Handbook of Heterocyclic Chemistry, Third Edition

981 Pages·2010·17.74 MB·English

by  Alan R. Katritzky, Christopher A. Ramsden, John A. Joule, Viktor V. Zhdankin

Elsevier
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Third edition 2010
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Part 1
Preliminaries
1.1
Foreword
The text Heterocyclic Chemistry by A. R. Katritzky and J. M. Lagowski was the subject’s first modern treatment; it
appeared 50 years ago, treating structure, reactivity, and synthesis systematically in terms of molecular structure. This
text and its sequels, which were translated into Chinese, French, German, Greek, Italian, Japanese, Polish, Russian, and
Spanish, revolutionized the practice and teaching of the subject worldwide. The 1st Edition of Handbook of Heterocyclic
Chemistry (Handbook-I) followed in 1985 as part of Comprehensive Heterocyclic Chemistry 1st Edition (CHEC-I).
Handbook-II appeared in 2000 alongside CHEC-II. We now present Handbook-III following the publication of
CHEC-III in 2008.
The importance and extent of the subject matter of heterocyclic chemistry continues to grow such that it is now
clearly the largest subdivision of organic chemistry. It plays a crucial role in biochemistry – increasingly so in medicine –
and manifest other areas of chemistry as applied to subjects as diverse as construction and agriculture. Such is the rate of
growth that this update is clearly needed.
Handbook-III retains the essentials of the treatments of Handbooks-I and -II in dividing the subject into the three
main areas of structure, reactivity, and synthesis. We have striven both to be reasonably comprehensive and to keep the
physical size of Handbook-III to a minimum, so it can be conveniently handled and consulted.
Handbook-III has four authors; three have prime responsibility for one section each: C. A. R. for Structure, J. A. J. for
Reactivity, and V. V. Z. for Synthesis. Although much of the original content has been retained, each author has brought
his own major experience throughout the revision, rewriting, and insertion of new material into the old.
Alan R. Katritzky, Christopher A. Ramsden, John A. Joule, and Viktor V. Zhdankin
2
1.3
Notes on the Arrangement of the Material in the
Handbook
Arrangement of Material in the Structure Chapters
The Structure chapters in Handbook-III follow the same general format as those in the Handbook-II with a few
relatively minor variations. Within this format, some sections have been largely rewritten whereas others have new
material added with mostly minimum changes. New material has been selected to illustrate principles and trends, or to
introduce new developments in the subject. Some material from Handbook-II has been deleted and replaced by
examples of more recent work. CHEC-III has been the major source of new material and, in addition to references to
the primary literature, relevant sections of CHEC-III are widely cited throughout the chapters.
In Chapter 2.1 a new section on computer-aided techniques has been introduced. This gives an overview of the
hierarchy of computational methods available to heterocyclic chemists and a guide to some of the terminology used.
This is followed by a glossary of general terms used throughout the structure chapters and an indication of sections
where examples can be found.
Chapters 2.2–2.5 cover the structures and related properties of heterocycles according to ring size. Each chapter
follows the same general format beginning with a survey of possible structures, their nomenclature, including common
names, and an emphasis on rings of special importance. Next, sections on theoretical methods are subdivided into
coverage of general trends, illustrated using the results of Hückel and AM1 calculations, followed by descriptions of
the results of more sophisticated calculations of molecular properties. Sections on experimentally determined struc­
tures (X-ray diffraction and microwave spectroscopy) are then followed by sections on spectroscopic methods
1 13 15
(including H, C, N NMR, IR, and UV) and mass spectrometry. Sections on thermodynamic aspects include
discussions of aromaticity and antiaromaticity, and conformations of nonconjugated rings. Each chapter concludes with
a discussion of tautomerism, which is subdivided into prototropic and valence tautomerism. As appropriate for each
ring category, prototropic tautomerism is further subdivided into annular tautomerism, substituent tautomerism, and
ring-chain tautomerism.
