Preview how to solve organic reaction mechanisms a stepwise approach by mark g moloney (2015)

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How to Solve Organic Reaction Mechanisms How to Solve Organic Reaction Mechanisms A Stepwise Approach MARK G MOLONEY Fellow and Tutor in Chemistry at St Peter’s College and Professor of Chemistry, University of Oxford, UK This edition first published 2015 © 2015 John Wiley & Sons, Ltd Registered office John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, United Kingdom For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988 All rights reserved 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 or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic books Designations used by companies to distinguish their products are often claimed as trademarks All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners The publisher is not associated with any product or vendor mentioned in this book 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 It is sold on the understanding that the publisher is not engaged in rendering professional services and neither the publisher nor the author shall be liable for damages arising herefrom If professional advice or other expert assistance is required, the services of a competent professional should be sought The advice and strategies contained herein may not be suitable for every situation In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read No warranty may be created or extended by any promotional statements for this work Neither the publisher nor the author shall be liable for any damages arising herefrom Library of Congress Cataloging-in-Publication Data Moloney, Mark G How to solve organic reaction mechanisms : a stepwise approach / Mark G Moloney   pages cm Originally published as: Reaction mechanisms at a glance (Malden, Mass : Blackwell Science, 2000) Includes index ISBN 978-1-118-40159-0 (pbk.) 1.  Organic reaction mechanisms.  I.  Title   QD502.5.M65 2015  547′.2–dc23 2014024070 A catalogue record for this book is available from the British Library ISBN: 9781118401590 Set in 10/12pt Helvetica Condensed by SPi Publisher Services, Pondicherry, India 1 2015 Contents Prefacevi Abbreviationsvii About the companion website viii Introductionix Nucleophilic substitution and elimination Alkene and alkyne chemistry 32 Nucleophilic additions to carbonyl groups 64 Enolate chemistry 96 Aromatic chemistry 128 6 Rearrangements 160 Ligand coupling processes 192 Index 224 v Preface This book is an upgraded version of Reaction Mechanisms at a Glance, first published in 2000 That book was an attempt to demonstrate that there is indeed an underlying set of rules suitable to working out plausible reaction mechanisms in organic chemistry and which can be grasped with a little effort More importantly, the use of these rules in a systematic fashion substantially reduces the burden on memory! This version has an expanded set of fully worked problems and a new chapter which applies the problem-solving strategy to ligand-coupling reactions using transition metals The latter is an addition which represents the exceptional growth and importance of this chemistry, and its widespread application in diverse areas of chemical science I would like to dedicate this book to my wife Julie and all the members of my family Mark Moloney 2014 vi Abbreviations Ac Acetyl (CH3C(O)-) cat catalytic Δ Heat DMF N,N-Dimethylformamide (Me2NCHO) MCPBA meta-chloroperbenzoic acid PPA Polyphosphoric acid THF Tetrahydrofuran p-TsCl p-Toluenesulfonyl chloride (p-MeC6H4SO2Cl) p-TsOH p-Toluenesulfonic acid (p-MeC6H4SO3H) py Pyridine (C5H5N) EWG Electron withdrawing group dil dilute conc concentrated vii About the companion website This book is accompanied by a companion website: www.wiley.com/go/moloney/mechanisms The website includes worked supplementary questions viii O + δ+ H Ph O H + – OH – CO2H H2O δ– CN O b Ph +CN – HO H a Ph Ph H +H2O C HO Ph OH2 Ph + H C HO –H2O H N H H + N O H Ph a + C HO H H +H2O H b a H H N HO Ph b C O