Heterocyclic Chemistry I

Heterocyclic Chemistry
R. R. Gupta, M. Kumar, V. Gupta

VolmneI: Principles, 1bree- and Four-Membered Heterocycles

Volmne II: Five-Membered Heterocycles

Volmne ill: Six-Membered and Higher Heterocycles

Springer
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R. R. Gupta, M. Kumar, V. Gupta

Heterocyclic Chemistry
Volume I:
Principles, Three- and Four-Membered Heterocycles

With 98 Figures and 34 Tables

, Springer
Prof. Radha Raman Gupta
Dr. Mahendra Kumar
Dr. VandanaGupta

Department of Chemistry
University of Rajasthan
Jaipur-302004 / India

ISBN-I3:978-3-642-72278-3 e-ISBN-I3:978-3-642-72276-9
001: 10.1007/978-3-642-72276-9

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Gupta, Radha R.: Heterocyclic chemistry / R. R. Gupta; M. Kumar; V. Gupta. -
Berlin; Heidelberg; New York; Barcelona; Hong Kong; London; Milan; Paris; Singapur;
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Vol. 1. Principles, three- and four-membered heterocycles: with 34 tables. - 1998
ISBN -13: 978-3-642-72278-3

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FOREWORD

Today, our world increasingly is conceived ofas being molecular. An ever

widening range ofphenomena are described logically in terms ofmolecular
properties and molecular interactions. The majority ofknown molecules
are heterocyclic and heterocycles dominate the fields of biochemistry,
medicinal chemistry, dyestuffs, photographic science and are ofincreasing
importance in many others, including polymers, adhesives, and molecular
engineering.
Thus, the importance ofheterocyclic chemistry continues to increase
and this three volume work by Drs. R. R. Gupta, Mahendra Kumar and
Vandana Gupta is a welcome addition to the available guides on the
subject. Its scope places it in a useful niche between the single-volume texts
and monographs ofheterocyclic chemistry and the multivolume treatises.
The authors have retained the well tried classical approach but have
succeeded in placing their own individual spin on their arrangement. They
have put together a well selected range from among the most important
of the vast array offacts available. This factual material is ordered in a
clear and logical fashion over the three volumes.
The present work should be of great value to students-and practitioners
of heterocyclic chemistry at all levels from the advanced undergraduate
upwards. It will be ofparticular assistance in presenting a clear and modem
view of the subject to those who use heterocycles in a variety of other
fields and we wish it well.

Alan R. Katritzky
April 1998 University ofFlorida
PREFACE

Our aim is to bring out a text-cum-reference book on heterocyclic

chemistry for undergraduate and graduate students, and research workers
who wish to choose heterocyclic chemistry in their research careers. This
will enable them to have a comprehensive knowledge of the syntheses,
properties, reactions and their mechanisms and applications ofheterocyclic
compounds. Efforts have been made to include recent developments in
heterocyclic chemistry and the subject is presented in a simple and lucid
manner, so that those who have some background knowledge of organic
chemistry can understand it well.
For the sake of convenience, subject matter covered in heterocyclic
chemistry has been divided into three volumes:
Volume I: Principles, Three- and Four-Membered Heterocycles
Introduction
Nomenclature ofHeterocycles
Aromatic Heterocycles
Nonaromatic Heterocycles
Heterocyclic Synthesis
Three-Membered Heterocycles
Four-Membered Heterocycles
Volume II: Five-Membered Heterocycles
Introduction
Five-Membered Heterocycles with One Heteroatom
Benzo-Fused Five-Membered Heterocycles with
One Heteroatom
Five-Membered Heterocycles with Two Heteroatoms
Five-Membered Heterocycles with More Than Two
Heteroatoms
Meso-Ionic Heterocycles
VIII

Volume ill: Six-Membered and Higher Heterocycles

Introduction
Six-Membered Heterocycles
Seven-Membered Heterocycles
Large Ring Heterocycles
Photochemistry ofHeterocycles
Since there are detailed contents at the beginning of each chapter, the
details for individual chapters are not given here.
We have :freely consulted edited scientific works such as Comprehensive
Heterocyclic Chemistry edited by A.R. Katritzky and C.W. Rees,
Advances in Heterocyclic Chemistry edited by A.R. Katritzky and the
Chemistry of Heterocyclic Compounds edited by A. Weissberger and
E.C. Taylor. We are very grateful to editors, authors and publishers of
these works.
We express our thanks to our colleagues and Ph.D. students who
assisted us in proofreading and in several other ways. Our sincere thanks
are also due to Dr. R. Stumpe and Dr. Joe P. Richmond editors at Springer
Verlag for providing valuable suggestions for the preparation ofthe book.

Jaipur, India R.R. Gupta

April, 1998 Mahendra Kumar
Vandana Gupta
Symbols and Abbreviations

Bond angle distortion or deviation / Coulomb integral (as stated)

A Karplus constant
AIBN 1;2,2'-Azobisisobutyronitrile
~ Resonance integral
Wave length
conc. Concentrated
DE Delocalization energy
DRE Dewar resonance energy
A Diamagnetic susceptibility exaltation
AO(Dae) Chemical shift difference
DIBAL Diisobutylaluminium hydride
Dil. Diluted
DMF N,N-Dimethylfonnamide
DMSO Dimethyl sulfoxide
E Bond angle strain / Torsional energy (as stated)
ERE Empirical resonance energy
Eu(fodh Tris-(6,6, 7,7 ,8,8,8-heptatluoro-2,2-dimethyl-3,5-octanedionato)-
europium
Extinction coefficient
Conformational free energy
Free energy of activation
Enthalpy difference between conformers
AH Heat offormation (exp.)
HMPAlHMPT Hexamethylphosphoric triamide
HOMO Highest occupied molecular orbital
Band intensity in vibrational spectra for axial and equatorial
conformers
x

J Coupling cosntant
Kc Rate of ring inversion
Ke Equilibrium constant of interconvertible conformers
Ke Bond bending force constant
A. Wave number
IDA Lithium diisopropylamide
LTA Lead tetraacetate
LUMO Lowest unoccupied molecular orbital
MCPBA m-Chloroperbenzoic acid
NBS N-Bromosuccinimide
hv Photochemical
run Nanometer (1 o-~
N-PSP N-Phenylselenophthalimide
pm Picometer (10- 12)
PPA Polyphosphoric acid
R Coupling constants ratio
REPE Resonance energy per x-electron
\II Internal torsional angle
Tc Coalescence temperature
TCNE Tetracyanoethylene
tert Tertiary
TFAA Tritluoroacetic anhydride
THF Tetrahydrofuran
1HP Tetrahydropyran
a Dihedral angle
TMEDA N,N,N,N-Tetramethylenediamine
Tos / Tosyl p-Toluenesulfonyl
VR Vilsmeier reagent
0) Dihedral angle deviation
Diamagenetic susceptibility
CONTENTS

Chapter 1. Introduction 1
Chapter 2. Nomenclature of Heterocycles 3
Chapter 3. Aromatic Heterocycles 39
Chapter 4. Nonaromatic Heterocycles 105
Chapter 5. Heterocyclic Synthesis 159
Chapter 6. Three-Membered Heterocycles 275
Chapter 7. Four-Membered Heterocycles 357
Subject Index 411
CHAPTER 1
INTRODUCTION

Heterocyclic Chemistry is an integral part of organic chemistry and constitutes a

considerable part of the syllabus for undergraduate and graduate students through
out the world. Heterocyclic chemistry deals with heterocyclic compounds which
constitute about sixty-five percent of organic chemistry literature. Heterocyclic
compounds are widely distributed in nature which are essential to life. Genetic
material DNA is also composed of heterocyclic bases-pyrimidines and purines. A
large number of heterocyclic compounds, both synthetic and natural, are
pharmacologically active and are in clinical use. Several heterocyclic compounds
have applications in agriculture as insecticides, fungicides, herbicides, pesticides
etc. They also [md applications as sensitizers, developers, antioxidants, copolymers
etc. They are used as vehicles in the synthesis of other organic compounds.
Chlorophyll-photosynthesizing and haemoglobin-oxygen transporting pigments
are also heterocyclic compounds.
Huge amount of research work is generated on various phases of heterocyclic
chemistry and for publication of such research work and review articles, there are
three specialized journals devoted to heterocyclic chemistry:
1. Journal of Heterocyclic Chemistry
2. Heterocycles
3. Heterocyclic Communications
In addition to theses specialized journals, research papers on heterocyclic
chemistry are being published in journals devoted to organic chemistry. There are
three continuing series in heterocyclic chemistry:
1. Advances in Heterocyclic Chemistry (edited by A. R. Katritzky, Academic
Press).
2. Chemistry of Heterocyclic Compounds (edited by E. C. Taylor, John Wiley).
3. General Heterocyclic Chemistry (edited by E. C. Taylor, Wiley-Interscience).
2 Heterocyclic Chemistry

In addition to these series, annual reports on "Progress in Heterocyclic

Chemistry" are being published under the sponsorship of International Society of
Heterocyclic Chemistry"(edited by H. Suschitzky and E. F. V. Scriven, Pergamon
Press) to highlight new developments in the field of heterocyclic chemistry. A
treatise "Comprehensive Heterocyclic Chemistry" (edited by A. R. Katritzky and
C. W. Rees) has appeared in an eight-volume set in 1984 (Pergamon Press) and
its second edition (edited by A. R. Katritzky and C. W. Rees) has appeared in 1996.
A. R. Katritzky has introduced "Handbook of Heterocyclic Chemistry" (Pergamon
Press, 1985) and a five-volume set on "Physical Methods in Heterocyclic
Chemistry" (Academic Press). One of the authors (R. R. Gupta) as editor has also
introduced a volume on "Physical Methods in Heterocyclic Chemistry" (Wiley-
Interscience, 1984). From time to time several textbooks have appeared:
The Chemistry of Heterocyles (T. Eicher and S. Hauptmann, Thieme, 1995).
Heterocyclic Chemistry (T.L. Gilchrist, Pitman, 1st edn. 1985; 2nd edn. 1992).
Contemporary Heterocyclic Chemistry (George R. Newkome and William
W. Paudler, Wiley-Interscience, 1982).
An Introduction to the Chemistry of Heterocyclic Compounds (R. M. Acheson,
3rd edn., John Wiley, 1976).
Heterocyclic Chemistry (D. W. Young, Longman, 1975).
Heterocyclic Compounds (K. Schofield, Ed., Butterworths, 1975).
Heterocyclic Chemistry (J. A. Joule and G. F. Smith, 2nd edn. Van Nostrand
Reinhold, 1972; J. A. Joule, K. Mills and G. F. Smith, 3rd edn. Chapman & Hall,
1994).
Principles of Modem Heterocyclic Chemistry (L. A. Paquette, Benjamin, 1968).
Heterocyclic Chemistry (A. Albert, 2nd edn. Oxford University Press, 1968).
The Principles of Heterocyclic Chemistry (A. R. Katritzky and J. M. Lagowski,
Academic Press, 1968).
The Structure and Reactions of Heterocyclic Compounds (M. H. Palmer,
E. Arnold, 1967).
The Chemistry of Heterocyclic Compounds (A. A. Morton, McGraw-Hill, 1946).
We feel the need for a text-cum-reference book in heterocyclic chemistry which
includes new developments in the field and can cater to the need of undergraduate
and graduate students and research workers who have chosen heterocyclic
chemistry, pharmaceutical chemistry and medicinal chemistry etc. in their research
careers. In the present book efforts have been made to include each and every
class of heterocyclic compounds with which students are concerned in their cour-
ses devoted to heterocyclic chemistry. The subject matter has been divided into
sixteen chapters spreading over in three volumes (as mentioned in the preface).
Each chapter except the first (introduction) contains a detailed table of contents.
At the end of each chapter references have been cited, so that readers who are
interested in having more information regarding synthetic pathways, reactions and
their mechanisms, properties, application etc. of heterocyclic compounds may be
able to locate the information they require.
CHAPfER 2
NOMENCLATURE OF HETEROCYCLES

CONTENTS

1 GENERAL 4
2 NOMENCLATURE SYSTEMS 4
21 Systematic Nomenclature System 4
(Hantzsch-Widman System)
22 Trivial System 10
23 Fusion Nomenclature System 18
24 Replacement Nomenclature System 25
24.1 Monocyclic Heterocycles 26
24.2 Fused Heterocycles 27
2.4.3 Spiro Heterocycles 29
2.4.4 Bridged Heterocycles 32
2.4.4.1 Bicyclic Systems 32
2.4.4.2 Polycyclic Systems 34
24.5 Heterocyclic Ring Assemblies 35
REFERENCES 38
4 Heterocyclic Chemistry

1 GENERAL

The systematic names of the chemical structures require essentially certain

nomenclature systems and for each nomenclature system the name and munbering
require appropriate nomenclature rules. Different nomenclature systems1-l2 are
available in the literature, however the most relevant systems recommended by
IUPAC for naming heterocycles are discussed.

2 NOMENCLATURE SYSTEMS

The most systematic nomenclature of heterocycles is based on the names of

carbocyclic analogs and, therefore, the nomenclature systems are modifications of
those used for carbocycles. However, the nomenclature system which is more
commonly used for heterocycles involves the combination of trivial and systematic
names.

2.1 Systematic Nomenclature System

(Hantzsch-Widman System)

This is the most widely used systematic method and is used for naming three- to
ten-membered mono cyclic heterocycles of various degree ofunsaturation containing
one or more heteroatoms. This nomenclature system specifies the ring size and the
nature, type and position(s) of the heteroatom(s). The heteromonocycles are
named by using following revised rules!3 of Hantzsch-Widman nomenclature
system.

(1) Combination of pretix(es) with stem

The heteromonocyclic system is named by combining one or more 'a' prefixes for
the heteroatom(s) with a stem indicating the size of the ring. If the stem begins
with vowel, the terminal letter 'a' of the 'a' prefix is dropped.
Pretixes : The prefixes indicate the heteroatoms present in the heterocyclic
systems. The prefixes for different heteroatoms are presented in Table 1 in the
preferential order.
Nomenclature of Heterocycles 5

Table 1. Prefixes for heteroatoms ('a' prefixes in decreasing order of priority)

Heteroatom Symbol (Valence) Prefix

Oxygen O(ll) Oxa

Sulfur S(ll) Thia
Seleniwn Se(ll) Selena
Telluriwn Te(ll) Tellma
Nitrogen N(Ill) Aza
Phosphorus P(Ill) Phospha
Arsenic As (ill) Arsa
Antimony Sb(lll) Stiba
Bismuth Bi(lII) Bisma
Silicon Si(IV) Sila
Gennaniwn Ge(IV) Genna
Tin Sn{lV) Stanna
Lead Pb(IV) Plwnba
Boron B(III) Bora
Mercury Hg(II) Mercura

Stems : The stems are used to indicate the size of the ring and the saturation or
unsaturation in the heteromonocyclic systems and are summarized in Table 2.

Table 2. Stems for tbree- to ten-membered heterocycles

Ring size Unsaturation Saturation

Three-membered -irene<i) -irane<ii)

Four-membered -ete -etane<ii)
Five-membered -ole -olane<ii)
Six-membered A* -ine -ane
B* -ine -inane
C* -inine -inane
Seven-membered -epine -epane
Eight-membered -ocine -ocane
Nine-membered -onine -onane
Ten-membered -ecine -ecane
6 Heterocyclic Chemistry

However, the following points should be considered while giving names to the
heteromonocycles :
(i) the stem 'irine' is used for three-membered nitrogen-containing unsaturated
heteromonocycles.
(n) the stems 'iridine', 'etidine' and 'olidine' are used for nitrogen-containing
saturated three-, four- and five-membered heteromonocycles respectively.
(m) the terminal vowel of a numerical prefix is not dropped even when the prefix
begins with the same vowel, e.g., cyclotetraazoxane.
(iv) the ending of the Dame depends on the presence or absence of nitrogen.
(v) unsaturated stems are used for the rings with maximum numbers of non-
cumulative double bonds possilbe, when the heteroatoms have the normal
valences given in Table 1.
(vi) saturated stems are used for the rings without double bond(s)
(vii) if the stems are not specified for partialy or completely saturated
heteromonocycles, the prefixes 'dihydro-', 'tetrahydro-', etc. should be
used.
(viii) the terminal 'e' used in all the stems is optinal (stems without terminal 'e'
for unsaturated non-nitrogenous rings with six or more ring members are
used in CAS index nomenclature, for example, dioxin, dithiin and oxathiin.
(Ix) the stems 'etine' and 'oline', which were formerly used for nitrogen
containing four- and five-membered rings respectively with one double
bond have no longer been recommended by IUPAC.
(x) the stems for six-membered rings depend on the least preferred heteroatom
in the ring, i.e., the heteroatom immediately preceding the stem. To
determine the proper stem for a six-membered ring, the following set
containing least preferred heteroatom is selected :
6A* = 0, S, Se, Te, Bi, Hg
6B* = N, Si, Ge, Sn, Pb
6C* = B, P, As, Sb
(Xl) the stems (syllables) indicating ring sizes (3, 4, 7, 8, 9 and 10) are considered
to be derived from numerical prefixes (Table 3).
(xil) trivial names e.g., pyrrole, pyrazole, imidiazole, pyridine, pyridazine,
pyrimidine, etc., permitted for some heteromonocyclic systems by IUPAC
should be prefered over the systematic names.
(xiiI) oxine must not be used for pyran because it has been used as a trivial name
for quinolin-8-01.
Nomenclature of Heterocycles 7

(xiv) azine must not be used for pyridine because of its use as a class name of
the compounds containing =N - N =
group.

Table 3. Stems (syllables) for different heterocyclic rings

Ring size Syllable Derived from

Three-membered -ir tri

Four-membered -et tetra
Seven-membered -ep hepta
Eight-membered -oc octa
Nine-membered -on nona
Ten-membered -ec deca

H
N

/\
HC====CH

Oxa + irane = Oxirane Aza + iridine = Aziridine Aza + irine = Azirine

Oxa + aza + iridine = Oxaziridine Aza + etidine = Azetidine

HN=CH
I I
HC=CH
o p

Aza + ete = Azete Thia + etane = Thietane Phospha + ole = Phosphole

Q
Oxa + olane = Oxolane
Q
Thia + olane = Thiolane
0
Thia + epane = Thiepane
8 Heterocyclic Chemistry

Aza
o N
H
+ epine = Azepine
o o
Oxa + epine = Oxepine
o
Aza + ocine = Azocine

(2) Presence of identical heteroatoms (Multiplicity ofheteroatoms)

When two or more heteroatoms of the same type are present in a ring, the prefixes,
di-, tri-, tetra, etc. are used and placed before the prefix used for the heteroatom.

17"
" N.... N
H
e~J
N
N

Pyrimidine
1,3-Dioxolane 1,2,4-Triazole (1,3-Diazine) 1,3,5-Triazine

(3) Presence of different heteroatoms (Order of preference)

When two or more different heteroatoms are present in the same ring, the prefixes
of heteroatoms are combined in the order of their appearance in Table 1.

H H

() S ()
N

()
N

o S

Thia + aza + ole =Thiazole Oxa + aza + ine = Oxazine Thia + aza + ine = Thiazine
(l ,3-Thiazole) (l,4-Oxazine) (1,4-Thiazine)

(4) Numbering
(i) With one heteroatom : The numbering in the ring starts from the
heteroatom giving the position-l and proceeds in such a way as to give the
lowest possible locant to the substituent if present.
Nomenclature of Heterocycles 9

0
S

:Q-Oi'
S

'0'
4
H~n
s ,3
7 f !J 3
6 ~ 2 6~ 2
N
1
N
1
CH 3 o 2 8~
N
2
1 1
Pyridine 2,5-Dimethylpyridine 3-Methyloxepin(e) Azocine

(li) With two or more identical heteroatoms : When two or more identical
heteroatoms are present in a ring, the ring is numbered in such a way that
the heteroatoms are assigned the lowest possible set of number locants.

t )'
4 1
4 N3 3 N4
BC ),
N N
SI[)2 2[)S
N1
H rf 6~
N
1
.... N2 s~
N
4
.... N3

[1,3] [1,4] [1,2,4] [1,3,4]

correct numbering incorrect numbering correct numbering incorrect numbering

(iii) With two or more different heteroatoms : When heterocyclic ring contains
two or more different heteroatoms, the numbering starts from the
heteroatom with the highest preference as in Table 1 : 0, S, N (oxygen takes
precedence over sulfur and sulfur over nitrogen). The remaining heteroatoms
are given the lowest number locants.

S05
4 3

2
o
1

1,3-Thiazole l,3-Oxazole 1,2-Oxathiolane

3 4 4 3

21/)\~
N s sl/)\~
N 2
'5 '5
1 1
1,2,4-Thiadiazole (correct) 1,3,5-Thiadiazole (incorrect)
10 Heterocyclic Chemistry

(5) Presence of saturated atom (Indicated hydrogen)

(i) When a heterocyclic ring with maximum number of noncumulative double
bonds contains a saturated atom, its position is given the lowest possible
locant and is numerically indicated by an italic capital H before the name
of heterocyclic ring system.

:c ):
H 4 4

:C):
N4 N
5C~
s 6 0
)2
1

4d
4H-l,4-Thiazine 2H-l,4-Thiazine 6H-l,3-Oxazine

4
4 3

502 5C~
1 )2 7
6 3 __ N1
N
1 S
2
2H-Pyrrole 2H-l,3-Thiazine 3H-Azepine

(ii) However, the heterocyclic system in which a carbon atom of the ring is
involved in the carbonyl group, the indicated hydrogen is normally cited
as an etalic capital H in parentheses after the locant of the additional
structural feature.

4 4

:Cl N1
H
0
:(1 N
1
0

Pyridin-2(1H)-one Pyrazin-2(3H)-one

2.2 Trivial System

This system of nomenclature is based on the trivial and semitrivial names of the
heterocycles which were given before their structural identifications. The trivial
Nomenclature of Heterocycles 11

and semitrivial names of the heterocycles were given on the basis of their
characteristic properties or on the sources from which they are obtained.
Therefore, the trivial and semitrivial names provide hardly any structural
information. However, trivial and semitrivial names of some heterocycles are
recognized by IUPAC and their names are retained in the fusion nomenclature
system. The following Table 4lists trivial and semitrivial names of the heterocycles
which are recognized by IUPAC and retained in IUPAC recommendations13.

Table 4. Heterocycles with their recognized trivial and semitrivial names

Structure Trivial name

Pyrrole

Furan

Thiophene

·502
4 3
Selenophene
Se
1

502
4 3

TeUurophene
Te
1

4 3

5 O~2 .... N
Pyrazole

N1
H
(lH-isomer)
12 Heterocyclic Chemistry

4 3

5()2 Imidazole
N1
H

(lH-isomer)

4 3

5 0 0
1
2
..... N Isoxazole

50'
4

6~ '2 N
Pyridine

50'
4

6~ ~2 N
.....
Pyridazine

5C~
6~
N
)2 Pyrimidine

5( J
4
N
Pyrazine
6~ 2
N
1

0'
4

Pyran
6' o. . . CH
2
2
1

(2H-isomer)
Nomenclature of Heterocycles 13

Pyrrolizine

(lH-isomer)

4 3

5~2 Indole
6~N{
7 H
(lH-isomer)

50:;4
~3 2
NH Isoindole
6~ ~
7 1

(2H-isomer)

Phosphindole

(lH-isomer)

50:;4
~3 2
PH Isophosphindole
6~ ~
7 1

(2H-isomer)

4 3

5~2 Arsindole
6~P{
7 H 1

(lH-isomer)
14 Heterocyclic Chemistry

sCC2
6~
7
:::::,....
1
AsH Isoarsindole

(2H-isomer)

4 3

sc:x;,~ Indazole
6 ~ N1
7 H
(lH-isomer)

4 3

sO:;~ Isobenzofuran
6~ :::::,....
7 1

7mJ
6~ N
4 3
2
Indolizine

2\]:7)'
9
N 4 N
Purine
N~ 5 N
6 H
(exception to systematic
numbering)

·co'
5 4
Quinoline

7~
I N~2
8 1

·OCt
5 4

7~
I ~N
2
Isoquinoline

8 1
Nomenclature of Heterocycles 15

6(01~3
7~
5 4

.0 2
Phosphinoline

8 ~
5 4

6CO~3 Isophosphinoline
7~ I AP2
8

5 4

6~3 Arsinoline
7~1\;2
8 As
1

5 4

6CO~3
7 ~ I AAs
2
Isoarsinoline

81

Phthalazine

6CC
7~
I ~3
5

)2
N Quinazoline

8 N
1

5 4

6CO~3
7 ~ I ~N2 Cinnoline

8 N
1

I ~~,
6OC' Quinoxaline
7~ ~2
8 N
1
16 Heterocyclic Chemistry

'C02
9 1

Quinolizine
7~ N 3
5
6 4

(4H-isomer)

·00'
5 4

Cbromene
7~ 0 2
8 1

(2H-isomer)

·OCr
5 4

Isocbromene
7~ 0
2
8 1
(lH-isomer)

.0)'
5 4

7~ 02
N N 1,8-Naphthyridine
8 1

(l,8-isomer)

.(JC~
7~N I )2
Pteridine
N
8 1

:0dJ2
6 5 4

Carbazole

8 Ng 1
H
(9H-isomer)
(exception to systematic munbering)
Nomenclature of Heterocycles 17

7O:SJ2
6 5 4

~-Carboline

8 N9 1
H
(9H-isomer)
8 9 1

I ~2
7COO~ Acridine
6~ ~ #3
N
5 10 4

(exception to systematic numbering)

9;~X)~2
80: Phenazine
7~ ~ #3
N
6 5 4

8 9 1

I ~2
7COO~ Acridarsine
6~ ~ #3
As
5 10 4

(exception to systematic numbering)

Phenanthridine

Arsanthridine
18 Heterocyclic Chemistry

70c0
6~
891

1
o
I ~2
#3
Xanthene

5 10 4

(9H-isomer)
(exception to systematic numbering)

9~ IW
~
7
~5
~4

HN ..... fiN
N
Perimidine

1 '" 3
2

(lH-isomer)

Phenanthroline

(l,7-isomer)

2.3 Fusion Nomenclature System

The systematic names of the fused heterocycles are given by this nomenclature
system. The fused heterocyclic system is considered to be constructed by the
combination of two or more cyclic structural units (components). The cyclic
structural units contain maximum number of non-cumulative double bonds and are
fused in such a way that each structural unit (component) has one bond common
with other. The names of the structural units can be trivial or systematic.
The fused heterocyclic system are named according to the following rules :
1. The fused heterocyclic system is dissected into its components in which
one is base component and other(s) is attached component(s).
Nomenclature of Heterocycles 19

ex)
~ 0 s
+ () S

erN) 0
Benzotbiazole Benzene Thiazole

~ N
+ C) N
H
H
Benzimidazole Benzene Imidazole

2 The components are giv~ their recognized trivial names, if possible, which
are selected from the Table of trivial names (Table 4). If mono cyclic
component has no recognized trivial name, the systematic name is used.
3. Base component should be a heterocyclic system. If there is choice, the
base component is determined by the order of preference.

Selection of Base Component:

(i) Nitrogen containing component a nitrogen containing component is
selected as the base component.

00
~N
1 "
S
(JO N
H
0

Base component : Pyridine Base component : Pyrrole

(n) Component(s) with heteroatom(s) other than nitrogen: if nitrogen is absent

in the heterocyclic ring(s), the ring with other heteroatom(s) is selected as
the base component.

~
~c!
~
~Sl
Base component : Furan Base component : Thiophene
20 Heterocyclic Chemistry

If both the components contain heteroatoms other than nitrogen, the

component which contains heteroatom appearing highest in Table 1 is
selected base component (component with heteroatom of highest group
in periodic table and with heteroatom of higher atomic number if
heteroatoms are of the same group).

Base component : Furan

(ill) Component with greatest number of rings: a component with as many rings
as possible is selected as the base component (bicyclic condensed systems
or polycyclic systems with recognized trivial names).

ocx
~
l ~

N
b
N~

N
~
Base component: Quinoline

(iv) Rings of unequal size : if fused heterocyclic system contains rings of

unequal size, the component with the largest size of the ring is selected as
a base component.

o
CQ
~

# 0

Base component : Thiepine Base component : Pyran

(v) Rings of equal size with different number ofheteroatoms : if the heterocyclic
system containing rings of equal size with different number of heteroatoms,
the ring with greater number of heteroatoms of any kind is considered as
a base component.
Nomenclature of Heterocycles 21

Base component: Oxazole

(vi) Rings of equal size with equal number of different heteroatoms : ifboth the
components contain rings of same size with equal number of different
heteroatoms, the component containing ring with greatest variety of
heteroatoms is selected as a base component.

N N

<X~
N 0
H
Base component: Oxazole

If two heteroatoms of the same group are present, the component

containing the ring with heteroatoms appearing first in Table 1 is preferred
as the base component.

<X) <X)
N S N S

o N Se N

Base component: Oxazole Base component : Thiazole

(vii) Rings of same size with same numbers and same kinds of heteroatoms : if
the components contain rings of the same size with same numbers and same
kinds of heteroatoms, the component containing ring with heteroatoms
which have the lowest locant numbers is preferred as a base component.

N H

N~N
~ (
( I
N
~
) (JC)
N N
H
Base component : Pyridazine Base component : Pyrazole
22 Heterocyclic Chemistry

4. The attached component (second component) is added as a prefix to the-

name of the base component. The prefix designating an attached
component is formed by changing terminal 'e' of a trivial or Hantzsch-
Widman name of a component into '0'. This '0' is not dropped when
followed by a vowe1.

Pyrazine Pyrazino-
Pyrazole Pyrazolo-
Thiazole Thiazolo-

However, there are some exceptions to this rule. The prefixes for some common
heterocycles used in the fused nomenclature are presented in Table 6.

Table 6. Prefixes for some common heterocycles

Heterocyclic compound Prefix

Pyridine Pyrido-
Quinoline Quino-
Isoquinoline Isoquino-
Furan Furo-
Thiophene Thieno-
Imidazole Imidazo-

5. The bonds of the base component are alphabetized with consecutive italic
letters starting with 'a' for 1,2- bond, 'b' for 2,3-bond, 'c' for 3,4-bond 'd'
for 4,5-bond and so on.
6. The atoms of ring system of second component (attached component) are
numbered in the normal way; 1,2,3,4,5, etc., observing the principle of
the lowest possible numbering.
7. The atoms common to both rings (side of fusion) are indicated by the
appropriate letters and numbers and are enclosed in a square bracket and
placed immediately after the prefix of the attached component. The numbers
(positions of attachment) of the second component are placed in the
sequence in which they are attached to the base component.

502 bOd
4 3 c

(I)S 0
=
S
+
a 0 e
1
Thieno[2,3-b]furan Thiophene Furan
(attached component) (base component)
Nomenclature of Heterocycles 23

(X I N~ (XI N)C 3co4

~
I I
~6
saO
b +
2 #7
~ S ~ o 1 8

Benzopyrano[3 ,4-b]benzothiazine [1,4]Benzothiazine Benzopyran

N~a
(base component) (attached component)

~I~
N

)
f OI
~
N~
a N b
d

C + 3(N~5
2
4

~6
N N N
1
Pyrazino[2,3-c]pyridazine Pyridazine Pyrazine
(base component) (attached component)

8. Common heteroatom : If a position of fusion is occupied by a heteroatom,

both the components (ring systems) are considered to possess that
heteroatom.

3
4 N N
()2
C
N" 0
d[)b
~TJ
+
5 N e 0 a
H1
Imichrzo[2,I-b]o~ole Imidazole Oxazole
(attached component) (base component)

9. Numbering of fused heterocyclic system :

(i) Fused heterocyclic system is numbered independently of the combining
components (base and attatched components). The numbering is started
from the atom adjacent to the bridgehead position with the lowest possible
locant(s) to the heteroatom(s). If there is choice, the heteroatom appearing

7C0~4
highest in Table 1 is preferred.

5~,
6
I 3

6~c! 8~ JO
7 1 9 N 2
1
Benzo[b]:f.Uran 3, I-Benzo~pine
24 Heterocyclic Chemistry

500
4 3

2
~:x5I N~,
S a N~ ~2
S 1
7 N
8 1

Thieno[2,3-b]furan Pyrazino[2,3-djpyridazine Imidazo[2,1-b]thiazole

(ii) Carbon atom common to two rings is given the lowest possible position,
but not numbered. However, the heteroatom at a position of fusion of two
rings (common heteroatom) is numbered.

4 5
3~N
2~_./NJs
N 8 7
1

Jmidazo[1,2-b]pyridazine 1,2,4-Triazolo[4,3-a]pyridine

(iii) The position of a saturated atom is indicated by an italic hydrogen and is

given the lowest possible number locant.

SOJa
5
I
a4
7

~
1

3
2

2H-Furo[3,2-b]pyran

9. Benzofused heterocycles :
(i) If a benzene ring is fused to the heterocyclic ring, the compound is named by
placing number(s) indicating position(s) of the heteroatom(s) before the prefix
benzo- (from benzene) followed by the name of the heterocyclic component.

7~a
8~3
S

9
5

1
4

2
SOCI )3 5

7 ::::::....
H
N4

s
2
8

3-Benzoxepin 4H-l,4-Benzothiazine 4H-3,1-Benzoxazine

Nomenclature of Heterocycles 25

(n) If two benzene rings are ortho-fused to a six-membered 1,4-dihetero-

monocyclic ring containing different heteroatoms, the heterocyclic system
is named by adding the prefix 'pheno-' to the Hantzsch-Widman name of
the heteromonocycle.

8
7CC~
1
ciJO~3 7CC6~ ~J04~
# I #2 8 # #
3
2
8
6

7CC~ oX)~3
#
5

S
4

#2
9 ~10 1 9 ~10 1
9 10 1
10H-Phenoxazine 10H-Phenothiazine Phenoxathiine

(JiJ.) However, the heterocyclic system in which two benzene rings are ortho-
fused to a six-membered 1,4-diheteromonocycle containing the same
heteroatoms are named by adding the replacement prefix for the heteroatom
(Table 1) to the term '-anthrene' with elision of an 'a'.

7CC~ ~X)~3 7((6:7~X)~ 3

8 #
S
#2 8~ ~N I #2
9 10 1 9 10 1

Thianthrene Phenazine
(exception to this rule)

2.4 Replacement Nomenclature System

Heterocyclic compounds are considered to be derived from the carbocyclic

compounds by the replacement of one or more carbon atoms by the heteroatom(s).
This forms the basis of replacement nomenclature of heterocycles and, therefore,
the rules of the replacement nomenclature are similar to those applied for the
carbocyclic compounds. This is the most systematic nomenclature and is used for
the heterocycles containing unusual heteroatom(s) and also for spiro- and bridged
heterocyclic systems.
26 Heterocyclic Chemistry

2.4.1 Monocyclic Heterocycles

1. The corresponding carbocyclic ring (the ring obtained from the heterocyclic
compound by replacing heteroatom(s) by C~, CR, or C according to the
valence of heteroatom(s)) is named by ruPAC rules.
2 The type ofheteroatom is indicated by a prefix according to Table 1. Since
all the prefixes end with the letter 'a' the replacement nomenclature is also
known as 'a' nomenclature. The position and prefix for each heteroatom are
placed before the name of the corresponding carbocyclic ring.

6
o

Oxacyclopropane
o
Oxacyclobutane
Q
Thiacyclopentane

o o
Oxacyclohexa-2,5-diene
c> N
H

1,3-Diazacyclopenta-2,4-diene

3. The replacement names derived from benzene are retained only if three
double bonds are present, otherwise the names with -ene, -diene, etc. as
necessary are used.

0 () 0 0 0
N

N N H P Bi

Azabenzene 1,4-Diazabenzene Silabenzene Phosphabenzene Bismabenzene

0 0
0 Si
H2
Oxacyclopenta-2,4-diene Silacyclopenta-2,4-diene
Nomenclature of Heterocycles 27

4. The sequence and numbering of the heteroatoms follow the rules as in

systematic nomenclature. However, the following preferential order is
followed:
(i) first preference heteroatom appearing highest in Table I
(ii) second preference other heteroatoms according to Table 1
(iii) third preference multiple bonds
(iv) fourth preference substituents, if there is choice alphabetical
order is considered

5(N)3
H4

6 S 2

I-Oxa-3-azacyclopenta-2,4-diene 1-Thia-4-azacyclohexa-2,5-diene

1-Thia-4-aza-2-silacyclohexane 1,4-Dithiacyclohexa-2,5-diene

2.4.2 Fused Heterocycles

In replacement nomenclature system following rules are applied for naming fused
heterocycles :
1. The position(s) and prefix(es) for the heteroatom(s) are written in front of
the name of the corresponding carbocyclic ring.

9 10 1

8~~
7~N~3
6 5 4

2,5-Diazaanthracene 3,9-Diazaphenanthrene
28 Heterocyclic Chemistry

2 The numbering of the corresponding carbocyclic ring is retained irrespective

of the position(s) of the heteroatom(s). However, the lowest possible
number locants are assigned to the heteroatoms in the complete fused
heterocyclic system and, if choice, Table 1 is followed.
3. The numbering of fused heterocyclic system in the replacement system of
nomenclature is frequently different from that given in fusion nomenclature
system. The heteroatom at the ring junction is assigned individual number
in the fusion nomenclature system, whereas in the replacement nomenclature
system the heteroatom at the ring junction is given the same locant as an
adjacent nonconjunction carbon atom but with a suffix 'a' or 'b', etc.

