Reaction Mechanisms in Organic Synthesis E-Book

Rakesh Kumar Parashar

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Postgraduate Chemistry Series
• Sprache: Englisch

Seitenzahl: 415

Veröffentlichungsjahr: 2013

Beschreibung

Organic chemistry is a core part of the chemistry curricula, and advanced levels texts often obscure the essential framework underlying and uniting the vast numbers of reactions as a result of the high level of detail presented. The material in this book is condensed into a manageable text of 350 pages and presented in a clear and logical fashion, focusing purely on the basics of the subject without going through exhaustive detail or repetitive examples. The book aims to bridge the gap between undergraduate organic chemistry textbooks and advanced level textbooks, beginning with a basic introductory course and arranging the reaction mechanisms according to an ascending order of difficulty. As such, the author believes the book will be excellent primer for advanced postgraduates

Reaction Mechanisms in Organic Synthesis is written from the point of view of the synthetic organic chemist, enabling students and researchers to understand and expand on reactions covered in foundation courses, and to apply them in a practical context by designing syntheses. As a further aid to the practical research student, the content is organized according to the conditions under which a reaction is executed rather than by the types of mechanisms. Particular emphasis is placed on controlling stereospecificity and regiospecificity.

Topics covered include:

• Transition metal mediated carbon-carbon bond formation reactions
• Use of stabilized carbanions, ylides and enamines for carbon-carbon bond formation reactions,
• Advanced level use of oxidation and reduction reagents in synthesis.

As a modern text, this book stands out from its competitors due to its comprehensive coverage of recently published research. The book contains specific examples from the latest literature, covering modern reactions and the latest procedural modifications. The focus on contemporary and synthetically useful reactions ensures that the contents are specifically relevant and attractive to postgraduate students and industrial organic chemists.

Leseprobe

Contents

Foreword

Preface

About the Author

Acknowledgements

Abbreviations

Chapter 1 Synthetic Strategies

1.1 An introduction to organic synthesis

1.2 Retrosynthetic analysis (disconnection approach)

1.3 Umpolung strategy

1.4 Atom economy

1.5 Selectivity

1.6 Protecting groups

Chapter 2 Reactive Intermediates

2.1 Carbocations

2.2 Carbanions

2.3 Free radicals

2.4 Carbenes

2.5 Nitrenes

2.6 Benzynes

Chapter 3 Stabilized Carbanions, Enamines and Ylides

3.1 Stabilized carbanions

3.2 Enamines

3.3 Ylides

Chapter 4 Carbon–Carbon Double Bond Forming Reactions

4.1 Introduction

4.2 Elimination reactions

4.3 Alkenation (alkylidenation) of carbonyl compounds

4.4 Reduction of alkynes

Chapter 5 Transition Metal-Mediated Carbon–Carbon Bond Forming Reactions

5.1 Carbon–carbon bond forming reactions catalyzed by transition metals

5.2 Transition metal-catalyzed coupling of organometallic reagents with organic halides and related electrophiles

Chapter 6 Reduction

6.1 Reduction of carbon–carbon double bond

6.2 Reduction of acetylenes

6.3 Reduction of benzene and derivatives

6.4 Reduction of carbonyl compounds

6.5 Reduction of α, β-unsaturated aldehydes and ketone

6.6 Reduction of nitro, N-oxides, oximes, azides, nitriles and nitroso compounds

6.7 Hydrogenolysis

Chapter 7 Oxidation

7.1 Oxidation of alcohols

7.2 Oxidation of aldehydes and ketones

7.3 Oxidation of phenols

7.4 Epoxidation

7.5 Dihydroxylation

7.6 Aminohydroxylation

7.7 Oxidative cleavage of C–C double bonds

7.8 Oxidation of anilines

7.9 Dehydrogenation

7.10 Allylic or benzylic oxidation

7.11 Oxidation of sulfides

7.12 Oxidation of aliphatic side chains attached to aromatic ring

Chapter 8 Pericyclic Reactions

8.1 Important classes of pericyclic reactions

8.2 Theoretical explanation of pericyclic reactions

8.3 Cycloaddition reactions

8.4 Electrocyclic reactions

8.5 Sigmatropic rearrangements

8.6 Ene reactions

8.7 Selection rules

Index

Postgraduate Chemistry Series

A series designed to provide a broad understanding of selected growth areas of chemistry at postgraduate student and research level. Volumes concentrate on material in advance of a normal undergraduate text, although the relevant background to a subject is included. Key discoveries and trends in current research are highlighted, and volumes are extensively referenced and cross-referenced. Detailed and effective indexes are an important feature of the series. In some universities, the series will also serve as a valuable reference for final year honours students.