H H C HO +H3O+ N + H CN b O H N – H b a δ– N C δ+ + H – SO2 –SO32– δ+ H Cl H b O + H K a – Na HSO3 a O H –H3O H + Ph OH H HO δ+ C Ph + H O NH2 –H+ + H+ C HO H + H N O H C HO O Ph H NH2 H –H2O +H3O+ H H + OH HO Ph C +H2O O –NH3, + –H3O H c NH HO b C HO O Ph H H a O + H2O –H+ + H+ HO a NH2 C H Ph O +H2O OH HO Ph NH2 C + O H b H H H Summary: Carbonyl compounds readily undergo addition and addition-elimination reactions: Nu Me H X O NuH X ≠ Leaving group Me O NuH X X = Leaving group Me Nu Now try question 3.9 81 3.9 O Ph HCl, H2O, Δ′ 4N Ph CO2H O2 AcHN Me Label electrophilic/nucleophilic and acidic/basic sites of all reactants, and number identical atoms in the starting material and product This oxazolone function has three possible electrophilic sites, but under acidic conditions is also capable of being protonated on the carbonyl group and amine groups Hydrochloric acid is a strong acid, which under aqueous conditions generates a hydroxonium ion Identify the most reactive sites, if more than one exists The imidate group is the most reactive site to protonation (N most basic), and this occurs on the nitrogen atom, giving an iminium cation intermediate Recall the characteristic reactions of the most reactive functional groups; and by considering the reaction conditions, decide which is the most appropriate Carbonyl species and their equivalents are very susceptible tonucleophilic addition and nucleophilic addition-elimination reactions, especially under aqueous conditions, leading to hydrolysis Work through the mechanism leading to the intermediate product Repeat the above four steps Recognise that this is not the final product, but is closely related to it Write down the structure of the final product 82 Such activated iminium species are very susceptible tonucleophilic addition-elimination reactions, which proceed by initial addition of the water nucleophile followed by a sequence of reversible proton transfers that lead to a tetrahedral intermediate which collapses with loss of carboxylate This breaks open the ring and generates the product Overall, the process is hydrolysis Not needed here δ+ Ph O N Ph δ+ O H3O – + H2O δ– Cl δ+ CO2H O Me NH Me Ph O Ph +H3O O2 N O + N –H2O Ph O H Me H b O H O N + H O O H b a Me Me a H + +H2O O Ph O HN Me O –H3O a H + O b N O Me OH +H3O H Ph O Ph H O +H2O H H N O + Me H OH2 + + H a Ph H O HN b O + H O Me HN O H –H2O + c Ph b Me O H Ph CO2H O O O NH a Me H Summary: Carbonyl compounds readily undergo multiple addition–elimination reactions: O Me X NuH X - Leaving group HO Nu Me X NuH X - Leaving group Nu Nu Me X 83 3.10 LiAlH4, Et2O then acidic work-up O O OH Label electrophilic/nucleophilic and acidic/basic sites of all reactants, and number identical atoms in the starting material and product Lactones (cyclic esters) are electrophilic at the carbonyl group, since oxygen is electronegative Lithium aluminium hydride is a source of hydride, which is an excellent nucleophile, especially when the lithium cation acts as a Lewis acid to further activate the carbonyl group Identify the most reactive sites, if more than one exists The carbonyl group is the only electrophilic site, and lithium aluminium hydride the only nucleophile Recall the characteristic reactions of the most reactive functional groups; and by considering the reaction conditions, decide which is the most appropriate Carbonyl groups readily interact with Lewis acids to generate an activated oxonium ion, which activates the carbonyl group to nucleophilic addition by a suitable nucleophile Work through the mechanism leading to the intermediate product Addition of the hydride nucleophile onto the activated carbonyl group leads to the formation of a lithium alkoxide salt, which fragments further by loss of alkoxide and in so doing generates another aldehyde; this is in turn intercepted by another hydride, which gives a lithium bisalkoxide Repeat the above four steps Recognise that this is not the final product, but is closely related to it Write down the structure of the final product 84 HO Not