Chapter 2.2 covers six-membered heterocycles. Chapters 2.3 and 2.4 cover five-membered rings and their benzo
derivatives. In this edition the coverage of the structures and spectroscopic properties of bicyclic 5-5 heterocycles has
been increased. Recent developments in the measurement of aromaticity using energetic, structural, and magnetic
indices are discussed in Chapter 2.2–2.4 and indices tabulated and compared. Chapter 2.5 covers small and large rings
and includes heterocycles that are formally antiaromatic if planar. Throughout the structure chapters, numerical data
useful to practicing heterocyclic chemists (e.g., bond lengths, chemical shifts, UV spectra) have been presented in
Tables for easy reference.
Arrangement of Material in the Reactivity Chapters
The Reactivity chapters in Handbook-III follow the same general format as in the previous edition with only a few
relatively minor variations. The philosophy and principles of the categorization and subdivisions of the Reactivity
sections have been retained. These include, where relevant, comparisons of heterocyclic reactivity with the chemistry
of benzenoid aromatic compounds and with carbonyl/enol/enamine chemistry. The use of ‘nucleophilic attack on ring-
or side-chain hydrogen,’ has been changed to ‘base attack on ring- or side-chain hydrogen,’ the term ‘nucleophile’ being
reserved for reactions at carbon (or nitrogen or sulfur).
Reactions of organometallic nucleophiles are reviewed mainly under ‘Reactivity of Substituents: Metals and Metal­
loids’ – this is a change from the Handbook-II policy of considering these under the reactions of ‘Reactivity of
Substituents: Halides.’ Transition metal-catalyzed reactions of halides are considered partly under ‘Reactivity of
Substituents: Halides’ and partly in the metalloids sections. Transition metal-catalyzed reactions of stannanes, boronic
acids, etc., are considered under ‘Reactivity of Substituents: Metals and Metalloids.’ These areas represent the largest
proportion of the additional new material since Handbook-II and are certainly the most important.
25
26 Notes on the Arrangement of the Material in the Handbook
Much of the material from Handbook II has been retained, but it was necessary to remove and/or replace substantial
portions to accommodate new chemistry and results. The new material is taken from CHEC-III and each item is given
its original reference. Most of the older references in Handbook-II, and references to early reviews and to CHEC-II
have been removed. Clearly, it was possible to include only a very small fraction of new work from CHEC-III, but it was
the aim to summarize representative and important results.
Section 3.1 is a brief overview; Section 3.2 deals with six-membered heterocycles, including those with more than one
heteroatom in the ring; Section 3.3 deals with five-membered heterocycles with one heteroatom; Section 3.4 deals with
five-membered heterocycles with more than one heteroatom in the ring; Section 3.5 covers small (three- and four-
membered) and large (>six) ring heterocycles.
In each of the five sections of Chapter 3, the chemistry is reviewed in the following order: (1) Reactivity of aromatic
rings (thermal reactions not involving reagents, substitutions at carbon, additions to nitrogen, metallations); (2) Reac­
tions of nonaromatic compounds (this enormous area, which overlaps extensively with nonheterocyclic chemistry, is
reviewed with emphasis on the heterocyclic aspects); (3) Reactions of substituents (with emphasis on situations in
which substituents behave somewhat differently when attached to a heterocycle; note that for benzene-fused hetero­
cycles, the benzene ring is treated as a substituent).
Arrangement of Material in the Synthesis Chapters
The Synthesis section (Chapters 4.1–4.6) retains the same general concepts and organization of material as in Hand­
book-II. Within this format, numerous new synthetic methods have been systematically presented along with the most
important previous material from Handbook-II. Preference has been given to the procedures most synthetically useful,
essential experimental details, reaction conditions, and original references are provided in our schemes. The relevant
sections of CHEC-III, which have been used as the major source of new material, are cited in each subsection of the
Synthesis part of Handbook-III.
The main aim of this part of the book is to provide an introduction to the most efficient ways of making a heterocyclic
compound, either by using a known method or by analogy with existing methods for related compounds. The
organization is in accordance with this aim. The synthesis of a heterocyclic compound can frequently be divided into
two parts: ring synthesis, and substituent introduction and modification. The basic principles and experimental
methodology for substituent introduction and modification are discussed in the Reactivity sections (Chapters 3.1–
3.5); however, brief summaries of these methods with reference to the related sections of the reactivity chapters are also
provided in the Synthesis chapters. The major part of the Synthesis section deals with ring synthesis.