Editorial Board

Professor James Coxon (Editor-in-Chief), Department of Chemistry, University of Canterbury, New Zealand

Professor Pat Bailey, Department of Chemistry, University of Manchester, UK

Professor Les Field, School of Chemistry, University of New South Wales, Sydney, Australia

Professor Dr John Gladysz, Institut für Organische Chemie, Universität Erlangen-Nürnberg, Germany

Professor Philip Parsons, School of Chemistry, Physics and Environmental Science, University of Sussex, UK

Professor Peter Stang, Department of Chemistry, University of Utah, USA

Titles in the Series

Protecting Groups in Organic Synthesis

James R. Hanson

Organic Synthesis with Carbohydrates

Geert-Jan Boons and Karl J. Hale

Organic Synthesis Using Transition Metals

Roderick Bates

Stoichiometric Asymmetric Synthesis

Mark Rizzacasa and Michael Perkins

Catalysis in Asymmetric Synthesis (Second Edition)

Vittorio Caprio and Jonathan M.J. Williams

Photochemistry of Organic Compounds: From Concepts to Practice

Petr Klán and Jakob Wirz

Practical Biotransformations

Gideon Grogan

This edition first published 2009

© 2009 Rakesh Kumar Parashar

Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing programme has been merged with Wiley’s global Scientific, Technical, and Medical business to form Wiley-Blackwell.

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Library of Congress Cataloging-in-Publication Data

Parashar, R. K. (Rakesh Kumar)

[1st ed.]

Reaction mechanisms in organic synthesis / Rakesh K. Parashar

p. cm. — (Postgraduate chemistry series)

Includes bibliographical references and index.

ISBN 978-1-4051-5072-9 (hardback: alk. paper) — ISBN 978-1-4051-9089-3 (pbk.: alk. paper)

1. Organic compounds—synthesis. 2. Organic reaction mechanisms. 3. Physical organic chemistry. I. Title.

QD262.P34 2009

547′.2—dc22 2008034864

A catalogue record for this book is available from the British Library.

To Riya, Manya and Indu with love and to my parents with immense respect

Foreword

Exciting new methods and reagents are being discovered and used everyday in the synthesis of organic molecules. Knowing the mechanism of these reactions is very important, without which it is almost impossible to carry out the synthesis of important molecules in the laboratory or in industry. Thus, the importance of organic reaction mechanisms continues to increase, and this book is a welcome addition to the available sources on the subject.

While teaching organic synthesis and practicing it in the laboratory, a need is often felt of a handy book combining organic synthesis and mechanisms of reactions employed in synthesis instead of large volumes or monograms on synthesis. There are not many such books covering these two very essential aspects of organic chemistry.

Writing a textbook for any level is always a challenge. However, Dr Parashar deserves praise for undertaking this project and interlinking these two areas of organic chemistry so well throughout the book.

The book is designed to provide fundamental aspects of organic chemistry in a flexible way rather than presenting a traditional approach. The mechanisms and stereochemical features of common reactions used in organic synthesis are discussed in a qualitative and quantitative manner. Specific examples are taken from the latest literature.

The contents of the book give a general impression about what is dealt with. The selection of topics has been done very carefully and judiciously. The material is condensed to a manageable text of 363 pages and presented in a clear and logical fashion over eight chapters. This is done by focusing purely on the basics of the subject without going through exhaustive detail or repetitive examples.

This book would be of immense help to students at the postgraduate level as well as to research workers because of its contents and the way those have been dealt with. I sincerely hope that the book will go a long way to satisfy the long-felt need of students and teachers who inspire the students to take up synthetic organic chemistry as their research topic and career.

I hope practitioners and professionals will be benefited from the experience of learning reaction mechanisms of important synthetic reactions.

I am happy to recommend this book as a self-guide for students and professionals.

Virinder S. Parmar, PhD, FRSCProfessor and Head, Department of Chemistry, andChairman of the Board of Research Studies University of Delhi, India

Preface

An organic chemist is primarily concerned with (a) the synthesis of organic molecules of particular interest to the pharmaceutical and agrochemical industries and (b) the way these molecules interact in biological pathways.

Synthesis involves a careful selection of reactions; new reactions are being developed everyday. Knowing how structure affects a reaction, a rational sequence of transformations can be used to synthesize target molecules. An understanding of organic reaction mechanisms is essential without which it is impossible to plan organic synthesis. It is also required to extend one’s knowledge of different areas related to organic chemical reaction mechanisms. The vital importance of the organic synthesis processes is established by the fact that many Nobel laureates have been associated with this field.