needed here Work-up proceeds by addition of weak aqueous acid This protonates both alkoxides in two successive steps, giving the final diol product H Li + H – Al H HO H OH LiAlH4 δ+ O O O O O Li Li O + + a – Li O O H O O + H b b –AlH3 Li O a H H Al Li O – + H H LiAlH4 – Li O H O Li + – Li + b δ+ O H + a H H Al Li O – Li + – + + Li O – O H H +H3O + H + Repeat protonation HO Li HO OH O – H + O b H a –H2O – Li O O + – Summary: Carbonyl compounds readily undergo addition and addition-elimination reactions: Nu Me H X O NuH X ≠ Leaving group Me O NuH X X = Leaving group Me Nu Now try question 3.16 85 3.11 HO CO2Me NH2 (i) tBuCHO, Et3N (ii) CH3COCl, Et3N CO2Me O N t-Bu Me O Label electrophilic/nucleophilic and acidic/basic sites of all reactants, and number identical atoms in the starting material and product Amino esters have carbonyl groups that which are electrophiles, and amine and alcohol groups which are nucleophiles Aldehydes are electrophiles, since oxygen is electronegative and the double bond is reactive to nucleophiles Triethylamine is a weak base Identify the most reactive sites, if more than one exists The amine is the most nucleophilic site of the amino ester (since N is less electronegative than O) and the pivaldehyde carbonyl is the most reactive electrophile Recall the characteristic reactions of the most reactive functional groups; and by considering the reaction conditions, decide which is the most appropriate Amines and aldehydes react to form imines; this reaction can be conducted under acidic or basic catalysed conditions Work through the mechanism leading to the intermediate product The amino group adds to the electrophilic carbon of the aldehyde function, and proton transfer generates an aminal; elimination of water forms the corresponding imine As a result of the proximity of the adjacent hydroxyl group, ring closure, followed by proton transfer, to form a cyclic oxazolidine will occur Repeat the above four steps Recognise that this is not the final product, but is closely related to it Write down the structure of the final product 86 Acetyl chloride is highly electrophilic, and converts the amine to the corresponding amide via an addition-elimination process Deprotonation mediated by triethylamine leads to the formation of the product Not needed here 3 CO2Me HO δ– O O O Et3N NH2 δ+ H tBu δ+ Cl H3C Me O CO2Me HO tBu NH2 O CO2Me HO – H δ+ N tBu b CO2Me + O a –H+ NH2 + H+ CO2Me HO b c HO tBu N tBu –H2O CO2Me O –H+ N tBu + H + H+ H CO2Me O N tBu Et3N +Et3N CO2Me HO b a – a H N tBu O c H3C O t Bu CO2Me δ– N b d δ+ Cl a + Et3N b a H CH3 CO2Me O O + N tBu H CO2Me O N –HNEt3+Cl– tBu Me O Et3N Summary: Carbonyl compounds readily undergo multiple addition-elimination reactions: O Me NuH X X ≠ Leaving group HO Me Nu X NuH Nu Nu X ≠ Leaving group Me X 87 3.12 OH O CHO O KCN O O Label electrophilic/nucleophilic and acidic/basic sites of all reactants, and number identical atoms in the starting material and product Aldehydes are electrophiles, since oxygen is electronegative and the double bond is reactive to nucleophiles Potassium cyanide is an excellent nucleophile (sp hybridised carbon atom), but also a weak base Identify the most reactive sites, if more than one exists The aldehyde is the only electrophilic site in the starting material, and cyanide is the only nucleophile Recall the characteristic reactions of the most reactive functional groups; and by considering the reaction conditions, decide which is the most appropriate Aldehydes are very susceptible to nucleophilic addition reactions, especially when the nucleophile is a good one like cyanide, but importantly these additions are reversible Work through the mechanism leading to the intermediate product Repeat the above four steps Recognise that this is not the final product, but is closely related to it Write down the structure of the final product 88 The aldehyde is directly attacked by the highly nucleophilic cyanide anion This leads to formation of a cyanoalkoxide product, which under the conditions of the