Heterocyclic Chemistry E-Book

John A. Joule

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1205

Veröffentlichungsjahr: 2013

Beschreibung

This book has so closely matched the requirements of its readership over the years that it has become the first choice for chemists worldwide.

Heterocyclic chemistry comprises at least half of all organic chemistry research worldwide. In particular, the vast majority of organic work done in the pharmaceutical and agrochemical industries is heterocyclic chemistry.

The fifth edition of Heterocyclic Chemistry maintains the principal objective of earlier editions – to teach the fundamentals of heterocyclic reactivity and synthesis in a way that is understandable to second- and third-year undergraduate chemistry students. The inclusion of more advanced and current material also makes the book a valuable reference text for postgraduate taught courses, postgraduate researchers, and chemists at all levels working with heterocyclic compounds in industry.

Fully updated and expanded to reflect important 21^st century advances, the fifth edition of this classic text includes the following innovations:

• Extensive use of colour to highlight changes in structure and bonding during reactions
• Entirely new chapters on organometallic heterocyclic chemistry, heterocyclic natural products, especially in biochemical processes, and heterocycles in medicine
• New sections focusing on heterocyclic fluorine compounds, isotopically labeled heterocycles, and solid-phase chemistry, microwave heating and flow reactors in the heterocyclic context

Essential teaching material in the early chapters is followed by short chapters throughout the text which capture the essence of heterocyclic reactivity in concise resumés suitable as introductions or summaries, for example for examination preparation. Detailed, systematic discussions cover the reactivity and synthesis of all the important heterocyclic systems. Original references and references to reviews are given throughout the text, vital for postgraduate teaching and for research scientists. Problems, divided into straightforward revision exercises, and more challenging questions (with solutions available online), help the reader to understand and apply the principles of heterocyclic reactivity and synthesis.