Beginning with basic introductory course, this book covers all aspects of organic reaction mechanisms, expands on the foundation acquired in chemistry courses, and enables students and research workers to understand the mechanisms and then to plan syntheses. This book will help postgraduate students to write reasonable mechanisms for organic chemical transformations, which are arranged according to an ascending order of difficulty.

Established reactions are being subjected to both technical improvements and increasing number of applications. For example, intense efforts are made in industry and university laboratories to devise innovative ways to speed up reactions, to carry them out in a continuous fashion and to provide for separation of complex mixtures. For example, ultrasound can dramatically affect the rates of chemical reactions. Microwave-assisted protocols often result in high yields and time efficiency. Solid-phase synthesis allows for easy separation of the resulting products while providing for libraries of compounds to be made. Although these methods have been discussed in special monographs and review articles, there is no recent single book covering reactions (modern or newer) with latest procedural modifications and also simultaneously explaining reaction mechanism and covering stereospecificity and regiospecificity.

The book contains examples from recently published research work to illustrate the important steps involved in synthesis. The discussion is organized by the conditions under which the reaction is executed rather than by the types of mechanisms as is the case in most textbooks at the graduate level.

The author believes that students are well aware of the basic reaction pathways such as substitutions, additions, eliminations, aromatic substitutions, aliphatic nucleophilic substitutions and electrophilic substitutions. Students may follow undergraduate books on reaction mechanisms for basic knowledge of reactive intermediates and oxidation and reduction processes. Reaction Mechanisms in Organic Synthesis provides extensive coverage of various carbon–carbon bond forming reactions such as transition metal catalyzed reactions; use of stabilized carbanions, ylides and enamines for the carbon–carbon bond forming reactions; and advance level use of oxidation and reduction reagents in synthesis.

Thus, this book may prove to be an excellent primer for advanced postgraduates in chemistry. This book will be useful both for instructors and those who are preparing for examinations.

Following is a brief account of the contents of the eight chapters of this book.

Chapter 1 is devoted to exploring strategies involved in organic synthesis. It seeks to explain concepts like retrosynthetic analysis, atom economy, umpolung approach, click chemistry and asymmetric synthesis. On the basis of interesting and relevant examples, protection and deprotection of different functional groups are explained and the most probable mechanism is also mentioned for important reactions.

Chapter 2 includes complete discussion on reaction intermediates including carbocations, carbanions, free radicals, carbenes, nitrines and benzynes. The structure, methods of generation and important reactions of all the intermediates are discussed in this chapter. The author has emphasized on their applications in the asymmetric synthesis.

Chapter 3 discusses ylides and enamines, and also deals with the extended examples of carbanions.

Chapter 4 reviews the role of various reagents used in organic synthesis for the formation of carbon–carbon double bond. Specific examples are included at each stage to illustrate the mechanism under discussion.

Chapter 5 includes complete coverage of the transition metals-mediated carbon–carbon bond forming reactions. Pd-, Ni-, Cr-, Zr- and Cu-catalyzed reactions such as Heck, Negishi, Sonogashira, Suzuki, Hiyama, Stille, Kumada reactions are covered in adequate details including the applications of these reactions in organic synthesis.

Chapter 6 focuses on selected examples of reduction methods and their mechanisms in detail. The chapter gives a detailed account of reducing reagents and their applications in organic synthesis.

The oxidation examples in Chapter 7 are arranged to elucidate key aspects of organic reaction mechanisms. The importance of oxidation reagents in synthesis and their mechanism of action have been explained in detail.

Chapter 8 covers extensively pericyclic reactions and also includes the aromatic transition state theory. Most of the examples are taken from latest literature and are useful for postgraduate and research students.

As an academic convenience to readers all reaction mechanisms leading to stereospecific products are highlighted. The book will also serve as an excellent reference book since references are offered at the end of each chapter.

The book seeks to cover the postgraduate syllabi of almost all the universities. Students will be spared the tedium of collecting all the information on the subject scattered in various books and journals. Even though a comprehensive effort was made to gather information from all sources, it is inevitable that some relevant papers and reviews may be left unscanned.

The author hopes that the book proves to be an easy-to-use general organic chemistry textbook and finds a place in libraries and personal bookshelves of the academic community.

All comments and suggestions will be received with gratitude.

Rakesh Kumar ParasharReader, Chemistry DepartmentKirori Mal CollegeUniversity of Delhi, India

About the Author

Dr Rakesh Kumar Parashar completed his PhD in 1990 from the University of Delhi, Delhi, in the field of synthetic organic chemistry. He is a Reader in Chemistry at Kirori Mal College, University of Delhi, Delhi. He has done his postdoctorate from the University of Barcelona, Spain. He has published 22 papers in various national and international journals and has delivered several lectures in India and abroad. He is also the author of several books. He is actively involved in teaching and research for the past 18 years.