The introductory Chapter 4.1 provides an overview of the main types of reactions used in the preparation of
heterocyclic rings based upon mechanistic considerations. The material in the following Chapters 4.2–4.6 is organized
by types of heterocycle according to increasing number of heteroatoms, size of monocyclic ring, number of fused rings,
and type of fused rings. Ring-fused systems with ring junction N- or S-atoms are considered separately from their more
numerous analogues with only C-atoms at the ring junctions. Mono-, bi-, and tricyclic systems are classified firstly
according to the number and orientation of their heteroatoms and secondly by the degree of unsaturation in the system.
Within this main classification, syntheses are further combined in groups as follows: (1) those of related classes of
compounds, (2) those from similar precursors, and (3) methods related mechanistically.
1.4
Explanation of the Reference System
As in CHEC-I and CHEC-II references are designated by a number-letter coding of which the first numbers record the
year of publication, the next one to three letters denote the journal, and the final numbers give the page. The system is
based on that previously used in the following two monographs: (1) A. R. Katritzky and J. M. Lagowski, ‘Chemistry of the
Heterocyclic N-Oxides’, Academic Press, New York, 1971; (2) J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, ‘The
Tautomerism of Heterocycles’, in ‘Advances in Heterocyclic Chemistry’, Supplement 1, Academic Press, New York, 1976, and
from Volume 40, 1986 generally in Advances in Heterocyclic Chemistry.
A list of journal codes is given in alphabetical order together with the journals to which they refer at the end of this
Handbook In addition a full list of references is provided at the end of the volume. For journals which are published in
separate parts, the part letter or number is given (when necessary) in parentheses immediately after the journal code
letters. Journal volume numbers are not included in the code numbers unless more than one volume was published in
the year in question, in which case the volume number is included in parentheses immediately after the journal code
letters. Patents are assigned appropriate three-letter codes.
27
Part 2

Structure of Heterocycles
2.1
Overview

2.1.1 Relationship of Heterocyclic and Carbocyclic Aromatic Compounds 30
2.1.2 Arrangement of Structure Chapters 30
2.1.3 Nomenclature 31
2.1.4 Computer-Aided Studies of Heterocycles 32
2.1.4.1 Hückel Calculations and Related π-Electron Methods 33
2.1.4.2 Semiempirical Methods 33
2.1.4.3 Ab Initio and DFT Calculations 34
2.1.4.4 Molecular Mechanics 35
2.1.5 Glossary of General Terms Used in Chapters 2.2–2.5 35
2.1.1 Relationship of Heterocyclic and Carbocyclic Aromatic Compounds
Heterocyclic compounds (like carbocyclic compounds) can be divided into heteroaromatic and heteroalicyclic types. In
general, the chemistry of heteroalicyclic compounds is similar to that of their aliphatic analogues, but that of hetero­
aromatic compounds involves additional principles. Aromatic compounds possess rings in which (1) each of the ring
atoms is in the same plane and has a p orbital perpendicular to the ring plane and (2) (4n + 2) π-electrons in cyclic
conjugation are associated with each ring.
For a better understanding of the genesis and electronic nature of basic heteroaromatic systems, it is convenient
to consider their carbocyclic precursors. The latter can be divided into three main groups: neutral (e.g., benzene 1),
anionic (e.g., the cyclopentadienyl anion 2), and cationic (e.g., the tropylium ion 3). Each of these carbocyclic
systems is parent to a large number of isoconjugate heteroaromatic compounds. Six-membered aromatic heterocycles
+ + –
are derived from benzene 1 by replacing CH groups with N, O , S , or BH , which are isoelectronic with the CH
group. One CH group can be replaced to give pyridine 4, the pyrylium ion 5, the thiinium (thiopyrylium) ion 6, or
the 1H-boratabenzene anion 7 <1995JA8480>. The heteroatom in all these molecules is in a double-bonded state
and formally contributes one π-electron to the aromatic π-system. Such a heteroatom is called ‘pyridine-like.’