Leseprobe

Contents

Preface to the Fifth Edition

Biography

Definitions of Abbreviations

1 Heterocyclic Nomenclature

2 Structures and Spectroscopic Properties of Aromatic Heterocycles

2.1 Carbocyclic Aromatic Systems

2.2 Structure of Six-Membered Heteroaromatic Systems

2.3 Structure of Five-Membered Heteroaromatic Systems5

2.4 Structures of Bicyclic Heteroaromatic Compounds

2.5 Tautomerism in Heterocyclic Systems6,7

2.6 Mesoionic Systems8

2.7 Some Spectroscopic Properties of Some Heteroaromatic Systems

References

3 Substitutions of Aromatic Heterocycles

3.1 Electrophilic Addition at Nitrogen

3.2 Electrophilic Substitution at Carbon6

3.3 Nucleophilic Substitution at Carbon33

3.4 Radical Substitution at Carbon45

3.5 Deprotonation of N-Hydrogen59

3.6 Oxidation and Reduction60 of Heterocyclic Rings

3.7 ortho-Quinodimethanes in Heterocyclic Compound Synthesis61

References

4 Organometallic Heterocyclic Chemistry

4.1 Preparation and Reactions of Organometallic Compounds

4.2 Transition Metal-Catalysed Reactions108

References

5 Methods in Heterocyclic Chemistry

5.1 Solid-Phase Reactions1 and Related Methods

5.2 Microwave Heating23

5.3 Flow Reactors

5.4 Hazards: Explosions

References

6 Ring Synthesis of Aromatic Heterocycles

6.1 Reaction Types Most Frequently Used in Heterocyclic Ring Synthesis

6.2 Typical Reactant Combinations

6.3 Summary

6.4 Electrocyclic Processes in Heterocyclic Ring Synthesis

6.5 Nitrenes in Heterocyclic Ring Synthesis8

6.6 Palladium Catalysis in the Synthesis of Benzo-Fused Heterocycles

References

7 Typical Reactivity of Pyridines, Quinolines and Isoquinolines

8 Pyridines: Reactions and Synthesis

8.1 Reactions with Electrophilic Reagents

8.2 Reactions with Oxidising Agents

8.3 Reactions with Nucleophilic Reagents

8.4 Metallation and Reactions of C-Metallated-Pyridines

8.5 Reactions with Radicals; Reactions of Pyridyl Radicals

8.6 Reactions with Reducing Agents

8.7 Electrocyclic Reactions (Ground State)

8.8 Photochemical Reactions

8.9 Oxy- and Amino-Pyridines

8.10 Alkyl-Pyridines

8.11 Pyridine Aldehydes, Ketones, Carboxylic Acids and Esters

8.12 Quaternary Pyridinium Salts

8.13 Pyridine N-oxides245

8.14 Synthesis of Pyridines

Exercises

References

9 Quinolines and Isoquinolines: Reactions and Synthesis

9.1 Reactions with Electrophilic Reagents

9.2 Reactions with Oxidising Agents

9.3 Reactions with Nucleophilic Reagents

9.4 Metallation and Reactions of C-Metallated Quinolines and Isoquinolines

9.5 Reactions with Radicals

9.6 Reactions with Reducing Agents

9.7 Electrocyclic Reactions (Ground State)

9.8 Photochemical Reactions

9.9 Oxy-Quinolines and Oxy-Isoquinolines

9.10 Amino-Quinolines and Amino-Isoquinolines

9.11 Alkyl-Quinolines and Alkyl-Isoquinolines

9.12 Quinoline and Isoquinoline Carboxylic Acids and Esters

9.13 Quaternary Quinolinium and Isoquinolinium Salts

9.14 Quinoline and Isoquinoline N-Oxides

9.15 Synthesis of Quinolines and Isoquinolines

Exercises

References

10 Typical Reactivity of Pyrylium and Benzopyrylium Ions, Pyrones and Benzopyrones

11 Pyryliums, 2- and 4-Pyrones: Reactions and Synthesis

11.1 Reactions of Pyrylium Cations4,5

11.2 2-Pyrones and 4-Pyrones (2H-Pyran-2-ones and 4.H-Pyran-4-ones; α- and γ-Pyrones)