Acknowledgements

I sincerely thank Prof. Jim Coxon who inspired me to take up this project. He also generously helped me to improve this book at the writing stage.

My special thanks are to Prof. Virinder S. Parmar, Head of Chemistry Department, University of Delhi, for writing foreword of this book. I acknowledge Prof. J. M. Khurana, University of Delhi, for his fruitful suggestions that helped me throughout the preparation of this manuscript. I also thank Dr S. Gera and Dr Geetanjali Pandey, Chemistry Department, Kirori Mal College, University of Delhi, for reviewing several chapters.

And, finally, I thank my wife, Indu, and daughters, Riya and Manya, for their love and encouragement during the lengthy, seemingly interminable period of writing this book.

Abbreviations

Ac

acetyl

AC

2

O

acetic anhydride

acac

acetylacetonate

AIBN

2,2′-azobisisobutyronitrile

All

allyloxycarbonyl

Ar

aryl

BBN

borabicyclo[3.3.1]nonane

BHT

butylated hydroxytoluene (2,6-di-

t

-butyl-

p

-cresol)

BINAL-H

2,2′-dihydroxy-1,1′-binaphthyllithium aluminum hydride

BINAP

2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

BINOL

1,1′-bis-2,2-naphthol

bipy

2,2′-bipyridyl

Bn

benzyl

Boc

t

-butoxycarbonyl

BOM

benzyloxymethyl

bp

boiling point

Bs

brosyl (4-bromobenzenesulfonyl)

BSA

N,O

-bis(trimethylsilyl)acetamide

Bu

n

-butyl

Bz

benzoyl

CAN

cerium(IV) ammonium nitrate

cat.

catalyst

Cbz

benzyloxycarbonyl

CHIRAPHOS

2,3-bis(diphenylphosphino)butane

CIP

Cahn–Ingold–Prelog priority rules

cod

cyclooctadiene

m

-CPBA

m

-chloroperbenzoic acid or

m

-chloroperoxybenzoic acid

CSA

10-camphorsulfonic acid

Cy

cyclohexyl

d

density

DABCO

1,4-diazabicyclo[2.2.2]octane

DAIPEN

1,1-dianisyl-2-isopropyl-1,2-ethylenediamine

DAST

N,N

-diethylaminosulfur trifluoride

dba

dibenzylideneacetone

DBU

1,8-diazabicyclo[5.4.0]undec-7-ene

DCC

N,N

-dicyclohexylcarbodiimide

DCE

dichloroethane

DCM

dichloromethane

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

De

diastereomeric excess

DEG

diethylene glycol

DET

diethyl tartrate

(DHQ)

2

PHAL

1,4-bis(9-

O

-dihydroquinine)phthalazine

(DHQD)

2

PHAL

1,4-bis(9-

O

-dihydroquinidine)phthalazine

DIBAH or DIBAL-H

diisobutylaluminum hydride (

i

-Bu

2

AlH)

2

DIEA

=DIPEA

DIOP

4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxolane or 2,3-

O

-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)

butane

DIPAMP

bis[(2-methoxyphenyl)phenylphosphino]ethane

DIPEA

diisopropylethylamine

DMA

dimethylacetamide

DMAP

4-(dimethylamino)pyridine

DME

1,2-dimethoxyethane, glyme or dimethyl glycol

DMEU

1,3-dimethylimidazolidin-2-one

DMF

dimethylformamide

DMPU

1,3-Dimethyltetrahydropyrimidin-2(1

H

)-one

DMS

dimethyl sulfide

DMSO

dimethyl sulfoxide

DPEN

diphenylethylenediamine

Dppe

1,2-bis(diphenylphosphino)ethane

DMMP

Dimethyl methylphosphonate

dppf

1,1′-bis(diphenylphosphino)ferrocene

dppm

1,1-bis(diphenylphosphino)methane

dppp

1,3-bis(diphenylphosphino)propane

Dod-S-Me

Dodecyl methyl sulfide

DTBP

di-

t

-butyl peroxide

E1cB

elimination conjugate

b

ase

ee

enantiomeric excess

equiv.

equivalent(s)

Et

ethyl

EWG

electron-withdrawing group

Fmoc

9-fluorenylmethoxycarbonyl

h

hour(s)

