence using the Baeyer-Villiger oxidation reaction as a worked example Chapter 3: Problem Solving Organic Reaction Mechanisms • Theoretical problem-solving strategies applied to reaction mechanism proposals • Experimental problem-solving strategies to support reaction mechanism proposals • Illustration of both kinds of problem-solving strategies using the acid-catalyzed cinenic acid to geronic acid rearrangement as a complete case study • Current state of pedagogy and research in physical organic chemistry Chapters 4–9: Solutions to 300 Problems Over the course of his teaching career Prof Alexander McKillop surveyed the literature and collected interesting examples on cards and used them in making up problem set exercises for his students Most of the posed problems originated from brief communications in the literature which contained transformations that could be classified as either anomalous, curious, yielded unexpected results, were challenging to rationalize, were explained by dubious mechanistic reasoning, or whose author-suggested mechanisms were outright incorrect His original book publication Advanced Problems in Organic Reaction Mechanisms (1998) was a transcription of these cards but did not include the original references and the problems were listed in a random order No doubt, these problems were a fertile training ground for his students to think logically about proposing rational mechanisms, particularly for students pursuing research in natural products synthesis and organic synthesis methodology All of the chemistries highlighted offer opportunities for further investigation which astute students could use to explore in their own research careers Hence, McKillop really offered his students ideas for their own research proposals if they were to pursue academic careers The good news is that there exists a never-ending supply of such examples in the literature for instructors and researchers to draw upon for posing future problems as training exercises The following template protocol was used for displaying solutions (i) A problem statement is given showing structures of substrates and products, reaction yields, and reaction conditions Corrections to any structural errors introduced by the posed questions in McKillop’s original book are made as appropriate (ii) The first solution given is the reaction mechanism as given by the authors (iii) All mechanisms are displayed according to the following convention: (1) all chemical structures are shown in the same structural aspect for enhanced visual clarity, (2) each elementary step is element and charge balanced, (3) the PREFACE xiii curly arrow notation is used to track all two- and one-electron movements, (4) reaction by-products are shown directly below step reaction arrows, and (5) target synthesis bonds made are highlighted using bolded notation throughout a given mechanism scheme (iv) At the conclusion of each mechanism an overall balanced chemical equation is provided which constitutes the sum of all elementary steps (v) A reference citation on which the problem is based is given The “key steps explained” section to each solution contains the following information: (1) an accompanying word description of the visual display of the mechanistic scheme showing descriptors of intermediate identification (enols, carbenes, thiiranium ions, etc.); (2) inclusion of all experimental evidences in support of the authors’ mechanism; (3) inclusion of alternative mechanisms not considered by the authors; (4) discussion of any controversies, errors, or weak or lack of evidence; (5) inclusion of alternative mechanisms that better agree with the experimental results and reaction conditions, or address our perceived errors in the authors’ posed mechanisms; (6) inclusion of ring construction mapping notation if the reaction produces at least one ring in the product structure; (7) suggestions for further work to improve any authors’ shortcomings (e.g., other experiments based on techniques described in Chapter 2, and theoretical (computational) work); and (8) inclusion of other circumstantial evidence found from our literature searches on more recent related work to the problem posed Finally, additional resources for the reader to consider to learn more about the type of reaction posed in the problem, synthetic utility, other applications, and so on, are given at the end of each solution ACKNOWLEDGMENTS We thank Dr Floyd H Dean for suggesting the cinenic acid to geronic acid rearrangement as a key example to illustrate problem-solving techniques and the application of the principle of conservation of structural aspect, and for generously offering his time to discuss some of the more difficult problems and his help in resolving them We also thank Amy Clark, Senior Editorial Project Manager at Elsevier, and her successor Peter Llewellyn for their extraordinary patience over the course of this 4-year odyssey We have climbed many small mountains and have grown intellectually along the way We hope this book inspires others to follow our footsteps and climb even higher mountains of their own In closing, we leave the reader with some interesting and relevant quotes from Justus von Liebig and Friedrich W€ ohler, who occupy the same position as Abraham in the hierarchy of contributors to chemical science, that touch on various points highlighted in this Preface In these quotes the pronouns “he,” “his,” and “him” are used throughout, but the reader should interpret them to include both genders As a student reading chemistry8: “It developed in me the faculty, which is peculiar to chemists more than to other natural philosophers, of thinking in terms of phenomena; it is not very easy to give a clear idea of phenomena to anyone who cannot recall in his imagination a mental picture of what he sees and hears, like the poet and artist, for example Most closely akin is the peculiar power of the musician, who while composing thinks in tones which are as much connected by laws as the logically arranged conceptions in a conclusion or series of conclusions There is in the chemist a form of thought by which all ideas become visible in the mind as the strains of an imagined piece of music This form of thought is developed in Faraday in the highest degree, whence it arises that to one who is not acquainted with this method of thinking, his scientific works seem barren and dry, and merely a series of researches strung together, while his oral discourse when he teaches or explains is intellectual, elegant, and of wonderful clearness.” Letter to Berzelius on experiments9: “The loveliest of theories are being overthrown by these damned experiments; it is no fun being a chemist any more.” Introduction to Liebig and W€ ohler’s paper on the elucidation of the structure of the benzoyl group10: “When in the dark province of organic nature, we succeed in finding a light point, appearing to be one of those inlets whereby we may attain to the examination and investigation of this province, then we have reason to congratulate ourselves, although conscious that the object before us is unexhausted.” .. .STRATEGIES AND SOLUTIONS TO ADVANCED ORGANIC REACTION MECHANISMS STRATEGIES AND SOLUTIONS TO ADVANCED ORGANIC REACTION MECHANISMS A New Perspective on McKillop’s Problems ANDREI HENT... synthesis and green chemistry Nevertheless, to understand reaction mechanisms one must understand the available experimental and theoretical tools that constitute the Strategies and Solutions to Advanced. .. help to expand the reader’s imagination with regard to what is possible in organic reaction mechanisms For now we wish to emphasize the fact that reaction schemes have much to reveal about reaction