Replacement of two or more CH groups in such a manner is possible with retention of aromaticity,
e.g., pyrimidine 14.
The five-membered aromatic heterocycles pyrrole 8, furan 9, and thiophene 10 are formally derived from the
–
cyclopentadienyl anion 2 by replacement of one CH group with NH, O, or S, each of which contributes two π­
electrons to the aromatic sextet. Heteroatoms of this type have in classical structures only single bonds and are called
‘pyrrole-like.’ Other five-membered aromatic heterocycles are derived from compounds 8, 9 and 10 by further
+ +
replacement of CH groups with N, O , or S , e.g., imidazole 15.
It is important to recognize the difference between ‘pyridine-like’ and ‘pyrrole-like’ heteroatoms when considering
the properties of heteroaromatic molecules. In pyridine 4 the nitrogen lone pair of electrons is not part of the aromatic
sextet, whereas in pyrrole 8 the nitrogen lone pair is part of the aromatic sextet. This results in the two molecules having
profoundly different properties. Imidazole 15 contains both types of nitrogen.
+
Transition from the tropylium ion 3 to its neutral heteroaromatic counterparts is possible by replacement of a CH group
by a heteroatom with a vacant p orbital. The latter effectively accepts π-electrons, thus providing ring-electron delocaliza­
tion. A typical example is the boron atom in 1H-borepine 11 <1992AGE1255>. Correspondingly, this type of heteroatom
can be referred to as ‘borepine-like.’ Other little-known representatives of this family are alumopine 12 and gallepine 13.
The three fundamental types of heteroatom (X, Y, and Z; Scheme 1) are also found in small and large heterocycles.
2.1.2 Arrangement of Structure Chapters
Each of the chapters on structure discusses six-membered, five-membered, or small and large rings and begins with a
survey of the possible heterocyclic structures covered by the chapter. Structures are generally subdivided into those in
30
Overview 31
Scheme 1 The relationship between carbocyclic and heterocyclic aromatic systems.
3
which the ring atoms are in cyclic conjugation (aromatic or antiaromatic) and those in which at least one sp -hybridized ring
atom interrupts cyclic conjugation. The first class is further subdivided into those possessing exocyclic conjugation and
those without.
The results of theoretical methods are surveyed, followed by data on molecular dimensions obtained from X-ray
1 13 14 15
diffraction or microwave spectroscopy. The results of NMR spectroscopy, including H, C, N, and N NMR, are
then surveyed. This is followed by a discussion of UV, visible, IR, and photoelectron spectroscopy and mass spectro­
metry. Each of the spectroscopic sections deals with both the parent rings and the effects of substituents.
The next section deals with thermodynamic aspects. This starts with a consideration of the intermolecular forces
between heterocyclic molecules and their influence on melting and boiling points, solubilities, and chromatographic
properties. This is followed by a section on stability and stabilization, including thermochemistry and the conformations
of saturated ring systems, and a discussion of aromaticity.
The last major section deals with tautomerism, including prototropic tautomerism, ring-chain tautomerism, and
valence tautomerism.
2.1.3 Nomenclature
A detailed discussion of the nomenclature for heterocyclic compounds can be found in the first edition of Compre­
hensive Heterocyclic Chemistry (CHEC-I, Section 1.02). Some of the rules of systematic nomenclature used in
Chemical Abstracts and approved by the International Union of Pure and Applied Chemistry are collected here.
Important trivial names are listed at the beginning of individual chapters.
The types of heteroatom present in a ring are indicated by prefixes: ‘oxa,’ ‘thia,’ and ‘aza’ denote oxygen, sulfur, and
nitrogen, respectively (the final ‘a’ is deleted before a vowel). Two or more identical heteroatoms are indicated by
‘dioxa,’ ‘triaza,’ etc., and different heteroatoms by combining the above prefixes in the following order of priority:
O>S>N.