11.3 Synthesis of Pyryliums1,7a

11.4 Synthesis of 2-Pyrones

11.5 Synthesis of 4-Pyrones

Exercises

References

12 Benzopyryliums and Benzopyrones: Reactions and Synthesis

12.1 Reactions of Benzopyryliums

12.2 Benzopyrones (Chromones, Coumarins and Isocoumarins)

12.3 Synthesis of Benzopyryliums, Chromones, Coumarins and Isocoumarins

Exercises

References

13 Typical Reactivity of the Diazine: Pyridazine, Pyrimidine and Pyrazine

14 The Diazines: Pyridazine, Pyrimidine, and Pyrazine: Reactions and Synthesis

14.1 Reactions with Electrophilic Reagents

14.2 Reactions with Oxidising Agents

14.3 Reactions with Nucleophilic Reagents

14.4 Metallation and Reactions of C-Metallated Diazines50

14.5 Reactions with Reducing Agents

14.6 Reactions with Radicals

14.7 Electrocyclic Reactions

14.8 Diazine N-Oxides79

14.9 Oxy-Diazines

14.10 Amino-Diazines

14.11 Alkyl-Diazines

14.12 Quaternary Diazinium Salts

14.13 Synthesis of Diazines

14.14 Pteridines

Exercises

References

15 Typical Reactivity of Pyrroles, Furans and Thiophenes

16 Pyrroles: Reactions and Synthesis

16.1 Reactions with Electrophilic Reagents5

16.2 Reactions with Oxidising Agents65

16.3 Reactions with Nucleophilic Reagents

16.4 Reactions with Bases

16.5 C-Metallation and Reactions of C-Metallated Pyrroles

16.6 Reactions with Radicals

16.7 Reactions with Reducing Agents

16.8 Electrocyclic Reactions (Ground State)

16.9 Reactions with Carbenes and Carbenoids

16.10 Photochemical Reactions120

16.11 Pyrryl-C-X Compounds

16.12 Pyrrole Aldehydes and Ketones

16.13 Pyrrole Carboxylic Acids

16.14 Pyrrole Carboxylic Acid Esters

16.15 Oxy- and Amino-Pyrroles

16.16 Synthesis of Pyrroles5,140

Exercises

References

17 Thiophenes: Reactions and Synthesis

17.1 Reactions with Electrophilic Reagents

17.2 Reactions with Oxidising Agents

17.3 Reactions with Nucleophilic Reagents

17.4 Metallation and Reactions of C-Metallated Thiophenes

17.5 Reactions with Radicals

17.6 Reactions with Reducing Agents

17.7 Electrocyclic Reactions (Ground State)118

17.8 Photochemical Reactions

17.9 Thiophene-C–X Compounds: Thenyl Derivatives

17.10 Thiophene Aldehydes and Ketones, and Carboxylic Acids and Esters

17.11 Oxy- and Amino-Thiophenes

17.12 Synthesis of Thiophenes146

Exercises

References

18 Furans: Reactions and Synthesis

18.1 Reactions with Electrophilic Reagents

18.2 Reactions with Oxidising Agents

18.3 Reactions with Nucleophilic Reagents

18.4 Metallation and Reactions of C-Metallated Furans

18.5 Reactions with Radicals

18.6 Reactions with Reducing Agents

18.7 Electrocyclic Reactions (Ground State)

18.8 Reactions with Carbenes and Carbenoids

18.9 Photochemical Reactions

18.10 Furyl-C–X Compounds; Side-Chain Properties

18.11 Furan Carboxylic Acids and Esters and Aldehydes

18.12 Oxy- and Amino-Furans

18.13 Synthesis of Furans

Exercises

References

19 Typical Reactivity of Indoles, Benzo[b]thiophenes, Benzo[b]furans, Isoindoles, Benzo[c]thiophenes and Isobenzofurans

20 Indoles: Reactions and Synthesis

20.1 Reactions with Electrophilic Reagents

20.2 Reactions with Oxidising Agents

20.3 Reactions with Nucleophilic Reagents (see also 20.13.4)

20.4 Reactions with Bases

20.5 C-Metallation and Reactions of C-Metallated Indoles

20.6 Reactions with Radicals

20.7 Reactions with Reducing Agents

20.8 Reactions with Carbenes

20.9 Electrocyclic and Photochemical Reactions

20.10 Alkyl-Indoles

20.11 Reactions of Indolyl-C–X Compounds

20.12 Indole Carboxylic Acids

20.13 Oxy-Indoles

20.14 Amino-Indoles

20.15 Aza-Indoles273,274

20.16 Synthesis of Indoles282

Exercises

References

21 Benzo[b]thiophenes and Benzo[b]furans: Reactions and Synthesis

21.1 Reactions with Electrophilic Reagents

21.2 Reactions with Nucleophilic Reagents

21.3 Metallation and Reactions of C-Metallated Benzothiophenes and Benzofurans

21.4 Reactions with Radicals

21.5 Reactions with Oxidising and Reducing Agents

21.6 Electrocyclic Reactions

21.7 Oxy-58 and Amino-Benzothiophenes and -Benzofurans

21.8 Synthesis of Benzothiophenes and Benzofurans

Exercises

References

22 Isoindoles, Benzo[c]thiophenes and Isobenzofurans: Reactions and Synthesis

22.1 Reactions with Electrophilic Reagents

22.2 Electrocyclic Reactions

22.3 Phthalocyanines21

22.4 Synthesis of Isoindoles, Benzo[c]thiophenes and Isobenzofurans

Exercises

References

23 Typical Reactivity of 1,3- and 1,2-Azoles and Benzo-1,3- and-1,2-Azoles

24 1,3-Azoles: Imidazoles, Thiazoles and Oxazoles: Reactions and Synthesis

24.1 Reactions with Electrophilic Reagents

24.2 Reactions with Oxidising Agents

24.3 Reactions with Nucleophilic Reagents

24.4 Reactions with Bases

24.5 C-Metallation and Reactions of C-Metallated 1,3-Azoles57

24.6 Reactions with Radicals

24.7 Reactions with Reducing Agents

24.8 Electrocyclic Reactions

24.9 Alkyl-1,3-Azoles

24.10 Quaternary 1,3-Azolium Salts

24.11 Oxy-103,104 and Amino-1051,3-Azoles

24.12 1,3-Azole N-Oxides

24.13 Synthesis of 1,3-Azoles119,120,121

Exercises

References

25 1,2-Azoles: Pyrazoles, Isothiazoles, Isoxazoles: Reactions and Synthesis

25.1 Reactions with Electrophilic Reagents

25.2 Reactions with Oxidising Agents

25.3 Reactions with Nucleophilic Reagents

25.4 Reactions with Bases

25.5 C-Metallation and Reactions of C-Metallated 1,2-Azoles42

25.6 Reactions with Radicals

25.7 Reactions with Reducing Agents

25.8 Electrocyclic and Photochemical Reactions

25.9 Alkyl-1,2-Azoles

25.10 Quaternary 1,2-Azolium Salts