7 1 6 1

.(~)2 5(~)2
5 4 3 4 3a 3

Imidazo[2,I-b]thiazole 1-Thia-3a,6-diazapentalene
(Fusion nomenclature) (Replacement nomenclature)

4. The corresponding carbocyclic ring without maximum number of non-

cumulative double bonds is named without using prefix for hydrogen atom.
The ring is named in its state of hydrogenation.

7 H
6(XN~
N
5~
I S/~
4 3

5. If the corresponding carbocyclic ring is without maximum number of non-

cumulative double bonds, the heterocyclic system is considered to be with
maximum number of conjugated or isolated double bonds. The corresponding
carbocyclic ring is named as it contains maximum number of non-cumulative
double bonds.
Nomenclature of Heterocycles 29

I ~)2
7(X· I 0)2
7(X.
6~ S 3 6~ 3
5 4
5 S
4

1,4-Dithianaphthalene l-Oxa-4-thianaphthalene

The additional hydrogen atom, if present, is indicated by an italic capital

'JI' with its position and placed before the position(s) and the prefix(es) of
the heteroatom(s).

7 6

IH-2-Oxacbrysene

2.4.3 Spiro Heterocycles

The compounds in which two rings are fused at a common point are known as
spiro compounds and the common atom which is quaternary in nature is
designated as spiro atom. The spiro compounds may be classified according to the
number of spiro atoms; (i) monospiro- (ii) dispiro- and (iii) trispiro ring systems.
Spiro heterocycles are named according to the rules adopted for naming spiro
hydrocarbons :
1. Spiro heterocycles with one spiro atom consisting of one or both
heterocyclic rings are named by prefixing spiro to the name of normal alkane
with same number of carbon atoms. The number of atoms in each ring are
indicated by arabic numbers separated by a full stop and enclosed in a
square bracket in ascending order and are placed between spiro prefix and
the name of hydrocarbon. The heteroatoms are indicated by the prefixes
and are prefixed with their positions to the name of spiro hydrocarbon.
30 Heterocyclic Chemistry

Spiro hydrocarbon Spiro heterocycle

Spiro[x..y]alkane Spiro[x..y]alkane
x = number of atoms other than x = foW' atoms
spiro atom in smaller ring. (spiro atom is not included)
y = number of atoms other than y = five atoms
spiro atom in larger ring (spiro atom is not included)
.J.. alkane: total number of atoms
Spiro[4.5]decane (including heteroatom)
are = 10 : decane
Prefix for heteroatom : oxa
.J..
6-Oxaspiro[4.5]decane

2 The numbering starts from the ring atom of the smaller ring (if rings are of
unequal size) attached to the spiro atom and proceeds first around the
smaller ring and then around the larger ring through the spiro atom. The
heteroatoms are assigned the lowest possible number locants.

5-Thiaspiro[3.4]octane

If there is choice between two different heteroatoms, the preferential

numbering is decided according to the appearance of the heteroatoms in
Table 1.

7tS~~2
6 0 3
5

5-0xa-9-thiaspiro[3.5]nonane
Nomenclature of Heterocycles 31

3. The heterocyclic ring is preferred over the carbocyclic ring of the same size.
If both the rings are heterocyclic, the preference is given to the heterocyclic
ring with heteroatom appearing first in Table 1.

3C{j,
~ 1 11 10

2-0xaspiro[5.5]undecane 1-0xa-6-thiaspiro[4.4]nonane

4. If the unsaturation is present in a ring, the pattern of munbering remains

the same but the direction around the ring remains in such a way that the
multiple bond is given number as low as possible. However, the heteroatom
is preferred over the multiple bond.

1-Oxaspiro[4.5]dec-6-ene 6-Oxaspiro[4.5]dec-9-ene

5. When one or both the components of spiro heterocycle are fused

polycyclic system, the names of both the components are cited after prefix
'spiro' in square bracket in alphabetical order and are separated by the
numbers of spiro atom. The components in such spiro heterocyclic system
retain their numbering, but the second component is numbered by primed
numbers.

Spiro[cyclopenta-2,4-diene-1,3'-3H-indole] Spiro[piperidine-4,9'-xanthene]
32 Heterocyclic Chemistry

6. If both the heterocyclic components are the same in spiro heterocyclic

system, 'spirobi-' is prefixed to the name of heterocyclic component.

3,3'-Spirobi(3H-indole)

2.4.4 Bridged Heterocycles

Bridged heterocyclic systems are named according to the rules for bridged
hydrocarbons. The heteroatoms with their locants are prefixed to the name of
bridged hYdrocabron.

2.4.4.1 Bicyclic Systems

1. Bridged heterocyclic system consisting of two rings with two or more

common atoms is given the name of acyclic hydrocarbon with the same
total number of carbon atoms, which is preceded by the prefix 'bicyclo-'
with the descending order of numbers separated by a full stop in square
bracket indicating number of atoms separating bridgehead atoms. The
prefixes indicating heteroatoms with their locants are prefixed to the name
of bridged hydrocarbon.
2 The numbering starts from one of the bridgehead atoms and proceeds
through the longest possible route to the second bridgehead atom and then
by the second longest route to the first bridgehead atom and finally by
shortest route from one bridgehead atom to the second bridgehead atom.
3. The heteroatom is given number as low as possible.
4. When there is choice between heteroatom and multiple bond, the
heteroatom is preferred.
5. If there is comparison between heteroatoms, the preference of numbering
is given according to their appearance in Table 1 and their prefixes with
locants are arranged alphabetically.
Nomenclature of Heterocycles 33

3-0xabicyclo[4.3.1 ]decane

Total number of atoms = 10 : acyclic hydrocarbon - decane derivative

Number of rings = 2 : prefix 'bicyclo-' is used
Number of atoms separating bridgehead atoms
in three routes and arranged in descending order: [4.3.1]
Prefix for heteroatom with its locant : 3-oxa
Thus, the name of heterocyclic compound is : 3-0xabicyclo[4.3.1 ]decane.

J:j,
7

7-0xabicyclo[2.2.1 ]heptane

5 4 3

6 5 4
H2C-CH-NH
1 91 13
70 CH 2 CH 2 4-Aza-2,7-dioxabicyclo [3.3.1 ]nonane
I I I
H2C-CH-O
812

3 2 1 10
H2C-HC=C-N
I 1 II
H2y4 11 ~H 9yH 10,1l-Diaza-8-0xabicyclo[5.3.1]undeca-l,5,9-triene

HC=CH-CH-O
5 6 7 8

6 H 2
HC-C-CH

II 7~~ \\ 7-Azabicyclo[2.2.1 ]hepta-2,5-diene

~C"'I /~H
CH
4
34 Heterocyclic Chemistry

2.4.4.2 Polycyclic Systems

1. Polycyclic bridged heterocycles are also named according to the rules

adopted for the bicyclic bridged heterocycles. However, the prefix
tricyclo-, tetracyclo-, etc., depending on the number of rings is used.
2 The prefix (cyclo-) is followed by the numbers separated by full stops in
square bracket in decreasing order indicating :
(i) the number of atoms of two branches of the main ring containing maximum
number of atoms,
(li) the number of atoms in main bridge excluding bridgehead atoms and
(tit") the number of atoms in secondary bridges.
3. The location of each secondary bridge (the position of bridgehead atoms
involved in the secondary bridges) is indicated by superscripts to the
numbers indicating its length and are seprated by a comma.
4. The prefix (tri- or tetracyclo- depending on the number of rings) with
numbers separatd by full stop in square bracket is followed by the name
of acyclic hydrocarbon of the carbon atoms equivalent to the total number
of atoms in the bridged heterocyclic system.
S. The prefixes for the heteroatoms and the substituents with their positions
are indicated and placed as usual.

5
N
~4
N
3/
N
I
9 CaH5
3-Phenyl-3,4,S-triazatricyclo[S.2.1.()2.6]decane

Total number of atoms = 10 : acyclic hydrocarbon - decane

Number of rings = 3 : prefix tricyclo- is used
Number ofheteroatoms = 3 (nitrogen at 3,4 and S positions) : prefix- 3,4,S-triaza-
Number of atoms in two branches of main ring : S and 2
Number of atoms in main bridge : 1
Number of atoms in secondary bridge : 0
Superscripts for the location of secondary bridge : 2,6 (positions of attachment
of secondary bridge)
Thus, the name of
heterocyclic compound is as 3-Phenyl-3,4,S-triazatricyclo[S.2.1.02, 6]decane.
Nomenclature of Heterocycles 35

1O-Methoxy-6-azatricyc10[4.3.l.0J ,8]decane

10 1 2 3
HN-CH-CH-S
I 9
11 I
CH 2 4
I
r
H2C 121 CH

I
HN-CH 2 -CH-CH
H2 I
8 7 6 5

3-Thia-8,l O-diazatricyc1o[5.3 .2.02,6]dodecane

2.4.5 Heterocyclic Ring Assemblies

Two or more heterocyclic ring systems, single or fused, joined to each other by
single or double bonds are called heterocyclic ring assemblies.

N ' f- ~
Q-C
-
N

Following rules are adopted for naming heterocyclic ring assemblies :

1. The heterocyclic ring assembly of two identical heterocyclic systems is
named by prefixing 'bi-' before the name of heterocyclic system or its
corresponding radical.
2 The numbering of heterocyclic ring assembly is similar to that of the
heterocyclic system or its corresponding radical. One heterocyclic system
is assigned with unprimed numbers and other with primed numbers. The
points of attachment are indicated and placed before the name.
36 Heterocyclic Chemistry

, , , ,

2{)s'
4 3 3 4 4 3 3 4

SC~2 102'10,
5~_~_/5
6 N N, ~ 0 2 0,
1 1 1

2,2'-Bipyridine or 2,2'-Bipyridyl 2,2'-Bifuran or 2,2'-Bifuryl

3. If there is choice, the heterocyclic ring with lower munbered point of

attachment is assigned with lUlprimed munbers.

4 3 4' 5'

sC)23'(),"
6 1 2 1 ,
5
,

2,3'-Bipyridine or 2,3'-Bipyridyl 2,3'-Bifuran or 2,3'-Bifuryl

2,3'-Biquinoline or 2,3'-Biquinolyl

4. The locants of the substituents are placed in the ascending order with the
preference of lUlprimed numbers over primed numbers (unprimed numbers
are considered as lower numbers).

2,2',5,5'-Tetramethyl-l,l'-bipyrrolyl
Nomenclature of Heterocycles 37

5. Non-identical heterocyclic ring assemblies are named by selecting one

heterocyclic system as a base component and other as a substituent. The
base component is numbered with unprimed numbers and the substituent
ring is with primed numbers. The heterocyclic ring assembly with non-
identical heterocyclic rings is named as :

,
5

2-(2'-Pyridyl)quinoline

6. The heterocyclic ring assemblies constructing of three or more identical

heterocyclic systems are named as follows :
(i) the appropriate numerical prefix, ter-, quater-, etc., is placed before the name
of the corresponding heterocyclic system.
(ii) unprimed numbers are assigned to the one of the terminal heterocyclic
systems and others are assigned single, double, triple, etc. primed numbers.
(iii) the points of attachment are assigned the lowest possible numbers.

3,3',3"-Terpyrrolidine

III 111
4 3

2,2':5',2":5",2"'-Quaterpyrrole
38 Heterocyclic Chemistry

REFERENCFS

1. A. Hantzsch and J.H.Weber, Ber. 20, 3119 (1887).

2 o. Widman, J. Prakt. Chem. 38(2), 185 (1888).
3. A. M. Patterson and L. T. Capell, The Ring Index (2nd Edn.), Am. Chern.
Soc., Washington, D. C., 1960 and Supplements 1,1963; 11,1964; III, 1965.
4. IUPAC Nomenclature of Organic Chemistry, Definitive Rules for sections
A-C (3rd Edn.), Butterworths, London, 1971.
5. J. H. Fletcher, o. C. Dermer and R. B. Fox (Eds.), Nomenclature of Organic
Compounds, Adv. in Chem. Ser. 126, Am. Chern. Soc., Washington, D. C.,
1974.
6. R. S. Chan, Introduction to Chemical Nomenclature, Butterworths,
London, 1974.
7. A. D. McNaught in A. R. Katritzky and A. J. Boulton (Eds.), Adv.
Heterocycl. Chem. Vol. 20, Academic Press, New York, 1976, pp. 175.
8. J. Rigaudyand S. P. Klesney, IUPAC Nomenclature of Organic Chemistry,
Definitive Rules, Sections A to H, Pergamon Press, Oxford, 1979.
9. IUPAC Commission on Nomenclature of Organic Chemistry, Pure Appl.
Chem. 55, 409 (1983).
10. A. R. Katritzky, Handbook of Heterocyclic Chemistry, Pergamon Press,
Oxford, 1985.
11. CRC Handbook of Chemistry and Physics (78th Edn.), C.R.C. Press, Boca
Raton, 1997.
12. A. D. McNaught and P. A. S. Smith, in A. R. Kartritzky and C. W. Rees
(Eds.), Comprehensive Heterocyclic Chemistry Vol. 1, Pergamon Press,
Oxford, 1984, pp. 7.
13. R. Panico, W. H. Powell and J. -C. Richer, A Guide to IUPAC Nomenclature
of Organic Compounds, Recommendations 1993, Blackwell Scientific
Publications, Oxford, 1993.
CHAPTER 3
AROMATIC HETEROCYCLES

CONTENTS

1 GENERAL 41
1.1 Chemical Behaviour of Aromatic Heterocycles 42
1.1.1 Six-Membered Aromatic Heterocycles 42
1.1.2 Five-Membered Aromatic Heterocycles 43
1.1.3 Mixed Aromatic Heterocycles 44
2 STRUCTURAL TYPES 44
2.1 Six-Membered Aromatic Heterocycles 44
22 Five-Membered Aromatic Heterocycles 46
2.3 Benzo-fused Aromatic Heterocycles 47
23.1 Benzo-fused Six-Membered Aromatic Heterocycles 47
23.2 Benzo-fused Five-Membered Aromatic Heterocycles 47
24 Other-fused Aromatic Heterocycles 48
3 AROMATICTIYINHETEROCYCLES 49
3.1 Relationship with Carbocyclic Aromatic Compounds 49
3.1.1 Structure of Benzene 50
3.1.2 Structure of Naphthalene 51
3.1.3 Cyclopentadienyl Anion System 52
3.2 Criteria of Aromaticity in Heterocycles 53
3.2.1 Structural Criteria 53
3.21.1 Bond Lengths 53
3.2.1.1.1 Five-Membered Aromatic Heterocycles 53
3.2.1.1.1.1 Aromaticity Order 54
3.2.1.1.1.2 Bond Alternation 54
3.2.1.1.2 Six-Membered Aromatic Heterocycles 56
3.2.1.1.3 Relationship of Bond Lengths with Bond 58
Orders
3.22 Electronic Criteria 58
40 Heterocyclic Chemistry

3.22.1 Ultraviolet Spectroscopy 58

3.2.2.1.1 Six-Membered Aromatic'Heterocycles 58
3.2.2.1.1.1 Monocyclic Azaheterocycles 58
3.2.2.1.1.2 Bicyclic Azaheterocycles ':f)
32.2.1.2 Five-Membered Aromatic Heterocycles 60
3.2.2.1.3 Benzo-fused Aromatic Heterocycles 61
3.22.2 Infrared Spectroscopy 61
3.22.3 Photoelectron Spectroscopy 62
3.2.2.4 Dipole Moments 63
3.2.2.4.1 Six-Membered Aromatic Heterocycles 63
3.2.2.4.2 Five-Membered Aromatic Heterocycles 65
3.2.3 Energetic Criteria 66
3.2.3.1 Empirical Resonance Energy 67
3.2.3.1.1 Heat of Combustion 68
3.23.1.2 Heat of Hydrogenation 70
3.2.3.2 Delocalization Energy 71
3.23.3 Dewar Resonance Energy 73
3.24 Magnetic Criteria 75
3.24.1 PMR-Spectra 75
3.2.4.1.1 Six-Membered Aromatic Heterocycles 77
3.2.4.1.2 Five-Membered Aromatic Heterocycles 77
3.24.2 Proton-Proton Coupling Constants and Bond Order ID
3.2.4.3 13C NMR Spectroscopy 80
3.2.4.3.1 Six-Membered Aromatic Heterocycles 80
3.2.4.3.2 Five-Membered Aromatic Heterocycles 83
3.2.4.4 Diamagnetic Susceptibility Exaltations 84
3.24.5 Faraday Effect (Magneto-optical Rotation) 84
3.3 Heteroaromatic Ring Systems 86
3.3.1 Five-Membered Heteroaromatic Ring Systems 86
3.3.1.1 Five-Membered Heteroaromatics with One Heteroatom 86
3.3.1.2 Five-Membered Heteroaromatics with Two Heteroatoms 87
3.3.1.3 Benzo-fused Five-Membered Heteroaromatics 89
3.3.2 Six-Membered Heteroaromatic Ring Systems 91
3.3.2.1 Pyridine 91
3.3.2.2 Fused-Ring Derivatives of Pyridine 92
3.3.2.3 Pyridones and Related Systems 94
3.3.2.4 Pyrylium Salts 95
3.3.2.5 Pyrones 95
4 HETEROAROMATIC REACTIVITY 96
4.1 Selectivity and Reactivity 97
4.1.1 Reactivity Indices 97
4.1.1.1 Electron Densities 98
4.1.1.2 Frontier Electron Densities 98
4.1.1.3 LocalizationEnergy 99
4.2 Selectivity and Reactivity in Heteroaromatic Rings 100
4.2.1 Six-Membered Heteroaromatic Rings 100
4.2.2 Five-Membered Heteroaromatic Rings 101
REFERENCES 102
Aromatic Heterocycles 41

1 GENERAL

Aromatic heterocycles are planar or nearly planar cyclic conjugated heterocycles

and are associated with (4n + 2) de10calized n-electrons. These are characterized
by their (i) enhanced stability, (ii) substitution reactions rather than addition
reactions with the retention of aromaticity, and (iii) special spectroscopic characteristics.
The aromatic heterocycles are considered to be derived from two aromatic ring
systems; benzene 1 and cyclopentadienyl anion 2.
1. Six-membered aromatic heterocycles: These heterocycles are considered to be
derived from benzene by replacing CH group of the benzene ring by
isoelectronic N, 0+ or S+ (scheme-I).

0 -CH
+X
.. 0 X
+ +
1 3 (X=N,O, S )

Scheme-1

2. Five-membered aromatic heterocycles: These heterocycles are considered to

be derived from cyclopentadienyl anion by the replacement of CH group by
°
NH, and S (scheme-2).

o2
-CH
+Y
o Y
4 (y=NH,0, S)

Scheme-2

The multiple replacement of CH groups in the six- and five-membered ring

systems is also possible with the retention of aromatic character, since the trivalent
and divalent heteroatoms contribute one or two electrons to the aromatic system.
42 Heterocyclic Chemistry

1.1 Chemical Behaviour of Aromatic Heterocycles

(Characteristics of Heteroatom in Ring)

1.1.1 Six-Membered Aromatic Heterocycles

Since the six-membered aromatic heterocycles are considered to be derived from

the benzene ring by the replacement of CH group by the electronegative
heteroatom, the chemical behaviour of these heterocycles can be considered to be
similar to that of benzene. The symmetry of benzene ring is, however, perturbed
by the introduction of a heteroatom. The electronegative heteroatom causes
withdrawal of electrons from the ring carbon atoms and thus affects localization
of electrons with the result of electron deficiency on the ring carbon atoms. The
six-membered heterocycles are, therefore, known as x-deficient aromatic heterocycles.
The introduction of further heteroatom(s) into six-membered ring reinforces the
electron-withdrawing effect and results in the further electron deficiency on the
ring carbon atoms. Thus, the chemistry of these heterocycles 5, 6 and 7 is affected
by the electron deficiency on the ring carbon atoms caused by the electron-
withdrawing effect of the heteroatom(s) (Fig. 1).

o N
5
() N
6
()
N

N
7

1 <1
1011 -CH <101 <1(electron density

1~ 1 +X <1 X <1
~
less than 1)

1 X = heteroatom
1 3

Fig. 1. Representation of electron density in six-membered heterocycles

The electron density on each carbon atom in the benzene ring is considered to
be one (1), the electron density in six-membered heterocycles, therefore, will be less
than one (1 ) due to the electron-withdrawal effect of the electronegative
heteroatom. The molecular orbital calculations also confirm this prediction as in the
following structures 5 and 6 (Fig. 2) :
Aromatic Heterocycles 43

0 11.064 C
0.932
37 N
1.1
~ 0.866 0.803 ~ ) 0.749
N N
1.166 1.225
5 6
Fig. 2. Distribution of 1t-electron density in six-membered heterocycles

Resonance theory also supports the theoretical predictions and leads to the
same conclusion (Fig. 3).

5 (i) (ii) (iii) (i~

Fig. 3. Resonating structures of pyridine

The 1t-deficiency in six-membered aromatic heterocycles is also reflected in their

characteristic spectroscopic and chemical properties.

1.1.2 Five-Membered Aromatic Heterocycles

Five-membered aromatic heterocycles are considered to be derived from

cyclopentadienyl anion 2 and the lone pair on the heteroatom is involved in the cyclic
delocalization of 1t-electrons. Six 1t-electrons are, therefore, delocalized over five
atoms. The electrons density on each carbon atom in the ring is approximated to be
greater than one (1) (615 = 1.2) in comparison to the benzene ring, a 1t-neutral system
in which one electron is on each carbon atom. The five-membered aromatic
heterocycles are, therefore, referred to as 1t-excessive aromatic heterocycles. The
electron-donor characteristic ofheteroatom and the 1t-excessiveness in five-membered
aromatic heterocycles can be evidenced by their resonating structures (Fig. 4) :

O~r::J~ C)-~-O~
4
X X
(i)
X
(ii)
X
(iii)
o X
(i~

Fig. 4. Resonating structures in five-membered aromatic heterocycles

44 Heterocyclic Chemistry

The molecular orbital calculations also support the theoretical predictions (Fig. 5).

1.064 1.036

01.030 00.912
N S
H
8 9

Fig. 5. Distribution of n-e1ectron density

1.1.3 Mixed Aromatic Heterocycles

(n-Deficient + n-Excessive Aromatic Heterocycles)

Five-membered aromatic heterocycles 10 containing both types of heteroatoms

(heteroatom with electron-withdrawing effect as in six-membered heterocycles and
heteroatom with electron-releasing effect as in five-membered heterocycles) are
considered to be mixed systems with the characteristics of both n-deficient and
n-excessive aromatic heterocycles. The chemistry of these heterocycles shows the
similarities with six-membered as well as with five-membered aromatic heterocycles
with one heteroatom.

pyridine-type nitrogen with

r:)~ electron-withdrawing effect
pyrrole-type nitrogen with
N •
H electron-releasing effect

10

2 STRUCTURAL TYPES

2.1 Six-Membered Aromatic Heterocycles

These are heterocyclic analogs of benzene in which CH group(s) of the benzene

ring is replaced by the heteroatom(s) with the distortion in symmetry due to
carbon-heteroatom bond(s). These heterocycles are planar with a complete and
Aromatic Heterocycles 45

uninterrupted cycle ofp-orbitals and are associated with (4n+2) 7t or 67t-cyclically

delocalized electrons 5-7, 11-15. Other fifth group elements (P, As, Sb and Bi)
can also replace CH group, but the aromatic character decreases with increasing
size of the heteroatom 16-18. Oxygen and sulfur can also replace CH group of
the benzene ring forming positively charged ionic species, pyrylium 19 and
thiopyrylium 20 cations, respectively (Fig. 6).

o eN

Pyridine
~)
N
N

Pyrimidine
~
~_jN
N

Pyridazine
()
N

Pyrazine

e
5 6 11 12

()
N
N
II
~ ..... N
N N
1,2,3-Triazine 1,2,4-Triazine 1,3,5-Triazine

o o o
13 7 14

N
N~
~N'....."~ p As Sb

1,2,4,5-Tetrazine Phosphabenzene Arsabenzene Stibabenzene

a a
15 16 17 18

o S

Pyrylium cation Thiopyrylium cation

19 20

Fig. 6. Six-membered aromatic heterocycles

46 Heterocyclic Chemistry

2.2 Five-Membered Aromatic Heterocycles

These are heterocyclic analogs of cyclopentadienyl anion and are considered to

be derived by replacing CH group by divalent heteroatom (8, 9 and 21). These
heterocycles are planar with sp2-hybridized atoms and involve a lone pair of
electrons on the heteroatom in cyclic delocalization. The aromaticity of these hete-
rocycles depends on the extent of involvement of lone pair on heteroatom in cyclic
delocalization which, in turn, depends on the electronegativity of the heteroatom.

o N
H
o s o o
8 9 21

Nitrogen is trivalent and it may be substituted for a CH group in the five-

membered heterocycles with one heteroatom. Thus, the analogs of pyrrole, furan
and thiophene (10, 22-26) are possible (Fig. 7).

()
N eN
N ON 0
() 0
H H
hnidazole Pyrazole Isoxazole Oxazole

10 22 23 24

ON S
() S
Isothiazole Thiazole
25 26
Fig. 7. Five-membered heterocycles with two heteroatoms

The pyridine-type nitrogen -N= is not involved in maintaining aromaticity and

induces electron-withdrawing effect similar to the meta directing effect in benzene.
The singly bonded heteroatom donates electrons to the ring carbon atoms and the
lone pair on the heteroatom is involved in the aromaticity and thus exerts
a-directing effect.
Aromatic Heterocycles 47

2.3 Benzo-fused Aromatic Heterocycles

The fusion of a benzene ring to an aromatic heterocyclic ring retains aromaticity

in the modified fonn. These aromatic heterocycles exhibit bond alternation
involving partial localization of the bonds.

2.3.1 Benzo-fused Six-Membered Aromatic Heterocycles

Benzo-fused six-membered heterocycles (27-34) (Fig. 8) are related to naphthalene

in the same way as pyridine with benzene. The fusion of a benzene ring, however,
causes decrease in the aromaticity due to the bond alternation.

CD
~
N
Quinoline
0
00
~ oN

Isoquinoline
(X)
~

Cinnoline
N~N

ex)
27 28 29

CC
~ I N)

Quinazoline
N

Quinoxaline
CX:
~ I o~
Phthalazine
N

ex
30 31 32

l N'1
~ ~N
N
1,2,3-Benzotriazine 1,2,4-Benzotriazine
33 34
Fig. 8. Benzo-fused six-membered aromatic heterocycles

2.3.2 Benzo-fused Five-Membered Aromatic Heterocycles

Benzo-fused five-membered aromatic heterocycles 35-38 (Fig. 9) also show some

bond alternation. However, the heterocyclic compounds 39-41 in which a benzene
48 Heterocyclic Chemistry

ring is fused to a five-membered aromatic heterocyclic ring by a carbon-carbon

single bond are less aromatic due to considerable bond alternation.

co
~

Indole
N
H
0)
~ 0

Benzo[b]:furan
CO
~ S

Benzo[b]thiophene
O=N~
~ N

Benzimidazole
H

35 36 37 38

CC
~ ~
NH
CCo CC
~ ~

Benzo[c]:furan
~ ~

Benzo[c]thiophene
S

Isoindole
39 40 41
Fig. 9. Benzo-fused five-membered aromatic heterocycles

2.4 Other-fused Aromatic Heterocycles

The fusion of two six-membered aromatic heterocyclic rings through a carbon-

carbon single bond results in the formation of heterocyclic analogs of naphthalene,
42 and 43. Similarly, the fusion of a six-membered aromatic heterocyclic ring with
a five-membered aromatic heterocyclic ring forms a bicyclic heterocycle 44 which
is also considered to be included in the class of aromatic heterocycles.

( N:C
N N
'7 -"::::N
("y~
I ) NV-N
N N H
1,5-Naphthyridine Pteridine Purine

42 43 44

The fusion of two rings across the C-N bond in such a way that the nitrogen atom
is common to both the rings also leads to the formation of bicyclic aromatic
heterocycles 45 and 46. These heterocycles are planar and possess lOn-electrons
required for the aromaticity according to the (4n + 2) n-rule.
Aromatic Heterocycles 49

Quinolizinium cation Indolizine

45 46

3 AROMATICITY IN HETEROCYCLES

3.1 Relationship with Carbocyclic Aromatic

Compounds

Carbocyclic aromatic compounds are planar cyclic conjugated systems with

(4n + 2) 1t-electrons. These compounds have specially stabilized 1t-electron system
in which all the bonding molecular orbitals are completely filled and the
antibonding orbitals remain vacant. Thus, the concept of aromaticity is not
particularly related to the nature and the number of the ring atoms, but is
associated with the molecular orbital energies.
The main characteristic features of the carbocyclic aromatic system are :
(i) unusual stability,
(ii) tendency to undergo substitution reactions with the retention of aromatic
character,
(iii) uniformity in bond lengths in the rings, and
(iv) special spectroscopic characteristics, particularly NMR-spectra.
All these characteristic features are also exhibited to a greater or lesser extent
by the aromatic heterocycles. Six-membered aromatic heterocycles are related to
benzene as these are derived by the replacement of one or more CH group(s) of
the benzene ring by the trivalent heteroatom(s), but the structural geometry of the
benzene ring is perturbed with the introduction of heteroatom. Similarly, five-
membered aromatic heterocycles are related to the cyclopentadienyl anion. Benzo-
fused aromatic heterocycles are considered to be analogs of naphthalene and are
related to naphthalene similarly as the six-membered aromatic heterocycles with
benzene. To correlate the aromaticity of aromatic heterocycles with carbocyclic
analogs, it is desirable to discuss the structures of benzene, naphthalene and
cyclopentadienyl anion.
50 Heterocyclic Chemistry

3.1.1 Structure of Benzene

In benzene trigonally hybridized (spl) carbon atoms form a strainless planar ring.
Thus, there are six (J C-H bonds, six (J C-C bonds and six 2pz orbitals (one on
each carbon atom). Six 2pz orbitals are perpendicular to the plane of the ring. Six
2pz orbitals overlap in two ways and thus two equivalent structures 1a and 1b are
obtained. Each 2pz orbital, however, overlaps with its neighbouring 2pz orbital
equally to form a completely delocalized molecular orbital embracing all the six
carbon atoms (Fig. 10).

- -.
~ . .
~:
- ' '" c-~
\ I ~~
-
\'8 I

" "
(i) (ii) (iii) (iv)

III III III

0 1a
0 1b
@ \ .....'.'

Fig. 10. Structure of benzene

Since six 2pz orbitals are involved, six-molecular orbitals are formed; three
bonding and three antibonding orbitals. Six 2pz electrons, in pairs, occupy three
bonding molecular orbitals which are of the lowest energy and the antibonding
orbitals remain vacant. The energy of three pairs of the delocalized 1t-electrons
is less than that of three pairs of the localized 1t-electrons and hence benzene
molecule is stabilized by resonance and has high delocalization energy (resonance
energy or stabilization energy). Thus, benzene has a regular hexagonal structure
with equal carbon-carbon bond distances (1.39A) which are intermediate between
carbon-carbon single bond (Csp2-CSp2 = 1.46A) and carbon-carbon double bond
(CSp~CSp2 = 1.34A).

:..· · ..: . .
@ ......
t----1.39A

1
Aromatic Heterocycles 51

3.1.2 Structure of Naphthalene

Ten carbon atoms of naphthalene are at the comers of two fused hexagons. All
the carbon atoms are sp2-hybridized and are attached to three other atoms by
a-bonds with all carbon atoms and hydrogen atoms in a single plane. Unhybridized
2pz orbitals with one electron on each carbon atom are perpendicular to the plane
of the ring. These 2pz orbitals on each carbon atom are combined in three ways
resulting in three structures 47a, 47b and 47c. However, 2pz orbitals are
overlapping equally with their adjacent 2pz orbitals and a cloud of 1t-electrons
is formed which is considered as two partial overlapping sextets with a common
pair of 1t-electrons (Fig. 11). Because of containing delocalized 101t-electrons
(according to the Huckel's rule i.e. (4n+2) 1t-electrons in a planar cyclic structure),
naphthalene is an aromatic molecule.
Naphthalene can be considered to be a resonance hybrid of following three
resonating structures 47a, 47b and 47c (Fig. 12) which are not usually equivalent
as central double bond in 47a is different from that in other two resonating

8~,
~
\
,

\
I

I
I

47a 47b 47c

47

Fig. 11 Structure of Naphthalene

52 Heterocyclic Chemistry

structures 47b and 47c. However,if three resonating structures are assumed to
contribute equally to the naphthalene structure; C 1-C2 bond has more double bond
character than C2-C3 bond. Molecular approximations also show bond orders of
1.724 and 1.603, respectively as compared to in benzene (1.667). C 1-C2 Bond is
expected to have more double bond character than the single bond and C2-C3
bond to have more single bond character than the double bond. In agreement with
these predictions, C 1-C2 and C2-C3 bond distances are 1.36A and 1.415A,
respectively. The non-equivalency of the bonds is called partial bond fixation and
is usually observed in all the fused aromatic systems.

700
6~
8

1
1

~2
#3
7CO~
6
8
~2 ~7~2
#
1

#3 6YV3
8 1

5 4 5 4 5 4
47a 47b 47c

Fig. 12. Resonating structures of naphthalene

3.1.3 Cyclopentadienyl Anion System

Cyclopentadienyl anion 2 has planar cyclic structure with delocalized six

x-electrons in three bonding molecular orbitals. The relative stability of this system
is reflected by the unexpected acidity of cyclopentadiene as the resulting
cyclopentadienyl anion is greatly stabilized by resonance (Fig. 13).

Q_b:~~
H H -H
[Q-O--O]=®
2a 2b 2c 2

Fig. 13. Resonating structures of cyclopentadienyl anion

Cyclopentadienyl anion is an isoelectronic with five-membered aromatic

heterocycles; pyrrole, thiophene and furan. These heterocyclic systems are
aromatic by virtue of an aromatic sextet. The planar cyclic conjugated systems with
(4n+2) x-electrons are stabilized by delocalization of x-electrons and are said to
be aromatic, while the systems with 4nx-electrons are considered antiaromatic.
Aromatic Heterocycles 53

3.2 Criteria of ~omaticity in Heterocycles1,2

Aromaticity can be defined qualitatively as a cyclic planar system associated with

(4n+2) 1t-electrons is said to be an aromatic. The degree of aromaticity depends
on the involvement oflone pair electrons on the heteroatom in cyclic delocalization
of 1t-electrons. The quantitative estimation of aromaticity is although difficult,
however it is based on the delocalization of 1t-electrons and on the physico-
chemical properties relating to the aromaticity particularly, molecular geometry,
enhanced stability and diamagnetic susceptibility exaltations.

3.2.1 Structural Criteria

3.2.1.1 Bond Lengths

Delocalization of 1t-electrons in an aromatic system causes carbon-carbon bond

to have typical bond length between that of a carbon-carbon single bond
[CSp2-CSp2] and carbon-carbon double bond [Csp2::Csp2]. Delocalization of
1t-electrons in benzene causes the bond lengths to be equal (1.39A), but in the
acyclic conjugated system the cyclic delocalization is not possible and the bond
lengths between sp2-hybridized carbon atoms are not equal and thus exhibits bond
alternation. It can be generalized that the compounds with non-alternating bond
lengths are considered to be aromatic, whereas the compounds with bond
alternations are non-aromatic. In heteroSromatic systems, carbon-heteroatom bond
is generally shorter than that in its saturated analogs.
Some single and double bond lengths in acyclic polyenesl with sp2-hybridized
atoms are given for the comparison with the bond lengths in aromatic heterocycles:

single bonds double bonds

C-C = I,4SA C=C 1.34 A
C-N 1,45 A C=N 1.27 A
C-O 1.36 A 0=0 = 1.22 A
C-S = 1.75 A C=S 1.64 A
N-N = 1,41 A N=N 1.23 A

3.2.1.1.1 Five-Membered Aromatic Heterocycles

Five-membered aromatic heterocycles exhibit cyclic delocalization of 1t-electrons

by which carbon-carbon single bonds acquire double bond character and carbon-
carbon double bonds acquire the character of single bond [CSp2-CSp2]. But as the
different heteroatoms of differing electronegativity are involved in the five-
54 Heterocyclic Chemistry

membered heterocycles, bond localization is also observed which is consistent-

with the localized structures. The degree of bond localization depends on the
electronegativity of the heteroatom. Bond lengths in five-membered heterocycles
are summarized in Tables 1 and 2.