reaction, equilibrates by proton transfer to generate a resonance stabilised carbanion This reacts with a second equivalent of the starting aldehyde to generate another alkoxide Proton transfer then regenerates the original cyanoalkoxide intermediate, which collapses (cyanide addition to a carbonyl group is reversible) to regenerate the original carbonyl group Not needed here OH K O CHO + – O K C δ+ H a – O b O O O CN + – CN C O O N –H+ + H+ C O H N – O – H CN O C δ+ H O O b – C O O O O N O O – CN O H H C δ+ H a –H+ + H+ H O OH O O O – O CN –CN – O O Summary: This is an example of the Benzoin condensation of aldehydes with cyanide: ArCHO O KCN Ar Ar OH Now try question 3.18 89 3.13 O H H NaOH then acidic work-up O O Label electrophilic/nucleophilic and acidic/basic sites of all reactants, and number identical atoms in the starting material and product Identify the most reactive sites, if more than one exists Recall the characteristic reactions of the most reactive functional groups; and by considering the reaction conditions, decide which is the most appropriate Work through the mechanism leading to the intermediate product Repeat the above four steps Recognise that this is not the final product, but is closely related to it Write down the structure of the final product 90 OH HO Aldehydes are electrophiles, since oxygen is electronegative and the double bond is reactive to nucleophiles This substrate, glyoxal, is especially reactive as there are two adjacent aldehydes whose dipoles reinforce reactivity Sodium hydroxide is an excellent base and nucleophile The aldehyde is the only electrophilic site in the starting material and of course both are equivalent Hydroxide is the only base and nucleophile Aldehydes are very susceptible to nucleophilic addition reactions, especially when the nucleophile is a good one like hydroxide The aldehyde is directly attacked by the highly nucleophilic hydroxide anion This leads to formation of an alkoxide product, which under the conditions of the reaction, undergoes a slow second addition of hydroxide to the other aldehyde carbonyl group to generate a dianion Intramolecular hydride transfer with loss of hydroxide gives another alkoxide intermediate Not needed here Protonation on work up generates the product O H H Na + HO – HO O H H Na HO – O O b H H O – OH H H c OH O b – – O OH H O OH O H OH a +H3O O O H –OH– b – b OH OH δ+ H H – a – a O O – OH O O + H – O OH + + H a – OH O O OH HO –H2O O Summary: This is an example of the Cannizarro reaction, although in this case hydride transfer is intramolecular: ArCHO ArCO2H + ArCH2OH Now try question 3.19 91 3.14 Br CO2Et 1 (i) P(OEt)3 (ii) NaH Ph (iii) Ph Ph CO2Et Ph Label electrophilic/nucleophilic and acidic/basic sites of all reactants, and number identical atoms in the starting material and product α-Haloesters are excellent electrophiles, since the halogen is electronegative and a good leaving group The ester carbonyl is also electrophilic Triethyl phosphite is a very good nucleophile Identify the most reactive sites, if more than one exists The carbon adjacent to the bromine is the most electrophilic position, and phosphorus is the only nucleophile Recall the characteristic reactions of the most reactive functional groups; and by considering the reaction conditions, decide which is the most appropriate Alkyl halides are very susceptible to nucleophilic substitution reactions, and this one especially so due to the adjacent ester group which further activates nucleophilic attack Work through the mechanism leading to the intermediate product Repeat the above four steps Recognise that this is not the final product, but is closely related to it Write down the structure of the final product 92 O Triethyl phosphite displaces the bromine in an SN2-like process, and back attack by the bromide which is released generates a phosphonate product, in which the α-protons are strongly acidic Sodium hydride is a strong base; deprotonation of the α-protons proceeds easily, generating a phosphonate anion, which reacts with the