25.11 Oxy- and Amino-1,2-azoles

25.12 Synthesis of 1,2-Azoles98

Exercises

References

26 Benzanellated Azoles: Reactions and Synthesis

26.1 Reactions with Electrophilic Reagents

26.2 Reactions with Nucleophilic Reagents

26.3 Reactions with Bases

26.4 Ring Metallation and Reactions of C-Metallated Derivatives

26.5 Reactions with Reducing Agents

26.6 Electrocyclic Reactions

26.7 Quaternary Salts

26.8 Oxy- and Amino-Benzo-1,3-Azoles

26.9 Synthesis

References

27 Purines: Reactions and Synthesis

27.1 Reactions with Electrophilic Reagents

27.2 Reactions with Radicals

27.3 Reactions with Oxidising Agents

27.4 Reactions with Reducing Agents

27.5 Reactions with Nucleophilic Reagents

27.6 Reactions with Bases

27.7 C-Metallation and Reactions of C-Metallated Purines

27.8 Oxy-and Amino-Purines

27.9 Alkyl-Purines

27.10 Purine Carboxylic Acids

27.11 Synthesis of Purines

Exercises

References

28 Heterocycles Containing a Ring-Junction Nitrogen (Bridgehead Compounds)

28.1 Indolizines2

28.2 Aza-Indolizines

28.3 Quinolizinium86 and Related Systems

28.4 Pyrrolizine and Related Systems

28.5 Cyclazines

Exercises

References

29 Heterocycles Containing More Than Two Heteroatoms

29.1 Five-Membered Rings

29.2 Six-Membered Rings

29.3 Benzotriazoles

Exercises

References

30 Saturated and Partially Unsaturated Heterocyclic Compounds: Reactions and Synthesis

30.1 Five- and Six-Membered Rings

30.2 Three-Membered Rings

30.3 Four-Membered Rings

30.4 Metallation

30.5 Ring Synthesis

References

31 Special Topics

31.1 Synthesis of Ring-Fluorinated Heterocycles

31.2 Isotopically Labelled Heterocycles28

31.3 Bioprocesses in Heterocyclic Chemistry38

31.4 Green Chemistry

31.5 Ionic Liquids48

31.6 Applications and Occurrences of Heterocycles

References

32 Heterocycles in Biochemistry; Heterocyclic Natural Products

32.1 Heterocyclic Amino Acids and Related Substances

32.2 Enzyme Co-Factors; Heterocyclic Vitamins; Co-Enzymes1

32.3 Porphobilinogen and the ‘Pigments of Life’

32.4 Ribonucleic Acid (RNA) and Deoxyribonucleic Acid (DNA); Genetic Information; Purines and Pyrimidines

32.5 Heterocyclic Natural Products

References

33 Heterocycles in Medicine

33.1 Mechanisms of Drug Actions3

33.2 The Neurotransmitters

33.3 Drug Discovery and Development

33.4 Heterocyclic Drugs4,5

33.5 Drugs Acting on the CNS

33.6 Anti-Infective Agents

33.7 Anti-Cancer Drugs

33.8 Photochemotherapy

References

Index

This edition first published 2010

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Library of Congress Cataloging-in-Publication Data

Joule, J. A. (John Arthur)

Heterocyclic chemistry / John A. Joule, Keith Mills. – 5th ed.

p. cm.

Includes bibliographical references and index.

ISBN 978-1-4051-9365-8 (pbk.)-ISBN 978-1-4051-3300-5 (pbk.) 1. Heterocyclic chemistry. I. Mills, K. (Keith) II. Title.

QD400.J59 2009

547′.59–dc22

2009028759

ISBN Cloth: 978-1-405-19365-8

ISBN Paper: 978-1-405-13300-5

Preface to the Fifth Edition

Heterocyclic compounds have a wide range of applications but are of particular interest in medicinal chemistry, and this has catalysed the discovery and development of much heterocyclic chemistry and methods. The preparation of a fifth edition has allowed us to review thoroughly the material included in the earlier editions, to make amendments in the light of new knowledge, and to include recent work. Within the restrictions that space dictates, we believe that all of the most significant heterocyclic chemistry of the 20th century and important more recent developments, has been covered or referenced.

We have maintained the principal aim of the earlier editions – to teach the fundamentals of heterocyclic reactivity and synthesis in a way that is understandable by undergraduate students. However, in recognition of the level at which much heterocyclic chemistry is now normally taught, we include more advanced and current material, which makes the book appropriate both for post-graduate level courses, and as a reference text for those involved in heterocyclic chemistry in the work place.

New in this edition is the use of colour in the schemes. We have highlighted in red those parts of products (or intermediates) where a change in structure or bonding has taken place. We hope that this both facilitates comprehension and understanding of the chemical changes that are occurring and, especially for the undergraduate student, quickly focuses attention on just those parts of the molecules where structural change has occurred. For example, in the first reaction below, only changes at the pyridine nitrogen are involved; in the second example, the introduced bromine resulting from the substitution and its new bond to the heterocycle, are highlighted. We also show all positive and negative charges in red.

In recognition of the enormous importance of organometallic chemistry in heterocyclic synthesis, we have introduced a new chapter dealing exclusively with this aspect. Chapter 4, ‘Organometallic Heterocyclic Chemistry’, has: (i) a general overview of heterocyclic organometallic chemistry, but most examples are to be found in the individual ring chapters, (ii) the use of transition metal-catalysed reactions that, as a consequence of a regularity and consistency that is to a substantial degree independent of the heterocyclic ring, is best treated as a whole, and therefore most examples are brought together here, with relatively few in the ring chapters.