Table 1. Bond lengths in five-membered heterocycles with one heteroatom

502
4 3

X X~ C2-<; C;-C4

0 1.362 A 1.361 A 1.431 A

S 1.714A 1.370 A 1.420 A
NH 1.370A 1.380 A 1.417 A

3.2.1.1.1.1 Aromaticity Order

The aromaticity in five-membered heterocycles depends on the availability of the

lone pair on heteroatom for the involvement in cyclic delocalization and hence
depends on the electronegativity of heteroatom. The oxygen-heterocycles exhibit
considerable degree of bond localization because of higher electronegativity of
oxygen than nitrogen and sulfur. Thus, oxygen atom has greater hold on the lone
pair of electrons and causes localization of the electrons which results in bond
alternation. The order of aromaticity in five-membered heterocycles is as :
sulfiu'-heterocycles > nitrogen-heterocycles > oxygen-heterocycles.

3.2.1.1.1.2 Bond Alternation

The aromaticity in five-membered heterocycles can be assessed by the bond

alternation which is the ratio of bond length of C2-C3 to C3-C4 • The closeness of
the ratio to Wlity is observed in the aromatic compounds. Thus, from the bond
alternation ratio it can be concluded that sulfur-heterocycles are normally more
aromatic than the nitrogen- and oxygen-heterocycles.
Aromatic Heterocycles 55

Table 2. Bond lengths in five-membered heterocycles with two heteroatoms

5
do.b
4

e
c 3

a
2

CompOlU1d a b c d e

1.349A 1.331 A 1.416A 1.373 A 1.359 A

()N
1.349A 1.326 A 1.378 A 1.358A 1.369A

1.309 A 1.425 A 1.356 A

()o
1.357 A 1.293 A 1.395 A 1.352A 1.370A

() S
1.724 A 1.304 A 1.372 A 1.367 A 1.713 A
56 Heterocyclic Chemistry

c;-<;
Bond alteniation ratio R =
C3-C4

If R R:i 1 the compound will be aromatic

tbiophene > pyrrole > foran

(0.964) (0.959) (0.950)

The fusion of a benzene ring to the five-membered aromatic heterocycles

reduces the aromatic character. Indole 3S is nearly planar and shows bond
alternation. However, in the heterocycles in which benzene ring is fused across the
carbon-carbon single bond, the aromaticity is further reduced due to the
considerable degree of bond alternation. Thus, isoindole 39 and benzo[c]furan 40
show much lower degree of aromatic character and exhibit diene-type character.

0)
~ 0
1.372 1.395 1.374

Indole Benzo[b]furan Benzo[b]tbiophene

3S 36 37

(C (Co
~ :::::::"...
NH
~ :::::::"...

Isoindole Benzo[c]furan Benzo[c]tbiophene

39 40 41

3.2.1.1.2 Six-Membered Aromatic Heterocycles

The bond lenghts in six-membered heterocycles are intermediate between single

and double bonds due to the cyclic delocalization. The further introduction of
heteroatom causes reduction in the aromatic character because more x-electrons
are partially localized on the heteroatoms and thus cause bond localization. The
bond lengths in six-membered nitrogen-heterocycles are summarized in Table 3.
The fusion of a benzene ring to the six-membered heterocyclic ring reduces
aromatic character causing partial bond localization as in naphthalene.
Aromatic Heterocycles 57

Table 3. Bond lengths in s.ix-membered azaheterocycles

Compowd Bond lengths

1-2 2-3 4-5 5--6 6-1

'0
6 ~
N
1
3
2
1.340 A 1.395 A 1.394 A

'(N
4

3
1.317 A 1.344 A 1.358 A
6
~ N
)2

5( )3
6~
N

2
1.314A 1.358A
N
1

4
N
5( )3 1.335A 1.314A 1.339A 1.317 A 1.401 A 1.317 A
6~ ..... N
N 2
1

1.319A
58 Heterocyclic Chemistry

3.2.1.1.3 Relationship of Bond Lengths with Bond Orders

Bond order is related to the bond length and provides a measure of the ring
aromaticity. The intermediate bond lengths caused by the cyclic delocalization of
1t-electrons are associated with the fractional bond orders. If C-C bond is assumed
to have bond order of unity and C=C and C=C bonds of two and three
respectively, a graph can be plotted between bond orders and bond lengths and
can be used to predict fractional bond order for the intermediate bond length
between C-C and C=C bonds. The cyclic conjugated compound is said to be
aromatic, if it shows neither strong first order nor second order double bond
fixation (Fig. 14).

1.6
1.55

~ 1.5
°bh 1.45
] 1.4
§ 1.35
r:o 1.3
1.25
1.2+------.-------"1
1 2 3
Bond orders

Fig. 14. Representation of relationship between bond orders and bond lengths

3.2.2 Electronic Criteria

3.2.2.1 Ultraviolet Spectroscopy"

The ultraviolet spectra of aromatic heterocycles are compared with their

carbocyclic analogs for the similarity in bonding pattern in order to assess
aromaticity qualitatively.

3.2.2.1.1 Six-Membered Aromatic Heterocycles

3.2.2.1.1.1 Monocyclic Azaheterocycles

Six-membered aromatic nitrogen-heterocycles possess basic 1t-electron system of

the benzene ring with the addition of non-bonding lone pair electrons on the
nitrogen atom and, therefore, two types of electronic transitions are involved :
Aromatic Heterocycles 59

(i) n~1t* transitions and (li) 1t41t* transitions. The lone pairs on the heteroatom
are responsible for the weak transitions, known as n~1t* transitions, at the longer
wavelength (270-34Onm). These absorptions are very weak as compared to 1t~1t*
transitions of 1t-electrons, but the bands due to n~1t* transitions are prominent
in the heterocycles with two or three nitrogen atoms. 1t~1t* Transitions which
are similar to as in aromatic six-membered carbocyclic analogs range from 240-
26Onm. 1t~1t* And n~1t* transitions in six-membered azaheterocycles are
summarized in Table 4 alongwith 1t~1t* transitions of benzene for comparison.

Table 4. UV-Absorption bands in six-membered azaheterocycles

Compound 1t~1t* bands n~1t* bands

"-m.,.(nm) log e "-m.,.(nm) log e

Benzene 254 204

Pyridine 251 330 270 2.65
Pyridazine 246 3.11 340 2.50
Pyrimidine 243 3.31 298 2.51
Pyrazine 260 3.75 328 3.02

The aromatic characters of phosphabenzene, arsabenzene, and stibabenzene can

be evidenced by their similar UV-spectra as of nitrogen analogs. The UV-spectra
of arsabenzene, stibabenzene and phosphabenzene exhibit bands at 219 nm and
268 nm; 230nm and 312nm; and 213nm and 246 nm, respectively. These absorptions
are attributed to the 1t~1t* transitions similarly as in nitrogen analogs. The
shifting of bands to the longer wavelength due to 1t~1t* transitions is attributed
to the weaker bonding in heteroaromatics with heavier atoms.

3.2.2.1.1.2 Bicyclic Azaheterocycles

Bicyclic azaheterocycles have much more complex electronic spectra with the
overlapping of 1t~1t* and n~1t* transitions. But 1t~1t* transitions are much more
intense and cover n~1t* transitions. The transition energies related to the 1t~1t*
transitions correspond fairly well with the aromatic carbocyclic analogs, however,
the band intensities are different. The absorption spectra of naphthalene,
quinoline, isoquinoline and quinolizinium ion are very similar except in the
intensities of the long-wavelength bands (Table 5).
60 Heterocyclic Chemistry

Table 5. UV-Spectral bands iIi bicyclic azaheterocycles

Compound 1t~1t* A.....x (nm)

(log e)

Naphthalene 219 Tl5 311

(5.10) (3.75) (2.39)
Quinoline 225 TlO 313
(4.48) (359) (3.37)
Isoquinoline 217 266 317
(4.57) (3.61) (3.49)
Quinoliziniwn 220 267 311
ion (4.61) (3.45) (3.32)

3.2.2.1.2 Five-Membered Aromatic Heterocycles

Five-membered aromatic heterocycles with one heteroatom exhibit a band of

moderate intensity followed by a band of high intensity at shorter wavelength. A
significant feature, the absence of bands due to promotion of an electron from the
lone pair orbital (non-bonding) to a 1t-orbital of the ring (n~1t*), is attributed to
the large s-character due to smaller ring angle in the five-membered rings. The
shifting of absorption to the longer wavelengths follows the sequence :
thiophene > pyrrole > furan.
The positions and the energy splitting of 1t~1t* transitions in the five-memberd
heteroaromatic rings are similar to that in benzene and are very different to those
for conjugated dienes (Table 6).

Table 6. UV -Spectral bands in five-membered aromatic heterocycles

Compound "'max (log e)

Pyrrole 210(4.20)

Furan 207(3.90)

Thiophene 215(3.80),231 (3.87)

Aromatic Heterocycles 61

3.2.2.1.3 Benzo-fused Aromatic Heterocycles

The annelation increases complexity of the spectra as in carbocyclic analogs. UV

spectra of benzo[b] heterocycles follow the same trend in the shifting to larger
wavelengths as observed in the heteromonocycles.
The absorption of benzo[c] heterocycles at longer wavelength than their
benzo[b] COWlterparts reflects lower aromaticity in benzo[c] heterocycles6.'.

3.2.2.2 Infrared Spectroscopy-lO

Infrared spectra also provide information on the aromaticity in heterocycles. The

vibrational frequencies in infrared spectra are related to the bond strengths which
in tum depend on the bond lengths. The vibrational frequency is expected to
increase, if the single bond acquires partial double bond character by conjugation
and similarly decreases, if the double bond acquires partial single bond
character. Infrared spectra, therefore, reflect conjugation and cyclic deloca1ization
in aromatic compoWlds.
In the six-membered aromatic heterocycles, vibrational modes of the ring
skeleton are related and approximate in the positions to those fOWld in the benzene
derivatives. The bending modes of the ring hydrogen atoms are similar to those
of the corresponding arrangement of the adjacent hydrogen atoms on a benzene
ring and these generalizations are applicable to all the azines. The bands relating
to four ring stretching modes for pyridine and pyrimidine are summarized in
Table 7 alongwith the corresponding bands of monosubstituted benzene.

Table 7. Approximate positions of ring stretching modes for pyridine, pyrimidine

and benzene.

CompoWld A B C D

Monosubstituted benzene 1610-1600 1590-1580 1520-1417 1460-1440

Pyridine 1610-1595 1570-1550 1520-1480 1420-1410
Pyrimidine 1600-1545 1575-1540 1510-1410 1470-1330

Aromatic stretching frequency can be distinguished from the saturated C-H

absorption as it gives absorption above 3000 em-I. Characteristic C-H bending
vibrations in the six-membered heteroaromatics appear in the region 1300-1000
em-I (in-plane C-H bending) and in the region 700-1000 cm- I (out-of-plane).
62 Heterocyclic Chemistry

3.2.2.3 Photoelectron Spectroscopyll,ll

Photoelectron spectroscopy involves the ejection of electrons from the occupied

molecular orbitals with the interaction of high energy ultraviolet radiations with the
molecule. The energy of an ejected electron can be measured and the difference
between the energy of radiation used and that of an ejected electron is the
ionization potential of an electron. A molecule containing electrons of differing
energy can lose anyone electron if its ionization potential is less than the energy
of radiation used. The photoelectron spectra consists of a series of bands and
each of which corresponds to the orbital of differing energy. The photoelectron
spectra provide identification of the orbitals of differing energies from which the
electrons are ejected Thus, photoelectron spectra can predict the changes in the
1t-bonding orbitals energy levels in a series of aromatic heterocycles.
The 1t-bonding electronic structure in benzene is very similar to that in pyridine
because of the similarity in 1t-bonding orbitals. As the interaction of six p-orbitals
in benzene results in the formation of six molecular orbitals; three bonding and
three antibonding, similarly six molecular orbitals are formed in pyridine. But the
difference is that the energies of the 1t-orbitals in pyridine are lowered as compared
to in benzene because of the electronegativity of nitrogen atom. 1t2 And 1t3 which
are degenerate in benzene become non-degenerate in pyridine in which 1t2 being
oflower energy (Fig. 15). The energy of1t2-orbital depends on the electronegativity
of the heteroatom and increases as the electronegativity decreases.

-- 1t6*

1t2& 1l 1t3
1t2#- 1l1t3
-#1t1 1l1t1

Benzene Pyridine
E

Fig. 15. Representation of orbital energies in benzene and pyridine

In the heterocyclic analogs of pyridine, in which nitrogen is replaced by the

elements of fifth group (p, As, Sb, Bi), the energy of 1t-orbital decreases with
increasing size of the heteroatom.
Aromatic Heterocycles 63

Similarly, 1t-bonding orbitals of the cyclopentadienyl anion and pyrrole show

similarity, but the introduction of the heteroatom causes splitting of 1t2 and ~
molecular orbitals (non-degenerate with lower energy) (Fig. 16).

Fig. 16. Representation of orbital energies in pyrrole

3.2.2.4 Dipole Moments 13-1S

The quantitative estimation of aromaticity by dipole moments is difficult because

the dipole mo~ent is the sum of the a-bond, 1t-bond and lone pair moments.
However, the dipole moments in aromatic heterocycles provide significant
information on the involvement of the heteroatom in the electronic distribution
and, in tum, indicate the presence of cyclic delocalization in the aromatic
heterocycles.

3.2.2.4.1 Six-Membered Aromatic Heterocycles

Six-membered aromatic heterocycles exhibit greater dipole moments than those in

their corresponding saturated analogs. The larger dipole moments in six-membered
aromatic heterocycles is attributed to the cyclic delocalization.
The larger dipole moment of pyridine 5 (2.20D) than that of piperidine 48 (1.57D)
supports the structure with charge-separation and confirms dipolar structures as
the contributing resonating structures in pyridine due to cyclic delocalization of

or I.~D
1t-electrons (Fig. 3).

H
Pyridine Piperidine
5 48
64 Heterocyclic Chemistry

5 (i) (ii) (iii) (iv)

Fig. 3. Representation of charge separation in pyridine

The large dipole moment in pyrimidine (2.40D) also predicts the delocalization
of 1t-electrons and thus confirms the contribution of the following resonance
structures to the ground state of pyrimidine 6 (Fig. 17).

6a (i) (ii) (iii)

t
(J-+(J-(J-(J
6b (iv) (v) (vi)

Fig. 17. Resonating structures in pyrimidine representing charge separation

Pyridazine 11 has appreciably high dipole moment (4.0D). The high value of the
dipole moment in pyridazine is attributed to the fact that both the nitrogen atoms
are present on the same side of the ring and, therefore, there is a greater pull of
the electrons towards the side of nitrogen atoms.
Aromatic Heterocycles 65

3.2.2.4.2 Five-Membered Aromatic Heterocycles

The dipole moments of the five-membered aromatic heterocycles are lower than
those of the corresponding tetrahydro derivatives. The lower dipole moments in
these heterocycles are attributed to the counteraction of two effects; inductive
effect and mesomeric effect. Thus, the existence of two opposing structural
effects supports the contributing resonating structures involving cyclic
delocalization of 1t-electrons in the five-membered aromatic heterocycles.
The tetrahydro derivatives have negative end at the heteroatom because of the
electron pull towards electronegative heteroatom due to the inductive effect. In
five-membered aromatic heterocycles; pyrrole, thiophene and furan, the inductive
effect is still operating, but this effect is superimposed by the mesomeric effect
operating in the opposite direction (Fig. 18).

:0: 1 inductive effect

9l5ID
Pyrrolidine
Ql6&D
Tetrahydrofuran
QlSID
Tetrahydrothiophene
49 50 51

9 Joon Q }7ID Q }S2D

8 21 9

Ll D = 3.37D 0.97D l.35D

Fig. 18. Dipole moments in five-membered heterocycles

The larger difference in thiophene reflects the involvement of d-orbitals of

sulfur. The direction of the dipole in pyrrole is reverse of that in pyrrolidine and
thus very large difference (3.37D) is due to the large contribution of the mesomeric
effect.
66 Heterocyclic Chemistry

The dipole moments in five-membered aromatic heterocycles are assumed to be

the evidence of charged resonating structures involving cyclic delocalization of
the x-electrons (Fig. 4).

V, ....... V ....... - ....... , ....... - ]

[0 X
0-000- X
-
X
-
X X

Fig. 4

3.2.3 Energetic Criteria

The energetic criteria are widely used for the quantitative estimation of aromaticity
in the aromatic compounds. The enhanced stability of delocalized structure over
the same localized structure is attributed to the resonance energy. The different
energy terms used for the stabilization in the aromatic compounds are; stabilization
energy, empirical and vertical energy, delocalization energy, conjugation energy
and binding energy. These all energy terms are nearly the same, the modified
treatment of the experimental data, however, leads to the different terminology of
the resonance energy.
Delocalization energy is the energy term calculated by the molecular orbital
theory, while the energy derived by the experimental methods is known as
empirical resonance energy.

Empirical resonance energy (ERE) : The difference between the energy of the
actual structure and the energy of the hypothetical localized structure is known
as empirical resonance energy and is represented as (Fig. 19) :

ERE = Energy of the real structure - Energy of the hypothetical structure

(delocalized structure) (localized structure)

PRE

o
cyclohexatriene
1 52
Fig. 19. Empirical resonance energy
Aromatic Heterocycles 67

Vertical resonance energy : The difference between the energy of the resonance
hybrid and the energy of one of the resonating structures contributing maximwn
to the resonance hybrid is known as vertical resonance energy (Fig. 20).

Vertical resonance energy = Energy of resonance hybrid - Energy of one of the

resonating structures

@ ··..........
1
Vertical
resonance
energy
..
0 la

Fig. 20. Vertical resonance energy

Distortion energy : The difference between empirical resonance energy and

vertical resonance energy is known as distortion energy and this energy is
required to compress the single bond and to stretch the double bond. The
distortion energy is represented as (Fig. 21) :

o
cyclohexatriene
Distortion
energy
.. o
52 la

Fig. 21. Distortion energy

These energy terms are inter-related and their correlationship is represented in

the schematic form (Fig. 22).

3.2.3.1 Empirical Resonance Energy16,17

Empirical resonance energies are determined by the thermochemical quantities

including the hybridization energy term because the energy term for the carbon-
carbon single bond between CSp2-CSp2 is of different energy from that between
CSp3_C Sp3.
68 Heterocyclic Chemistry

o 52
Empirical resonance
energy

o 1a
Fig. 22. Energy cycle involving different energy tenns

Empirical resonance energies for the heteroaromatic systems are detennined from:
(i) heat of combustion and (ii) heat of hydrogenation

3.2.3.1.1 Heat of Combustion

Heat of combustion is the heat evolved when one mole of the substance is
completely burnt in oxygen. Thus the heat change associated with the combustion
of pyridine is :

CsHsN (g) + ~ 02~ 5C02(g) + .2.. Hp +_1 N2 (g) .....(1)

4 2 2
The heats of combustion of heterocycles can be determined experimentally from
which heats of fonnation are determined. The heat of fonnation (MI) of a
compound is equal to the sum of the heats of fonnation of the products obtained
by the combustion of the compound minus the heat of combustion of the
compound as :
AH (obsd.) = Sum of the heats of fonnation of - Heat of combustion
the produc~ (obtained by of the compound
combustion of the compound) .... (2)
The heat of fonnation is calculated theoretically by adding bond energy tenns
(~E)for the bonds in localized structure. The empirical resonance energy (ERE) of
a compound can be calculated by the heat of fonnation.
ERE = Observed heat of formation - Calculated heat of fonnation ..... (3)
Aromatic Heterocycles 69

Thus, the difference in the heat of formation determined from the experimental
value of the heat of combustion and the theoretically calculated value is a measure
of the stabilization in the delocalized system and is known as empirical resonance
energy and represented as :

Llli = LE + ERE .....(4)

ERE = Llli - LE ..... (5)

= Heat of formation determined from the experimental heat of combustion

Llli
LE = Heat of formation calculated by bond energy terms

The value of the empirical resonance energy depends on the bond energy terms
and thus suffers from some shortcomings :
(i) Same bond energy term is used for the carbon-carbon single bond for both
the CSp3_CSp3 and CSp2-CSp2 single bonds.
(ii) Hybridization energy for carbon-heteroatom bond : the same bond energy
is used for the carbon-heteroatom bond (C-X) without giving due
consideration to the hybridization.
(iii) There are energy difference between primary, secondary and tertiary C-H
bonds.
(iv) Strong 'next-nearest-neighbour' interactions in the oxygen ring compounds.
However, these differences are accounted for by the energy term known as
conjugation energy. Empirical resonance energies of some aromatic heterocycles
calculated from the heats of combustion are summarized in Table 8.

Table 8. Empirical resonance energies of aromatic heterocycles (from heats of

combustion)

Compound ERE
kcallmol kl/mol

Benzene (for comparison) 35.9 150

Pyridine 27.9 117
Quinoline 48.4 200
Pyrrole 21.6 SO
Indole 46.8 196
Thiophene 29.1 122
Furan 16.2 68
70 Heterocyclic Chemistry

3.2.3.1.2 Heat ofHydrogenation

Heat of hydrogenation can also be used for the determination of empirical

resonance energy in the aromatic compoWlds. The empirical resonance energy is
the difference between the heat of hydrogenation of a compoWld and that of the
hypothetical compoWld of similar structure with localized bonds. For example in
benzene:

ERE = Heat of hydrogenation - Heat of hydrogenation

of benzene of cyc10hexatriene .....(6)

Heat of hydrogenation for cyc10hexene :

---..~~ 0 +28.6kcal1mol

----t~~ 0
Heat of hydrogenation for cyc10hexadiene :

+ 28.6 x 2 =51.2 kcalImol

Heat of hydrogenation for cyc10hexatriene :

----t~~ 0 + 28.6 x 3 = 85.8 kcallmol

Difference in heats of hydrogenation =

Heat of hydrogenation - Heat of hydrogenation
of benzene of cyclohexatriene
(-49.8) (-85.8)
36.0 kcallmol (150 kJ/mol)
This difference is the empirical resonance energy of benzene.
However, certain objections are raised against this method;
(i) Strain energy of localized structure : Since cyclohexene is taken as the
reference compoWld in the determination of empirical resonance energy of
benzene, the strain energy of the cyc10hexene ring which makes heat of
hydrogenation more favourable appears quite irrelevant as a component of
the resonance energy of benzene.
Aromatic Heterocycles 71

(ii) Hybridization change : The hydrogenation involves conversion of Csp2-H

to Csp3-H bonds. The energy difference associated with this change has
not been included in deriving empirical resonance energies.
Both the classical procedures do not evaluate the energy that is the property
of a molecule, but an energy that is the enthalpy change for the particular reaction.
Thus, the modified method16 has been developed for the calculation of empirical
resonance energies of the aromatic heterocycles including the contributions of
structural factors contributing empirical resonance energies. In this method the
empirical resonance energies are calculated by using the contributions of the
composite bond energy terms. The composite bond energy terms are evaluated
from the heats of atomization determined from the experimental heats of
combustion and are used in the estimation of empirical resonance energies of the
aromatic heterocycles.
However, inspite of the certain objections against the determination of empirical
resonance energies (ERE) by thermochemical quantities, the empirical resonance
energies (ERE) have provided widest ranging energy data for the quantitative
assessment of the aromaticity in heteroaromatic systems.

3.2.3.2 Delocalization E nergy16,17

Delocalization energy is the additional bonding energy which results from the
delocalization of 1t-electrons originally constrained in the isolated double bonds
and corresponds to the vertical resonance energy. For the determination of
delocalization energy, the 1t-electrons of the planar heterocycles are considered
independently as they have no interaction with a-electrons because of the
different planes of a- and 1t-orbitals. The interaction between two types of
electrons is therefore neglegible in a planar molecule.
The molecular orbitals for 1t-electrons in the conjugated system may be treated
independently of a-electrons. The energies of 1t-electrons in a 1t-molecular orbital
are expressed in terms of two quantities; a and p. The first term a is the coulomb
integral and represents approximately the energy of an electron in an isolated
p-orbital before overlapping. The second term p is called resonance integral and
expresses the degree of stabilization resulting from the 1t-orbital overlapping.
The energies of six 1t-electrons in six 1t-orbitals in benzene can be calculated by
Hiickel molecular orbital treatment in terms of a and p constants. The energies can
be represented as a series of energy levels above and below an energy zero (a).
The energies of six molecular orbitals (three bonding orbitals and three
antibonding orbitals) are in the increasing order; a + 2P, a + p, a + p; a - p,
a - p, a - 2p. Thus, the total energy of six 1t-electrons in the occupied bonding
molecular orbitals is 6a + Sp (as there are two electrons in each occupied orbital).
72 Heterocyclic Chemistry

The energy of x-electrons in a localized carbon-carbon double bond is :

2(0. + (3) = 20. + 213. The energy of six x-electrons in three isolated double bonds
is : 6(0. + (3) = 60. + 613. The delocalization energy of benzene is : (60. + 8(3) -
(60. + 6(3) = 213. The arrangement of x-electrons in benzene is, therefore, more stable
by 213 and it is associated with the delocalization of six x-electrons (Fig. 23).

i:e-€~
tlO

-(0.-213)

~ 0 (0.-13) - --(0.-13) -(0.-13)

0. ------------------------------------
(0.+13) -#- -#-(0.+13)
-#-(0.+13)

-#-(0.+213) Ethene
Benzene
E
Fig. 23. Energy level diagram showing delocalization energy

Since pyridine is considered to be derived from benzene by replacing -CH= by

a nitrogen atom, pyridine is assumed to have the same delocalization energy as
in benzene (2 (3). However, the introduction of a nitrogen atom, because of its more
electronegativity than carbon, causes uneven distribution of the electrons in
pyridine. In the calculation of delocalization resonance energies of the aromatic
heterocycles, appropriate parameters are added to coulomb integral for the
heteroatom and to resonance integral for carbon-heteroatom bond to include the
structural changes. The resonance energies in units of 13 are summarized in
Table 9.

Table 9. Resonance energies in units of 13 for heterocycles

Compound Total x-energy

Benzene (for comparison) 8.000

Pyridine 7.249
Thiophene 5.186
Furan 4.598
o.-Pyrone 7.081
y-Pyrone 6.999
Aromatic Heterocycles 73

3.2.3.3 Dewar Resonance E nergy17,19,20

The resonance energy determinations by the conventional methods involve pure

single and double bonds without giving due consideration to the contributions
associated with the change in hybridization. Dewar redefined the resonance energy
in order to differentiate clearly aromatic, nonaromatic and antiaromatic conjugated
molecules. Dewar based his theory on the reference energy relative to which
aromatic stabilization is calculated. The reference energy of a reference structure
uses 'double' and 'single' bond energies appropriate to the nonaromatic systems
(rather than those for non-conjugated systems).
Acyclic polyenes exhibit both effective energies; Ee=c of the carbon-carbon
double bond and Ec-c of the carbon-carbon single bond. The x-energy of a linear
polyene is directly proportional to the chain length and each addition of a carbon-
carbon single bond and a carbon-carbon double bond contributes similarly as in
butadiene or octatetraene. Conjugation has the same energetic consequences (per
bond) in all the nonaromatic systems.
The energy of any acyclic polyene is an additive function of the individual bond
energy terms. With the same bond energies, the reference energy for a cyclic
conjugated system is estimated. The reference energy of a compound represents
the energy if the compound is absolutely olefinic in nature. The difference in the
x-energies is termed as Dewar resonance energy (ORE) and can be represented as :
DRE= E-EO .....(7)
E = Energy of the cyclic conjugated system determined by the heat of
combustion
EO = Energy for reference structure
The Dewar resonance energies can also be evaluated for the aromatic
heterocycles. On the basis of Dewar resonance energies, the following assumptions
are made for the clear distinction of aromatic, nonaromatic and antiaromatic
heterocycles :
(i) the cyclic systems with appreciable positive resonance energy (additional
x-energy) are termed as aromatic and the additional stabilization energy has
been called Dewar resonance energy!8.
(11) cyclic systems with negative value of resonance energy or with less
x-energy than that of reference structure are termed as antiaromatic.
(ill) cyclic systems having resonance energy close to zero (within 1 or 2 kcall
mol) are classified as nonaromatic.
Dewar resonance energies (ORE) for the heterocyclic compounds are summarized
in Tables 10 and 11.
74 Heterocyclic Chemistry

Table 10. Dewar resonance energy (ORE) data for six-membered heterocycles

Compo1.U1d DRE
(kcallmol) (kJ/mol)

Benzene (for comparison) 22.60 94.56

Pyridine 23.10 96.65
Pyrazine 17.10 71.55
Pyrimidine 20.20 84.52
Naphthalene 33.60 140.58
Quinoline 34.10 142.67
Isoquinoline 34.10 142.67
1,5-Naphthyridine 33.20 138.91
1,8-Naphthyridine 36.40 152.30
Quinoxaline 28.10 117.57
Quinazoline 30.39 127.15
Acridine 41.30 172.80

Table 11. Dewar resonance energy (ORE) data for five-membered heterocycles

Compo1.U1d DRE
(kca1lmol) (kJ/mol)

Pyrrole 5.30 22.18

Indole 23.80 99.58
Isoindole 11.60 48.53
Carbazole 40.90 171.13
hnidazole 15.43 64.65
Benzimidazole 30.90 129.29
Thiophene 6.50 27.20
Benzo[b]thiophene 24.80 103.76
Benzo[c]thiophene 9.30 38.91
Dibenzothiophene 44.60 186.61
Furan 4.30 17.99
Benzo(b]furan 20.30 84.94
Benzo[c]furan 240 10.04
Dibenzofuran 39.90 166.94
Arqmatic Heterocycles 75

In order to compare aromaticity in different heterocycles, the resonance energies

are calculated in the framework of HOMO and the total 'It-energy is divided by the
number of 'It-electrons to calculate energy contribution of per 'It-electron. The
resonance energies per 'It-electron are summarized in Table 12.

Table 12. Resonance energies per 'It-electron (REPE) of some heterocycles

Compound REPE(I3)

Pyridine 0.058
Pyrimidine 0.049
Pyrazine 0.049
Pyrrole 0.039
Thiophene 0.032
Furan 0.007
Pyrazole 0.055
Imidazole 0.042
Quinoline 0.052
Isoquinoline 0.051
Indole 0.047
Benzo[b]thiophene 0.044
Benzo[b]furan 0.036
Isoindole 0.029
Benzo[c]thiophene 0.025
Benzo[c]furan 0.002

3.2.4.6 Magnetic Criteria

3.2.4.6.1 PMR-Spectra21- 14

The ring current in an aromatic compound due to cyclic delocalization of

'It-electrons causes deshielding of the proton and results in the shifting of its
signal to the low field. This forms a basis for diagnostic criterion of aromaticity.

Shielding and Deshielding :

The electrons around the nucleus create secondary magnetic field that opposes
the applied magnetic field. The nuclei in the region of high electron density
experience a field proportionately weaker than that in a region of low electron
76 Heterocyclic Chemistry

density and higher field (low frequency) has to be applied to bring them into
resonance. Such nuclei are said to be shielded by the electrons. The high electron
density shields nucleus and causes resonance to occur relatively at high field (with
low 8-value). The low electron density causes resonance to occur relatively at low
field (higher 8-value) and nucleus is said to be deshielded.
Low (high frequency) field High (low frequency) field
8H lO< )0
I Deshielded Shielded I
Ring Current and Chemical Shift in Aromatic System:

The 1t-electrons of an aromatic molecule are delocalized in the extended circular

orbitals above and below the plane of the ring. A magnetic field applied at the right
angle to the plane of the molecule causes the highly mobile delocalized electrons
to circulate around their orbitals much in the same way as do electrons in a loop
of wire and a ring current of much greater magnitude than the small circuit current
associated with a-electrons is induced. The induced ring current, in turn, produces
a secondary magnetic field that opposes the applied field inside the ring, but out-
side the ring the applied field is reinforced. Thus, the proton lying on the periphery
of the ring are deshielded and their signals are shifted to the lower field (high
frequency with high 8-value) (Fig. 24).

Aplied field Induced field

(Applied field causes 1t-electrons to (The induced magnetic field due to
circulate around the orbital producing ring current strengthens applied field
ring current) around the protons out-side the ring
giving higher 8-value)

Fig. 24. Ring current in aromatic system

Aromatic Heterocycles 77

The ring current effects are increased with the size of the ring and are higher
for the six-membered ring compared to the five-membered ring. The effect of the
ring current can qualitatively be observed by comparing aromatic with non-
aromatic compounds. The proton chemical shift depends on the density of the
electrons at a ring carbon to which hydrogen is attached. Ring current follows the
order:
benzene > pyridine> thiophene > pyrrole > furan

3.2.4.1.1 Six-Membered Aromatic Heterocycles

The deshielding effect due to aromatic ring current in the benzene ring causes the
chemical shift of protons to () 7.24 ppm. The same ring current persists in the
azabenzenes. But the introduction of electronegative atom(s) in the benzene ring
providing six-membered heterocycle(s), nitrogen in pyridine, exerts a strong
deshielding effect on the a-hydrogens and a similar, but smaller, on the
y-hydrogens. The protons in the J3-position in pyridine are slightly shifted to the
higher field. Further introduction of the nitrogen atom produces similar effects, but
strict additivity is not observed. Two adjacent nitrogen atoms, as in pyridazine,
exert a much larger deshielding effect on the a-protons than the sum of a- and
p-effects of a single nitrogen atom. Proton chemical shifts in the six-membered
azaheterocycles are summarized in Table 13.

3.2.4.1.2 Five-Membered Aromatic Heterocycles

P:MR-spectra of the parent five-membered aromatic heterocycles exhibit two

multiplets of which one at the lower field (high a-value) is assigned to the
a-protons. The chemical shift for p-protons, except for pyrrole, increases with
decreasing electronegativity of the heteroatom. However, the chemical shifts due
to a-protons do not show any trend because of the paramagnetic shielding
contributions which increase with the involvement of d-orbitals. The proton
chemical shifts for parent five-membered aromatic heterocycles are summarized
alongwith their saturated counterparts for the comparison in Table 14.
Proton chemical shifts for imidazole and pyrazole are comparable and indicates
the existence of ring current in imidazole and pyrazole rings. The ring protons of
thiazole are deshielded relative to those of imidazole. Isothiazole ring has been
observed to have the same degree of aromatic character as in the benzene ring.
IH NMR spectral data for the five-membered heterocycles with two heteroatoms
are summarized in Table 15.
78 Heterocyclic Chemistry

Table 13. lH NMR spectral data in six-membered azaheterocycles

Compound o ppm*
H-2 H-3 H-4 H-5 H-6

0
(for comparison)
7.24 7.24 7.24 7.24 7.24

0 N
8.52 7.16 7.55 7.16 8.52

0~
N
..... N
N 9.17 7.52 7.52 9.17

eN
~)
N
9.26 N 8.78 7.36 8.78

()
N
8.60 8.60 N 8.60 8.60
N

()
N
N 9.63 N 8.53 9.24
N

N~N
9.18 N 9.18 N 9.18
~)
N

*In CDC13 solution using TMS as internal reference.

Aromatic Heterocycles 79

Table 14. IH NMR spectral data for five-membered heterocycles with one hetero-
atom

Pyrrole Furan Thiophene Selenophene Tellurophene

(Pyrrolidine) (Tetrahydro- (Tetrahydro- (Tetrahydro- (Tetrahydro-
furan) thiophene) selenophene) tellurophene)

H-2 6.68 729 7.18 7.88 8.87

(2.77) (3.62) (2.75) (2.79) (3.10)
H-3 622 6.24 6.99 7.22 7.78
(1.63) (1.79) (1.92) (1.96) (203)

Table 15. IH NMR spectral data for five-membered heterocycles with two hetero-
atoms

Compound oppm
H-2 H-3 H-4 H-5

ON
N N 7.61 7.31 7.61

H
Pyrazole

[)
N 7.86 N 725 725

H
Imidazole

ON S
N 8.54 7.26 8.72

Isothiazole

() S
8.88 N 7.98 7.41

Thiazole
80 Heterocyclic Chemistry

3.2.4.2 Proton-Proton Coupling Constants and Bond Order

The variation of vicinal proton-proton coupling constants with bond order has
been used to assess the aromaticity in five- and six-membered aromatic hetero-
cyclesl 5,l6. The vicinal coupling constants provide evidence for the bond fixation
and delocalization27• The ratio of the ortho coupling constants J(rarlo) = Jab: J bc = 1
for the heteroaromatic rings fused to the benzene ring may be considered as the
reference value for the complete delocalization, whereas the value 0.55 is
considered as the reference value for the complete localization. However, the
vicinal coupling constants are considerably influenced by the ring angles and the
inductive effects alongwith the effects of heteroatoms (Fig. 25).

-+--- hetero ring

Ha
Fig. 25. Coupling constant in fused aromatic heterocycles

The ratio of the vicinal coupling constants can also be correlated qualitatively
with the resonance energy per 7t-electron (REPE) to know about the cyclic
delocalization in the heteroaromatic SYStems28. The ratio of the coupling constants
and REPE for the azaheterocycles are summarized in Table 16.
It is obvious from the table that REPE increases with increasing J(ratio) and the
linear relationship between two quantities has been observed. This relationship
can, therefore, give an indication of delocalization of the electrons.

3.2.4.3 13C NMR Speetroseopy19,30

13C NMR spectra can also be used to assess qualitatively the aromaticity in
aromatic heterocycles. In 13C NMR spectra the correlation exists between
7t-electron density and the 13C-chemical shifts as the J3C-shielding of the ring
carbon atoms are approximately proportional to the 7t-electron density.
In the five-membered aromatic heterocycles (with one heteroatom), the carbon
atom signals appear at more shielded positions (0 100-150 ppm), while in the six-
membered aromatic heterocycles the signals appear in the range 0 150-170 ppm.