HMDS

hexamethyldisilazane or 1,1,1,3,3,3,-hexamethyldisilazane

HMPA

hexamethylphosphoric triamide

HWE

Horner–Wadsworth–Emmons

i

iso

Ipc

isopinocampheyl

isc

intersystem crossing

IR

infrared

kcal

kilocalorie

KHDMS

potassium hexamethyldisilazide

LAH

lithium aluminum hydride

LDA

lithium diisopropylamide

LHMDS

LiHMDS

LiHMDS

lithium hexamethyldisilazide

LiTMP

lithium 2,2,6,6-tretramethylpiperidide

LTA

lead tetraacetate

LTEAH

lithium triethoxyaluminohydride

LVT

low-valent titanium

2,6-Lutidine

2,6-dimethylpyridine

M

metal; also molar

Me

methyl

MEM

(2-methoxyethoxy)methyl

min

minutes

mL

millilitre

MMPP

magnesium monoperoxyphthalate

MOM

methoxymethyl

mp

melting point

Ms

mesyl or methanesulfonyl

MS

molecular sieves

MTM

methylthiomethyl

MW

molecular weight; microwave

NaHMDS

sodium hexamethyldisilazide

NBA

N

-bromoacetamide

NBS

N

-bromosuccinimide

NCS

N

-chlorosuccinimide

NIS

N

-iodosuccinimide

NMO

N

-methylmorpholine

N

-oxide

NMP

N

-methyl-2-pyrrolidinone

NMR

nuclear magnetic resonance

Nu

nucleophile

OTf

Triflate or trifluoromethanesulfonate, functional group with the formula

PCC

pyridinium chlorochromate

PDC

pyridinium dichromate

Ph

phenyl

PhH

benzene

pent

pentyl

Piv

pivaloyl

PMB

p

-methoxybenzyl

pmIm

1-methyl-3-pentylimidazolium

PMP

1,2,2,6,6-p entamethylpiperidine

PPTS

pyridinium

p

-toluenesulfonate

Pr

n

-propyl

PTC

phase transfer catalyst/catalysis

PTSA

p

-toluenesulfonic acid

py

pyridine

R

alkyl group

R

clockwise (R, for rectus)

rt

room temperature

S

counterclockwise (S, for sinister)

S

N

1

nucleophilic substitution reaction unimolecular

S

N

2

nucleophilic substitution reaction bimolecular

salen

bis(salicylidene)ethylenediamine

SET

single electron transfer

SMEAH

red-Al or sodium bis(2-methoxyethoxy)aluminum hydride

t

tertiary

TASF

tris(diethylamino)sulfonium difluorotrimethylsilicate

TBAB

tetrabutylammonium bromide

TBAF

tetrabutylammonium fluoride

TBAP

tetrabutylammonium perruthenate

TBDPS

t

-butyldiphenylsilyl

TBHP

t

-butyl hydroperoxide

TBS

t

-butyldimethylsilyl

TEMPO

2,2,6,6-tetramethylpiperidinoxyl

TES

triethylsilyl

TFA

trifluoroacetic acid

TFAA

trifluoroacetic anhydride

tfp

tri-2-furylphosphine

THF

tetrahydrofuran

THP

tetrahydropyranyl

TIPS

triisopropylsilyl

TMEDA

N, N, N

′

N

′-tetramethylethylenediamine

TMS

trimethylsilyl

TMSOTf

trimethylsilyl trifluoromethanesulfonate

Tol

p

-tolyl

TPAP

tetrapropylammonium perruthenate

TPP

tetraphenylporphyrin

Ts

tosyl or

p

-toluenesulfonyl; also transition state

TSOH

p

-toluenesulfonic acid (PTSA)

TTBS

tri-t-butylsilyl

Chapter 1

Synthetic Strategies

1.1 An introduction to organic synthesis

Organic synthesis is the construction of complex organic compounds from simple starting compounds by a series of chemical reactions. The compounds synthesized in nature are called natural products. Nature provides a plethora of organic compounds and many of these possess interesting chemical and pharmaceutical properties. Examples of natural products include cholesterol (1.1), a steroid found in most body tissues; limonene (1.2), a terpene found in lemon and orange oils; caffeine (1.3), a purine found in tea leaves and coffee beans; and morphine (1.4), an alkaloid found in opium.

The synthesis of organic molecules is the most important aspect of organic chemistry. There are two main areas of research in the field of organic synthesis, namely total synthesis and methodology. A total synthesis is the complete chemical synthesis of complex organic molecules from simple, commercially available or natural precursors. Methodology research usually involves three main stages, namely discovery, optimization and the study of scope and limitations. Some research groups may perform a total synthesis to showcase the new methodology and thereby demonstrate its application for the synthesis of other complex compounds.