Other innovations in this fifth edition are discussions in Chapter 5 of the modern techniques of: (i) solid-phase chemistry, (ii) microwave heating and (iii) flow reactors in the heterocyclic context. Reflecting the large part that heterocyclic chemistry plays in the pharmaceutical industry, there are entirely new chapters that deal with ‘Heterocycles in Medicine’ (Chapter 33) and ‘Heterocycles in Biochemistry; Heterocyclic Natural Products’ (Chapter 32).

We devote a new chapter (31) to some important topics: fluorinated heterocycles, isotopically labelled heterocycles, the use of bioprocesses in heterocyclic transformations, ‘green chemistry’ and the somewhat related topic of ionic liquids, and some the applications of heterocyclic compounds in every-day life.

1. The main body of factual material is to be found in chapters entitled ‘Reactions and synthesis of…’ a particular heterocyclic system. Didactic material is to be found partly in advanced general discussions of heterocyclic reactivity and synthesis (Chapters 3, 4 and 6), and partly in six short summary chapters (such as ‘Typical Reactivity of Pyridines, Quinolines and Isoquinolines’; Chapter 7), which aim to capture the essence of that typical reactivity in very concise resumés. These last are therefore suitable as an introduction to the chemistry of that heterocyclic system, but they are insufficient in themselves and should lead the reader to the fuller discussions in the’ Reactions and Synthesis of.’ chapters. They will also serve the undergraduate student as a revision summary of the typical chemistry of that system.

2. More than 4000 references have been given throughout the text: the references to original work have been chosen as good leading references and are, therefore, not necessarily the first or last mention of that particular topic or method or compound; some others are included as benchmark papers and others for their historical interest. The extensive list of references is most relevant to post-graduate teaching and to research workers, however we believe that the inclusion of references does not interfere with the readability of the text for the undergraduate student. Many review references are also included: for these we give the title of the article; titles are also given for the books to which we refer. The majority of journals are available only on a subscription (personal or institutional) basis, but most of their web sites give free access to abstracts and a few, such as Arkivoc and Beilstein Journal of Organic Chemistry give free access to full papers. Free access to the full text of patents, with a search facility, is available via government web sites. Organic Syntheses; the ‘gold standard’ for practical organic chemistry, has totally free online access to full procedures.

3. Exercises are given at the ends of most of the substantive chapters. These are divided into straightforward, revision exercises, such as will be relevant to an undergraduate course in heterocyclic chemistry. More advanced exercises, with solutions given on line at www.wiley.com/go/joule, are designed to help the reader to develop understanding and apply the principles of heterocyclic reactivity. References have not been given for the exercises, though all are real examples culled from the literature.

4. We largely avoid the use of ‘R’ and ‘Ar’ for substituents in the structures in schemes, and instead give actual examples. We believe this makes the chemistry easier to assimilate, especially for the undergraduate reader. It also avoids implying a generality that may not be justified.

5. Structures and numbering for heterocyclic systems are given at the beginnings of chapters. Where the commonly used name differs from that used in Chemical Abstracts, the name given in square brackets is the official Chemical Abstracts name, thus: indole [1H-indole]. We believe that the systematic naming of heterocyclic substances is of importance, not least for use in computerised databases, but it serves little purpose in teaching or for the understanding of the subject and, accordingly, we have devoted only a little space to nomenclature. The reader is referred to an exposition on this topic1 and also to the Ring Index of Chemical Abstracts in combination with the Chemical Substances Index, from whence both standardised name and numbering can be obtained for all known systems. Readers with access to electronic search facilities such as SciFinder and Crossfire can easily find the various names for substances via a search on a drawn structure.

6. There are several general reference works concerned with heterocyclic chemistry, which have been gathered together as a set at the end of this chapter, and to which the reader’s attention is drawn. In order to save space, these vital sources are not repeated in particular chapters, however all the topics covered in this book are covered in them, and recourse to these sources should form the early basis of any literature search.