3.2.4.3.1 Six-Membered Aromatic Heterocycles

The ring carbon atoms 0.- to the heteroatom are highly deshielded and the carbon
atoms y- to the heteroatoms are also deshielded relative to those in benzene ring.
The introduction of second nitrogen atom causes further deshielding at the 0.- and
y- carbons of approximately 10 ppm and 3 ppm, respectively and the shielding
Aromatic Heterocycles 81

Table 16. J(ratio) and REPE of nitrogen heterocycles

Conjugated system REPE(P)

0.61 0.007

0.71 0.027

0.74 0.029

0.71 0.029

~
V-N/
0.91 0.047

H
82 Heterocyclic Chemistry

effect at the J3-carbon is of approximately 3 ppm. The 13C-chemical shifts in six-

membered aromatic heterocycles are summarized in Table 17.

Table 17. 13C-chemical shifts in six-membered azaheterocycles*

oppm
Compound C-2 C-3 C-4 C-5 C-6

0 128.5 128.5 128.5 128.5 128.5

0 N
150.6 124.5 136.4 124.5 150.6

0~ ,....N
N 152.8 127.6 127.6 152.8

eN
N

~) 159.5 N 157.5 122.1 157.5

N

()
N
145.6 145.6 N 145.6 145.6
N

()
N
N 163.6 N 142.0 150.2

N~N
167.5 N 167.5 N 167.5
~)
N

*In CDCl3 solution using TMS as internal reference.

Aromatic Heterocycles 83

3.2.4.3.2 Five-Membered Aromatic Heterocycles

In 13C NMR spectra of five-membered 1t-excessive heterocycles, the carbon atom

resonances appear at much shielded positions (100-150 ppm). The signal for
pyrrole a-carbon atom is broadened because of the coupling with an adjacent
nitrogen at the position-I. The frequencies for J3-carbon atoms show systematic
shifting to the higher field with increasing electronegativity of the heteroatom. All
the shifts are comparable with benzene (0 = 128.5 ppm). 13C-chemical shifts for the
five-membered aromatic heterocycles are summarized in Table 18.

Table 18. 13C-chemical shifts in 1t-excessive heterocycles*

Compound oppm
~2 ~3 C-4 ~5

0 128.5 128.5 128.5 128.5

® \ .:'l 103 103 103 103

0 N
H
118.5 1082 1082 118.5

0 0
142.6 109.6 109.6 1426

0 S
125.4 1272 1272 125.4

0 Se
127.3 129.8 129.8 1273

0 Te
1273 138.0 138.0 1273

*In CDCl3 solution using TMS as internal reference.

84 Heterocyclic Chemistry

3.2.4.4 Diamagnetic Susceptibility Exaltations31,31

Diamagnetic susceptibility is an additive property and can be calculated by adding

susceptibility contributions of the atoms and bonds. The aromatic compounds
possess larger diamagnetic susceptibilities than the expected from the comparison
with the values of alkenes. The diamagnetic susceptibility of an aromatic
compound can be expressed as :
.....(8)
where A is diamagnetic susceptibility exaltation and is considered to be associated
with the specific aromatic properties of the aromatic compounds.
The diamagnetic susceptibility exaltation can be defined as the difference
between the observed diamagnetic susceptibility and that calculated from the
atomic and bond susceptibility contributions. Thus, diamagnetic susceptibility
exaltation can be expressed as :
A = XM - XM' .....(9)
where XM = observed diamagnetic susceptibility and
XM' = estimated diamagnetic susceptibility.
XM' can be estimated by using several empirical methods.
The compounds with diamagnetic susceptibility exaltation (XM - XM' = A > 0) are
classified as aromatic. The aromatic compounds are found to exhibit large
diamagnetic susceptibility exaltations and the non-aromatic compounds exhibit
zero exaltation (XM - XM' = A = 0) and this forms a basis for using diamagnetic
susceptibility exaltation as a criterion of aromaticity. The diamagnetic susceptibility
exaltations of aromatic heterocycles are summarized in Table 19.
From the diamagnetic susceptibility exaltations, it can be inferred that there
exists a correlation between the diamagnetic susceptibility exaltations and the
aromaticity. These results clearly justify to conclude that the diamagnetic
susceptibility exaltation is the valid criterion of aromaticity and provides clear
demarcation between aromatic and non-aromatic heterocycles.

3.2.4.5 Faraday Effect (Magneto-optical Rotation)33

The rotation of the plane of the polarization of light by transparent substance

placed in a magnetic field is called magneto-optical rotation and this effect is
known as Faraday effect. The magneto-optical rotation is an additive property and
can be calculated by the contributions of the rotation of the bonds. The
compounds with delocalized x-electrons exhibit magneto-optical exaltation over
the calculated rotation. The aromatic compounds are characterized by the large
magneto-optical rotation which is influenced by the nature of the substituents. The
substitution of hydrogen by the electron-withdrawing groups decreases magneto-
optical rotation exaltation, while the substitution by the electron-releasing groups
increases exaltation.
Aromatic Heterocycles 85

Table 19. Diamagnetic susceptibility exaltations in aromatic heterocycles

Compound XM(exp.) XM' (calcd.) A

(10"6 cm3lmol)

Benzene 54.8 41.1 13.7

(for comparison)

Pyridine 49.2 35.8 13.4

Pyrazine 37.6 30.5 7.1

Naphthalene 91.9 61.4 30.5

Quinoline 86.0 56.1 29.9

Isoquinoline 83.9 56.1 27.8

Pyrrole 47.6 37.4 10.2

Thiophene 57.4 44.4 13.0

Furan 43.1 34.2 8.9

Pyrazole 426 36.0 6.6

1,3-Thiazole 50.6 38.3 123

1,3,4-Thiadiazole 373 322 5.1

3,5-Dimethyloxazole 59.7 51.5 8.2

The aromaticity order in the six-membered aromatic heterocycles on the basis of

magneto-optical rotation exaltation is as follows :
benzene> pyridine> pyridine N-oxide
The aromaticity order in the five-membered aromatic heterocycles has been
observed to be as :
thiophene > pyrrole > furan
86 Heterocyclic Chemistry

3.3 Heteroaromatic Ring Systems34-36

3.3.1 Five-Membered Heteroaromatic Ring Systems

3.3.1.1 Five-Membered Heteroaromatics with One Heteroatom

Five-membered heteroaromatics are heterocyclic analogs of the cyclopentadienyl

anion, which is planar symmetrical pentagon with five sp2-hybridized carbon atoms
containing six n-electrons to form an aromatic sextet. Similarly, in the five-
membered heteroaromatics with one heteroatom, five sp2-hybridized atoms sustain
six n-electron system. Each carbon atom contributes one electron, while
heteroatom provides two electrons to the aromatic sextet (Fig. 26). Thiophene, with
sulfur heteroatom, expends its valence shell by using vacant d-orbitals in
hybridization. Thiophene, instead of six electrons in five-orbitals, has six electrons
in six-orbitals using pd2 hybrid orbitals.

.
{j
o X
.
o
.

x = NH, 0, S, Se, Te
5
Fig. 26. Structural representation of five-membered heterocycles

Five-membered heteroaromatics with one heteroatom are n-excessive as six-

electrons are distributed over five atoms. These heterocycles possess considerable
aromatic character as these are characterized by high degree of reactivity towards
electrophilic substitution reactions rather than addition reactions.
The aromatic nature of these heterocycles is evidenced by their bond lengths,
dipole moments and resonance energies. The shorter carbon-heteroatom bond
lengths in these heterocycles indicate partial double bond character.
The aromatic character in these heterocycles depends on the availability of the
lone pair on the heteroatom for delocalization and in turn depends on the
electronegativity of the heteroatom. The order of electronegativity in the
heteroatoms is : oxygen> nitrogen> sulfur. The oxygen atom because of its high
electronegativity has strong attraction on the lone pair and restricts the lone pair
upto some extent to take part in the delocalization of n-electrons causing partial
Aromatic Heterocycles 87

localization of the 1t-electrons. The order of aromaticity on the basis of

electronegativity of heteroatoms is : thiophene > pyrrole > furan.
The resonance energy in five-membered aromatic heterocycles follows the
order: thiophene> pyrrole > furan. The higher degree of stabilization energy and
thus aromaticity of thiophene is attributed to the following reasons :
(i) release of angle strain due to larger bonding radius of sulfur than nitrogen
and oxygen,
(ii) sulfur being less electronegative than the nitrogen and oxygen atoms and
(iii) use of d-orbitals of sulfur for bonding.
The following resonating structures also contribute to the resonance hybrid
(Fig. 27).

Fig. 27. Additional resonating structures in thiophene using d-oribitals

Thus, in the five-membered heteroaromatics the greatest aromaticity is associated

with thiophene and the aromaticity falls along the series : thiophene, pyrrole and
furan.

3.3.1.2 Five-Membered Heteroaromatics with Two Heteroatoms

Five-membered heteroaromatics with two heteroatoms (azoles) are of two types

depending on the relative position of pyridine-type nitrogen.
(i) 1,2-Azoles: containing additional nitrogen atom (pyridine-type) at the
position-2.

Pyrazole Isoxazole Isothiazole

22 23 24
88 Heterocyclic Chemistry

(n) 1,3-Azoles with additional nitrogen atom (pyridine-type) at the

position-3.

() N
() 0
() S
H

Imidazole Oxazole Thiazole

10 24 26

These heterocycles are aromatic as they have similar electronic structures as in

pyrrole, thiophene and furan and possess an aromatic sextet of six 1t-electrons.
Each carbon atom and the pyridine-type nitrogen contribute one electron, while the
other heteroatom, similar to that in pyrrole, thiophene and furan, contributes a lone
pair of electrons to the aromatic sextet. The lone pair on nitrogen (pyridine-type)
is situated orthogonally to the 1t-electron cloud and does not participate in the
cyclic delocalization, but provides basic character to the azoles. These heterocycles
are considered as mixed system with the features of 1t-excessive and 1t-deficient
heterocycles, and are contributed by the following resonating structures (Figs. 28
and 29) :

1,2-Azoles :

Fig. 28. Resonating structures in 1,2-azoles

All the resonating structures for azoles are not equivalent in their contribution
+
to the resonance hybrid. The resonating structures, anion with a. C=N and C=X,
are stabilized and contributing more to the resonance hybrid.
Aromatic Heterocycles 89

t,3-Azoles :

- N
C> X

Fig 29. Resonating structures in 1,3-azoles

The azoles are more basic than their monoheteroaromatic analogs because the
lone pair on the additional pyridine-type nitrogen is not involved in maintaining
aromaticity, but is available for the protonation. The direct linking of two hetero-
atoms decreases basicity and thus 1,3-azoles are more basic than 1,2-azoles.
The stability of the azoles decreases with increasing substitution of nitrogen for
the carbon atoms with the stabilities of pyrazole and imidazole being comparable.
Pyrazole and imidazole are aromatic with resonance energies; 123 kJ/mol and 56
kJ/mol, respectively38 (pyrazole is more aromatic than imidazole).
The structure of thiazole is closely related to the structure of thiophene and has
the same degree of aromatic character as in benzene and involves cyclic
delocalization of the x-electrons.
Oxazole ring is planar and shows considerable bond fixation. Oxazole although
possesses a sextet of x-electrons, but because of higher electronegativity of the
oxygen atom, the delocalization of x-electrons is not extensive and causes
localization of the x-electrons.

3.3.1.3 Benzo-fused Five-Membered Heteroaromatics

The aromaticity ofbenzo-fused five-membered aromatic heterocycles is comparable

to that of naphthalene. The order of aromaticity depends on the electronegativity
of the heteroatom and decreases with increasing electronegativity:
Benzo[b]thiophene > Benzo[b]pyrrole (indole) > Benzo[b]furan
(103.76kJ/mol) (99.58kJ/mol) (84.94kJ/mol)
90 Heterocyclic Chemistry

The resonating structures of theseo-heterocycles do not involve the destruction of

six 1t-electron system of the benzene ring (Fig. 30).

co
Fig. 30. Resonating structures involving five-membered ring

The fusion of five-membered heteroaromatic ring to the benzene ring across

the carbon-carbon single bond decreases aromaticity of the system considerably
and, therefore, different order of the aromaticity is observed :
benzo[c]pyrrole (isoindole) > benzo[c]tbiophene > benzo[c]furan
(48.53 kllmol) (38.91 kl/mol) (l0.04 kl/mol)
Isoindole 39 is considered to be contributed by the following resonating
structures (Fig. 31) :

cG+
H H

()::; . .. ~+
~
I_ .
::::::".....
:N-H ~ N-H ~
~ I A N- H

H H
39 (i) (ii)

~
H H

~+ ..
# -
N-H

H
~

ex{
I # Art-H

(iv) (iii)

Fig 31. Resonating structures of isoindole

Aromatic Heterocycles 91

Indolizine 46 is a 1On:-electron system. The bridgehead nitrogen influences the

properties of both the rings; five-membered ring with characteristic properties of
electron rich pyrrole; and six-membered ring with characteristic properties of
x-deficient pyridine. Indolizine is considered to be contributed by the following
resonating structures in which five-membered ring has increased charge density
(Fig. 32).

Fig. 32. Resonating structures of indolizine

The fusion of the second benzene ring to the benzo-fused five-membered

heterocyclic ring causes a further reduction in the aromaticity of the heterocyclic
ring as is evidenced by the results of calculations of Dewar resonance energy of
some five-membered heterocyclic rings fused with two benzene rings 53, 54 and
55.
Benzene Pyrrole Thiophene Furan
(94.56 kJ/mol) (22.18 kJ/mol) (27.20 kJ/mol) (17.99 kJlmol)

o:D 0:0 0:0

~ N
H
.# ~ S .# ~ 0 .#

Carbazole Dibenzothiophene Dibenzofuran

(171.13 kJ/mol) (186.61 kJlmol) (166.94 kJlmol)
53 54 55

3.3.2 Six-Membered Heteroaromatic Ring Systems

3.3.2.1 Pyridine

Pyridine is a heteroaromatic system and is most similar to benzene. However,

qualitatively substitution of one sp2-carbon atom in the benzene ring by one Sp2_
92 Heterocyclic Chemistry

nitrogen atom causes perturbation in the hexagonal structure because of the

difference in the carbon-nitrogen and carbon-carbon bond lengths. The bond
lengths in pyridine are intermediate between normal double and single bond
lengths (C-C = 1.39A and C-N = 1.34A). The introduction of a nitrogen atom in
the benzene ring makes it less symmetrical with the decrease in resonance energy
and allows more resonating structures to contribute the resonance hybrid in which
the negative charge is localized on the heteroatom (Fig. 33).

&t-

.. &><()~~-
........
"

0+

Fig. 33. Structure of pyridine

The effect of the nitrogen atom in pyridine is similar to the effect of an electron-
withdrawing substituent in the benzene ring. The lone pair on nitrogen atom is not
required to maintain aromatic sextet of 7t-electrons because of being orthogonal to
the plane of the ring. The lower basicity of pyridine than the aliphatic amines is
attributed to the sp2-hybridized nitrogen. Thus, pyridine appears to have same or
somewhat less aromatic character than in the benzene ring. The ring current of
benzene and pyridine is reported to be close to unity, the energy estimations of
pyridine, however, suggest it to be less aromatic than benzene. Conjugation
energies of pyridine and benzene are 79.50 kJ/mol and 92.0 kJ/mol, respectively.
Delocalization energy of pyridine is less than that of benzene and obeys the
following eqation :
ERE = 15.8DE .....(10)

3.3.2.2 Fused-Ring Derivatives of Pyridine

The fusion of a pyridine ring with a benzene ring in three different ways provides
quinoline 27, isoquinoline 28 and quinolizinium cation 45.
Aromatic Heterocycles 93

These heterocycles are aromatic with lOn-electrons and the lone pair on the
nitrogen atom is not involved in an aromatic sextet. These closely resemble
naphthalene in the same way as pyridine to benzene. Quinoline 27 is highly
aromatic with resonance energy of 47.3 kcallmol (197.90 kJ/mol) and is considered
to be contributed by the following resonating structures (Fig. 34) :

co .
~
27 N
,&
. CO .. .. CO
# ~ ~ I
(i) N
,&
(li) N

+
t
CD
~
(IV)
N
.. .. 00
~
(iii)
N +

Fig. 34. Resonating structures of quinoline

These structures are similar to those of naphthalene, but the charged structures
are also possible because of the electronegative nitrogen. The dipole moment of
quinoline (2.lOD) indicates charge-separation.
Isoquinoline 28 is also highly aromatic with high dipole moment (2.6D) and is
contributed by the following resonating structures (Fig. 35) :

00 .. ...
OJ . .
CO
r
~ ,&N # hN ~ ~ N
28 (i)
U
)

C(} .. ... 00
~

(iv)
~
I N
#

(iii)
+
N-

Fig. 35. Resonating structures of isoquinoline

94 Heterocyclic Chemistry

The fused-ring derivatives of pyridine sustain ring current and the diamagnetic
susceptibility exaltations for quinoline and isoquinoline are : -29.9 x 10.6 and
-27.8 x 10.6 cm3/mol, respectively and are comparable with that of naphthalene
(-30.5 x 10-6 cm3/mol).
Bicyc1ic six-membered heteroaromatics with nitrogen atom in both the rings are
called naphthyridines.

(O
I ~
~
N
~
N
~
~ ~-.)..
N N

1,5-N aphthyridine 1,8-Naphthyridine

42 42a

The values of delocalization energy for the various members of naphthyridines

are in the range of3.76-3.85~ and are comparable with that of naphthalene (3.68~).

3.3.2.3 Pyridones and Related Systems

2-Pyridones 56 and 4-pyridones 57 are potentially six 7t-electron systems and are
considered to be aromatic with the charge-separated resonating forms (Fig. 36) :

Gltt°
N
H
.., .- U+~
N
H
()
56 56a

0-

© 6
0)

.., ..
N N
H H
57 57a

Fig. 36. Resonating structures of 2- and 4-pyridones

Aromatic Heterocycles 95

2-Pyridone is 6 kcal/mol (25.10 kJ/mol) less aromatic than 4-pyridone. Similarly,

quinolones 58 and isoquinolones 59 retain much of the resonance energy of the
quinoline and isoquinoline structures. 2- And 4-pyridones and 1- and 2-quinolones
have substantial aromatic characters. NMR-chemical shift estimated aromaticity of
2-pyridone to be 35% of benzene and indicates relatively localized 1t-electron
system.

~
~NAo
~
~NH
H
o
58 59

3.3.2.4 Pyrylium Salts

The oxygen atom can replace a carbon atom in the benzene ring only if the lone
pair on oxygen atom is involved in the bonding and oxygen bears positive charge.
Pyrylium cation 60 is a six 1t-electron system with an aromatic sextet and
possesses aromatic character similar to that of benzene. Pyrylium cation 60 is
considered to be contributed by the following resonating structures (Fig. 37). The
high value of the aromaticity constant (+96) of pyrylium cation reflects its
electrophilicity. The aromatic character of pyrylium ring is evidenced by the
absorptions of ring protons in the range of 3 8.5-9.6 ppm and by the qualitative
agreement between chemical shift and 1t-electron density.

Fig. 37. Resonating structures of pyrylium cation

3.3.2.5 Pyrones

a-Pyrones 61 and 'Y-pyrones 62 are expected to have some aromatic character

due to the contributing resonating structures involving an aromatic sextet (Fig. 38).
Since oxygen is more electronegative than nitrogen, it causes localization of the
electrons making a- and 'Y-pyrones less aromatic than 2- and 4-pyridones. The high
96 Heterocyclic Chemistry

value of the dipole moment (3.7D) supports the contribution of charge-separated

resonating structures. The delocalization energies of a-pyrone and 'Y-pyrone are
very close (2.896/3 and 2.863 /3).

@Lf)
o
.. 0
.-
Cl-
o 0
61 61a

-
0)

6
0

~ 0
.. .-
~+
0
62 62a
Fig. 38. Resonating structures of a,- and 'Y-pyrones

4 HETEROAROMATIC REACTIVITyJ9,40

Aromatic compounds are characterized by their extra stability due to delocalized

1t-electron system, and substitution reactions rather than addition reactions with
the retention of aromatic character. The aromaticity is related with the stability
which, in turn, may be considered to be related with the reactivity. However, the
reactivity may not be considered to be a criterion of aromaticity.
The presence of heteroatom in the heteroaromatic system usually affects the
reactivity. The basic principles governing the degree and the type of reactivity in
the heteroaromatic systems are :
(i) Nucleophilic attack: The heteroatom (oxygen, nitrogen or sulfur) bonded
to the carbon atom with multiple bond can accept shared pair of 1t-electrons
and permits the attack of nucleophilic reagent. The attack of nucleophile is
facilitated when heteroatom is positively charged (Fig. 39).
Aromatic Heterocycles 97

Fig. 39. Nucleophilic attack in heteroaromatic ring system

(n) Electrophilic attack : A pair of electrons on the heteroatom (oxygen,

nitrogen or sulfur) attached to an unsaturated system can be made available
for the electrophilic attack through the following system. This can also be
operative when the heteroatom is negatively charged (Fig. 40).

+~~C=C-X
E·
"n ('.. E
t"-
+~~C=C-X "n
/ I / I
Fig. 40. Electrophilic attack in heteroaromatic ring system

(iii) Retention of aromaticity : Aromatic heterocycles tend to retain their

aromatic character. However, ring oxygen atom, increasing nwnber of ring
heteroatoms and benzannelation reduce the aromaticity.

4.1 Selectivity and Reactivity

The relative reactivity and the selectivity of the diferent positions in the
heteroaromatic systems to be attacked by the reagents can be predicted by the
reactivity indices.

4.1.1 Reactivity Indices

The reactivity indices method involves the correlation between activation free
energy of the process and some intrinsic parameters i.e. reactivity indices, related
to the electronic properties of the heteroaromatic system involved in the reaction.
The introduction of heteroatom in an aromatic system causes considerable
changes in the electronic properties and, therefore, the parameter relating to the
heteroatom is used in the molecular orbital calculations in the heteroaromatic
system. The reactivity indices are :
98 Heterocyclic Chemistry

4.1.1.1 Electron Densities

The x-electron densities refer to the electron density at a given carbon atom
obtained by summing up the contributions from all the filled molecular orbitals. The
x-electron densities directly determine the orientation of electrophilic and
nucleophilic substitutions. Electrophilic attack is considered to occur at the
position where the electron density is highest, while nucleophilic attack takes place
at the centre of low electron density. The x-electron densities in homolytic
substitution are not appreciably affected by the electron density distribution.

4.1.1.2 Frontier Electron Densities41

The frontier electron densities are a property of an isolated molecule and their use
as reactivity indices involves the assumption that the electron distribution in the
transition state resembles that in the initial state. The frontier electron distribution
is much more uneven and the relative order of the frontier electron densities is not
changed when approached by the reagent. The frontier electron densities are
associated with the electron exchange rather than with electrostatic interaction and
if electron exchange (charge transfer) is significant in stabilizing transition state,
the frontier electron densities influence the reactivity.
In electrophilic substitution, the frontier electron density is the density in the
highest filled molecular orbital (HOMO) and these electrons are considered to be
analogous to the valence electrons of an atom. The electrophilic substitution
reaction involves the interaction of highest occupied molecular orbital (fi'ontier
orbital) of heteroaromatic system with the lowest unoccupied molecular orbital of
electrophile. The activation energy depends on the extent of mixing which, in turn,
depends on the difference in the energy between these two types of orbitals. If
smaller is the difference in the energy, lower will be the activation energy and faster
will be the reaction with more efficient mixing of the orbitals.
In nucleophilic substitution, the frontier molecular orbital is the lowest
unoccupied molecular orbital (LUMO). Nucleophilic substitution reaction involves
the mixing of lowest unoccupied molecular orbital of the heteroaromatic system
with a filled molecular orbital of nucleophile. The heteroaromatic compound tends
to accept the electron pair in the transition state and the frontier electron density
at the carbon atom is then the electron density in this molecular orbital as if it were
occupied by two electrons. The electrophilic and nucleophilic reactions occur at
the carbon with the greatest appropriate frontier electron density (Fig. 41).
Aromatic Heterocycles 99

Frontier orbital for

- - - - - . . - - - - - - - - - - - nucleophilic attack
o 0 . . - - - - - - - - - - - Frontier orbital for
electrophilic attack
o 0
o 0
E

Fig. 41. Diagrammatic representation of frontier orbitals for electrophilic and

nucleophilic substitutions

4.1.1.3 Localization Energytl

The localization energy refers to the energy difference between the 1t-electron
energy in the isolated molecule and the transition state complex. The relative
stabilities of the different transition states in the same molecule are in the same
order as the localization energies. The localization energy in the heteroaromatic
system reflects the relative stability of the transition state complex and therefore
predicts the orientation in substitution reactions.
Thus, the following inferences on orientation can be drawn on the basis of
reactivity indices in the heteroaromatic systems :
(i) The 1t-electron distribution is the main factor controlling the orientation.
The transition states very closely resemble to the unpurturbed molecule
and the electrostatic interactions contribute significantly to the orientation.
(ii) The physical picture for correlation of reactivity with frontier electron
densities is less clear, but probably involves electron transfer interaction
between the reagent and the slightly purturbed aromatic system in which
the cyclic conjugation is retained.
(iii) The correlationship between orientation and localization energies implies
that the transition state is very different from the initial state, since
transition state reflects the structure of a- complex in which loss of cyclic
conjugation is partly compensated by the formation of a new a-bond.
100 Heterocyclic Chemistry

4.2 Selectivity and Reactivity in Heteroaromatic Rings

4.2.1 Six-Membered Heteroaromatic Rings

The relative reactivity of the ring atoms in six-membered heteroaromatic compounds

can be predicted on the basis of reactivity indices which predict that the ring-
nitrogen atom of 1t-deficient heteroaromatic ring is the most reactive site for the
electrophiles and the electrophilic attack at the ring carbon atoms is exceptionally
difficult. Under acidic conditions, nitrogen of pyridine is protonated and further
decreases reactivity of the ring carbon atoms toward electrophiles (Table 20). The
comparison of reactivity indices for both pyridine and pyridinium ion accounts for
the less reactivity of carbon atoms of azines. The preferential electrophilic and
nucleophilic attacks in the azines are represented (Fig. 42).

(1)
(2)
~
• first preferential position for electrophilic attack
first preferential position for nucleophilic attack
(3) ~ second preferential position for electrophilic attack
(4) ._--...- second preferential position for nucleophilic attack
Fig. 42. Selective positions for electrophilic and nucleophilic substitutions

These effects can also be applied to the benzo analogs of the azines where
electrophilic attack preferentially occurs at the carbon atoms of the benzo-fused
ring (Fig. 43).

Fig. 43
Aromatic Heterocycles 101

Table 20. Reactivity indices of pyridine and pyridinium ion

Compound Atoms Net total n-charge n-electron

charge density

N -0.06 -0.04 1.19

'0'
3
C-1 -0.02 +0.02 0.92
51 n 1 C-2 -0.09 -0.03 -1.00
N C-3 -0.04 +0.04 0.95

N 0.02 -0.35 1.62

0'
3
C-1 0.05 +0.10 0.76
~+ 11 C-2 -0.08 -0.02 1.01
N
I C-3 +0.04 +0.19 0.83
H'

4.2.2 Five-Membered Heteroaromatic Rings

Five-membered heteroaromatic rings with one heteroatom possess partial positive

charge on the heteroatom which restricts the reaction with electrophilic reagents.
While the presence of partial negative charge on the carbon atoms facilitates the
electrophilic attack at the ring carbons. This charge distribution follows from the
valence bond approach as a contribution to the resonance hybrid of the resonating
structures (Fig. 44).

o X
o-X

Fig. 44. Charge distribution in five-membered heteroaromatic rings

The valence bond approach provides a general method of predicting relative

reactivities of the different positions of a particular heteroaromatic compound.
Molecular orbital calculations also lead to the similar predictions.
The preferential attack of electrophile at a-position rather than at J3-position can
be rationalized in terms of more effective delocalization of charge in the
intermediates or a-complexes. The relative stabilities of the a-complexes are
correlated with the localization energies and thus predict the relative reactivity of
the positions in the aromatic heterocycles (Fig. 45).
102 Heterocyclic Chemistry

+
cxE
'/ .. +
~ H
~
QE
+ ..
~ H
~
CxE =
~+-

~ H
~/E
~~.A
N H
Y
H

oH"'( E E E
ctH___ (j H= t:JH
N

N N N
H H H

Fig. 45. Relative stabilities of a-complexes

Benzo[b] heterocycles are expected to favour ~-substitution in the heterocyclic

ring over a-substitution which is based on the a-complex stability. However,
benzo[b]furan undergoes mainly a-substitution due to the strong directing effect
of the oxygen atom to the a-position (Fig. 46).

-: ; -
CQ< H
~E
H

~
. . .,. . ~+
X E ~1
a-substitution ~-substitution

Fig. 46. a- And ~-electrophilic substitutions in benzo-fused heterocycles

REFERENCFS

1. M. J. Cook, A. R. Katritzky and P. Linda in A. R. Katritzky (Ed.), Adv.

Heterocycl. Chem. Vol. 17, Wiley-Interscience, New York, 1974, pp. 255 :
C. W. Bird and G. W. H. Cheeseman in A. R. Katritzky and C. W. Rees
(Eds.), Comprehensive Heterocyclic Chemistry Vol. 4, Pergamon Press,
Oxford, 1984, pp. 1.
Aromatic Heterocycles 103

2 A. R Katritzky, P. Barczynski, G. Musumarra, D. Pisano and M. Szafran, J.

Am. Chem. Soc. 111~ 7 (1989); A. R Katritzky, V. Frygelman, G. Musumara,
P. Barczynski and M. Szafran, J. Prakt. Chem. 332, 853 and 870 (1990); A.
R Katritzky and P. Barczynski, J. Prakt. Chem. 332, 885 (1990); A. R
Katritzky et al., Heterocycles 32,127 (1991); V.G.S. Box, Heterocycles, 32,
2023 (1991).
3. M. Burke-Laing and M. Laing, Acta Crystallogr. (B) 32, 3216 (1976).
4. S. F. Mason in A. R Katritzky (Ed.), Physical Methods in Heterocyclic
Chemistry Vol. 2, Academic Press, New York, 1963, pp. 1.
5. A. R Katritzky, Handbook of Heterocyclic Chemistry, Pergamon Press,
Oxford, 1985, pp. 64.
6. R Bonnett, R F. C. Brown and R G. Smith, J. Chem. Soc. Perkin Trans.
1,1432(1973).
7. D. Wege, Tetrahedron Lett. 2337 (1971).
8. A. R Katritzky and A. P. Ambler inA. R Katritzky (Ed.), Physical Methods
in Heterocyclic Chemistry Vol. 2, Academic Press, New York, 1963, pp. 61.
9. A. R Katritzky and P. J. Taylor in A. R Katritzky (Ed.), Physical Methods
in Heterocyclic Chemistry Vol. 4, Academic Press, New York, 1971, pp. 265.
10. A. T. Balaban, S. Badilescu and I. I. Badilescu in R R Gupta (Ed.),
Physical Methods in Heterocyclic Chemistry, Wiley-Interscience, New
York, 1984, pp. 1.
11. H. Bock, Pure Appl. Chem. 44,343 (1975).
12. C. N. R. Rao and P. K. Basu in R R Gupta (Ed.), PhYSical Methods in
Heterocyclic ChemiStry, Wiley-Interscience, New York, 1984, pp. 231.
13. R Zahradnik and J. Koutecky in A. R Katritzky (Ed.), Adv. Heterocycl.
Chem. Vol. 5, Academic Press, New York, 1965, pp. 69.
14. T. J. Barton, R W. Roth and J. G. Verkade, J. Am. Chem. Soc. 94, 8854
(1972).
15. K. Schofield, Heteroaromatic Nitrogen Compounds : Pyrroles and
Pyridines, Butterworths, London, 1967, pp. 124.
16. P. George, Chem. Rev. 75,85 (1975).
17. A. Streitwieser, Jr., Molecular Orbital Theory for Organic Chemists,
Wiley-Interscience, New York, 1961.
18. N. C. Baird, J. Chem. Ed. 48,509 (1971).
19. M. J. S. Dewar, The Molecular Orbital Theory of Organic Chemistry,
McGraw-Hill,NewYork, 1969.
20. M. J. S. Dewar and A. J. Holder, Heterocycles 28, 1135 (1989).
104 Heterocyclic Chemistry

21. R. K. Harris, Nuclear Magnetic Resonance Spectroscopy, Pitman,

London, 1983.
22. R. C. Haddon, V. R. Haddon and L. M. Jackman, Top. Curro Chem. 16, 103
(1971).
23. J. Aihara, J. Am. Chem. Soc. 103,5704 (1981); I. Hasan and F. W. Fowler,
J. Am. Chem. Soc. 100, 6696 (1978).
24. J. A. Elvidge and L. M Jackman, J. Chem. Soc. 859 (1961).
25. W. B. Smith, W. H. Watson and S. Chiranjeevi, J. Am. Chem. Soc. 89, 1438
(1967).
26. N. Jonathan, S. Gordon and B. P. Dailey, J. Chem. Phys. 36,2443 (1962).
27. H. Gunther, Tetrahedron Lett. 2967 (1967).
28. B. A. Hess, Jr. and L. J. Schaad, Tetrahedron Lett. 535 (1977).
29. G. C. Levy and G. L. Nelson, 13C Nuclear Magnetic Resonance for
Organic Chemists, Wiley-Interscience, New York, 1972.
30. R. J. Radel, B. T. Keen, C. Wong and W. W. Paudler, J. Org. Chem. 42,
546 (1977) and references therein.
31. H. J. Dauben, J. D. Wilson and J. L. Laity in J. P. Snyder (Ed.), Non-
benzenoid Aromatics Vol. 2, Academic Press, New York, 1971, pp. 167.
32 E. A. Boudreux and R. R. Gupta in R. R. Gupta (Ed.), PhYSical Methods in
Heterocyclic Chemistry, Wiley-Interscience, New York, 1984, pp. 281.
33. J. F. Labarre and F. Crasnier, J. Chem. Phys. 64, 1664 (1967).
34. P. J. Garratt, Aromaticity, Wiley-Interscience, New York, 1986.
35. P. Jutzi, Angew. Chem. Int. Edn. Engl. 14,232 (1975).
36. A. J. Ashe, Accounts Chem. Res. 11, 153 (1978).
37. G. Marino in A. R. Katritzky (Ed.), Adv. Heterocycl. Chem. Vol. 13,
Academic Press, New York, 1971, pp. 235.
38. M. Roche and L. Pujol, J. Chem. Phys. 68,465 (1971).
39. J. Ridd in A. R. Katritzky and A. J. Boulton (Eds.), Physical Methods in
Heterocyclic Chemistry Vol. 1, Academic Press, New York, 1963, pp. 109.
40. M. Speranza in A. R. Katritzky (Ed.), Adv. Heterocycl. Chem. Vol. 40,
Academic Press, New York, 1986, pp. 25.
41. I. Fleming, Frontier Orbitals and Organic Chemical Reactions, Wiley-
Interscience, London, 1976.
42 A. R. Katritzky and R. Taylor in A. R. Katritzky (Ed.), Adv. Heterocycl.
Chem. 47, Academic Press, New York, 1990, pp. 467.
CHAPTER 4
NONAROMATIC HETEROCYCLES

CONTENTS

1 GENERAL 107
2 S1RAIN 107
3 FACTORS 108
3.1 Bond Angle Strain 109
3.1.1 Bond Angle Strain in Small Ring Heterocycles 109
3.1.2 Bonding in Small Rings 111
3.1.21 Bonding in Three-Membered Rings 111
3.1.2.1.1 Bonding in Cyclopropane 111
3.1.2.12 Bonding in Three-Membered 112
Heterocycles
3.1.2.2 Bonding in Four-Membered Rings 114
3.1.2.2.1 Bonding in Cyclobutane 114
3.1.2.2.2 Bonding in Four-Membered 116
Heterocycles
3.1.3 Consequences of Bond Angle Strain in Small 117
Ring Heterocycles
3.1.3.1 IR Spectra 117
3.1.3.2 NMR. Spectra 117
3.1.3.3 Conjugative Effect 118
3.1.3.4 Basicity 118
3.1.3.5 Pyramidal Inversion at Nitrogen 119
3.1.4 Angle Strain in Larger Rings 121
32 Torsional Strain 122
3.21 Single Bonds 123
3.22 Double Bonds 126
106 Heterocyclic Chemistry

3.23 Partial Double Bonds 126

4 CONFORMATIONS OF FLEXIBlE HETEROCYClES 129
4.1 Conformations of Five-Membered Rings 130
4.1.1 Conformations of Cyclopentane 130
4.12 Conformations of Five-Membered Heterocycles 132
4.2 Conformations of Six-Membered Rings 132
4.21 Conformations of Cyclohexane 132
42.1.1 Chair Conformation 133
42.12 Flexible Conformations 133
4.2.12.1 Boat Conformation 133
4.2.1.2.2 Twist-Boat Conformation 134
42.2 Conformations of Six-Membered Heterocycles 135
4.2.2.1 Molecular Geometry (Shape of the Ring) 135
4.22.2 Barriers to Ring Inversion 137
4.22.3 Pyramidal Inversion 140
4.2.2.4 1,3-DiaxialInteractions 142
4.22.5 Conformational Preferences of Substituents 143
on Heteroatom
4.2.2.5.1 Thermodynamic Method 143
4.22.52 Spectroscopic Methods 143
4.22.5.2.1 Vibrational Spectra 143
4.22.5.2.2 NMR Spectra 144
4.2.2.6 Conformational Preferences of Lone Pair and 145
Substituents on Nitrogen
5. STEREOELECTRONIC EFFECTS IN SATURATED SIX-MEMBERED 146
HEIEROCYa.ES
5.1 Anomeric Effect 146
5.1.1 Factors Affecting Anomeric Effect 148
5.1.1.1 Effect of Substituents 148
5.1.1.2 Solvent Effect 148
5.1.2 Consequences of Anomeric Effect 149
5.1.2.1 Bond Distance 149
5.1.2.2 Chemical Reactivity 150
52 Other Related Effects 150
5.21 Reverse Anomeric Effect 150
5.22 Double Anomeric Effect 151
5.23 Rabbit-Ear Effect (Lone Pair-Lone Pair Interactions) 151
5.24 Repulsive-Gauche Effect (Hockey-Sticks Effect) 152
5.3 Attractive Interactions 'Through Space' 153
5.3.1 Intramolecular Hydrogen Bonding 153
5.3.2 Intramolecular Nucleophilic-Electrophilic Attractive 154
Interactions
REFERENCES 155
Nonaromatic Heterocycles 107

1 GENERAL

Saturated and partially lll1Saturated alicyclic compounds closely resemble acyclic

analogs in most of the chemical and physical properties. However, relatively small,
but significant differences exist in their properties due to the conformational
effects, the size of the ring and overall shape of the molecule. Similarly, the
heterocycles (without cyclic delocalization) are the cyclic analogs of amines,
ethers, amides, enamines, sulfides etc. and possess many properties common with
their acyclic analogs. However, when the heteroatom is constrained in a ring the
properties relating to the relative ring size and the steric requirement of the lone
pair on the heteroatom are considerably changed. The ring constrain causes
considerable enhancement in the reactivity of the three-membered heterocyles and
to a lesser extent, but still significant, in the four-membered heterocycles.
The heteroatom in the nonaromatic hetrocycles exhibits characteristic properties.
Trivalent nitrogen inserts conformational properties in the ring due to its pyramidal
inversion and lone pair of electrons. The introduction of an oxygen atom into the
ring produces strong dipolar effects (anomeric effect) and sulfur causes effects due
to the expansion of its valence shell. In addition to the characteristic atomic
property, the heteroatom alters geometry of the ring with respect to the alicyclic
(carbocyclic) analog by changing the bond distances and bond angles adjacent
to the heteroatom. The alteration may be small or large depending on the nature
or the number of the heteroatoms and their relative positions. The striking
differences that exist between the forces controlling the carbocyclic and
heterocyclic conformations are due to :
(i) Torsional interactions: torsional interactions along the carbon-heteroatom
bonds differ from those along the carbon-carbon bonds.
(ii) Non-bonded interactions : non-bonded interactions are different in the
heterocyclic and carbocyclic systems.
(iii) Dipolar interactions : the presence of the heteroatoms increases dipolar
interactions.
(iv) Force constants: the force constants for the bond angle deformations of
the heteroatoms are different from those of carbon.
(v) Hydrogen bonding: internal hydrogen bonding between hydroxyl group
and heteroatoms can influence the molecular conformations.