Ring size and the number of double bonds are indicated by the suffixes shown in Table 1. Maximum unsaturation is
defined as the largest possible number of non-cumulative double bonds (O, S, and N having valencies of 2, 2, and 3,
respectively). Partially-saturated rings are indicated by the prefixes ‘dihydro,’ ‘tetrahydro,’ etc.
Numbering starts at an oxygen, sulfur, or nitrogen atom (in decreasing order of preference) and continues in such a
way that the heteroatoms are assigned the lowest possible numbers. Other things being equal, numbering starts at a
substituted rather than at a multiply bonded nitrogen atom. In compounds with maximum unsaturation, if the double
32 Overview
Table 1 Stem suffixes for Hantzsch–Widman names
Rings with nitrogen Rings without nitrogen
Ring size Maximum unsaturation One double bond Saturated Maximum unsaturation One double bond Saturated
3 -irine – -iridine -irene – -irane
4 -ete -etine -etidine -ete -etene -etane
5 -ole -oline -olidine -ole -olene -olane
6 -ine – – -in – -ane
7 -epine – – -epin – -epane
8 -ocine – – -ocin – -ocane
9 -onine – – -onin – -onane
10 -ecine – – -ecin – -ecane
bonds can be arranged in more than one way, their positions are defined by indicating the nitrogen or carbon atoms that
are not multiply bonded and consequently carry an ‘extra’ hydrogen atom, by ‘1H-,’ ‘2H-,’ etc. In partially-saturated
compounds, the positions of the hydrogen atoms can be indicated by ‘1,2-dihydro,’ etc. (together with the 1H-type
3
notation, if necessary). Alternatively, the positions of the double bonds can be specified; for example, ‘Δ -’ indicates
that a double bond is between atoms 3 and 4. A positively charged ring is denoted by the suffix ‘-ium.’
The presence of a ring carbonyl group is indicated by the suffix ‘-one’ and its position by a numeral, e.g., ‘1-one,’ ‘2­
one,’ etc.; the numeral indicating the position of the carbonyl group is placed immediately before the name of the
parent compound unless numerals are used to designate the position of heteroatoms, when it is placed immediately
before the suffix. Compounds containing groups 17 or 20 are frequently named as derivatives of either groups 16 and 19
or groups 18 and 21.
Ring C¼S and C¼NH groups are denoted by the suffixes ‘-thione’ and ‘-imine’; cf. ‘-one’ for the C¼O group.
2.1.4 Computer-Aided Studies of Heterocycles
Computational methods are now widely used to calculate the properties of heterocyclic molecules and their reaction
pathways. An overview of these methods is provided here; the results of specific calculations are given in the appropriate
sections of Chapters 2.2–2.5. Although modern computational models are available in packages that are easy to use, a
sound knowledge of the underlying theory and the strengths and weaknesses of individual models is necessary for
effective and useful applications. The outcome of a theoretical study should be (1) insight into a chemical problem that
cannot be obtained using traditional qualitative analysis and/or (2) the direction of attention to new experiments or areas of
chemistry worthy of investigation. A study that does not result in either useful predictions or a solution to a well-defined
problem is rarely of value. A review of computational studies of heterocycles, including a survey of recommended
methods, was published in 2001 <2001AHC(81)1>.
An essential requirement of quantum chemical methods is to solve the Schrödinger equation, i.e., to obtain (1) the
eigenfunctions which describe the molecular orbitals (MOs) and (2) the eigenvalues which are the energies of the MOs.
In practice the best one can do is to find approximate solutions. Molecular properties are related to the eigenfunctions
and eigenvalues, and these properties include molecular geometry, electron density, net atomic charges, bond orders,
frontier MO electron densities, free valences, electrostatic potential maps, dipole moments, ionization potentials,
electron affinities, and delocalization and localization energies. Several levels of approximation are applied to solving
the Schrödinger equation in order to calculate these properties. The accuracy and reliability of the calculated properties
depend upon the method used. These methods range from simple Hückel calculations to ab initio and density
functional theory (DFT) calculations, and these approaches are summarized in the following sections.