7. The literature of heterocyclic chemistry is so vast that the series of nine listings-‘The Literature of Heterocyclic Chemistry’, Parts I–IX2-is of considerable value at the start of a literature search. These listings appear in Advances in Heterocyclic Chemistry,3 itself a prime source for key reviews on heterocyclic topics; the journal, Heterocycles, also carries many useful reviews specifically in the heterocyclic area. Progress in Heterocyclic Chemistry4 published by the International Society of Heterocyclic Chemistry5 also carries reviews, and monitors developments in heterocyclic chemistry over a calendar year. Essential at the beginning of a literature search is a consultation with the appropriate chapter(s) of Comprehensive Heterocyclic Chemistry, the original7 to the series. It is important to realize that particular topics in the three parts of Comprehensive Heterocyclic Chemistry must be read together-the later parts update, but do not repeat, the earlier material. Finally, the Science of Synthesis series, published over the period 2000–2008, contains authoritative discussions of information organized in a hierarchical system.8 Volumes 9–17 discuss aromatic heterocycles.

8. There are three comprehensive compilations of heterocyclic facts: the early series9 edited by Elderfield, discusses pioneering work. The still-continuing and still-growing series of monographs10 dealing with particular heterocyclic systems, edited originally by Arnold Weissberger, and latterly by Edward C. Taylor and Peter Wipf, is a vital source of information and reviews for all those working with heterocyclic compounds. Finally, the heterocyclic volumes of Rodd’s Chemistry of Carbon Compounds11 contain a wealth of well-sifted information and data.

P.1 Hazards

This book is designed, in large part, for the working chemist. All chemistry is hazardous to some degree and the reactions described in this book should only be carried out by persons with an appropriate degree of skill, and after consulting the original papers and carrying out a proper risk assessment. Some major hazards are highlighted (Explosive: general discussion (5.4), sodium azide (29.1.1.5.3), tetrazoles: diazonium salts and others (29.1.1.3), perchlorates (5.4; 11 (introductory paragraph)), tosyl azide (5.4). Toxicity: general (31.6.1), fluoroacetate (31.1.1.4), chloromethylation (e.g. 14.9.2.1)),12 but this should not be taken to mean that every possible hazard is specifically pointed out. Certain topics are included only as information and are not suitable for general chemistry laboratories – this applies particularly to explosive compounds.

P.2 How to Use This Textbook

As indicated above, by comparison with earlier editions, this fifth edition of Heterocyclic Chemistry contains more material, including more that is appropriate to study at a higher level, than that generally taught in a first degree course. Nevertheless we believe that undergraduates will find the book of value and offer the following modus operandi as a means for undergraduate use of this text.

The undergraduate student should first read Chapter 2, which will provide a structural basis for the chemistry that follows. We suggest that the material dealt with in Chapters 3 and 4 be left for study at later stages, and that the undergraduate student proceed next to those chapters (7, 10, 13, 15, 19 and 23) that explain heterocyclic principles in the simplest terms and which should be easily understandable by students who have a good grounding in elementary reaction chemistry, especially aromatic chemistry.

The student could then proceed to the main chapters, dealing with ‘Reactions and Synthesis of…’ in which will be found full discussions of the chemistry of particular systems-pyridines, quinolines, etc. These utilise many cross references that seek to capitalise on that important didactical strategy-comparison and analogy with reactivity already learnt and understood.

Chapters 3, 4 and 6 are advanced essays on heterocyclic chemistry. Sections can be sampled as required-‘Electrophilic Substitution’ could be read at the point at which the student was studying electrophilic substitutions of, say, thiophene-or Chapter 3 can be read as a whole. We have devoted considerable space in Chapter 3 to discussions of radical substitution, and Chapter 4, because of their great significance, is devoted entirely to metallation and the use of organometallic reagents, and to transition metal-catalysed reactions. These topics have grown enormously in importance since the earlier editions, and are of great relevance to heterocyclic chemistry.

Acknowledgements

We thank Richard Davies, Sarah Hall and Gemma Valler and their colleagues at Wiley, and earlier Paul Sayer at Blackwell, for their patience and support during the preparation of this fifth edition. We acknowledge many significant comments and corrections by Rob Young and Paul Beswick, and thank Mercedes Álvarez, Peter Quayle, Andrew Regan and Ian Watt for their views on the use of colour in schemes. We are greatly indebted to Jo Tyszka for her meticulous and constructive copy-editing. JAJ thanks his wife Stacy for her encouragement and patience during the writing of Heterocyclic Chemistry, Fifth Edition.

References

1 ‘The nomenclature of heterocycles’, McNaught, A. D., Adv. Heterocycl. Chem., 1976, 20, 175.

2 Katritzky, A. R. and Weeds, S. M., Adv. Heterocycl. Chem., 1966, 7, 225; Katritzky, A. R. and Jones, P. M., ibid., 1979, 25, 303; Belen’kii, L. I., ibid., 1988, 44, 269; Belen’kii, L. I. and Kruchkovskaya, N. D., ibid., 1992, 55, 31; idem, ibid., 1998, 71, 291; Belen’kii, L. I., Kruchkovskaya, N. D., and Gramenitskaya, V. N., ibid., 1999, 73, 295; idem, ibid., 2001, 79, 201; Belen’kii, L. I. and Gramenitskaya, V. N., ibid., 2005, 88, 231; Belen’kii, L. I., Gramenitskaya, V. N., and Evdokimenkova, Yu. B., ibid., 2004, 92, 146.