2 STRAIN

The molecule preferentially exists in the most stable energetically favourable

staggered conformations in which bonding attractive interactions are maximized
108 Heterocyclic Chemistry

and the non-bonding repulsive interactions are minimized. The molecule cannot
adopt the energetically unfavourable eclipsed conformations without the distortion
of the normal bond angles and the bond distances because of the increased
internal energy of the system. When the bonds are forced to form a cyclic structure
of a molecule, causing deviation in the internal angle from the normal bond angle,
the molecule cannot attain the features of the staggered conformer. Thus, there
exists strain in the molecule and the molecule is said to be strainedl . The deviation
of bond angle from the normal valence bond angle causing strain in the molecule
is associated with the internal energy of the molecule. The greater bond angle
deviation is associated with the higher energy and the lower stability of the
molecule.
Baeyer has proposed a theory of strain that the deviation of an internal bond
angle from the normal bond angle causes internal strain on the ring and the amount
of the deviation depends on the size of the ring. Baeyer strain theory, however,
is not consistent with the experimental results because it is based on the wrong
assumption that all the rings are planar. The strain theory is applicable to the small
rings, but not to the six-membered and large-membered rings because such rings
are puckered and exist in a completely strain free chair form. Thus, the concept of
non-planar structure of the rings exists and the distortion of the bond angle (angle
strain) is one of the contributing factors to the ring strain.

3 FACTORS

The ring strain that exists in the cyclic molecule can be considered to be
contributed by the following factors which increase the internal energy of the
molecule affecting molecular conformation:
(i) Bond angle strain (angle strain or classical strain or Baeyer strain) :
deviation from the normal bond angle.
(n) Bond strain : the alteration of interatomic distances i.e. the stretching or
compression of the chemical bonds.
(iii) Torsional strain (eclipsing strain or Pitzer strain) : forced deviation from the
most favourable staggered conformations.
(iv) Non-bonded interactions (sterlc strain) : the intramolecular van der Waals
forces or the sterlc repulsion between closely spaced atoms.
(v) Dipole-dipole interactions : the positions of the non-bonded atoms that
minimize dipole-dipole repulsions or maximize dipole-dipole attractions.
These factors are interdependent and the change in anyone factor affects the
other and ultimately molecular conformation. The molecule will adopt such
conformation in which sum of all these strains is at a minimum.
Nonaromatic Heterocycles 109

3.1 Bond Angle Strain

The deviation of bond angle from the normal value of the tetrahedral angle
(109°28') causes strain within the ring which, in turn, brings instability to the ring.
The energy required to deviate the bond angle from the normal value is known as
bond angle strain.
The deviation or distortion in the bond angle (a.) can be calculated from (Eq. 1) :

a. = 21 (109°28' -actual bond angle) .....(1)

or in the generalized form it can be represented as (Eq. 2) :

a. = _1_ [109028' _ 2 (n - 2) x 90] .....(2)
2 2
where n is the number of member~ in the rings.
The deviation of bond angles is maximum in the three-membered rings and
decreases with increasing ring size (minimum with five-membered rings). Bond
angle strain is particularly significant in the small rings (three-and four-membered),
while less significant or negligible in the five-and six-membered rings.
The bond angle strain is related to the bond angle deviation or bond distortion.
The bond angle strain (energy required to distort the bond angle from its normal
value, E) is proportional to the square of the angle of deviation (a.), and is
represented as (Eq. 3) :
E ex: a.2 .......(3)
K9
E I'::i - a.2 kJ/mol .......(4)
2
where K9 I'::i 0.0840 (bond bending force constant)
0.084
or E I'::i - - a.2 kJ/mol .......(5)
2
E I'::i 0.042 a.2 kJ/mol .......(6)
The bond angle deviations of 5° and 10° require energy of 1 kJ/mol and 4 kJ/
mol, respectively.

3.1.1 Bond Angle Strain in Small Ring Heterocycles

The replacement of a -CHz group in the small ring cycloalkanes by a heteroatom

leads to the saturated small ring heterocycles and causes changes in the structural
parameters. The carbon-heteroatom bond distances are often appreciably different
from the carbon-carbon bond distance. Thus, carbon-oxygen bond (1.436A) and
110 Heterocyclic Chemistry

carbon-nitrogen bond (1.475A) are shorter than the carbon-carbon bond (1.54A).
The variation in the bond angles is less important for oxygen and nitrogen, but
C-S-C bond angle is substantially different.
In the small ring heterocycles (three-and four-membered), bond angle strain is
large and the ring strain is mostly due to the bond angle deviation. The ring strain
in three-and four-membered heterocycles is approximately of the same magnitude
and depends on the nature of the heteroatom than on the size of the ring
(cyclopropane=115 kJ/mol; cyclobutane=112 kJ/mol). The introduction of
unsaturation in the small ring heterocycles further increases angle strain. Some
molecular dimensions in the saturated three-membered rings with their strain
energies2 are summarized in Table 1.

Table 1. Molecular dimensions of saturated three-membered rings and their strain

energies

Compound Cyclic compound Acyclic analog Strain

C-C (A) c-x (A) c-x-c c-c (A) c-x (A) kl/mol

H2
C

H2C
/\ CH 2
1.510 1.510 1.54 115

H
N

H2C
/\ CH 2
1.481 1.475 1.54 1.470 113

H2C
/\ CH 2
1.472 1.436 1.54 1.430 114

H2C
/\ CH 2
1.49 1.820 48.50 1.54 1.810 83
Nonaromatic Heterocycles 111

3.1.2 Bonding in Small Rings

Small ring heterocycles have relatively similar bonding pattern as in small ring
cycloalkanes. It is essentially suitable to mention bonding in the small ring
cycloalkanes (cyclopropane and cyclobutane) in order to establish their relationship
with the small ring heterocycles and to analyze conformational changes caused by
introduction of the heteroatom.

3.1.2.1 Bonding in Three-Membered Rings

3.1.2.1.1 Bonding in Cyclopropane

In cyclopropane ring, carbon-carbon bond is not formed by maximwn overlapping

of sp3-hybrid orbitals along the axes required for the strong carbon-carbon a-bond
with the bond angle of 109°28', but formed by the oblique overlapping of Sp3_
hybrid orbitals being neither head-to-head (along the axes as in normal C-C bond)
nor side-to-side (parallel overlapping as in normal C=C x-bond) (Fig. 1). The
carbon-carbon bonds in cyclopropane are called bent or banana bonds and

bent bonds

8 1 =60°
82 = 1()60
83 = 116°

Fig. 1. Bonding in cyclopropane (orbital overlapping)

112 Heterocyclic Chemistry

possess the charecters of both the a- and x-bonds. Therefore, carbon-carbon

bond in cyclopropane is weak and behaves as a carbon-carbon double bond3• The
electron density along the bond axis is therefore low, but is directed away from
the ring.
In cyclopropane, four sp3-hybrid orbitals on a carbon atom are not equivalent.
The two sp-hybrid orbitals which are involved in the formation of ring bonds have
greater p-character than those forming a normal sp-hybrid a-bond. Therefore, each
of the three carbon-carbon bonds is considered to be formed by Sp4 to sr-hybrid
orbitals and the bond angle is somewhere between the tetrahedral angle (109°28')
for sp-carbon orbitals and the angle for p-orbitals (90°). The two orbitals directed
to the out-side bonds have more s-character than a normal sp3-orbital because
greater p-character of the ring bonds are balanced by the increased s-character of
the orbitals forming C-H bonds. The external orbitals have about 33% s-character
and are expected to be approximately sp2-hybrid (S#08). Carbon uses sp2-hybrid
orbitals for carbon-hydrogen bonds which are shorter and strong, while Sp4 to sps
(Sp402) hybrid orbitals are used for the ring carbon-carbon bonds (approximately
with 17% s-character and 83% p-character).
Thus, this type of arrangement of the bonding orbitals is usually considered to
raise the total energy of the molecule which renders the molecule strained and
reactive. The strain has effect on the physical and chemical properties of the
molecule.

3.1.2.1.2 Bonding in Three-Membered Heterocycles

The bonding in saturated three-membered heterocycles is similar to that in

cyclopropane because these are formally derived by replacing -CH2 group by
heteroatom. The orbitals associated with the ring bonds are not sp3-hybridized but
have greater p-character and are considered to be spcsps hybridized. These
orbitals are directed outside the axes joining the nuclei of the ring atoms and
involve oblique overlapping resulting in the formation of bent or banana bond. The
change in the hybridization of the orbitals forming ring bonds (with greater
p-character) is balanced by the increasing s-character of the hybrid orbitals forming
external bonds (to the substituents). Thus, the internal bond angles in the
saturated three-membered heterocycles, similar to cyclopropane, reflect more
p-character than in sp-hybrid orbitals and this is compensated by the external
bond orbitals having greater s-character and less p-character than the normal
sp-hybrid orbitals. The increase in the p-character of the hybrid orbitals forming
ring bonds results in much .less distortion in the interorbital angle than in the
internuclear angle and the bond angle is reduced from 109°28' to 106° to form
banana-shaped bonds (Fig. 2).
Nonaromatic Heterocycles 113

~o

H ~~?~\~J..
.V/
C----------C
H

/~~,
H ~ H
x= heteroatom
Fig. 2. Bonding in three-membered heterocyclic rings

The bond angles in three-membered heterocycles alongwith cyclopropane are

summarized in Table 2.

Table 2. Bond angles in three-membered heterocycles

Compound Internal bond angle External bond angle

c-x-c H-C-H

H2
C

H2C
/\ CH 2
116°

H
N

H2C
/\ CH 2
116.6°

H2C
/\ CH 2
61° 116.4°

H2C
/\ CH 2
48S 116.0°
114 Heterocyclic Chemistry

The bonding system in three-membered heterocycles4 can be considered to be

constructed from the interaction of x and x* orbitals of two structural groups;
basal group and apical group (Figs. 3 and 4). Basal group is consisting of c-c
bond, while heteroatom forms apical group. The basal group (C-C bond behaving
as C=C bond in three-membered rings) forms x-complex with an apical group
involving electron donation from the filled olefinic x-orbitals to the unfilled orbitals
of apical group. This electron donation, in turn, is balanced by the electron
donation in the reverse direction. Apical group (acceptor) in x-complex has filled
p-orbitals, that can be used to form a reverse dative bond in which x* orbital of
olefin (basal group) acts as acceptor. Three-membered saturated rings can be
considered as x-complexes with back-coordination in which the basal group and
acceptor are doubly linked by two opposite dative bonds. The saturated three-
membered heterocycles involve two types of interactions :
(1) interactions involving transfer of electron density from the ethylene
fragment to the heteroatom (x-orbital of ethylene with unfilled orbital on
heteroatom)
(Ii) interactions involving transfer of the electrons from the heteroatom to the
ethylene fragment (x*-orbital of ethylene with filled orbital on heteroatom)
If heteroatom is extremely electronegative, the second type of interactions are
negligible and first type of interactions dominate. The distribution of the electrons
in the ring are determined by the relative strength of both the interactions.

Figs. 3 and 4. Bonding system in three-membered saturated heterocycles

(x-complex with back-coordination)

3.1.2.2 Bonding in Four-Membered Rings

3.1.2.2.1 Bonding in CyclobutaneS

In cyclobutane, similarly in cyclopropane, the orbitals are not in a condition of

regular sp-tetrahedral overlapping, but are bent outward from the hypothetical
Nonaromatic Heterocycles 115

internuclear straight line. This effect is not so pronounced in cyclobutane as in

cyclopropane, although exists to the extent of about 20% as compared to in
cyclopropane. This arrangement results in the overlapping with the increased,
although small, p-character of the ring bonds. The increased p-character of Sp3_
hybrid orbitals involved in the ring bonds is compensated for by the decrease in
the p-character or increase in the s-character of the sp3-hybrid orbitals involved in
the external (C-H) bonds. The overlapping of the orbitals is depicted in Fig. 5.

oblique
~ overI ·
appmg

Fig. 5. Bonding in cyclobutane

The molecule of cyclobutane may be represented by two conformations: planar

and puckered. If cyclobutane molecule is considered to be planar, there will be
angle strain as well as bond eclipsing strain due to four pairs of C-H bonds thus
causing increased strain in the molecule (Fig. 6). The puckering of the ring with
one carbon atom either below or above the plane of other three carbon atoms
(Fig. 7) causes additional strain, but reduces considerably the eclipsing strain
(eclipsed hydrogen interactions) and torsional strain. The repulsion between the
pairs of non-bonded carbon atoms probably accounts for some what longer C-C
bonds in cyclobutane than in cyclopropane. Thus, four-membered rings are less
strained than the three-membered rings.

0°
planar 0° = puckering angle

Fig. 6. Planar conformation of cyclobutane

116 Heterocyclic Chemistry

A'

puckered
puckered puckered

Fig. 7. Puckered conformation of cyclobutane

3.1.2.2.2 Bonding in Four-Membered Heterocycles

The bonding in four-membered heterocycles can be considered very similar to that

in cyclobutane involving oblique overlapping of the sp3-hybrid orbitals. The
azetidine molecule 1 is puckered with the puckering angle of 33°, but oxetane 2
and thietane 3 are essentially planar molecules with low energy barrier because the
replacement of -CH2 in cyclobutane by a divalent heteroatom causes reduction in
the number of non-bonding interactions. However, the oxidation of thietane to
thietane sulfone 4 causes reintroduction of non-bonding interactions making the
molecule puckered.

oq

Azetidine ex = NH) 1b
1a
Nonaromatic Heterocycles 117

Oxetane Thietane sulfone

2 3 4

3.1.3 Consequences ofBond Angle Strain in Small Ring Heterocycles

Bond angle strain in small ring heterocycles accounts for their chemical reactivity
and, therefore, small ring heterocycles undergo ring opening reactions more readily
than the normal rings. The effect of bond angle strain can be visualized well in
their structures.

3.1.3.1 IR Spectra6,7

Bond angle strain affects the frequencies of vibrations and causes relatively large
shift to higher frequency. In small ring heterocycles, C-H stretching vibrations
move to higher frequency (3000-3080 cm- I ) as compared in the unstrained
molecules and the C-H stretching frequency decreases with increasing ring size
(aziridine-3047 cm- I and azetidine-2966 cm- I ). Analogous changes have been
observed in the saturated oxygen heterocycles (oxirane-3052 cm- I and oxetane-2928
cm- I ) and in sulfur heterocycles (thiirane-3047 cm- I and thietane-2959 cm- I ). The
increase in the stretching frequency is attributed to the bond angle strain in the
small rings. The bond angle in small rings is substantially contracted and results
in the increased s-character in C-H bonds. Therefore, with the increase in
s-character the bond becomes shorter and the frequency increases. The higher
C=N stretching frequency (1800 cm- I ) in 2H- azirines as compared in unstrained
acyclic imines (1650 cm- I ) is also attributed to the bond angle strain. Relatively
higher frequencies for exocyclic C=O bond in a-Iactams (aziridinones-1830-1850
cm- I ) and 13-lactones (azetidinones-1745-1765 cm- I ) as compared in unstrained
amides (1680 cm- I ) are associated with the increased s-character in c=o bond due
to the bond angle strain. The exocyclic c=o bond is shortened and strengthened
and, therefore, c=o bond frequency is increased.

3.1.3.2 NMR Spectra

The effect of bond angle strain in small ring heterocycles can be evidenced by
I3C-H coupling constants in their NMR-spectra. The coupling constants increase
with increasing s-character in the C-H bonds within a series of small ring
118 Heterocyclic Chemistry

heterocycles. The order of J (J3C-H) coupling constants in three membered

heterocyclic rings8 is as : oxirane (176) > thiirane (170) > aziridine (168) >
cyclopropane (164) (Fig. 8).

1i\~H H, / \,H
N

/C C, /C C,
H5C6 H H H
176Hz 168Hz 132Hz

H, /0\ ~H
/C C,
H H
176Hz 148Hz 140Hz

Fig. 8. Coupling constants for some small ring heterocycles

The higher value of J3C-H coupling constant for methylene hydrogen in

2-phenyl-1-azirine (176 Hz) as compared to that in aziridine (168 Hz) is attributed
to the greater s-character of the orbitals at carbon involved in the C-H bond9 •

3.1.3.3 Conjugative Effect

Bond angle strain in small ring heterocycles results in rehybridization of the ring
atoms giving additional p-character to the orbitals forming ring bonds. Thus, the
ring bonds behave in some respects like double bonds. If the small ring is
conjugated with a 1t-electron system (containing double bond), the conjugation is
transmitted through the small ring due to overlapping of the double bond 1t-orbital
withp-like orbitals of the small ringlO.
The transmission of conjugation through the small heterocyclic ring can be
evidenced as the A.",.x appears at high wavelength in the ultraviolet absorption
spectrall of substituted aziridine 5.

3.1.3.4 Basicity

Aziridine itself is less basic than the acyclic secondary amines. The low basicity
of aziridine is attributed to the bond angle strain and can be explained by
Nonaromatic Heterocycles 119

R
N

H5CS
A~ C-CSH5
5

considering the hybridization of lone pair on nitrogen. The bond angle strain in
aziridine results in an increase in s-character of the lone pair and the hybridization
of lone pair on nitrogen will be between Sp2 and Sp3. The increased s-character of
the hybrid orbitals brings the lone pair closer to the nucleus and therefore, will be
less available for the protonation than that in acyclic amines. Thus, the lone pair,
due to increased s-character, interacts less effectively with 7t-electron system to
which aziridine is co~ugated. The order of basicity in small ring heterocycles is
as follows:
four-membered nitrogen heterocycles > three-membered nitrogen heterocycles.

3.1.3.5 Pyramidal Inversion at Nitrogen

Pyramidal inversion l2 is a property of nitrogen which distinguishes it from the

tetravalent carbon. The trivalent nitrogen in a flexible ring inserts another
conformational property to the ring. Hydrogen or a substituent at the nitrogen
atom in a ring can attain two equilibrating configurations by virtue of inversion
of the nitrogen atom. The rate of atomic inversion is affected by the size of the
ring in which nitrogen is inserted and the substituent(s) attached to nitrogen. But
when nitrogen atom is involved in three-membered ring i.e. aziridine, the
conformational changes arise mainly from the pyramidal inversion of nitrogen
because the aziridine ring is planar and rigid. The pyramidal inversion in aziridine
is reduced because of much higher energy barrier in aziridine (L1G* = 72.0 kJ/mol)
as compared to the energy barrier in acyclic unstrained compounds which have
very low energy barrier (NH3 = 24-25 kJ/mol and (CH3)3N = 34.4 kJ/mol) (Fig. 9).

b
0N a"",0 a\,/c
N-c N
/!\
b b~Q Q
Sp3 Sp2 Sp3

Fig. 9. Pyramidal inversion in unstrained acyclic compound with low energy barrier
120 Heterocyclic Chemistry

The relatively high energy barrier in aziridine is attributed to the highly strained
transition state involving sp2-hybrldized nitrogen (for which nonnal valence angle
is 120°) constrained to the angle of approximately 60° (Fig. 10).

Sp3

a. = 11 0°-60~50°
Fig. 10. Pyramidal inversion in aziridines

The energy barrier to pyramidal inversion in aziridines depends on the nature

of the substituent attached to the nitrogen atom :
(i) Electron delocalizing substituents on small ring nitrogen lower the inversion
barrier by lowering the energy of the transitonal 'flat' geometry in which
three substituents of nitrogen are in the same plane (with acyl, aryl or
carboalkoxy-energy barrier reduced)!3.
(ii) The substituents bearing unshared electron pairs (NH2' CI, OCR3) increase
the energy barrier considerably and the enantiomers can be isolated!4. The
increased energy barrier is probably due to the unfavourable lone pair-lone
pair interactions in the planar transition state .

6 R Cps 81.0 kJ/mol.

7 R = C(~h 71.0 kJ/mol.
8 R C6H, 49.0 kJ/mol.
9 R CON(~h 41.0kJ/mol.
10 R = C~ 30.0 kJ/mol.
11 R ~,CI,OCR3 90.0 kJ/mol.
Energy barriers to N-inversion in substituted aziridines
(ill) Sterle effect destabilizes pyramidal fonn and lowers the energy barrier!s.
(iv) The solvents which stabilize ground state confonner through the hydrogen
bonding or by solvation raise the energy barrier.
Nonaromatic Heterocycles 121

3.1.4 Angle Strain in Larger Rings

Larger ring heterocycles exhibit large angle strain arising out of the angle deviation
due to the larger values of the bond angles than that of the normal bond angles.
l-Azabicyclo[3.3.3] l.U1decane 12, commonly named manaxine l6,17 exhibits interesting
physical features (lower pI(., value = 9.9 than the related tert-amine, in ultraviolet
spectra A....x = 240 nm (8 = 2935) at exceptionally longer wave length than that in
tert-amine) which are attributed to the flattening of the bridgehead regions which
affects the hybridization of nitrogen atom. The chemical shift of the bridgehead
H-5 at relatively low field (0 = 2.57 ppm) in IH NMR spectra is ascribed to the
l.U1usual hybridization arol.U1d H-5 due to the proximity of nitrogen atom. Thus, the
flattening of the bridgehead regions of the molecule is accompanied by the
widening of the angles in bridges and affects the hybridization of the bridgehead
atoms with the result of strain in the molecule.

~::tL4 2
I--'-V:::::!
~

12

The constraining effect is more pronol.U1ced in out-6H-l-azabicyclo[4.4.4]

tetradecane 13 and causes the molecule to adopt preferential conformation in
which molecule behaves as an exceptionally weak base. The weak basicity of the
molecule is ascribed to the adoption of preferential conformation with an inwardly
pyramidalized nitrogen with a hiden lone pairlS.

13

Cadged structure
122 Heterocyclic Chemistry

3.2 Torsional Strain

The forced deviation from the most favourable conformation causing relative
instability to the molecule is known as bond torsion and the energy that creates
bond torsion is called torsional strain. Torsional energy is a measure of the
torsional strain for a molecule and changes with the change in dihedral angle. The
torsional energy E is expressed as (Eq. 7) :
E = 5.87 (1 - cos 3m) ......(7)
where m is the deviation of dihedral angle from the most favourable conformation.
Torsional strain may be called as Pitzer strain or eclipsing strain or bond
opposing strain and is considered to be repulsive force between electrons of the
bonding orbitals (bond pair-bond pair repulsion). The repulsive force will be
highest in the eclipsed conformation in which bonds are closest to each other,
while it will be lowest in the most favourable staggered conformation in which
bonds tend to remain as far as possible. The energy corresponding to the eclipsed
conformation serves as the energy barrier between the conformers.
The rotation aroWld the single bond is not completely free as the potential
energy of the molecule is changed with the change in dihedral angle. The rotation
is, therefore, some what restricted by the energy barrier. The energy barrier to
rotation of single bond in ethane (the energy difference between the most stable
staggered conformation with lowest energy and the least stable eclipsed
conformation with highest energy) is very low (12-12.5 kJ/mol) and, therefore, the
interconversion of conformers is fast and even takes place at room temperature.
The energy barrier (torsional strain in eclipsed form) is contributed by (i) sterlc
repulsion and (ii) bond pair-bond pair repulsion. The sterlc contribution due to the
non-bonded interaction between hydrogens at the adjacent carbon atoms in
ethane is negligible because the internuclear distance (0.23nm) is almost equal to
twice of the van der Walls atomic radius of hydrogen (0.12 nm).
Torsional strain, referred to as bond eclipsing strain, can be relieved in the
acyclic compoWlds by the rotation of single bond to give staggered conformation.
But in cyclic compoWlds the rotation of single bond is not possible and the strain
resulting from the eclipsing of the bonds makes substantial contribution to the
strain. Cyclohexane assumes two conformations; chair form (most stable with
minimum potential energy) known as staggered form which is without eclipsing
strain, and boat form (least stable with maximum potential energy) known as flexible
(eclipsed) form with eclipsed strain. The energy barrier (energy difference between
two forms) is 21-25 kJ/mol. The increased energy of the boat form is attributed to
the eclipsing strain due to four pairs of eclipsed C-H bonds and to the sterlc
repulsion or van der Waals strain due to crowding between 'flag pole' hydrogens.
Nonaromatic Heterocycles 123

The replacement of carbon atom(s) by heteroatom(s); oxygen, sulfur and

nitrogen, causes considerable change in the rotational energy barrier. The
presence of lone pairs on the heteroatoms considerably influence the preferred
conformations.

3.2.1 Single Bonds

The rotation around the carbon-heteroatom bond is not quite free and, therefore,
leads to the conformers of different energies. The lone pairs on the heteroatom
serve as the missing substituents. The rotational energy barriers for carbon-
heteroatom bonds are relatively lower than for carbon-carbon bond 19 • The lower
rotational energy barrier for carbon-heteroatom bond may be attributed to the
reduction in the non-bonding interaction due to H-H eclipsing. The rotational
energy barriers for carbon-heteroatom bonds are summarized in Table 3.

Table 3. Rotational energy barriers for single bonds

Compound Energy barrier

CH3-CH3 12.2kJ/mol
CH3-~ 8.3kJ/mol
CH3-OH 4.6kJ/mol
CH3-SH 5.3kJ/mol

However, the rotational energy barrier in carbon-nitrogen bond is increased

considerably with increasing substituents than in carbon-carbon bond (Table 4).

Table 4. Effect of substitution on rotational energy barriers

Compound Energy barrier

CH3-ClIz~ 13.80kJ/mol
CH3-NH-CH3 13.72kJ/mol
C~-N-CH3 18.40kJ/mol
I
~
CH3~ 10.46kJ/mol

C~-S-CH3 8.91 kJ/mol

124 Heterocyclic Chemistry

The increase in rotational energy barrier is attributed to the adoption of

preferential conformation by the molecule in which a lone pair is placed gauche
to a bulky group.
The rotational energy barriers to rotation about heteroatom-heteroatom bonds
are higher than that for carbon-carbon bond ~-~ = 49.7 kJ/mol). The higher
energy barrier to rotation about heteroatom-heteroatom bond is ascribed to the
lone pair-lone pair interaction on the adjacent heteroatoms. The compound with
two heteroatoms at the adjacent positions exists in the conformation in which two
lone pairs are gauche to eact other. Thus, the lone pairs on two adjacent
heteroatoms tend to occupy preferentially skew position or gauche to each other
and this is known as gauche effect20 (Fig. 11).

Fig. 11. Gauche effect

The consequences of the torsional strain (energy barrier) can be evident in the
heterocyclic compounds containing heteroatom-heteroatom bond. These
compounds exist in the conformation in which lone pairs on the adjacent
heteroatoms are perpendicular to each other. The conformation in which the lone
pairs on adjacent heteroatoms are eclipsed is destabilized (Fig. 12).

14a

Fig. 12. Conformers of diaziridinone

Nonaromatic Heterocycles 125

The structure of diaziridinones provides information on the conformational effect

of the lone pairs on the adjacent nitrogen atoms. The properties of
diaziridinones are changed with the change in the conformation of lone pairs.
Diaziridinone exists in two conformations21 (Fig. 12) : the conformer with eclipsed
arrangement of the lone pairs on the heteroatoms 14a and the conformer with the
lone pairs perpendicular to each other (lone pair-lone pair dihedral angle-l200) 14b.
The conformer 14b with perpendicular arrangement of the lone pairs on
heteroatoms is more stable than the conformer with eclipsed arrangement of the
lone pairs22.
The bicyclic diaziridinone 15 exhibits different properties from those of
monocyclic diaziridinone 14 because bicyclic diaziridinone is forced to adopt the
conformation in which the lone pairs on the adjacent heteroatoms (nitrogen atoms)
are eclipsed. The eclipsed arrangement of the lone pairs (Fig. 13) makes bicyclic
diaziridinone less stable and undergoes readily decarbonylation (scheme-I).

15

Fig. 13. Conformation of bicyclic diaziridinone

N
N
1>=0
~

~
104.6 kJ/mol
(25 kcal/mol)
.. N
II + CO
N

~ 146.44 kJ/mol
~ (35 kcallmol)

Scheme-1
126 Heterocyclic Chemistry

3.2.2 Double Bonds

The rotation around the double bond is highly restricted due to high energy barrier
to rotation, and the molecule is considered to be rigid. Moreover, the incorporation
of the double bond into cyclic structure compels the n-bonding system to be
twisted causing strain in the molecule.
The twisting of n-bond about the axis joining two olefinic atoms causes four
bonding atoms involved not to be in the same plane and prevents optimum
overlapping. The distortion of n-bond is accompanied by the change in
hybridization with admixture of s-character into p-orbitals with the result of
increasing p-character in cr-bond. Two olefinic atoms neither achieve the usual
coplanar arrangement with four atoms bonded to them nor they have normal bond
angle of 120°.
Small bicyclic compounds with the double bond at a bridgehead position are
highly strained and, according to the Bredt's rule, cannot exist. The instability of
such bicyclic systems is a result of increased ring strain. However, this rule is
violated in larger rings23,24 because the planarity of the n-bond is accommodated
by puckering of larger rings 16.
The instability criterion of Bredt's rule is also applicable to the unsaturated
heterocycles 17 containing C=N bond at the bridgehead which is highly reactive
and cannot be isolated, but may be trapped with methanol 18. The instability is
because of the structural similarities to carbocyclic bridgehead olefin and the
planarity required by a n-bond cannot be maintained in the system2S ,26.

16 17 18

3.2.3 Partial Double Bonds

The rotation about the single bond in molecules with conjugated double bonds
or double bond conjugated with an atom having lone pair of electrons is restricted
because of acquiring partial double bond character. The higher rotational energy
barrier (- 75 kJ/mol) to carbon-nitrogen bond in amide is attributed to the partial
double bond character of carbon-nitrogen bond due to delocalization of nitrogen
Nonaromatic Heterocycles 127

lone pair (Fig. 14). The carbon-nitrogen bond in amide is shorter (1.32 A) than the
normal carbon-nitrogen bond, while the carbon-oxygen bond, on the contrary, is
longer than the normal carbon oxygen double bond. The partial double bond
character in the carbon-nitrogen bond creates certain barrier to rotation and thus
leads to two isomers.

+
-C=NH 2
I
Q
Fig. 14. Delocalization in planar amides

The incorporation of an amide linkage into four-membered ring forms planar

J3-lactam (nitrogen with exocyclic c=o bond) 19 and causes change in hybridization
of the atoms with a corresponding change in the preferred ring geometry21.

C3-N-C1 95 ± 1 A C2 - - C 1 N-C1 1.49 ± 1 A

N~-O 131±IA C1-C2 1.58 ± 2 A
C2~-N 93 ± 1 A C2-C3 1.52 ± 1 A
N-C 1-C2 86± 1 A n
O~
C3 N, C3-N 1.36 ± 1 A
Cl-C2~ 86± 1 A C3-O 1.21 ± 1 A
19

J3-Lactam system shows difference from the simple azetidine non-planar ring in
dihedral angle (azitidine-171 ° and J3-lactam-1800) and in bond distances and bond
angles. In J3-lactam the angles around the nitrogen (95°) and carbonyl carbon (93°)
are larger than in azetidine ring and the other two ring angles are consistently small
(86°). This change can be explained in terms of change in hybridization from Sp3
to Sp2. The nitrogen-carbon bond (carbonyl carbon) is shorter than the carbon-
nitrogen bond in azetidine which can be ascribed to the resonance due to
delocalization of nitrogen lone pair giving partial double bond character to the
carbon-nitrogen bond (Fig. 15).

Fig. 15. Canonical forms of J3-lactam ring

128 Heterocyclic Chemistry

In. bicyclic fused system, the fusion of four-membered heterocyclic ring to a

larger ring causes strain and distortion. The amount of distortion depends on the
size and nature of the fused ring as well as the substituents on both the rings.
The distortion causes disruption of deloca1ized system (particularly with bridgehead
nitrogen). The distortion is extremely significant in the biologically active
molecules such as penicillins 20 and cephalOspOrins2I,27,2B 21.

o
II H
R-C-N S
'rl~l
C-N~
cf COOR

20 21
Penicillins Cephalosporins

In. bioactive penicillin molecule, the bridgehead nitrogen is bent (0.40 ± O.Q1A)
out of the plane of the other three carbon atoms in the 13-lactam ring. Ability of
nitrogen lone pair to participate in 1t-bonding decreases and conform more to
tetrahedral geometry favouring nucleophilic attack at the carbonyl carbon atom.
The higher carbonyl stretching frequency (1780 em'I) in penicillin than in unfused
13-lactam (1730 em'I) is attributed to the decrease in the planarity of bridgehead
nitrogen. Distortion restricts delocalization and causes lengthening of the carbon-
nitrogen bond and the shortening of the carbon-oxygen bond.
In. cephalosporins 21, the deviation of bridgehead nitrogen from the planarity
is less than in penicillins 20 (0.21 ± 0.01 ). The carbonyl strectching frequency
(1776 cm'I) indicates the disruption of delocalization with the carbon-nitrogen
bond distance (1.40A) and carbon-oxygen bond distance (1.21A). The reason, that
the cephalosporins do not require much deviation from the planarity to be active,
is that they involve second mechanism for isolating of carbon-oxygen double
bond in which the lone pair on the nitrogen atom interacts with the six-membered
ring involving some degree of enamine resonance and restricts amide resonance
(Fig. 16).