added ketone by nucleophilic addition Cyclisation to form an oxaphosphetane intermediate is followed by collapse with formation of a P=O bond giving the product alkene Not needed here δ– Br P(OEt)3 δ+ CO2Et Na Br + H Ph δ+ Ph Ph CO2Et O b +P(OEt)3 CO2Et Ph – O Br CO2Et (EtO)2P a –Br P(OEt)3 CO2Et + – +Br– a – O EtO P EtO CO2Et H b H O +NaH a P –EtBr b P EtO CO2Et + O CO2Et EtO O P CO2Et Br O EtO EtO O EtO OEt H –H2 EtO P EtO – c EtO – CO2Et a – P Ph δ+ Ph Ph CO2Et EtO O Ph – b O CO2Et Ph EtO –(EtO)2P(O)O – EtO O – b a P CO2Et Ph a c Ph Ph P EtO b O O EtO – O CO2Et Ph Ph Summary: Carbonyl compounds readily react with phosphonate anions to give alkenes (Horner-Wadsworth-Emmons reaction): CO2Et O R EtO2CCH2P(O)(OEt)2 R Base Me R Now try question 3.20 93 3.15 CH3CHO Label electrophilic/nucleophilic and acidic/basic sites of all reactants, and number identical atoms in the starting material and product Identify the most reactive sites, if more than one exists Recall the characteristic reactions of the most reactive functional groups; and by considering the reaction conditions, decide which is the most appropriate Work through the mechanism leading to the intermediate product Repeat the above four steps Recognise that this is not the final product, but is closely related to it Write down the structure of the final product 94 (i) NaCN, NH4Cl (ii) HCl, H2O NH2 H3C CO2H Aldehydes are electrophiles, since oxygen is electronegative and the double bond is reactive to nucleophiles Ammonium chloride is in equilibrium with ammonia, an excellent nucleophile; sodium cyanide is an excellent nucleophile (sp hybridised carbon atom) The aldehyde is the only electrophilic site in the starting material Cyanide and ammonia are both nucleophiles Cyanide reacts reversibly with aldehydes, so imine formation is preferred Aldehydes are very susceptible to nucleophilic addition reactions, especially in the presence of good nucleophiles like ammonia, to give imines Under the conditions of this reaction, further addition by cyanide occurs The aldehyde is attacked by the nucleophilic ammonia, which after a series of proton transfers and loss of water, leads to the formation of an imminium ion which is in turn intercepted by the nucleophile, cyanide This leads to formation of a aminonitrile product * Hydrochloric acid is a strong acid, which protonates the nitrile and activates it to attack by water A series of proton transfers and finally tautomerisation then leads to theamide product * Further reaction with hydrochloric acid protonates the carbonyl group and activates it to attack by water again A series of proton transfers and finally elimination then leads to the acid product Not needed here O – + Na + H CN Cl – H3C δ+ H Me NH4+ + H2O NH3 + H3O+ NH2 H2O δ– CO2H H H b a O + H H b O Me – H2O δ+ H Me + O H O +NH3 Me Hb H b a H N –H3O Me + NH2 H a H +H3O+ O H δ– N H C H +CN δ+ – CN – H a + H OH2 Me NH2 Me NH2 NH2 + Me –H2O NH2 H –H2O b H N C HO Me C HO Me NH2 H H N +H2O + H + O NH2 N +H2O H H HO a Ph a b C O H H b a O H NH2 + C HO O O H b Ph H –H2O Ph +H2O + + H –H3O + H +H3O N NH2 + HO Ph NH2 δ+ C –H+ + H+ HO C O Ph H H + H OH H H + NH2 H2O C HO Ph C HO O O H H H a H + +H3O+ C Me O NH2 + OH +H2O + H a O H H NH3 HO b a –H+ + H+ c NH HO b C HO O Ph OH H H OH a H HO H –NH3, + –H3O O H Ph C O H Summary: This is an example of the Strecker synthesis of amino acids: RCHO (i) NH4Cl + KCN (ii) Hydrolysis H2N R CO2H R′ Now try question 3.21 95 ... Moloney, Mark G How to solve organic reaction mechanisms : a stepwise approach / Mark G Moloney   pages cm Originally published as: Reaction mechanisms at a glance (Malden, Mass : Blackwell Science,... How to Solve Organic Reaction Mechanisms How to Solve Organic Reaction Mechanisms A Stepwise Approach MARK G MOLONEY Fellow and Tutor in Chemistry at St Peter’s College and Professor... intended to give a detailed explanation of the answer, but to provide a guide to the approach to arriving at the answer The right hand page will have a complete worked solution Placing a piece of A4