3Adv. Heterocycl. Chem., 1963–2007, 1–94.

4Progr. Heterocycl. Chem., 1989–2009, 1–21.

5http://euch6f.chem.emory.edu/ishc.html and the related Royal Society of Chemistry site: http://www.rsc.org/lap/rsccom/dab/perk003.htm

6 (a) ‘Comprehensive heterocyclic chemistry. The structure, reactions, synthesis, and uses of heterocyclic compounds’, Eds. Katritzky, A. R. and Rees, C. W., Vols 1–8, Pergamon Press, Oxford, 1984; (b) ‘Comprehensive heterocyclic chemistry II. A review of the literature 1982–1995’, Ed. Katritzky, A. R., Rees, C. W., and Scriven, E. F. V., Vols 1–11, Pergamon Press, 1996; (c) ‘Comprehensive heterocyclic chemistry III. A review of the literature 1995–2007’, Eds. Katritzky, A. R., Ramsden, C. A., and Scriven, E. F. V., and Taylor, R. J. K., Vols 1–15, Elsevier, 2008.

7 ‘Handbook of heterocyclic chemistry, 2nd edition 2000’, Katritzky, A. R. and Pozharskii, A. F., Pergamon Press, Oxford, 2000; ‘Handbook of heterocyclic chemistry. Third edition 2010’, Katritzky, A. R., Ramsden, C. A., Joule, J. A., and Zhdankin, V. V., Elsevier, 2010.

8 ‘Science of Synthesis’, Vols. 9–17, ‘Hetarenes’, Thieme, 2000–2008.

9 ‘Heterocyclic compounds’, Ed. Elderfield, R. C., Vols. 1–9, Wiley, 1950–1967.

10 ‘The chemistry of heterocyclic compounds’, Series Eds. Weissberger, A., Wipf, P., and Taylor, E. C., Vols. 1–64, Wiley-Inter science, 1950–2005.

11 ‘Rodd’s chemistry of carbon compounds’, Eds., Coffey, S. then Ansell, M. F., Vols IVa-IVl, and Supplements, 1973–1994, Elsevier, Amsterdam.

12 United States Department of Labor, Occupational Safety & Health Administration Reports: Chloromethyl Methyl Ether (CMME) and Bis-Chloromethyl Ether (BCME); see also: Berliner, M. and Belecki, K., Org. Synth., 2007, 84, 102 (discussion).

Web Site

Power Point slides of all figures from this book, along with the solution to the exercises, can be found at http://www.wiley.com/go/joul.

Biography

John Arthur Joule was born in Harrogate, Yorkshire, England, but grew up and attended school in Llandudno, North Wales, going on to study for BSc, MSc, and PhD (1961; with George F. Smith) degrees at The University of Manchester. Following post-doctoral periods in Princeton (Richard K. Hill) and Stanford (Carl Djerassi) he joined the academic staff of The University of Manchester where he served for 41 years, retiring and being appointed Professor Emeritus in 2004. Sabbatical periods were spent at the University of Ibadan, Nigeria, Johns Hopkins Medical School, Department of Pharmacology and Experimental Therapeutics, and the University of Maryland, Baltimore County. He was William Evans Visiting Fellow at Otago University, New Zealand.

Dr. Joule has taught many courses on heterocyclic chemistry to industry and academe in the UK and elsewhere. He is currently Associate Editor for Tetrahedron Letters, Scientific Editor for Arkivoc, and CoEditor of the annual Progress in Heterocyclic Chemistry.

Keith Mills was born in Barnsley, Yorkshire, England and attended Barnsley Grammar School, going on to study for BSc, MSc and PhD (1971; with John Joule) degrees at The University of Manchester.

Following post-doctoral periods at Columbia (Gilbert Stork) and Imperial College (Derek Barton/ Philip Magnus), he joined Allen and Hanburys (part of the Glaxo Group) at Ware and later Stevenage (finally as part of GSK), working in Medicinal Chemistry and Development Chemistry departments for a total of 25 years. During this time he spent a secondment at Glaxo, Verona. Since leaving GSK he has been an independent consultant to small pharmaceutical companies.

Dr. Mills has worked in several areas of medicine and many areas of organic chemistry, but with particular emphasis on heterocyclic chemistry and the applications of transition metal-catalysed reactions.