Fig. 16. Resonance in cephalosporins

Nonaromatic Heterocycles 129

4 CONFORMATIONS OF FLEXIBLE
HETEROCYCLES

The conformations of the flexible heterocycles 19,29,31 are qualitatively very similar
to those of the alicYclic compmmds, but differ quantitatively due to the changes
in the structural parameters caused by the replacement of one or more C~ groups
by heteroatom(s). In addition to the torsional strain, other factors also affect
considerably to the conformations and determine preferred ones in flexible
heterocycles. The structural factors which affect preferred confonnations in flexible
heterocycles are :
(i) Bond distances : The carbon-heteroatom bond distances are appreciably
different from the carbon-carbon bond distance. Carbon-oxygen bond (1,43A) and
carbon-nitrogen bond (1.47A) are shorter than the carbon-carbon bond (1.54A),
whereas the carbon-sulfur bond (1.82A) is longer.
(ii) Bond angles : The variation in the bond angles for oxygen and nitrogen is
less significant, but C-S-C bond angle is substantially different in heterocycles
from the near tetrahedral angle in alicyclic compounds.
(iii) Dipole interactions : Heteroatoms produce appreciable dipole moment. If
there is only one heteroatom in the ring, the dipole moment has no effect on the
confonnations, but when two or more heteroatoms are present in the ring or when
there is hetero substituent (OH or OR) on the heterocyclic ring, dipole-dipole
interactions considerably affect the confonnations. However, these interactions are
solvent dependent and are inversely proportional to the dielectric constant of the
solvent. Thus, the conformations vary with the solvent.
(iv) van der Waals radii: The van der Waals radii of oxygen, nitrogen and sulfur
are different from that of carbon. The van der Waals radii follow the order :
C~ (200 pm) > S (185 pm) > NH (150 pm) > 0 (140 pm)
Thus, other non-bonded atoms are able to approach closer to oxygen than amino
group and closer to an amino group than to sulfur which is closer than to a C~
group. Moreover, the presence of a lone pair of electrons on the heteroatom which
is considered absent ligand reduces non-bonded repulsive interactions because of
the smaller volume (size) of the lone pair than the size of hydrogen atom.
(v) Torsional interactions and Force constants: The torsional interactions along
the carbon-heteroatom bonds differ from those along the carbon-carbon bonds.
Torsional energy about carbon-heteroatom bond is generally lower than that
about carbon-carbon bond which, in turn, is lower than that about heteroatom-
heteroatom bond.
130 Heterocyclic Chemistry

The bending force constants for the bond angles C-X-C and X-C-C (X =
heteroatom) are different from those of carbon atoms.
(vi) Hydrogen bonding (attractive interactions through space): The intramole-
cular hydrogen bonding between hydroxyl group and heteroatoms can influence
the conformations. The intermolecular hydrogen bonding between heteroatoms
and hydrogen-donor solvent may also affect the conformations in flexible
heterocycles.
The attractive interactions caused by the attraction of nucleophilic centre with
electrophilic centre (space interaction) in the same molecule also determine the
preferred conformation.
(vii) Pyramidal inversion: Pyramidal inversion at heteroatom especially nitrogen
atom has an effective role in the conformational analysis of the nitrogen
heterocycles.

4.1 Conformations of Five-Membered Rings

The replacement of -CH2 group(s) by heteroatom(s) affects conformations in five-

membered rings, however the conformations of five-membered heterocyclic rings
are very similar to those of five-membered carbocyclic rings. The conformational
analysis of cyclopentane is included in order to determine the preferred
conformations in five-membered heterocycles.

4.1.1 Conformations of Cyclopentane

Cyclopentane may be expected to be planar. In planar structure the bond angle

deviation from the normal bond angle is less than 1° (+ 0° 44' ) as shown by the

[( ; (109°.28' - 1080 »)= + 0°44' ]

expression and thus experiences minimum of angle strain. However, the presence
of five pairs of eclipsed C-H bonds should have caused an additional strain of
about 63 kJ/mol, bringing instability to the ring. These interactions, however, can
be minimized by puckering of the ring. Puckered conformation of cyclopentane
involves some angle strain, which is compensated by the reduction in C-H bonds
eclipsing effect, and the strain energy falls down to 27 kJ/mol due to the change
into non-planar conformation. The puckering is not fixed but rotates around the
ring in constant wave like motion. This effect is termed as pseudorotation (energy
barrier = 17 kJ/mol). Thus, cyclopentane exists in two non-planar conformations :
envelope form 17a and half-chair form 17b (Fig. 17).
Nonaromatic Heterocycles 131

H
H H
H

.. H H

H H
H
H H
H
envelope form half-chair form
17a 17b
Fig. 17. Conformations in cyclopentane

In the envelope conformation, four carbon atoms are in a plane and fifth carbon
atom is displaced outside the plane. The half-chair conformation has three carbon
atoms in a plane and the other two carbon atoms are placed one above and one
below the plane. In the forms 18a and 18b (Fig. 18) the numbers indicate (in A)
twisting of the carbon atoms above (+ive) or below (-ive) the plane. The
interconversion between two conformers does not involve substantial amount of
the potential energy and thus exists equilibrium between them.

-0.51 -0.10

+ 0.20 -0.37
+ 0.63 -0.60
+0.20 0

-0.51 + 0.37
18a 18b

Fig. 18. Numbers (in A) indicate out of plane twisting of carbon atoms

The carbon-carbon single bonds in cyc10pentane are some what longer (1.546A)
than the normal carbon-carbon single bond in alkanes (l.54A), which is accounted
for by the transannular type repulsions, since the distance between non-bonded
carbon atoms is smaller in cyclopentane (2.44A) than in alkane (2.545A)32.
132 Heterocyclic Chemistry

4.1.2 Conformations of Five-membered Heterocycles

The replacement of ring carbon of cyclopentane by heteroatom such as oxygen,

sulfur and nitrogen leading to five-membered heterocycles results in the change
in bond angles, bond distances and diminishing of C-H bond eclipsing
interactions. Five-membered heterocycles are non-planar and exist in two
conformers similar to cyclopentane; envelope and half-chair form. Five-membered
heterocycles are considered to prefer half-chair conformation with the heteroatom
in the middle of three atoms plane (three adjacent atoms coplanar), since this
conformation possesses minimum of non-bonded repulsive interactions between
remaining hydrogen atoms.
Tetrahydrofuran33,34 and pyrrolidinel4 are freely pseudorotating systems (or
slightly restricted in pyrrolidine) with pseudorotation among various half-chair and
envelope conformations. The half-chair conformations are slightly more stable than
the envelope conformations (barrier to pseudorotation is about 0.7 kJ/mol in
tetrahydrofuran). The appreciably increased size of the heteroatom in
tetrahydrothiophene results in the restricted rotation with higher energy barrier to
pseudorotation and preferentially adopts half-chair conformations.
2,3-Dihydrofuran and 2,3-dihydrothiophene are also non-planar in which C-2
methylene group is out of the plane of the other ring atoms with the energy barriers
to ring inversion of about 1 kJ/mol and 4 kJ/mol, respectively35,36. The higher
energy barrier for 2,3-dihydrothiophene is presumably due to a decrease in the
ring strain (due to increased size of sulfur than oxygen). Torsional forces are
comparable for both molecules and tend to overcome the lower ring strain forces
of dihydrothiophene and pucker the ring to a larger degree.

4.2 Conformations of Six-Membered Rings

Saturated six-membered heterocycles have many common conformational

characteristics with those of cyclohexane and its derivatives and as such
conformations of cyclohexane are being discussed to correlate with the
conformations of six-membered heterocycles and to determine the structural
factors affecting molecular conformations.

4.2.1 Conformations ofCyclohexane

Cyclohexane ring is puckered and exists in chair, boat and twist-boat conformations.
The chair conformation is the most stable and boat conformation is the least stable.
The stability of the twist-boat conformation is more than that of the boat but less
than that of the chair conformation.
Nonaromatic Heterocycles 133

4.2.1.1 Chair Conformation

Cyclohexane ring exists almost exclusively in chair conformation in which alternate

carbon atoms occupy two separate planes: 1, 3, 5 in one plane and 2, 4, 6 in the
other plane, with axial C-H bonds (a) and equatorial C-H bonds (e). The chair
conformation is slightly flattened becauses of the increased C-C-C bond angle
(111°), so that the dihedral angles between the adjacent bonds are 56° and C-H
axial bonds are not exactly vertical but directed outwards by 7°. The interaction
between Ie : 2e and Ie : 2a (skewed bonds) is known as 1,2-interaction, while
la : 3a (parallel bonds) interaction is known as 1,3-interaction or synaxial
interaction.
The interconversion of one chair conformation of cyclohexane into another chair
conformation requires 46.0 kJ/mol energy, however both the forms are identical
(Fig. 19). The chair conformation of cyclohexane is strainless and is (i) free of angle
strain, (ii) free of eclipsing strain because all C-H bonds are staggered and each
carbon atom exhibits tetrahedral arrangement, (iii) free of van der Waals strain as
the distance of adjacent H-atoms (249-251 pm) is greater than the sum of van der
Waals radii of two H-atoms (240 pm) and (iv) free of dipole-dipole interactions
because of carbon and hydrogen atoms.

Fig. 19. Chair conformation of cyclohexane with axial and equatorial bonds

4.2.1.2 Flexible Conformation

4.2.1.2.1 Boat Conformation

Cyclohexane ring may also assume a boat-shaped conformation (Fig. 20). Boat form
is free of bond angle strain because of the ring puckering: the C-C-C and
H-C-C bond angles are 109°28'. Boat conformation has four eclipsed C-H bonds
on C2-C3 and CS-C 6• Thus, appreciable eclipsing effect (torsional strain) brings
instability to the ring. In addition, van der Waals strain due to overcrowding
between flag pole H-atoms which are 1.85 A (185 pm) apart, closer than the sum
of van der Waals radii 2.40 A (240 pm), brings instability to the ring.
134 Heterocyclic Chemistry

H H

Fig. 20. Boat conformation of cyclohexane.

The boat form is sufficiently strained and contains 28.46 kJ/mol more energy than
the chair conformation.

4.2.1.2.2 Twist-Boat Conformation

The C-C bonds of the boat conformation are rotated in such a way that flagpole
hydrogen interaction and the eclipsing effect of four pairs of C-H bonds are
reduced, the conformation is known as twist-boat form. This conformation is the
most stable of the flexible conformations of cyclohexane (Fig. 21).

moving apart

moving together
Boat form Twist-boat form

Fig. 21. Flexible forms of cyclohexane

Nonaromatic Heterocycles 135

The twist-boat conformation has eclipsing strain but less than that in the boat
conformation. Flagpole hydrogen interactions are less in the twist-boat conformation
than that in the boat conformation. Thus, twist-boat conformation is less strained
than the boat conformation and its energy is 5.46 kJ/Iilolless than that of the boat
conformation, but 23.0 kJ/mol more than that of the chair conformation.

4.2.2 Conformations of Six-Membered Heterocycles

Six-membered heterocycles also assume chair, twist-boat and boat conformations.

The replacement of carbon atom(s) in t4e cyclohexane ring by heteroatom(s)
although causes changes in the conformational properties, six-membered
heterocycles exist almost exclusively in the chair conformation. The boat form is
less favourable because of its higher energy. The conformational properties of the
six-membered heterocycles are described in the light of the effects caused by the
introduction of the heteroatom(s).

4.2.2.1 Molecular Geometry (Shape of the Ring)

The replacement of carbon atom(s) in the cyclohexane ring by heteroatom(s) to

form six-membered heterocycles can alter the structural parameters because of the
introduction of electronic interactions due to the lone pair of electrons on the
heteroatom(s) and affects molecular geometry. The geometry (chair conformation)
of tetrahydropyran and piperidine are expected to be slightly more puckered than
then that of cyclohexane because of some what shorter C-O and C-N bonds.
The shape of six-membered rings3l can be determined by vicinal NMR coupling
constants. The coupling constant (J) between two protons depends on the number
of separating bonds, nature of neighbouring substituents and the dihedral angle
in vicinal protons. The coupling constant (J) is related to the dihedral angle by
Karplus equation (Eq. 8):
J=Acos2<p+C .....(8)
or J = A cos2<p .....(9)
(A is constant, C is very small and can be neglected)
However, this equation cannot be applied as such to the heterocyclic rings
because it is not possible to evaluate constant A for vicinal protons attached to
the atoms of different electronegativity (H-C-X-H or H-Y-X-H), as it depends
on the electronegativity and the orientation of substituents. This method involves
the use of two coupling constants that contain identical effect of the
electronegativity and the other factors included in Karplus equation37 • The ratio
of both the coupling constants determines the shape of the heterocyclic ring.
J (trans) A cos2<p (trans)
.....(10)
J (cis) A cos2<p (cis)
136 Heterocyclic Chemistry

J (trans) A cos2cp (trans) = R

J (cis) .....(11)
A cos2cp (cis)

J (trans)

J (cis) =
=

+
2
1
(Jaa + Jee)

(Jea + Jae)
J
The ratio R = J (trans) dose not depend on the electronegativity and the
J (cis)
orientation of substituents, but on the conformation38 •
The molecules with R = (1.9-2.2) adopt conformation 22 similar to that of
unsubstituted cyclohexane, i.e. chair form. A flattened distortion 23 in which the
methylene groups are more nearly eclipsed results in a decrease in the R-value and
a puckering distortion 24 causes an increase in R-value (Fig. 22). The ratio of the
coupling constants, therefore, gives a direct measure of the deviation of fragment
conformation from that of an undistorted cyclohexane (Table 5).

i€$:
\II H
R= 1.9-2.2 R = < 1.8
\11=56-58° \II = < 55°
22 23

R= > 2.3
\II = > 59°
24

Fig. 22. Relationship of conformation with R-value

Nonaromatic Heterocycles 137

Table 5. Ring shapes determined by R-value

Hetero group Segment J(trans) J(cis) R

(HJ (HJ
:NH a,~ 7.88 3.77 2.09 57
:N-CH3 a,~ 7.52 3.65 2.06 57
0 a,~ 7.41 3.87 1.91 56
S a,~ 8.15 2.96 2.65 61
S ~,y 8.47 3.28 2.58 ro
+
:SH a,~ 8.5 3.9 2.2 58
+
SCH31 a,~ 8.63 3.24 2.66 61

The R-value is related to the internal torsional angle \jf by (Eq. 12)39 :
Cos \jf = [3/(2 + 4R)]1I2 ..... (12)
Thus, the undistorted R-value 1.9-2.2 corresponds to a torsional angle of 56-58°
(which is in agreement with the nontetrahedral geometry of cyclohexane). The
flattened geometry (R < 1.8) corresponds to \jf = < 55°, and the puckered geometry
(R> 2.3) corresponds to \jf = > 59°. The R-value of 1.91-2.2 supports the chair
conformations of tetrahydropyran and piperidine.

4.2.2.2 Barriers to Ring Inversion

Six-axial and six-equatorial hydrogens of cyclohexane are chemically non-

equivalent and have different chemical shifts in NMR spectra. The axial hydrogens
appear at slightly higher field (0.4-0.5 ppm). However, at room temperature, NMR-
spectra of cyclohexane shows sharp singlet due to the rapid ring reversal than
NMR time scale and interchanging axial and equatorial hydrogens. At low
temperature, the rate of the ring inversion is decreased with the non-equivalent
hydrogens and the ring inversion is accompanied with the interchange of 1,3,5 and
2,4,6 carbon planes leading to the inverted chair conformation.
The ring inversion involves conformational change, but not in the configuration
and proceeds via boat and twist-boat conformations (Fig. 23).
Bond angle deformation in the chair form is accompanied by the increased
torsional energy and leads to the transition state (boat form) with high energy
(42-43 kJ/mol). The transition state is then changed into twist-boat conformation
which is without angle strain but with some torsional strain and corresponds to
the energy of 23 kJ/mol. The twist-boat conformation is converted to the inverted
chair conformation. Similarly, in six-membered heterocycles the process of chair-
chair ring inversion converts the ring to its mirror image and interchanges the axial
138 Heterocyclic Chemistry

I n m

--
IV v
Fig. 23. Ring inversion in cyclohexane

or equatorial nature of all the substituents (Fig. 24). The barrier to ring inversion
can be detennined by examining NMR-spectrum as a function of temperature.

--
Fig. 24. Ring-inversion in six-membered heterocycles

The transition state of chair-chair ring inversion is generally considered to be

the half-chair conformation in which four ring atoms are coplanar. Six-membered
heterocycles with one heteroatom have the choice of three such conformations
depending on the energy barriers (Fig. 25). The increased energy barrier in the
transition state is attributed to the increased torsional interaction and the bond
angle strain.
Torsional energy barrier of C-X bond (X = heteroatom) is different from the
C-C bond and, therefore, the energy barrier for the ring inversion in six-membered
heterocycles will be different from that in cyclohexane ring. The barriers to ring
inversion depend directly on the magnitude of the carbon-heteroatom torsional
Nonaromatic Heterocycles 139

~ X
(I) (II) (llI)

Fig. 25. HaIf-chair conformations of six-membered heterocycles

energy. If the C-X torsional barrier is lower than that of the carbon-carbon bond,
the transition state (I) is preferred, since heteroatom relieves the angle strain. If the
torsional barrier is higher, the transition state (III) is preferred because the
heteroatom is in the least eclipsed position of the ring. However, if there is little
difference between carbon-heteroatom and carbon-carbon torsional barriers, any
of the transition states (I-III) may be involved in the ring inversion.
The rate of ring inversion Kc may be obtained at coalescence temperature Tc by
(Eq. 13):
.....(13)

where Av is the chemical shift difference between two uncoupled nuclei at an

exchange and Eq. 14 is used for the process between coupled nuclei.

Kc =( ~ ) (All + 6P)112 .....(14)

+
The free energy of activation AG+ can be obtained by (Eq. 15).
+
AG+ = 2.3 RTc (10.32 + logTjKJ ......(15)
Free-energy of activation for the ring inversion of some six-membered heterocycles
is summarized in Table 6 :

Table 6. Free energy of activation for ring inversion of six-membered heterocycles

+
Compound AG+ (kJ/mol) Temperature
eC)
Cyclohexane (for comparison) 432 -67°C
Piperidine 43.6 -62.5°C
Tetrahydropyran 39.S -SO°C
Thiane 37.7 -93°C
140 Heterocyclic Chemistry

4.2.2.3 Pyramidal Inversion

Pyramidal inversion l2,4o is a characteristic property which distinguishes hetero-

atoms, nitrogen, oxygen and sulfur, from the tetravalent carbon atom. Trivalent
nitrogen atom in a conformationally flexible ring inserts another conformational
property to the ring. The hydrogen atom or substituent attached to the nitrogen
atom and the lone pair on nitrogen attain two equilibrating conformations due to
the pyramidal inversion of nitrogen.
Nitrogen containing flexible heterocycles, i.e. piperidine, undergo two types of
conformational changes; ring inversion and pyramidal inversion. Both the
processes are rapid and go side by side and cannot be separated from the
complicating set of conformations. The pyramidal inversion is the lower energy
process (E = < 42 kJ/mol) than the ring inversion (E = > 42 kJ/mol) and the ring
inversion process is slower than the pyramidal inversion of nitrogen (Fig. 26).

ring inversion..

H
I
R~N/H
P:::::/\;J
ring inversiot;

[)
R

Fig. 26. Pyramidal inversion and ring inversion in piperidine

Two inversions bring out the same conformational changes i.e. N-H (axial) to
N-H (equatorial) and vice-versa. The N-H prefers equatorial position in gas phase
and in non-interacting solvents. The energy difference between N-H (equatorial)
and N-H (axial) is approximately 1.68 kJ/mol. The alkyl group attached to nitrogen
also preferentially occupies equatorial position and the energy difference between
axial and equatorial methyl groups is 11.30 kJ/mol.
Nonaromatic Heterocycles 141

The ring inversion leads to the change in conformation, whereas the nitrogen
inversion (pyramidal inversion) results in the change in configuration. The
difference can be evident in 1,3-dimethylpiperidine (Fig. 27) :

H G
N ring inversion
~'CH3
>

CH 3
cis cis

~
S·
~
g'

CH 3
H I
ring inversion
~N~
CH 3
trans trans

Fig. 27. Ring inversion and pyramidal inversion in 1,3-dimethylpiperidine

The rate of pyramidal inversion is affected by the substituent on nitrogen and

by the attachment of nitrogen with other ring heteroatom and varies from one
heteroatom to another"I,42. An oxygen atom attached directly to nitrogen in the ring
decreases inversion rate to an extent that the nitrogen atom is almost locked
because the energy barrier to nitrogen inversion is raised. The energy barrier to
nitrogen inversion in hexahydropyridazine 25 is 48.5 kJ/mol (Fig. 28).

CH 3
I
r - - - - - ; N - CH3
f------- N~-CH3 C:::;;:NCH,
25a 25b

Fig. 28. Pyramidal inversion in hexahydropyridazine

142 Heterocyclic Chemistry

The oxygen heteroatom also illldergoes inversion, but it is not as interesting as

of nitrogen. The oxygen-inversion does not cause appreciable change because two
lone pairs of oxygen exchange their position during the atomic inversion. The
sulfur heteroatom in sulfur heterocycles behaves similarly towards atomic
inversion.

4.2.2.4 1,3-Diaxial Interactions

1,3-Diaxial interactions, referred to as synaxial interactions, are increased in six-

membered heterocycles due to shorter bond distance than in cyclohexane because
of increased puckering of the chair conformation in six-membered heterocycles.
2-Methyl-l,3-dioxane 2630,43 assumes two conformations (26a and 26b) in which
the conformer (26a) with equatorial methyl group is more favoured than in even
methylcyclohexane. The shorter c-o bond distance causes larger 1,3-diaxial
interactions in the conformer (26b) of2-methyl-l ,3-dioxane with axial methyl group
than in methylcyclohexane.

26a 26b

However, 1,3-diaxial interactions are considerably reduced when hydrogen is

replaced by a lone pair of electrons which are effectively smaller in the size than
that of hydrogen. 5-Methyl-l,3-dioxane 27 shows only a slight preference for the
conformer (27a) with equatorial methyl group. The conformer (27b) with axial
methyl group is preferred because in the axial conformation the interactions of
methyl group with lone pairs on oxygen are reduced. Bulky groups also adopt axial
position at C-5 due to very small 1,3-diaxial interactions43 •

27a 27b
Nonaromatic Heterocycles 143

4.2.2.5 Conformational Preferences of Substituents on

Heteroatom

In six-membered heterocycles bearing a substituent at the position-I, a simple

equilibrium exists between axial and equatorial conformations (Fig. 29). The
properties of the compounds exhibiting conformational isomerism cannot be
determined on the basis of any single rigid structure, but depend on the nature
of contributing conformers, their relative populations and their kinetic stability3l.
Different methods have been used to determine the conformational preferences of
the substituents attached on the heteroatom in six-membered heterocycles.

c:::JX: I
c
..
Fig. 29. Axial and equatorial conformations

4.2.2.5.1 TbennodynamicMethod

Conformational free energy (AGO) provides valuable information on the relative

stability of the conformers. The direct integration of resonances from both
interconvertible conformers in slow exchange NMR-spectrum gives equilibrium
constant K., from which AGO can be calculated (Eq. 16).
.1\GO = -RT InK. ......(16)
(.1\GO is usally negative and represents the free energy difference between
equatorial and axial conformers).
However, the failure to observe distinct resonances can arise beacause (a) only
one conformer is predominantly present in equilibrium (a biased equilibrium), (b)
slow exchange limit is not obtainable and (c) the spectra are fortuitously
superimposed.

4.2.2.5.2 Spectroscopic Methods

4.2.2.5.2.1 Vibrational Spectra

The separate vibrational bands in the vibrational spectrum for axial and equatorial
conformers also provide information on the conformational stability. The vibrational
time scale is adjusted in such a way that two separate bands are obtained. The
intensity ratio (of axial Ia and equatorial Ie) as a function of temperature, however,
gives enthalpy difference (MfO) between isomers (Eq. 17).
144 Heterocyclic Chemistry

...... (17)

where K( and K.z are equilibrium constants and T( and T z are temperatures.

4.2.2.5.2.2 NMR Spectra

Since vicinal coupling constants depend on the dihedral angle (H-C-X-H) and as
such coupling constants are used to identify whether a proton on the heteroatom
is axial or equatorial. The larger coupling constant in 29 is to be due to the axial
orientation of a proton on the heteroatom.

H
1+
£::::fS~
H
(J=14.1 Hz)

29

In NMR-spectrum ofthiane oxide 30 the axial isomer(a) invariably has the smaller
chemical shift difference (Au = 0.48 ppm) and larger coupling constant (J = 13.7
Hz), while the equatorial conformer (b) has larger chemical shift (Au = 1.87 ppm)
and smaller coupling constant (J = 11.7 Hz). However, the nature of the heteroatom
and the substituents alter the absolute values of these spectral parameters and
this criterion cannot be applied unless both the isomers are observed.

..

30a 30b
Nonaromatic Heterocycles 145

4.2.2.6 Conformational Preferences of lone Pair and Substituents

on Nitrogen

Piperidine and its derivatives with substituents on nitrogen only exist in the chair
conformation with R-value 2.06-2.09 and torsional angle 57°. Piperidine has been
controversial for the orientation of lone pair and hydrogen atom on the nitrogen
atom. However, considerable evidences have been given in the support of both
N-H axial and N-H equatorial conformations.
It is accepted that the large groups have a greater preference for the equatorial
conformation than the small group. Thus, the position of the equilibrium between
two conformations may be determined by the relative size of the N-substituent and
the lone pair (size of lone pair means its preference for equatorial position relative
to the other N-substituent).
Molecular polarizability and Kerr constant measurements of piperidines lead to
conclude that the lone pair is larger than a covalently bonded hydrogen atom and
the volume oflone pair is nearly comparable to that of the methyl group. The order
of smallest to largest is; NH : lone pair: N-CH344, and thus favours the preferred
conformation with N-H axial and lone pair equatorial. Moreover, microwave
studies also favour N-H axial conformation. Contrary to these studies, Katritzky
et a1. 45 have reported that a lone pair has smaller steric requirement than the
covalently bonded hydrogen atom which, in turn, is smaller than the methyl group.
The order of the size : N-CH3 > N-H > lone pair, favours N-H equatorial
conformation46 •

Evidences in favour ofN-H equatorial:

(i) IR-spectrum of gaseous piperidine shows two bands in the N-H ftrst
overtone region which can be ascribed to the N-H equatorial and N-H axial
conformations. The ratio of the band absorbances indicates an enthalpy
difference of 2.1 kJ/mol favouring N-H equatorial conformation.
(n) Dipole moment of 4-p-chloromethylpiperidine favours N-H equatorial
conformation by 2.2 kJ/mol (0.4-0.5 kcal/mol).
(ill) The axial position of the lone pair on nitrogen (N-H equatorial) can be
evidenced by the chemical shift difference criterion in NMR-spectra31 ,47. The
chemical shift difference (oae) between the axial and equatorial positions of
piperidine is larger (0.44 ppm similar to cyclohexane = 0.4-0.5 ppm) with the
axial protons at higher fteld. The enhanced value of oae is attributed to the
interaction between axial C-H group and a vicinal lone pair (axial position)
on nitrogen. Thus, the larger oae value should occur with an equatorial
N-H conformation.
146 Heterocyclic Chemistry

Evidences in favonr ofN-alkyl equatorial:

In N-alkylpiperidines, the conformer with equatorial alkyl group and with axial lone
pair is favoured. The evidences in favour of equatorial position of N-alkyl group
are:
(i) Dipole moment studies suggest the piperidine conformation with alkyl
group in equatorial position and lone pair on nitrogen in axial position.
(ii) Infrared spectral studies of the Bohlmann bands appearing in the region
2500-2820 cm- 1 indicate that the lone pair on nitrogen is axially oriented,
while N-alkyl group is in the equatorial position.
(Iii) Chemical shift difference (oae) criterion in NMR-spectra suggests the
equatorial position of the alkyl group and axial position of the lone pair on
nitrogen. The larger chemical shift difference (oae) for N-methylpiperidine
(oae = 0.94 ppm) is due to the interaction of vicinal axial C-H proton with
axial lone pair on nitrogen because such interaction leads to the shielding
of proton. The enhanced chemical shift difference (oae) occurs only with
equatorial N-C~ and axial lone pair.

5 STEREOELECTRONIC EFFECTS IN
SATURATED SIX-MEMBERED
HETEROCYCLES
(ANOMERIC AND RELATED
EFFECTS)48,49

The presence of one or more heteroatoms in the ring affects the conformational
preferences and hence conformational properties of the heterocycles due to the
existing stereoelectronic effects.

S.l Anomeric Effect

This effect was first studied in pyranose sugars and observed that the
electronegative groups (halogen, acetoxy, methoxy, hydroxyl, amino etc.) situated
on the carbon atom adjacent to oxygen in the pyranose ring prefer axial orientation.
Nonaromatic Heterocycles 147

2-Alkoxytetrahydropyran 31 assiimes two possible conformations; with an

equatorial31a and axial substituent 31b. The conformation with axial alkoxy group
is preferred over the equatorial orientation and attributed to the anomeric effect.

OR

~ H

31a 31b

The anomeric effect is defined as the extra preference for axial orientation of an
electronegative (polar) substituent attached at the anomaric carbon, i.e. a. to the
ring heteroatom. Quantitatively, anomeric effect may be defined as the free energy
difference between the axial and equatorial conformers (Geo-GaO) plus the
conformational free energy (aGO) of the substituent (which is assumed to be similar
as in cyc1ohexane). Thus, the anomeric effect can be represented as :
Anomeric effect of axial substituent = (G.o-GaO) - aGO axial substituent

Explanation:
The anomeric effect is caused by the interaction of an exocyclic polar substituent
(electronegative group) with an endocyclic heteroatom and forces the molecule to
adopt the stable conformation. The anomeric effect is considered to be contributed
by:
(i) Non-bonding interactions and (li) dipole-dipole interactions.
(i) Non-bonding interactions: The anomeric effect is contributed partly due to
the non-bonding interactions of the non-bonding lone pair electrons on the
heteroatom with the 0'* antibonding orbital of the antiparallel a-bond of carbon
with an electronegative group. The anomeric effect can be explained by
considering X-C-Y fragment of cyclic system in which X is a heteroatom with lone
pair electrons and Y is an electronegative substituent with antiperiplanar
a-bond and can be represented as (Fig. 30) :

>Q C--
cf'
Fig. 30. Anomeric effect : antiperiplanar interaction of lone pair and a-bond
148 Heterocyclic Chemistry

Thus, n-cr* interaction results in the transfer of electron density from the lone pair
to the cr*orbitals with the strengthening of C-X bond due to the introduction of
double bond character and the weakening of C-Y bond.
(ii) Dipole-dipole interactions : Dipole-dipole interactions also contribute to the
anomeric effect by which an equatorial orientation of the substituent is destabilized
with respect to an axial orientation of the polar group (Fig. 31). The instability of

.x I
~ =;--;0
t
o~~
X
unfavourable orientation favourable orientation
ofC-X bond ofC-X bond

Fig. 31. Representation of dipolar interactions

the equatorial orientation is considered to be caused by the unfavourable

orientation of the dipole of C-X bond and of the ring oxygen (orientation of free
electron pairs) because two dipoles are parallel. The dipole interaction of ring
oxygen and C-X bond (electronegative group) is more favourable when the
orientation of substituent X is axial because two dipoles are divergent.

5.1.1 Factors Affecting Anomeric Effect

5.1.1.1 Effect of Substituents

The magnitude of the anomeric effect depends on the electron donor capacity of
the heteroatom and the acceptor capacity of the electronegative substituent. It
decreases in the following order :
+
Halogens> C6H sCOO > CH3COO > RO > RS > HO > NH2 > N
The magnitude of the anomeric effect is not considerably affected with an increase
in the size ofR (methyl, ethyl, propyl, butyl, etc.) in alkoxy group (OR).

5.1.1.2 Solvent Effect

The equilibrium of the equatorial-axial conformers is influenced by the nature of

the solvent. The proportion of axial conformer in solution decreases with
Nonaromatic Heterocycles 149

decreasing dielectric constant of the solvent because the equatorial conformers are
more polar. The equatorial form increases with increasing dielectric constant since
the dipole-dipole repulsion diminishes.

5.1.2 Consequences of Anomeric Effect

5.1.2.1 Bond distance

The bond distances are considerably affected in the heterocycles exhibiting

anomeric effect. cis-2,3-Dichloro-l ,4-dioxane 32 with chloro group in both axial and
equatorial positions exhibits abnormally long and short bond distances. The axial
C-CI bond is longer (1.82 A) than the equatorial C-CI bond (1.78A), whereas the
C-O bond, adjacent to the axial C-CI bond is shorter (1.39A) than the normal
C-O bond (1.42 A) (Fig. 32).
C2-0 1 = 1.39 A
5 6 0 C2-CI = 1.82 A
4~1
0--,../3 1 2
C3-CI = 1.72 A
CI CI C3-04 = 1.42 A
32

Fig. 32. Bond distances in cis-2,3-dichloro-l,4-dioxane

However, the bond distances in 2-alkoxytetrahydropyran 33 are not considerably

changed because the exocyclic c-o bond (carbon-alkoxy group) can rotate in such
a way that the lone pair on exocyclic oxygen becomes antiperiplanar to the ring
carbon-oxygen bond. The anomeric effect is exerted in the opposite direction
causing it less effective (Fig. 33).

33a 33b

Fig. 33. Anomeric effect in both directions

150 Heterocyclic Chemistry

5.1.2.2 Chemical Reactivity

The anomeric effect results in the weakening of the bonds antiparallel to the lone
pairs on heteroatom and thus affects chemical reactivity of the molecule. Cyclic
acetal 34 with an axial substituent is much more reactive than with an equatorial
substituent and is easily hydrolyzed. The reactivity is attributed to the bond
weakening effect due to the anomeric effectSo •

equatorial axial

34a 34b

The bond weakening effect due to anomeric effect is also exhibited by other ring
systems. Tricyclic orthoamide 35 adopts the conformation in which the lone pairs
of nitrogen atoms are antiperiplanar to the C-H bond and involves anomeric effect
causing weakening of the C-H bonds1 ,s2.

3S

5.2 Other Related Effects

5.2.1 Reverse Anomeric Effect

The direction of the anomeric effect is reversed when the partial charge on a given
substituent is to be positive instead of a negative (pyridinium type). The effect is
Nonaromatic Heterocycles 151

known as reverse anomeric effect. The conformer with equatorial orientation is

preferred (Fig. 34). The reverse anomeric effect is attributed to the attractive
interaction of the dipoles which contribute to the conformational energy of the
substituents, thus results in predominance of the equatorial conformation.

~
(iJ
N

N
H

Fig. 34. Reverse anomeric effect

5.2.2 Double Anomeric Effect

1,3-Dioxanes substituted with an electronegative substituent at the position-2 36

exhibit double anomeric effect. The conformer with the substituent in an axial
orientation is preferred over the equatorial conformer. However, the synaxial
interactions of an axial substituent with the axial hydrogen atoms at C4 and C6 exist
due to the shortened carbon-oxygen bond by the anomeric effect.

..... CH 3

~
HH1A
.... O~/ 'H
5 4 0
3

36

5.2.3 Rabbit-Ear Effect (Lone Pair-Lone Pair Interactions)

This effect involves the interaction of endocyclic heteroatoms in 1,3-position with

each other. In the six-membered rings containing two heteroatoms in 1,3-positions,
the conformation in which two lone pairs on two heteroatoms are synaxial is
destabilized by the lone pair-lone pair repulsion (Fig. 35). This destabilizing effect
of 1,3-synaxial lone pairs is known as rabbit-ear effectS3 • Thus, the most stable
conformation will be with the least number of rabbit-ear effects.
152 Heterocyclic Chemistry

Fig. 35. 1,3-Synaxiallone pair-lone pair interactions (Rabbit-ear effect)

The preference of an axial orientation 37b over an equatorial orientation 37a of

the substituent is attributed to the destabilizing effect of 1,3-synaxiallone pair-lone
pair repulsion. The preferred axial orientation of an alkoxy substituent on C-2 in
2-alkoxy-l,3-dioxane can be explained similarly on the basis of rabbit-ear effect.

destabilized conformer
o
DO~NG
~
stabilized conformer
37a 37b

5.2.4 Repulsive-Gauche Effect (Hockey-Sticks Effect)

In l,4-dioxanes, the axial orientation of an electronegative substituent (polar group)

on the a-carbon 38 is preferred over the equatorial orientation, although to a lesser
extent than in 1,3-dioxanes. This is attributed to the anomeric effect resulting from
the interaction between endocyclic oxygen and exocyclic polar group.

~H X

38
Nonaromatic Heterocycles 153

In 1,4-oxathianes, the conformer with an equatorial orientation of the electro-

negative substituent (polar group) on the a.-carbon atom is much more preferred
than that with an axial orientation. The destabilization of the conformer with axial
orientation of substituent 39 is ascribed to the effect known as repulsive-gauche
effect (hockey-sticks effect) (Fig. 36). The repulsive-gauche effect is contributed
by the repulsive interactions between p-orbitals of the electronegative substituent
and the lone pair orbital on the heteroatom, which are absent when interacting
orbitals are antiparalleL The magnitude of the effect is increased with increasing
the size of heteroatom and thus the effect in 1,4-oxathianes is much more
pronounced than in 1,4-dioxanes because of the larger atomic size of sulfur.

Of::::1H
o OXC)
39

Fig. 36. Repulsive gauche effect (hockey-sticks effect) in 1,4-oxathianes

Thus, the molecule exhibiting hockey-sticks effect is forced to adopt the

conformation with an equatorial orientation of the substituent to minimize the
repulsive interactions (lone pair-lone pair interaction) (Fig. 37).

0c:1
o OXC)
H

39a

Fig. 37. Preferred conformation in 1,4-oxathianes

5.3 Attractive Interactions 'Through Space'

5.3.1 Intramolecular Hydrogen Bonding

In certain cases, the ring heteroatoms are involved in the intramolecular hydrogen
bonding formation with OH and ~ groups present in the heterocyclic molecule
and affect the conformational preferences of the heterocycles.
154 Heterocyclic Chemistry

5-Hydroxy-l,3-dioxane 40 exists in the preferred conformation with an axial·

hydroxyl group to form hydrogen bonding with the ring oxygen atom (Fig. 38).

R1
0 ............ ,,'
H
40
Fig. 38. Hydrogen bonding in 5-hydroxy-l,3-dioxane

3-Hydroxypiperidines 41 also exist preferantially in the conformation with an

axial orientation of hydroxyl group (Fig. 39).

41a 41b
Fig. 39. Hydrogen bonding in 3-hydroxypiperidines

5.3.2 Intramolecular Nucleopbilic-Electropbilic Attractive Interactions

The attractive interactions between nucleophilic centre and electrophilic centre

within the same molecule affect conformational preferences in the heterocycles.
3-Phenyl-3-benzoyltropane 42 involves interactions between nucleophilic centre
and electrophilic centre (transannular interactions) which force the molecule to
adopt the boat conformation.

42
Nonaromatic Heterocycles 155

The comparison of IR and UV spectra of 3-phenyl-3-benzoyltropane 42 with

3-benzoyltropane 43 shows the normal bands of the carbonyl group in 3-benzoyl-
tropane and not in 3-phenyl-3-benzoyltropane. This is considered to be a
consequence of the flipping of the piperidine into the boat form and of the
transannular interactions of the nucleophilic nitrogen with an electrophilic
carbon of the carbonyl group, whereas such interactions are not present in
3-benzoyltropanes4 •

43

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156 Heterocyclic Chemistry

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in Heterocyclic Chemistry, Wiley-Interscience, New York, 1984, pp. 314.
22. C. A. Renner and F. D. Greene, J Org. Chem. 41,2813 (1976).
23. W. L. F. Armarego, Stereochemistry of Heterocyclic Compounds Part-I,
Wiley-Interscience, New York, 1977.
24. G. Kobrich, Angew, Chem. Int. Edn. Engl. 12,464 (1973).
25. K. B. Becker and C. A. Gabutti, Tetrahedron Lett. 1883 (1982).
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Academic Press, New York, 1972.
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32. W. J. Adams, H. J. Geise and L. S. Bartell, JAm. Chem. Soc. 92,5013 (1970).
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A. L. Esteban and E. Diez, Can. J Chem. 58,2340 (1980);
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37. J. B. Lambert, Accounts Chem. Res. 4,87 (1971).

38. J. B. Lambert, J. Am. Chem. Soc. 89, 1836 (1967).
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J. B. Lambert, Top. Stereochem. 6, 19 (1971); W. L. F Armarego,
Stereochemistry of Heterocyclic Compounds Part-I, Wiley-Interscience,
New York, 1977,pp.157.
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20,521 (1981).
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Proc. Chem. Soc. 257 (1964).
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3345 (1964); N. L. Allinger, J. G. D. Carpenter and F. M. Karkowski, J. Am.
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Lambert, R. G. Keske, R. E. Carhart, and A. P. Jovanovich, J. Am. Chem. Soc.
89,3761 (1967).
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Oxygen, Springer-Verlag, Heidelberg, 1983.
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Consequences, ACS Symposium Series No. 87, Am. Chern. Soc.,
Washington, D.C., 1979.
SO. J. Kirby and R. J. Martin, J. Chem. Soc. Chem. Commun. 803 (1978).
51. T. J. Atkins, J. Am. Chem. Soc. 102,6364 (1980).
52. J. M. Erhardt, E. R. Grover and J. D. Wuest, J. Am. Chem. Soc. 102, 6365
(1980).
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CHAPfER 5
HETEROCYCLIC SYNTHESIS

CONTENTS

1 GENERAL 160
2 TYPES OF REACTIONS 160
21 Cyclization Reactions 160
21.1 Nucleophile-Electrophile Cyclization 161
2.1.1.1 Intramolecular Nucleophilic Substitution 165
2.1.1.2 Intramolecular Nucleophilic Addition 173
to Double Bonds
2.1.1.3 Intramolecular Nucleophilic Addition 188
to Triple Bonds
21.2 Radical Cyclizations 194
21.3 Carbene and Nitrene Cyclizations 200
21.4 Electrocyclic Reactions 211
22 Cycloaddition Reactions 225
221 1,3-Dipolar Reactions [3 + 2~5] 225
22.2 [2 + 2~4] Cycloadditions 246
223 Hetero-Diels-Alder Reactions 249
[4 + 2~6] Cycloadditions
224 Cheletropic Reactions 260
2.24.1 [2 + 1] Cycloadditions 260
2.24.2 [4 + 1] Cycloadditions 261
2.25 Valence Bond Isomerization 261
23 Ene Reactions 265
REFERENCFS 267
160 Heterocyclic Chemistry

1 GENERAL

General methods of heterocyclic synthesis involve ring formation and the choice
of method for .the synthesis of a particular heterocycle depends on:
(i) size of the ring being synthesized,
(li) degree of WlSaturation required and
(ill) pattern of substituents required.
The nature of the ring closure reaction is ~ost1y dependent upon the size of the
ring being synthesized and its degree of WlSaturation than upon the type(s) of
heteroatom(s) present. A large number of methods of wide variety are available for
the synthesis of heterocyclic compounds. Here an attempt is made to give a few
general guidelines (for most common ring sizes and heteroatoms).
(i) In the synthesis of a monocyclic compound, the ring closure step often
involves the formation of carbon-heteroatom bond.
(li) If the system contains two adjacent heteroatoms, it is unusual for the ring
closure step to involve heteroatom-heteroatom bond formation (except in
the cases where nitroso, nitro, nitrene or diazonium group acts as
electrophilic moiety).
(ill) A bicyclic ring system is formed almost invariably by the annelation of
second ring on a monocyclic compound.

2 TYPES OF REACTIONS

The reactions involved in the ring synthesis can be broadly classified into two
groups. In the first group of reactions, a single bond is formed in the ring closure
step. Such reactions are known as cyclization reactions. The second group of the
reactions involves the simultaneous formation of two bonds between usually two
different molecules without elimination of small molecules. Such reactions are
called cycloaddition reactions. However, in practice there is not always a clear-cut
distinction between the two groups. This simple classification is followed here.

2.1 Cyclization Reactions

In the cyclization reactions, n-membered ring is formed by the cyclization of a chain

of 'n' atoms. Cyclization reactions i.e. ring closure reactions comprise intramolecular
variants of the reactions, the most common of which involve the interaction
between electrophilic and nucleophilic centres.
Heterocyclic Synthesis 161

2.1.1 Nueieophile-Eieetrophile CyeIization

Such kinds of reactions can occur either between a binucleophile and a

bielectrophile or between two molecules. each containing both nucleophilic and
electrophilic centres. The various types of possible interactions are shown in Fig.l.

Fig. 1

Heterocyclic compounds of different ring sizes can be constructed by such

interactions. Baldwin has suggested a systematic method for classifying the
various types of nucleophilic-electrophilic cyclization processes'. One of the
important factor which determines the feasibility of a ring closure is the geometry
of approach of the nucleophile to the electrophile in the transition state. The
geometry of these transition states has led to the formulation of Baldwin rules for
ring closure'. If a transition state is obtained with a serious distortion of the normal
bond angles or distances, it follows that the ring closure will occur with difficulty
(or not at all) and such processes are called 'disfavoured'. A 'favoured' process
occurs more readily than one which is 'disfavoured'. However, it does not mean
that a 'favoured' process will necessarily occur readily in every case. It depends
on the other factors also in addition to the angle strain (i.e. distortion of the normal
bond angles), such as unfavourable sterlc interactions and distance factor. The
efficiency of a cyclization reaction also depends upon the free energy of activation
AG++, which consists of enthalpy (AH++) and entropy (T AS++) terms (Eq. 1) :
AG++ = AH++ + TLlS++ •••••(1)
where T is the absolute temperature.
A nucleophilic attack at a tetrahedral carbon occurs at the side opposite to that
occupied by the leaving group and the resulting transition state has an N-C-Y
angle of 1800 (scheme-I). The attack of a nucleophile on a trigonal carbon (as in
162 Heterocyclic Chemistry

R
h\~f'
N .C-y
8- I 8-
N- - -C----y ----t.~ N-C
/R _
+ Y
\,
c
"
~
H
\,.
~
H H
~".
H
~~H
H
Scheme-l

carbonyl carbon) takes place preferentially from above or below the plane of the
molecule at an angle of 1090 to C=Y bond (scheme-2). The reactions in which the

, N
111111'\
··C-Y
_

Scheme-2

electrophilic carbon is diagonal (as in alkyne/cyano group), the approach of the

nucleophiJe is at an angle of 600 to C=Y bond (scheme-3).

N
-
N
120" 1.
12W(&~ ---Cc) 12<1'
~­
I Y

Scheme-3

Baldwin's classification of cyclization i.e. ring closure reactions is based on three

considerations:
(i) size of the ring being synthesized,
(n) whether the atom or group Y is a part of the ring system (endo) or lies
outside the ring being synthesized (exo) (scheme-4) and
(m) geometry of the electrophilic carbon (tetrahedral, trigonal or diagonal).
Heterocyclic Synthesis 163

o
N * Y

Exo

-
Y

Scheme-4

Thus, a reaction of the type depicted in scheme-S can be classified as 6-Exo-Tet

(6-membered ring, Y outside the ring being formed, tetrahedral carbon undergonig
substitution).

n+ N-C-
I
-
Y

Scheme-5

Baldwin's rules for the cyclization reactions involving the nucleophilic atom of
a first row element e.g. C, N or 0 are summarized as :
Rille No.1 (for tetrahedral systems): (scheme-6)
3 to 7-Exo-Tet are all favoured.
5 to 6-Endo-Tet are disfavoured.
Rille No.2 (for trigonal systems): (scheme-7)
3 to 7-Exo-Trig are favoured.
3 to S-Endo-Trig are disfavoured.
6 to 7-Endo-Trig are favoured.
164 Heterocyclic Chemistry

3-Exo-Tet 4-Exo-Tet 5-Exo-Tet 6-Exo-Tet

7-Exo-Tet 5-Endo-Tet 6-Endo-Tet

Scheme-6

N~
L/
3-Exo-Trig
t,l1
4-Exo-Trig
V1
5-Exo-Trig
01
6-Exo-Trig

QCy
N
N
L/
/Q ~
N/'...Y
~II)
rY(J
U
7-Exo-Trig 3-Endo-Trig 4-Endo-Trig 5-Endo-Trig

C"~ ('):".;)
V U
6-Endo-Trig 7-Endo-Trig

Scheme-7
Heterocyclic Synthesis 165

Rule No.3 (for diagonal systems): (scheme-8)

3 to 4-Exo-Dig are disfavoured.
5 to 7-Exo-Dig are favoured.
3 to 7-Endo-Dig are favoured.

N~rtV
"'L,/ 01 q Gl~ N Y

3-Exo-Dig 4-Exo-Dig 5-Exo-Dig 6-Exo-Dig

(rl u ~~ f)
0
()
/v= rv~
N v~ L/
7-Exo-Dig 3-Endo-Dig 4-Endo-Dig 5-Endo-Dig

(l
N v~
LIII
n~~~
0
6-Endo-Dig 7-Endo-Dig

Scheme-8

An intramolecular nucleophilic substitution reaction is an exo-tet process.

Nucleophilic addition and addition-elimination reactions of the carbonyl compounds
are exo-trig processes. In addition to these, heterocycles can also be prepared by
the intramolecular radical cyclization, carbene and nitrene cyclizations and by
electrocyclization of the conjugated x-electron systems, all of which are included
in the succeeding sections.

2.1.1.1 Intramolecular Nucleophilic Substitution

Synthesis of heterocyclic compounds by intramolecular nucleophilic displacement

at a saturated carbon atom is an exo-tet process. Examples of such intramolecular
cyclization reactions include the synthesis of oxiranes (epoxides), aziridines,
lactones, furans, azetidines, etc. The convenient formation of the five-membered
rings are due to the best balance between enthalpy and entropy forms.
166 Heterocyclic Chemistry

Three-membered heterocycles can be conveniently prepared by intramolecular

cyclization reactions, which occur by the back-side attack of heteroatom at the
carbon atom bearing the leaving group with inversion of configuration
(scheme-9). An important method of synthesizing an mcirane ring involves various

fJ,H
i~1 -HX

C*
-C-C-

I
Y=O,NH,S
X = halogen

Scheme-9

ring closure reactions. For example, a trans-chlorohydrin (obtained by the addition

of hypochlorous acid to an alkene) wdergoes a bimolecular dehydrohalogenation
in the presence of a base resulting in cyclization to an oxirane ring (scheme-IO)2.

alkali
• ~A
_-C-I-t..

()CH~OCl O'I~C;
---t.~
.\
\CI

Scheme-IO

The kinetic and products study of the basic decomposition of a series of methyl
substituted I,3-halohydrins in aqueous methanol shows that the fragmentation
reaction competes with the ring closure3 and the cyclic products are formed in poor
yields (scheme-II).
The cyclization of erythro- and threo-3-bromo-2-hydroxybutanes yields trans-
and cis-epoxides, respectively (scheme-12)4. The rate of ring closure is favoured
by the presence of substituents at C-2, e.g., I-chloro-2-methyI-2-propanol cyclizes
eleven times faster than I-chloro-2-propanol. Epoxide formation occurs several
thousand times faster in diaxial3b than in diequatorial isomer 3a (scheme-I 3)5.
Heterocyclic Synthesis 167

U
CH 20H base
•
I
CH 2CH 2CI CH30H
14%
+==V0H +
~c:
+
OCH 3 OH

(CH 3hC-OH
I
CH 2CH 2CI
base
CH30?
-b 81%
+
=X H

(CH 3hC-CH 2CI

I
CH 20H
base
CH30H •
-b 4()01o
+
>=
Scheme-II

?
H3C~H _
OH
HO Br c ..

H\'
CH3

la (erytbro) 2a (trans)

~CH3
HO y... Br ::::::;::OH::::::>:::::::
H¥ CH 3

Ib (thero) 2b (cis)

Scheme-12
168 Heterocyclic Chemistry

H
Br
HO~'--......

H I
alkali slow
3a +
CH 3

H
3c

alkali
OH
t fast

CH 3
H

H
3b

Scheme-13

Another significant ring closure reaction is Darzens condensation6 • It yields an

intermediate 4b by the reaction of a carbonyl compound with a.-halo ketones or
a.-halo esters 4a under the basic conditions which cyclizes by an internal
nucleophilic displacement process (scheme-14). Like oxiranes, thiiranes 5b have
been prepared

4c
Scheme-14
Heterocyclic Synthesis 169

by the cyc1ization of 2-halo mercaptans 5a with an alkali (scheme-IS)? The

I alkali
-C-SH
-C-CI
I •
I
Scheme-15

cyclization of trans-2-chlorocyc1ohexanethiol 6a in the presence of sodium

bicarbonate provides cyc10hexene sulfide 6b (scheme-16)8.

ct 6a
SH
NaHCO••
0>
6b

Scheme-16

The best preparative methods for the aziridines involve cyclization reactions. One
of these is Gabriel ring closure method9 which involves an intramolecular displacement
of halogen atom by a free amino group. The cyclization is stereospecific and occurs
with the inversion at a carbon bearing the leaving group (scheme-17).

H HsCs H

H"'\ /~CsHs
~ ~
.~~ KOH
H2~~H5 EtOH
•
N
-§ I
HsCs H H
7a (erythro) 8a (trans) 80%
HsCs ~PsHs
CsHs

H"'\ /~H
.~~ KOH
~ .'
•
H~~
-§
EtOH
N
I
HsCs H H
7b (thero) 8b (cis) 96%
Scheme-17
170 Heterocyclic Chemistry

Wenker method also involves the conversion of J3-amino alcohol 9a to J3-amino

hydrogen sulfate 9b, followed by cyclization in the presence of a base
(scheme-18)lo.

H+
_ HsCs '\7
CaHs-CH-CH 2
1 1 ---....
OH NH2 H2SO4
CaHs-CH-CH 2
H03SO
1 +.1
NH3
OH
.1.
.. N
H
9a 9b 9c

Scheme-18

Hassner synthesis involves stereospecific addition of iodoisocyanate to an

alkene via trans-addition with the formation of iodoisocyanate 10c which on
treatment with methanol and subsequent cyclization under basic conditions yields
an aziridine derivative lOr (scheme-19)11.

Scheme-19

a-Lactones 11b have been prepared by the cyclization of ro-bromoalkanoic acids

11a in the presence of a strong base (scheme-20)l2. The rate constants for the
lactonization in 99% dimethyl sulfoxide for ring sizes n = 3-16, 18 and 23 have
shown that the formation of four-, five- and six-membered rings are especially
favourable. a-Lactams 13a,b are obtained by the cyclization ofN-halo- or a-halo
tert-butyl amides with a strong base (scheme-21)13. The cyclization of
J3-chlorohydroxomates 14a yields J3-lactams 14c (scheme-22)14.
Heterocyclic Synthesis 171

/0
-Bl
(CH:Vn"
n= 1-21
b= 0

118 11b

Scheme-20

CSH5CH-C=0
, I
N
I
128 138 C(CH 3h

Cf
Br O=OC
N-C(CH 3)
(CHJ3COK+
C-N-C(CH 3h - - -......~
II H
o
12b 13b

Scheme-21

NaH
DMF

148 14b

Scheme-22
172 Heterocyclic Chemistry

The ring closure procedures have also been used to prepare furans. The
reactions of J3-keto esters and J3-diketones with allenic salts 1Sa produce furan
derivatives in high yields1s • The sulfonium group renders the 1,2-carbon-carbon
double bond of allene extremely susceptible to nucleophilic addition and itself is
readily displaced by the nucleophilic attack at the adjacent carbon atom (scheme-23).

+
CH3COCH2C02C2H5 + (CH3)2SCR1=C=CHR2
1Sa
C2H50-C2H50H

,...-----'-------, R1 =H
R2 =CH 3

1Sc

-(CH 3hS C2H50 ~

~CHCH3
H C-C 7
2, \
0, ~C-C02C2H5
C
I
CH 3
1Se

/
H3C-H2Ct!:.2C2H5

o CH 3
1Sf

Scheme-23
Heterocyclic Synthesis 173

Another cyclization reaction for the synthesis of furan derivatives is Fiest-

Benary synthesis16• It consists in aldol condensation of a-halo ketone or
a-halo aldehyde with (3-keto ester or (3-diketone in the presence of a base. The
ester anion attacks the carbonyl group of a-halo ketone followed by the formation
of an intermediate 16b and cyclization by the intramolecular displacement of
chloride ion with the loss of water molecule (scheme-24).

COOR
I
CH2
COOR
Hz;) (
°
CH3
I NaOH
C=O .. /C~ CH2C1
I
CH3
H3C GO
16a

Scheme-24

2.1.1.2 Intramolecular Nucleophilic Addition to Double Bonds

The intramolecular nucleophilic attack at the carbonyl group of aldehydes,

ketones, acid halides, esters, etc. comprises the most common method for the
synthesis of some common heterocycles viz. pyrrole, thiophene, indole, quinoline,
isoquinoline, etc. In some cases, cyclization involves the attack by nucleophilic
carbon. The Madelung synthesis of indole involves the cyclic dehydration of
N-acylated o-toluidine 17a in the presence of a strong base at high temperature
(scheme-25) 17. Hinsberg thiophene synthesis involves the reaction between
a-diketones and thiodiacetates 18b (scheme-26)lB. In Knorr pyrrole synthesis
the cyclization step also involves the nucleophilic attack at the carbonyl carbon,
followed by the loss of water molecule. It is an acid catalyzed reaction
(scheme-27).
Some cyclization reactions occur through the nucleophilic heteroatoms e.g.,
Paal-Knorr pyrrole synthesis, Robinson-Gabriel oxazole synthesis, Reissert indole
synthesis etc. Paal-Knorr method19 for the synthesis of pyrrole (condensation of
174 Heterocyclic Chemistry

o
II
HCCI
...

CO
~
l' N
H
17c
Scheme-25

~~
CH2COOR RO(C- CH 2
I _ + \
S (CH)3COK _
1_ .. 0 S
CH (C~)3C-OH I /
I C H -C-C-CH
COOR 6 5 II I \.
o C6H5 COOR
18a 18b 18c

o LeaH, f) l) I
~~s ..-.-_OR_ R~~=C-C6H5 S

6~COOR 0 COOR
H C6 5 H~ CsH5
18e OC(CH 3h 18d H

+0II H5 C6 C6 H5
H5C6-C-C- C6H5
II - + ... ):( - +
ROOC-C ...... CH2COOK ROOC S COOK
's
18f 18g

Scheme-26
Heterocyclic Synthesis 175

CH3
b=o + {COOR
1H ........---..... -H20
?H3jCOOR
C= 0
/ C (~ • I
ROOC "vo CH
NH2 ~ CH3 ROOC/ 'N CH3
I 19a

H3C~OH HsC ~O COOR

ROOC f) COOR L y~(
H
+~
~ CH3
ROocA'N~CH
H 3

1ge ~-H 19b

-~~ ~~R
ROOC N CH3
H
19d
Seheme-27

1,4-diketone with ammonia or primary amine) involves the nucleophilic attack

of an amino group at the carbonyl carbon followed by the cyclic dehydration
(scheme-28).

20a 20b

~
.. ---2H20 I
H3C N CH3 -H+
H
20e
Seheme-28

In Reissert indole synthesis, o-nitrophenyl pyruvate 21a obtained by the

condensation of o-nitrotoluene with oxalic acid ester undergoes reductive
176 Heterocyclic Chemistry

cyclization involving nucleophilic attack at the carbonyl carbon to yield indole

(scheme-29)20. Robinson-Gabriel oxazole synthesis presents an example where
cyclization occurs by the nucleophilic attack at a carbonyl carbon by the acylamino
group in a-acylamino ketones 22a, followed by dehydration to yield oxazole 22e
(scheme-30)21. Synthesis of benzo-fused heterocycles involves the nucleophilic
attack of an ortho carbon of the o-substituted benzenes on the carbonyl carbon.
One such example is the Skraup synthesis22 of quinoline (scheme-31). The vacant

CO
l"
~ N
H
(i) hydrolysis

(ii) decarboxylation

2Ie
Seheme-29

Seheme-30

Seheme-3I
Heterocyclic Synthesis 177

ortho position of aniline derivative attacks the carbonyl carbon. The cyclization is
followed by the dehydration and oxidation to yield quinoline 23d . The cyclization
of a Schiff base 24a in the presence of an acid, followed by the dehydration yields
quinoline derivative 24b (scheme-32)23.

24b
Scheme-32

Bischler-Napieralski isoquinoline synthesis24 involves the cyclodehydration of

an acyl derivative of J3-phenylethylamine 25a. Cyclization occurs by the
nucleophilic attack at the protonated carbonyl group. 3,4-Dihydroisoquinoline
formed undergoes dehydrogenation to yield isoquinoline 25d (scheme-33).

(('1H /C~
25a R ~O

~H
V ~::::'~OPOCI
I !
R CI

~4
~N -H2

R
25d 25c

Scheme-33
178 Heterocyclic Chemistry

Bischler synthesis2S for indoles proceeds with the nucleophilic attack at the
carbonyl group of an a-arylamino ketone or aldehyde 26a. It is an acid catalyzed
reaction (scheme-34).

26a

+
-H

26c 26b

Scheme-34

The construction of the heterocyclic compounds by the nucleophilic attack at

the carbon-carbon double bond is the commonly used method. Organoseleniwn
induced ring closure leads to the various cyclic systems often with a high degree
of regio- and stereoselectivity26. The phenylseleno compounds 27c formed in
these cyclizations serve as excellent intermediates for the elaboration to a variety
of products under mild conditions. Removal of the phenylseleno group oxidatively
and reductively yields unsaturated and saturated systems respectively
(scheme-35). The initial step of cyclization is preswned to be reversible
electrophilic addition of the phenylselenoniwn ion to the double bond of the
compound 27a leading to the reactive intermediate 27b which subsequently
suffers intramolecular reaction providing phenylselenolactone 27c. Based on a
preswned SN2 mode of capture of the selenoniwn ion and by analogy to the
related halolactonization reaction, the stereochemistry of phenylselenolactones
is asswned to be trans.
Organoseleniwn based techniques also provide sulfur herterocycles (scheme-36).
This technique has also been extended to the macrolide synthesis (scheme-37).
Heterocyclic Synthesis 179

c5 ~sSe
<
+
.
c5 en
"~+
Se
I
~

~SeCsH
CsH5
278 27b 27c

27f 27e 27d

Scheme-35

6.
SeCSH5
~s-.---<
,\\1 'CH,

288
~ 28b

28c

Scheme-36
180 Heterocyclic Chemistry

~N--SeC.H5
o
camphor sulfonic acid,
CH2CI2, room tempt.

29a

o SeC6HS

29b 29c

29d(100%)

Scheme-37

The usefulness of this organoseleniwn based technology is in the construction

of advanced intermediates and in the synthesis of a series of 0- and S-containing
prostacyclins. The synthesis of O-containing prostacyclins is depicted in
(scheme-38). Intramolecular ureidoselenenylation of the double bonds followed by
the allylative deselenenylation which thus accomplishes a net ureidoallylation27
has been found to be useful. Intramolecular ureidoselenenylation of the general
system 31a using N-phenylselenophthalimide (N-PSP) establishes the carbon-
nitrogen bond. An allyl group is introduced by the reaction of31b with tri-n-butyl
Heterocyclic Synthesis 181

COOCH 3
COOCH 3

OH ~

OH
30a 30b

1 (i)HP2
(ii) syn elimination

COOCH 3

OH
30d 30e

Seheme-38

allylstannane with an initiation by azobisisobutyroriitrile (AIBN) (scheme-39). In

a similar way, indoline 32b has been prepared from N-Cbz-o-a1lylaniline 32a
(scheme-40).
182 Heterocyclic Chemistry

31a 31b 31c

Scheme-39

~ N (ii) (n-C 4 HghSnCH 2 -CH=CH 2

H..... 'Cbz AIBN-CeH5CH 3

32a
Scheme-40

Heterofunctionalized alkenes activated by mercuric salts lUldergo intramolecular

addition to the double bonds and lead to the development of a general method
for the synthesis of heterocycles28 . A few examples are depicted in scheme-41.
Organomercury intermediates 34a-c lUldergo heterogenolysis cleaving carbon-
mercury bond with anhydride.
A synthesis of p-Iactams 36b has been achieved by intramolecular Michael
addition of a substituted acrylamide 36a (scheme-42)29.
Cyclization lUlder Vilsmeier conditions also yields hererocycles. Vilsmeier
reaction is primarily concerned with the formylation of a wide variety of substrates.
It involves the reaction of a Vilsmeier reagent derived from a tertiary amide and
an acid chloride. In heterocyclic synthesis, the most commonly used Vilsmeier
reagent (VR) is derived from dimethylformamide and phosphoryl chloride (Fig. 2).
The activated C=N bond acts as an electrophile. Methyl group a or y to an annular
nitrogen in an N-heteroaromatic system easily lUldergo Vislmeier reaction. When
an amino group is ortho to the methyl group, cyclization yields a fused pyrrole
(scheme-43)30. The product ofVilsmeier reaction of aminopyrimidine acetic ester
38a depends upon the ratio of the reagent used (scheme-44)31. Furanoquinoxaline
39c is obtained by Vilsmeier reaction of quinoxalone 39a (scheme-45)32.
Pyrazoles 41a-c can be obtained by diformylation and cyclization lUlder
Vilsmeier conditions from hydrazones, semicarbazones and azines (scheme-46)33-35.
Heterocyclic Synthesis 183

(X0 0
33a 34a 35a(90%)

o
(XN~~ N~HgX (X)'CH
I I 3
R R
33b 34b 35b(93%)

yt¥~~~HgX
H2N 33c
/ H .... N 34c

H
I
:t ~j<
35c(80%)

Scheme-41

CSH5N-CH(COOCH 3h
l
piperidine
0=6-CH=CHCsH4N0 2-P
36a CSH5 N- C(COOC
I I
0=C-CH-CH 2CsH4 N0 2-
36b
Scheme-42

Fig. 2
184 Heterocyclic Chemistry

37a 37b 37c

Scheme-43

39c 38d

Scheme-44

Benzimidazole 42c has been prepared by the reaction of Vilsmeier reagent with
N, N'-diacetyl-o-phenylenediamine 42a (scheme-47)36. 3-Aminopyrimidine-2-thiones
43a with Vilsmeier reagent forms amidines 43b which cyclize to give
thiadiazolopyrimidines 43c (scheme-48)37.
6-Arylaminouracils on cyclization with 'aza-Vilsmeier reagent' (obtained by
N-nitrosodimethylamine and phosphoryl chloride) forms alloxazines 44b and
isoalloxazines 45b (scheme-49)38.
Nucleophilic carbon-sulfur bond formation forms an important method for the
synthesis of five- and six-membered sulfur containing heterocycles39 . Bromine
induced cyclization of a y,8-unsaturated thioamide 46a yields 5-bromomethyl-
thiolan-2-one 46c (scheme-50).
Heterocyclic Synthesis 185

39a
(X I N~COOC2H5 39b

~ N~;
39c
Scheme-45

--<, N
R2 acb R2
CH 3
HN ....
VR
. ~ ~
....N
R'1 R
N
'1
40a 41a

CH 3 --<, N
Ar
VR
.-
acbPJ
,
HN ....

CONH 2
~
N,
~
....N

CONH 2
40b 41b

CH 3 --<,.... N
R2

VR
..
OHCbR' ~ ~

Ar)lcH 3
N
N
Ar-C=CH 2
, ..... N

40c 41c
R 1 and R2 = alkyl! myl groups

Scheme-46
186 Heterocyclic Chemistry

OC
~I
NHCOCHs

NHCOCH3
VR

42c

Scheme-47

43c

Scheme-48
Heterocyclic Synthesis 187

45a 45b(60%)

Scheme-49

46a / 46b
/H 0 2

BrCH2~O
S
46c

Scheme-50

Methyl sulfide group (-SCH3) also serves as a nucleophile in the cyclization step
and the equilibrium with an intermediate sulfonium salt is driven to the right by
the removal of methyl bromide (scheme-51). Cyclization via free thiolate is highly
stereospecific and C-S bond formation takes place anti to the departing group
(scheme-52).
188 Heterocyclic Chemistry

47a 47b 47c

Scheme-51

48a 48b

Scheme-52

2.1.1.3 Intramolecular Nucleophilic Addition to Triple Bonds

The intramolecular cyclization of acetylenic compounds containing ftmctional

groups leads to the fonnation of five and six-membered heterocycles. Acetylenic
compound having an alcoholic ftmction at y-position 49a yields dihydrofuran 49c
on distillation over sodamide (scheme-53)40. If a heteroatom is present between the
acetylenic and alcoholic ftmctions, a convenient synthesis of various heterocycles
can be achieved. N-Propargylethanolamines 50a cyclize to give 4-alkyl-2-
methylenemorpholine 50b under the basic conditions (scheme-54)41.

49a 49b 49c

Scheme-53

The intramolecular cyclization of acetylenic acid 51a yields lactone 51b

(scheme-55)42. Phenylpropynamidoximes 52a on heating undergo cyclization to
yield isoxazoles 52b (scheme-56)43.
Heterocyclic Synthesis 189

I R
HC=CCH 2NCH 2CH 20H
NaOHlH 20
----I~..
(OjCH 2

49a N
I
R
50b

Scheme-54

+
RC=C-CH=CH-COOH
H R~O
H °
51a 51b

Scheme-55

11 HsCa-C=CH
----I.,.. I \
0, ~C-NH2
N
52a 52b

Scheme-56

Acetylenic amines 53a under the action of heat cyclize to give pyrroles 53b
(scheme-57)44, Similarly, o-aminophenylacetylene 54a on heating yields indole 54b
(scheme-58)45, The base catalyzed cyclization of thioureas containing acetylenic
fimctions 55a yield imidazolidinethiones 55b (scheme-59)46,

53a 53b

Scheme-57
190 Heterocyclic Chemistry

(XC=CH
~
54a
NH2
!l.
Cu20 2
•
CO
~ H
H
54b

Scheme-58

S S
II II
C C
R2-N/ 'NHR1 R2-N".... 'N-R1
base
I
R3_ C • 3 I
R-C-C
I
,( 'C=CH I ~
R R4 CH2

55a 55b

Scheme-59

The nucleophilic addition to arynes is useful for the synthesis of some benzo-
fused heterocycles e.g. the synthesis of phenanthridine 56d by intramolecular
nucleophilic addition to benzyne 56c by ortho carbon atom of another benzene
ring (scheme-60)47.

~CI

)
('yCI

~N---( ~N---( )
56a

56d

Scheme-60
Heterocyclic Synthesis 191

The nucleophilic addition to nitriles also comprises an important method for the
synthesis of amino substituted heterocyclic compounds. The reaction of ethyl
carboethoxyformimitate 57a with a-aminonitriles 57b yields amidines 57e
(scheme-61 )48.

C2HsOyNH R

COOC 2HS
"NH 2
+ RCH,
CN
~ NCANH
1
~C ...
HN ~ .... COOC 2HS
57a 44
57b

57e

Seheme-61

A versatile synthesis of heterocycles involves the endo cyclization of isonitriles.

A variety of heterocycles such as oxazolines, thiazolines, oxazoles, oligooxazoles,
thiazoles, triazoles, imidazolines, imidazolinones, pyrroles, oxazines, thiazines etc.,
can be obtained from a-metalated isonitriles49 • The importance of a-metalated
isonitriles lies in their ambivalent nature. They have a nucleophilic centre (the
metalated anionized carbon atom) which can add to the polar multiple bonds and
an electrophilic centre (the isonitrile carbon atom) which permits cyclization of the
adducts 58b on protonation to form heterocycles (scheme-62). With carbonyl
compounds, the reaction of a-metalated isonitriles 59a yields 2-oxazolines 59d.

:N v
~C
C
II
:N :X-
_ M+ A/
N X
/ 1 1
+ 1 1
1- X H
-C: M+ + II ~ -C-y ~ -C-y
I y" I " I "
58a 58b 58e

Seheme-62
192 Heterocyclic Chemistry

59c (the tautomeric equilibrium 59b =

The intermediate carbonyl adducts 59b and the tautomeric 2-metalated 2-oxazolines
59c lies almost entirely on the left hand
side) are transformed into 2-oxazolines 59d (scheme-63).

M
. qc
·N o :N?'
~C _ M+
~o N~O
I I
L :+ " I
-C: M + /C,-""'.~ --C--C-
I ~
.. -C-C-
I I I I I
59a 59b 59c

N~O
I I ~
CH 0H
3
-C-C-
I I
59d

Scheme-63

The cyclization of 3-ethyl-2-isocyano-3-mercaptopentanoic ester 60c (obtained

by the reaction of diethyl thioketone and lithio isocyanoacetic ester) provides
5,5-diethyl-2-thiazoline-4-carboxylic ester 60d (scheme-64).

s NC

" I
C2H5-C-C2H5 + Li CH -COOC 2H5
'\..H+
60.
60b "

Scheme-64
Heterocyclic Synthesis 193

a-Metalated isocyanides can also· add to azomethine group. The reaction of

lithiomethyl or lithiobenzyl isocyanides 61a with schiff bases yields 2-imidazolines
61d (scheme-65).

;o:C
:N 7
L lit
-C:
I
61a
61b 61c

61d

Scbeme-65

Oxazoles 62d are obtained from a-metalated isocyanides by their reaction with
acylating agents (scheme-66). The intermediate a-isocyano ketones 62b cyclize via

M=metal
62a X = halogen 62b

62d 62c

Scbeme-66
194 Heterocyclic Chemistry

enols 6Zc to yield oxazoles 6Zd. An important method of synthesis of imidazoles...

63c includes the reaction of p-tolylthiomethyl isocyanide 63a to alkyl or aryl
cyanides (scheme-67)50.