Heterocyclic Chemistry was first published in 1972, written by George Smith and John Joule, followed by a second edition in 1978. The third edition (Joule, Mills and Smith) was written in 1995 and, after the death of George Smith, a fourth edition (Joule and Mills) appeared in 2000; these authors also published Heterocyclic Chemistry at a Glance in 2007.

Definitions of Abbreviations

1

Heterocyclic Nomenclature

A selection of the structures, names and standard numbering of the more common heteroaromatic systems and some common non-aromatic heterocycles are given here as a necessary prelude to the discussions which follow in subsequent chapters. The aromatic heterocycles have been grouped into those with six-membered rings and those with five-membered rings. The names of six-membered aromatic heterocycles that contain nitrogen generally end in ‘ine’, though note that ‘purine’ is the name for a very important bicyclic system which has both a six- and a five-membered nitrogen-containing heterocycle. Five-membered heterocycles containing nitrogen general end with ‘ole’. Note the use of italic ‘H’ in a name such as ‘9H-purine’ to designate the location of an N-hydrogen in a system in which, by tautomerism, the hydrogen could reside on another nitrogen (e.g. N-7 in the case of purine). Names such ‘pyridine’, ‘pyrrole’, ‘thiophene’, originally trivial, are now the standard, systematic names for these heterocycles; names such as ‘1,2,4-riazine’ for a six-membered ring with three nitrogens located as indicated by the numbers, are more logically systematic.

A device that is useful, especially in discussions of reactivity, is the designation of positions as ‘α’, ‘β’, or ‘γ’. For example, the 2- and the 6-positions in pyridine are equivalent in reactivity terms, so to make discussion of such reactivity clearer, each of these positions is referred to as an ‘α-position’. Comparable use of α and β is made in describing reactivity in five-membered systems. These useful designations are shown on some of the structures. Note that carbons at angular positions do not have a separate number, but are designated using the number of the preceding atom followed by ‘a’-as illustrated (only) for quino-line. For historical reasons purine does not follow this rule.

A detailed discussion of the systematic rules for naming polycyclic systems in which several aromatic or heteroaromatic rings are fused together is beyond the scope of this book, however, a simple example will serve to illustrate the principle. In the name ‘pyrrolo[2,3-b]pyridine’, the numbers signify the positions of the first-named heterocycle, numbered as if it were a separate entity, which are the points of ring fusion; the italic letter, ‘b’ in this case, designates the side of the second-named heterocycle to which the other ring is fused, the lettering deriving from the numbering of that heterocycle as a separate entity, i.e. side a is between atoms 1 and 2, side b is between atoms 2 and 3, etc. Actually, this particular heterocycle is more often referred to as ‘7-azaindole’-note the use of the prefix ‘aza’ to denote the replacement of a ring carbon by nitrogen, i.e. of C-7-H of indole by N.

The main thrust of this book concerns the aromatic heterocycles, exemplified above, however Chapter 30 explores briefly the chemistry of saturated or partially unsaturated systems, including three- and four-membered heterocycles.

2

Structures and Spectroscopic Properties of Aromatic Heterocycles

This chapter describes the structures of aromatic heterocycles and gives a brief summary of some physical properties.1 The treatment we use is the valence-bond description, which we believe is appropriate for the understanding of all heterocyclic reactivity, perhaps save some very subtle effects, and is certainly sufficient for a general textbook on the subject. The more fundamental, molecular-orbital description of aromatic systems is less relevant to the day-to-day interpretation of heterocyclic reactivity, though it is necessary in some cases to utilise frontier orbital considerations,2 however such situations do not fall within the scope of this book.

2.1 Carbocyclic Aromatic Systems

2.1.1 Structures of Benzene and Naphthalene

The concept of aromaticity as represented by benzene is a familiar and relatively simple one. The difference between benzene on the one hand and alkenes on the other is well known: the latter react with electrophiles, such as bromine, easily by addition, whereas benzene reacts only under much more forcing conditions and then typically by substitution. The difference is due to the cyclic arrangement of six -electrons in benzene: this forms a conjugated molecular-orbital system which is thermodynamically much more stable than a corresponding non-cyclically conjugated system. The additional stabilisation results in a diminished tendency to react by addition and a greater tendency to react by substitution for, in the latter manner, survival of the original cyclic conjugated system of electrons is ensured in the product. A general rule proposed by Hückel in 1931 states that aromaticity is observed in cyclically conjugated systems of 4 + 2 electrons, that is with 2, 6, 10, 14, etc., π-electrons; by far the majority of monocyclic aromatic and heteroaromatic systems are those with six π-electrons.