R = alkyVaryl

63c

Scheme-67

A new synthesis of indole derivatives involves the ortholithiation of an alkyl

group in o-alkylphenyl isocyanides 64a and subsequent intramolecular ring
closure (scheme-68)SI.

ex:2:
R R

IDA
-78°C
.. ~-c .. ():)
~ N
H
64a 64b 64c
R=alkyl

Scheme-68

2.1.2 Radical Cyclizations

The synthesis of heterocycles is also achieved by the intramolecular addition of

a radical to an olefinic bond or to an aromatic ring under kinetic control
preferentially in exo mode. However, the substituents at the double bond disfavour
the addition at the substituted position. The homolytic cleavage of
N-chloroalkylamines with double bond(s) yields chlorine and aminyl radicals
Heterocyclic Synthesis 195

which lUldergo intramolecular cyclization reactions. The nature of the aminyl

radical (neutral, protonated or complexed to metal ion) plays an important role in
cyclization. A variety of J3-ftmctionalized, fused or bridged, azaheterocyc1es have
been synthesized regio- and stereoselectively in good yield by the radical
cyc1ization reactions52 • The neutral aminyl radicals can be generated by the
photolysis of N-chlorodialkylamines in neutral media. The sluggishness of the
neutral dialkylaminyl radicals to add to olefins, as well as their strong tendency
towards non-selective abstraction of hydrogen seems to rule out reactions that
could be of preparative value. However, the photolysis of N-chloro-N-propyl-4-
pentenyl amines 65a in aqueous acetic acid provides only 2-chloromethyl-1-
propylpyrrolidine 65d (scheme-69).

65a 65b 65c 65d(70%)

Scheme-69

The protonated aminyl radicals behave very differently from the neutral species.
The main difference is the pronolUlced tendency of the protonated radicals to add
efficiently to many types of the unsaturated hydrocarbons and arenes in
preference to abstract allylic or benzylic hydrogen atoms. Protonated aminyl
radicals can be obtained by the homolytic decomposition ofN-chlorodialkylamines.
Due to the electrophilic character of protonated aminyl radicals, they cyc1ize more
readily than the neutral species. The intramolecular cyclization of protonated N-
chloroamine 66a is depicted in scheme-70.
The decomposition ofN-chloroamines 67a catalyzed by the reducing metal salts
in the neutral solution produces aminyl radicals complexed to metal ions 67b. The
complexation is presumed to take place via the lone pair of electrons of the aminyl
radicals. The reactivity is intermediate between neutral and protonated aminyl
radicals. The cyc1ization of the aminyl radicals complexed to metal ions is depicted
in scheme-71.
According to the redox mechanism, the cyc1ization ofN-chloroalkenylamines in
non-protonating media, where metal in a polydentate complex permits a relatively
rigid transition state, an efficient stereospecific radical reaction should occur.
Thus, trans- and cis-N-chloro-N-methyl-4-hexenylamines 69a react with reducing
metal salts to form erythro- and threo-2-(1-chloroethyl)-1-methylpyrrolidines 69b,
69c (scheme-72).
196 Heterocyclic Chemistry

J:)N
Ct/ t'R
H

66a

base
+
-H

66b

Scheme-70

=0 N
M+,.. JJ ~
~
+ ~N, + ~N,
Ct/ 'R MCt R MCt R
67a 67b 67c

+ + 67b
M

68a 68b
Scheme-71

The cyclization of acyclic N-chloroamines with two double bonds e.g. N-allyl-
N-chloro-4-pentenylamine 70a with titanium trichloride in aqueous acetic acid
leads to 2-chloromethylpyrrolizidine 70c. The cyclization of 70a to the five-
membered ring affords carbon centered radical 70b which further undergoes
homolytic cyclization and this appears to be faster than the transfer of chlorine.
The reaction proceeds via a typical radical chain mechanism involving transfer of
a chlorine atom from N-chloroamine 70a. The compound 70a in the same solvent
with copper (I) chloride in the presence of copper (II) chloride does not form
Heterocyclic Synthesis 197

CI H ~\
HC\~
3 H N
.)
I
CH 3
69c (threO)

Scheme-72

bicyclic product, but N-allyl-2-chloromethylpyrrolidine 70e is obtained exclusively,

which indicates that the transfer of chlorine from copper (II) chloride is faster than
the cyclization of 5-hexenyl radical 70d (scheme-73).

TiCl 3
M--T!
()
--
~ CH3~H
"

;I~-CI
CH 2 CI
H2 O 70b 70c

M_ -- Q+CUCI
i(
CuCI
70a CUC' 2
CU0 2
aCH
"I(
70d 70e

Scheme-73

The intramolecular radical addition reactions are not only limited to the olefmic
bonds, but additions to the aromatic rings also occur. Indolines and tetrahydroquino-
lines can be prepared by such reactions. The decomposition ofN-chloro-2-phenyl-
ethylamine 71 in conc. sulfuric acid catalyzed by Fe+2 yields N-methylindoline 72a
and benzyl chloride (scheme-74). However, in case ofN-chloro-3-phenylpropylamine
198 Heterocyclic Chemistry

73 l3-scission does not occur and only N-methyltetrahydroquinoline 74 is

produced (scheme-7S). Similarly, photolysis ofN-chloroamine in cone. sulfuric acid
gives N-methylhexahydrocyclopentaquionline 76 (scheme-76).

~
cone. H2 S04
•
V i, CI CH 3

71 72a(27%) 72b(44%)

Scheme-74

CD ~
CI
/
N
\
CH 3
cone. H2SO 4

Fe+2
•
CD
~ N
I
CH 3
73 74 (81%)

Scheme-75

~ ..
2J>
cone. H2SO 4

C~N H3;
hv

I
CH 3
75 76 (9()01o)

Scheme-76

The CYclization ofN-chloro-N-methyl-2-(I, l-dimethyl-2-methylenecyclopropane)-

ethylamine 77 in aqueous acetic acid catalyzed by titanium trichloride provides
3-azabicyclo[4.1.0] heptane derivative 78. The overall endo-regioselectivity follows
the Baldwin's rules and the general behaviour of the irreversible radical cyclization
(scheme-77).
Heterocyclic Synthesis 199

77 78

Scheme-77

Radical cyclization of N-chlorocycloalkenylamines 79 under solvolytic

conditions forms a simple route to provide azapolycycles 80 (scheme-78).

~'~
s~-~' CI
CH30H
AgN0 3
~

b N
..... CH 3
79a 80a

@OCH'
~ \
CI
79b
3
CH30H
Ag20
~

N,
CH 3

80b

~OH
..
vaCH,
Agp
N
..... CH 3

79c 80c

Scheme-78
200 Heterocyclic Chemistry

Hofinann-Lofiler reaction53 which involves the transfomation of N-haloamines

into the cyclic amines is also a radical cyclization reaction, in which a carbon-
nitrogen bond is formed instead of addition to a multiple bond. The salt of
N-chloroamine 81a is homolytically cleaved under the action of heat, light, etc. to
yield aminium radical 81c, which, in 1;um, intramolecularly abstracts a sterically
favoured hydrogen to give an alkyl radical 81d. The alkyl radical in a chain reaction
abstracts chlorine intramolecularly. The transformation of alkyl chloride 81e into
cyclic amine 81f takes place in the presence of an alkali (scheme-79).

H2C--CH 2
H3 C
I I
...... CH 2
H
+
.. H2C--CH 2
I
H3C + . . . CH 2
N
I -Cl
.
. H2C--CH 2
I
H3C +· ...... CH 2
N
I

N
/ \ I'
CI R CI/A'H R H
81a 81b 81c

+
H2C--CH 2
I I
H2 C ............ CH 2
N
-HCI
l1li(

-H
+
H2 C--CH 2
I
H2C + . . . CH 2
I . H
+

C4H9NCIR
H2C--CH 2
I
H2 C + . . . CH 2
- N
I

R
I CII H/~'H /1'
H R H

81f 81e 81d

Scheme-79

2.1.3 Carbene and Nitrene Cyclizations

Carbene and nitrene are highly reactive species and are useful in synthetic organic
chemistry. The tendency of the singlet carbene and nitrene to undergo insertion
into unactivated C-H bond and the addition to multiple bonds are useful for the
synthesis of heterocycles. The photolysis of azides yields nitrenes which undergo
intramolecular addition to double bond(s) to yield azirines. The cyclization of the
conjugated dienyl azides 82 gives 2H-azirines 83 which on isomerization at high
temperature yields 2,2-dicyano-2H-pyrrole 84. Over all, the reaction is a two-stage
thermolysis of the azide (scheme-80)54.
Heterocyclic Synthesis 201

HsCs CN
!=\ FN HsCs r==(
N3 ~-
6O-80"C
'd eN
CN N
82 83

~14ffC

F\/CN
HsCs
A N... /\CN ~

84

Scheme-80

2-(2-Benzofuryl)-2H-azirine 86 obtained by the photolysis of azide 85 undergoes

thermal ring opening to yield nitrene. Vinyl nitrene 87 thus produced undergoes
intramolecular addition reactions to yield a condensed pyrrole 88, pyridine 89 or
azepine 90 depending on the substituents (scheme-81)55.
Annelated pyridines 92, 94, and 96 are obtained by the pyrolysis of aryl vinyl
azides 91, 93, 95 involving nitrene insertion into methyl group (scheme-82)56.
Lactam 99 is synthesized from acylnitrenes 98 which is obtained by the
photolysis of sulfilimine 9757 . Isocyanate 100 accompany the photolysis and is
considered to be formed by a non-nitrene process (scheme-83).
Photolysis of nitrile oxides 10158 also provides acylnitrene 102 which cyclizes
to lactam 103 (scheme-84).
Variously substituted sulfilimines 104 on flash vacuum pyrolysis yields
interesting cyclopenta[d]pyrimidines 106 along with carbodimides 107
(scheme-85)59.
Azepines 113 are formed during the photolysis of ary azide 108 in diethylamine.
It is the singlet phenylnitrene which undergoes rearrangement (scheme-86)60.
Thermolysis of O,N-bis(trimethylsilyl)-N-phenylhydroxylamine 114 at 100°C
yields 2-diethylamino-3H-azepine 115 (scheme-87)61.
202 Heterocyclic Chemistry

R R

85

R
R=H

COOC 2 H5
87
~~rn3
H H H

NH

0 COOC 2 H5
#
COOC 2 H5

~ +-H2
NH ~

COOC 2 H5 COOC 2 H5

88 (100%) 89 (100%)

H H
90(67%)

Scheme-81
Heterocyclic Synthesis 203

91

92
93

94

n-H~i3
CH 3 N3

'Z.S)-./"COOC 2 H5
.
95

96
Scheme-82
204 Heterocyclic Chemistry

CH 3

H3C--< ~CO-N=S(C.H5h
CH 3
97 98

CH 3 I
H3C--< ~NCO +
o

CH 3
100 99

Scheme-83

+ -
C=N-O
CH3 hv H3C
~

101 102 103

Scheme-84
Heterocyclic Synthesis 205

104 105

106 107

Scheme-85

108 109 110 111

/
113 114

Scheme-86
206 Heterocyclic Chemistry

114 115

Scheme-87

Azepines 117 and 118 are also obtained from nitrobenzenes (deoxygenated by
triethylphosphite) via arylnitrenes. A marked influence of the nuc1eophile upon the
direction of the apparent migration of nitrene away or towards an ortho-
subsititution has been noted (scheme-88)62.

117 118

Scheme-88
Heterocyclic Synthesis 207

Carbazoles 119c are synthesized in high yields by thermolysis or photolysis of

2-azidobiphenyls, photolysis of 2-isocyanatobiphenyls and deoxygenation of nitro
and nitroso aromatics. Singlet nitrene causes cyclization to carbazole
(scheme-89)63. Sulfonylnitrene insertion into aromatic C-H bonds also yields
heterocycles (scheme-90)64. Intramolecular addition reactions of carbenes (as (l-

~
119a 119b
X = N 3, NCO, N02, NO

~
~N)V
H
119c

Scheme-89

120a
l
120c (61%)

Scheme-90
208 Heterocyclic Chemistry

oxocarbenes) 121a,b provide heterocycles 122a,b (scheme-91)65 . Thermolysis of

sodium o-bromobenzenethiolate 123a has been found to yield a 1 : 1 mixture of
thianthrenes 124a and 124b via a benzothiirene intermediate 123b (scheme-92)66.

122a

R-C-CO-N-R1 R-C-CO-N-R1 0)r+/R1

~
2
b
1/\
Cu(acac)2
..
b
11\
~ fI N
I \\
o CSH5 0 CSH5 R O./"'-. CSH5
121b 122b

Scheme-91

~SNa

CH 3 ~ Br
123a

~A

[H3COS:::::;==:::::'H3COS
123b

124a 124b

Scbeme-92
Heterocyclic Synthesis 209

Synthesis of I-sila, I-germa ~and~ I-stannaindanes 127 have been achieved in

good yields by the multiple carbene-carbene rearrangements (scheme-93)67. The
initial carbene 126 is obtained by flash pyrolysis of phenyldiazomethanes 125.

-M
1-0-
f "
I -
CH=N-N-Tos
Na SOO"C
SmmHg
.. -~-O-" CH
I -

0"/
125 126a

y:::::;::::::::::;
(yCH
I~ #
-M- -M

. /
I I

q
126b

~ # ~
(X
~ I /~
CH
~
V-M/
M / '\.
-M- / '\.
I 126c 127
M= Si, Ge, Sn

Scheme-93

The insertion of arylcarbenes 129 into ortho side chains yields dihydro-
benzofurans and related compounds 130 (scheme-94)68. Thermolysis of diazo
compound 132 results in aromatic C-H insertion of the resulting arylsulfonyl-
carbene 133 to yield sulfoxide 134. Addition to a benzenoid double bond also
takes place and the ring expansion yields cycloheptatriene 135 (scheme-9S)69.
210 Heterocyclic Chemistry

(X~&3 - . . . [(X:~3]
N2
128 129

x=o, S,N~H5

130 (37-76%) 131 (2-7%)

Scheme-94

132 133

/
+

134 135

Scheme-95
Heterocyclic Synthesis 211

2.1.4 Electrocyclic Reactions

An electrocyclic reaction involves the interconversion of two n-bonds into a

a-bond and a n-bond. An open chain reagent having kn-electrons will give a cyclic
product with (k-2)n-electrons and two electrons in a new a-bond (Fig. 3).
According to the principles of orbital symmetry conservation developed by
Woodward and Hoffinann, the kn-electrons must constitute a conjugated system
and the formation of a new single bond and the rebonding in the resultant n-
system of (k-2)n-electrons must occur in a concerted fashion.

6n-electrons (6-2) = 4n-electrons + a a-bond

Fig. 3

The reaction can be performed thermally or photochemically without any

additional reagent and either condition is completely stereospecific. An equilibrium
is set up between acyclic and cyclic counterparts. In cases where an acyclic
counterpart predominates, the electro cyclic reaction may be a ring opening rather
than a ring forming reaction. The electro cyclic ring closures are of two types. The
first, in which p-orbitals of the n-electron system rotate in the same direction to
form a new a-bond is known as conrotatory process and the other, in which they
rotate in the opposite direction is known as disrotatory process. The Woodward-
Hoffinann rules for electro cyclic ring closure are based on the number of n-
electrons in the open chain reagent and whether the reaction takes place in the
ground state (thermal reaction) or in the first excited state (photochemical reaction).
The selection rules for the electrocyclic reactions are summarized in Table 1.

Table 1. Selection rules for electrocyclic reactions

Number of n-electrons Thermal Photochemical

4n Conrotatory Disrotatory
4n+ 2 Disrotatory Conrotatory
212 Heterocyclic Chemistry

However, when one of the terininal atoms of the open chain reagent is a
heteroatom, stereochemical distinction between conrotatory and disrotatory
process is lost. The commonly encountered electrocyclic reactions for the
synthesis of heterocycles can be divided into fom types :
(i) Reactions in which open chain reagent contains 41t-electrons in a 1,3-dipolar
species. In general, such type of reaction can be represented as in Fig. 4. Here the

<
•

Fig. 4

ring opening is a more common process. Only a very few examples of the ring
closme are available and are usually photochemical process. The electrocyclic ring
closme of thiocarbonyl ylides 137 yields episulfides 138. The best method of
preparing thiocarbonyl ylides 137 is the thermal decomposition of thiadiazoline
136 which mayor may not be isolated (scheme-96)1°.

136a 137a 138a

136b 137b 138b

Scheme-96

The ring closme of compound 139 yields 3-ethylthioxirane 140 which

decomposes to give propionaldehyde (scheme-97)71.

Scheme-97
Heterocyclic Synthesis 213

An azoxy compmmd 141 is converted photochemically to an oxadiaziridine 142

which reverts thermally to the azoxy reactant (scheme-98)72.

o- p,
1+ hv
(CH3hC- N=N- C(CH3h • (CH3hC- N- N- C(CH3h
141 141

Scheme-98

(ii) Reactions in which the open chain reagent contains 41t-electrons in a

heterodiene (Fig. 5). The ring opening is a more common process. A few example

B-C B=C
9 ~ q
>
I I
A D A-D
Fig. 5

of the electrocyclic ring closures are described; 2, 3, 4, 4-tetramethyloxetene 144

is obtained by the irradiation of 3,4-dimethyl-3-penten-2-one 143. Oxetene 144 is
reverted thermally to the reactant (scheme-99)73. In some cases, o-quinomethides
145 cyclize to benzoxetenes 146 (scheme-l00)14.

H3C CH 3 H3C l=( CH 3

H3C~CH3
hv
q

H3C -T-0
o CH 3
143 144

Scheme-99

145 146

Scheme-l00
214 Heterocyclic Chemistry

A cyclobutene 148 having three heteroatoms is formed only as an intermediate in

the thermal decomposition of compound 147 (scheme-l0l)'s.

w
CaH5-C- N=S= 0
~ ?-fOl--i~"CaH5C=N + S~
[ CaH5-C=N
147 148

Scheme-101

(iii) Reactions in which an open chain reagent contains 61t-electrons in a I,S-dipolar

species (Fig. 6). Such types of reactions are more common and referred to as 1,5-
dipolar cyclization reactions. Both ring opening and ring closure reactions are
observed. Some examples of the ring closure reactions are described which are
usually thermally induced process.

C
c
> B~ '0:
\ I
A-E
Fig. 6

The heterolysis of an oxirane 149 yields a dipolar intermediate 150 which

undergoes ring closure with the formation of 151 (scheme-l 02)76.

~
o o o
149 150 151

Scheme-102

Indolizines 153 are obtained by the electrocyclization of pyridinium ylides 152

(scheme-l 03)77.
Heterocyclic Synthesis 215

0
-+0 •
" COCH 3
C,
COOC2Hs
0
152 153

Scheme-103

1,5-Dipolar electrocyclization of tbiocarbonyl ylides 156 yields dihydrotbiophenes

157 and eventually tbiophenes 158 (scheme-104)1B.

n
CH3S~S~COR
157 158

Scheme-104
216 Heterocyclic Chemistry

Vinyl substituted nitrile yIides -160 obtained by the photolysis of arylazirines

159 cyclize to form arylpyrroles 162. The vinyl substituent causes
1,5-electrocyclization (scheme-l 05)79.

hv + -
CsHsC=N-CH~
160 COCsHs

!
COCsHs
159

162 161

Scheme-105

Azomethine ylides 164 formed by the thermal opening of aziridines 163 yield
oxazoles 165 (scheme-106)80.

Scheme-106
Heterocyclic Synthesis 217

Oxazoles 168 are obtained from acylazirines 166 via nitrile ylides 167 (scheme-
107)19. Iminoazirine 169 on photochemical ring opening yields iminosubstituted

Ar'y -N
- - - t..~
+ -
ArC: N- CH- CHO ---i"~

CHO
166

Scheme-107

nitrile ylide 170 which cyclizes to an imidazole 171 (scheme-108f9. Electro-

cyclization ofthiocarbonyl imines (thione-S-imides) 172 affords heterocycles 173
(scheme-1 09)81.

hv + _
- - l...... CsHsC:N-CH-CH=N-CsHs

CH=N-CsHs 170 "

169
/ \
NyN-CsHs

CsHs
171
Scheme-108

o
+ - II above
S-N-C-CsH s
-30"C

172 173
Scheme-l09
218 Heterocyclic Chemistry

(iv) Reactions in whicn open chain reagent contains 61t-electrons in a heterotriene

(Fig. 7). Electrocyclic ring closure is a versatile method for the synthesis of six-
membered heterocycles. The reverse reaction also occurs (scheme-lID).

C=D C-D
I \
B E :::;::::==~::: BII \\
E
~ II \ I
A F A-F
Fig. 7

~
~oll hv

Scheme-110

Electrocyclization82 of o-quinomethide 176 (obtained by Claisen rearrangement

of 174 and 1,5-hydrogen shift) provides chromene 177 (scheme-lI1). 2-Pyrones
179 are synthesized from ketenes 178 having cis-enone substituent by the
electrocyclization process (scheme-l 12)83.
Heterocyclic Synthesis 219

aO'9
~
174
In
CH
H'
~
.. (X0H

.,.. I
175
CH=C=CH,

+
00
~ 1.#
177
.. (X)
~ ~ I
176
Scheme-H1

--D ~o C~o

178
.. ·n o
179
0

Scheme-112

Synthesis of coumarins 182 is achieved by the electro cyclic ring closure of

isocyanates 181 (scheme-113)84.

180 / 181

Scheme-l13
220 Heterocyclic Chemistry

Electrocyclization of dienthiones 184 yields thiapyrans 185 (scheme-114)85.

R2
1 /'" R1 C
'C~ ~CH-R2
..
R-C=C-CH
/),. 1
'S 4....... C' ~S
R4-HC=C/ HMPA R H C
13
"R3 R

R4n •
183
R1
H
R1 C
'C/ ~CH-R2
I~ "'if II
4/C, ~S
R3 S R2 R C
13
R
185
184
Scheme-1l4

Ring closure of konig's salts 186 by electro cyclic process yields N-phenyl-
pyridinium ion 187 and aniline (scheme-115)86.

[
C6 HS
I
H
I
.;"N~N,
H

C6HS
l +

~
HC
S 6,
~~N
H iL
..... C6 HS
+ H
+

186 H

Cl N
1
NHC 6Hs = CsHsN fIl NHC6HS

C6 HS

o N
1
CsHs
+

187

Scheme-1l5
Heterocyclic Synthesis 221

Dienoximes 189 having a central cis double bond undergo reversible electrocyclic
ring closure to N-hydroxydihydropyridines 190 which irreversibly yields pyridine-
N-oxides 191 when a good leaving group is present at C-2 (scheme-116)87,

Cln
CaH5
I
CI

CI
c'
CHO
+ NH20H~
CI~CI
CaH5
)l~,l
CI N
CI

I
188 189 OH

CI CI

CI~CI CI~CI
A:.) H5Ca~.,)
H5Ca N CI N
1- I
o OH
191 190

Scheme-116

2-Azatriene 193 undergoes electrocyclization to yield dihydropyridine derivative

194 (scheme-117)88,

(1 ( \H, • (XCH'
N
I N~CH3 N CH 3
C2H5
192 193 194

Scheme-117

The thermally induced electrocyclization of 1,4,8-triphenyl-2,5-diazooctatetraene

195 yields dihydropyrazine 196 (scheme-118)89, The extension of this reaction is
used to synthesize condensed pyrazines 199 (scheme-119)90,
222 Heterocyclic Chemistry

CSH5
I
CSH5CH=N-CH=C-N=CH-CH=CH-CsH5
195

l~

J:NC
H5CS N CSH5
196
Scbeme-118

OC2 H5
I
CH3-C-N(CH3h
I
OC2H5
198

Scbeme-119
Heterocyclic Synthesis 223

Isocyanates 201 and isothiocyanates 204 also undergo electrocyclization91 to

produce benzopyrimidine derivatives 203 and 205 (scheme-120).

QI
~
F2Ho
NH a
[Q &N=C=O]
~ ~ N~CeHs
<

NACeHs
200 201

ct cX>
0 0

NH
~ NACeHs • ~ ~N~CeHs
203 202

Q cC
S

N=C=S a .-
~ NACeHs ~
NH
NACeHs
204 205

Scheme-120

Conversion of 2-azobenzaldoxime 206 into 1,2,3-benzotriazine type compound

208 can be considered as exocyc1ization which involves the addition of an
unshared pair of electrons from oxime to diazonium ion (scheme-121)92.

Scheme-121
224 Heterocyclic Chemistry

The synthesis of pyrylium salts 212 from enamines 209 involves an

electrocyclic-elimination reaction (scheme-122)93. The process of electocyclic-
elimination has been extended for the synthesis of heterocycles e.g. quinolines
214, pyrimidines 218, etc. (scheme-123)94.

CH=CHCOC sHs - - - .
I
CI

0-

o
211

Scheme-122

ro
~ CsHs

~ I ~ N
214

215
N(CH 3h

~N
~ . Ll IN
N N(CH 3)2 N
~ N(CH3h
218 217
Scheme-123
Heterocyclic Synthesis 225

2.2 Cycioaddition Reactions

The cycloaddition reactions represent a large group of reactions which involve the
interaction of 1t-electron systems in a concerted manner and proceed via acyclic
transition state. These are generally described as symmetry controlled reactions
and the mechanisms are considered in terms of frontier orbital theory. The
reactions occur by the interaction of the highest occupied molecular orbital
(HOMO) of one component with the lowest unoccupied molecular orbital (LUMO)
of the other. A wide variety of heterocycles especially containing four- to six-
membered rings are prepared by the cycloaddition reactions. The important types
of cycloaddition reactions for the construction of heterocyclic compounds
includes 1,3-dipolar cycloaddition, hetero-Diels-Alder reactions, [2 + 2] cycloadd-
itions, valence bond isomerization and cheletropic reactions.

2.2.1 1,3-Dipolar Reactions [3 + 2~5]

The cycloaddition reactions of type [3 + 2~5] constitute an extremely large

number of examples, the major portion of which have been investigated by
Huisgen and co-workers95 • This group of transformations is more commonly
referred to as 1,3-dipolar reactions. In such reactions, a neutral five-membered ring
is formed by the combination of a dipolar species (generally a triatomic 1,3-dipole)
and an unsaturated acceptor (dipolarophile). These reactions are analogous to
Diels-Alder reaction in that they are concerted additions of [4 + 2]type96 • These
reactions are customarily represented as in Fig. 8 in which a-b-c is referred to as
1,3-dipolar molecule and d-e as dipolarophile, where 'a' has only six-electrons in
the outer shell and 'c' has at least one pair of unshared electrons.

Fig. 8

1,3-Dipole can be defined as a three atom 1t-electron system with four

1t-electrons delocalized over three atoms. These 1,3-dipole species have more than
one resonance structures. Each molecule has at least one resonance structure
which indicates separation of opposite charges in 1,3-relationship (scheme-124).
1,3-Dipolar species contain a heteroatom as the central atom. In some cases the
226 Heterocyclic Chemistry

dipolar component is an isolable species, such as a diazoalkane or an azide, but'

usually it has to be generated as a reactive intermediate (scheme-124). Some
important I,3-dipolar compounds which undergo I,3-dipolar cycloaddition are
presented in Table 2.

+ .. - +- - + .. +
..
RN-N=N: ~
..
RN=N=N: ~ RN-N=N: ~ RN-N=N:

Scheme-124

Table 2. 1,3-Dipolar compounds

Name Structure

+ +
Diazoalkane N=N- CR2 ~ N=N= CR2
+ +
Azide N=N-NR ~ N=N=NR
+ + -
Azomethine ylide R2C-N-CR 2 ~ R2C=N-CR 2
I I
R R

Azomethine imine + - +
R2C- N- NR ~ R2C=N-NR
I I
R R

Nitrone
- +
R2C-N=O
I
.. .. R2C=N-O
I
+ -
R R

+ + -
Azimine RN-N-NR ~ RN=N-NR
I I
R R
Heterocyclic Synthesis 227

Name Structure

Azoxy compound +
RN-N-O
I
-
...... RN=N-O
I
+ -

R R

Nitro compound
+
O-N-O
I
...... +
O=N-O
I
R R

Nitroso imine
+
RN-O-NR
- ...... +
RN=O-NR
-

Nitroso oxide +
RN-O-O
- ...... + -
RN=O-O

Nitrile ylide +
RC=N- CR2 ...... +
RC=N- CR2
-

Nitrile imine +
RC=N-NR
- ...... + -
RC=N-NR

Nitrile oxide +
RC=N-O
- ...... + -
RC=N-O

Nitrile sulfide
+
RC=N-S ...... RC=f:J-S

Carbonyl ylide
+
R2C-0-CR2
- ...... +
R2C=0- CR2

Carbonyl oxide R2C-0-O

+ ...... R2C=0-0
+

Carbonyl imine +
R2C- 0 - NR ...... R2C=0-NR
+

Ozone
+
0-0-0 ...... +
0=0-0
-

Thiocarbonyl ylide
+
R2C-S-CR2
-
...... +
R2C=S-CR2
-

Selenocarbonyl ylide
+
R2C- Se-CR2
- ...... +
R2C=Se-CR2

R = alkyl/aryl
228 Heterocyclic Chemistry

The other reactants utilized in dipolar cycloaddition are known as dipolarophiles

and contain either double or triple bond between two carbon atoms, a carbon
atom and a heteroatom, or two heteroatoms. Scheme-125 lists some commonly
used dipolarophiles. Variations in the structures of both the 1,3-dipolar compounds

Ethylenic dipolaropbiles
CHz~C~=CHR,C~=CHOR
C~=C~, C~=CHCOR, C~=CHC02R, CHz=CHCN,
R'CH=CHN02,R'C(CI)=CHN02,R'CH~ R'CH=CHR',
NCCH=CHCN,RC02CH=CHCO~

GNR
o o

Heterocumulenes
~CON=C=O,~CON=C=S,

RN=C=O, RN=C=S

Acetylenic dipolaropbiles
R"C-=CH,R"CsCR", HC-=CC02R,
R'C-=CCO~ R'COCSCCOR,
NCC=CCN, CF3C-=CCF3, R02CCsCC02R, benzyne
R=alkyl, R'=alkyll aryl, R"=aryl / heteroaryl
N
N~ 'N-CsH s

~
l
219 220

?'"COOOl,
..... N~
HsCa-N .... N

'----Z..COOCH 3
221

Scheme-125
Heterocyclic Synthesis 229

and dipolarophiles make this a versatile and useful reaction in the synthesis of
heterocyclic compounds. The most significant structural feature of 1,3-dipolar com-
pounds is that they possess a 1t-system containing four electrons over three atoms
and are isoelectronic with the alkyl anion. According to the Woodward-Hoffinann
rules, 1,3-dipolar cycloaddition is a thermally allowed process97 • The transition
state of 1,3-dipolar cycloaddition can be represented as in Fig. 9, in which 41t-
electron system of the dipole interacts with 21t-electron system of the dipolaro-
phile. Frontier orbital theory provides a means of accounting for the variations in
the reactivities of 1,3-dipoles and dipolarophiles98 • The formation of transition state
I (Fig. 9) will take place, if there is a favourable interaction between a filled

o
0/8"-...0
a c
0, 0
~-~
o 0 I
Fig. 9

1t-orbital of one reactant and an empty 1t* -orbital of the other. For such favourable
interactions, the conditions required are; the interacting orbitals are of the correct
phase and energy and the interaction must be sterically feasible. These
interactions are, therefore, dominated by the highest occupied 1t-orbitals (HOMO)
and the lowest unoccupied 1t-orbitals (LUMO) of the two reactants. The relative
energies of these so called frontier orbitals can vary as shown in Fig. 10.
Reactions are favoured if one component is strongly 'nucleophilic' and the other
is strongly 'electrophilic'. The more electrophilic dipolarophiles have the lower
energy LUMO values, whereas the more nucleophilic species have the higher
energy HOMO values. Therefore, for a given 1,3-dipole molecule, the dominant
interaction is of type :
(i) HOMO (dipole) and LUMO (dipolarophile) for electron-deficient dipola-
rophile, and
(ii) LUMO ( dipole) and HOMO (dipolarophile) for electron-rich dipolarophiles.
Often the reactions are not performed with the simple unsubstituted dipoles and,
therefore, the effect on the energies of the substituent(s) present have to be
assessed. 1,3-Dipolar cycloadditions are highyl regioselective, for example, the
reaction of phenyl azide with I-hexene, which is a LUMO(dipole)-HOMO
(dipolarophile) interaction, gives mainly I-phenyl-5-butyltriazoline 220. But with
methyl acrylate, I-phenyl-4-carboxylic ester 221 is formed (scheme-125). The
230 Heterocyclic Chemistry

reaction is HOMO(dipole)-LUMO(dipolarophile) controlled because of the

lowering of the energies of the frontier orbitals of dipolarophile by the ester
group and change in the relative magnitudes of the atomic orbital coefficients in
the interacting frontier orbitals of the two components99 • In some reactions
electronically preferred orientations may be disfavoured by the steric effects 100.

(a) HOMO LUMO

LUMO HOMO

"
(b) LUMo-- LUMO-, - ; ( LUMO
,
" , ,"
>,

energy _it ~ HOMO j(" "~

"Jr IfHOM0"lr 1f HOMO
dipole di!ar- dipole dipolar- dipole dipolar-
ophile ophile ophile
(i) (ii) (iii)

Fig. 10 (a) Frontier orbital combinations in 1,3-dipolar addition

(b) Types of interactions
(i) HOMO (dipole)-LUMO (dipolarophile) dominant
(ii) LUMO (dipole)-HOMO (dipolarophile) dominant
(iii) Neither dominant.
1,3-Dipolar cycloaddition reactions are also highly stereoselective, however a
few exceptions are due to the isomerization either before or after the cycloaddition 101.
For example, cis azomethine ylide 222 with acetylene dicarboxylic ester yields
exclusively pyrrolidine tetracarboxylate 224 with cis ester groups at C-2 and C-5
(scheme-l 26). The isomeric trans-azomethine 225a ylide provides only trans-
pyrrolidine derivative 225b (scheme-127)102. In cases, where two chiral centers are
created in the cycloaddition interplay of two generally opposing forces in the
transition state; attractive 1t-orbital overlap of unsaturated substituents favours an
endo-transition state, and repulsive van der Waals steric interactions favour an
exo-transition state. Thus, in the cycloaddition reactions of N-methyl-C-
phenylnitrone 226 with a dipolarophile the stereochemical results are not
consistent, sometimes favour endo-227a and sometimes exo-228a transition state
(scheme-128)103.
Heterocyclic Synthesis 231

Ar
I
CH300C~ N 'Y""'COOCH 3
17 + 1 + CH300C-C::C-COOCH3
H H ~A ll3
222 Ar
I
CH300C~ N ~COOCH3

H~H
CH 300C COOCH 3
224
Scheme-126

Ar
I
CH300CytJyH
+ CH300C-C=C-COOCH3

~A
H COOCH3
225a
Ar
I
CH300C~ N ~H

H~COOCH'
CH300C COOCH 3
225b
Scheme-127

The cycloaddition reactions of some widely used 1,3-dipolar compounds e.g.,

azomethine ylides, nitrile oxides, nitrones, diazoaikanes, azides, etc. are discussed.
Azomethine ylides 229 on cycloaddition with olefinic and acetylenic dipolarophiles
yield pyrrolidines 230 and A3-pyrrolines 231, respectively. N-Pyrrolines can be
easily converted to pyrrole (scheme-129).
Azomethine ylides required for the cycloaddition are generated in situ. The
synthesis of stabilised azomethine ylides with an electron-withdrawing substituent
involves the thermolysis or photolysis of substituted aziridines. The generated
azomethine ylides in the presence of dipolarophiles react in a stereospecific manner
to yield pyrrolidines or pyrrolines directly in one step. The cycloaddition reactions
of monosubstituted olefins are regiose1ective (scheme-130).
232 Heterocyclic Chemistry

t
CH 3
1
...(N,<
HsCs '--10
"f/ R

227b 228b
Scheme-128

R
1+ _
-CH=N-CH-
229

R1CH CHy ~1C=CR2

R
R
1

-0- ---s::c
1

R1 R1 R2
230 231

Scheme-129
Heterocyclic Synthesis 233

234

Scheme-130

Intramolecular cycloaddition reaction of azomethlne ylide 236 (obtained from

aziridine 235) occurs readily yielding pyrrolidine 237 as a single stereoisomer
(scheme-131)104, As compared to stabilized azomethlne ylides non-stabilized ones

Scheme-130

H
'\\\\'OCH 2CaH5 H

\?yO
R 0

235 / 236

~ H H H
NV/I"~"\\'OCH2C6H5
'~1YO
o
237

Scheme-131
234 Heterocyclic Chemistry

are not as readily available, hoWever one important method involves the
desilylation of trimethylsilylmethyl iminium salts. Azomethine ylide generated by
the reaction of imine 238 and trimethylsilylmethyl tritlate in acetonitrile, and treated
subsequently with cesium tluoride and with dimethyl acetylenedicarboxylate to
give pyrroline derivative 241 (scheme-132)10S.

t
trimethylsilylmethyl tritlate
C6H5CH =NCH 3
acetonitrile
238
cesium fluoride

Scheme-132

Nitrile oxides react readily with ethylenic and acetylenic dipolarophiles to form
a2-isoxazolines andisoxazoles(scheme-133)106. Usually, nitrile oxides are generated

T.
-C::N-O ......If---.l.,... -C=N=O
- +

243 244

Scheme-133
Heterocyclic Synthesis 235

in situ. The commonly used methods include, the dehydrochlorination of

hydroxymoyl chlorides with triethylamine, dehydration of primary nitro compounds
with an aryl isocyanate or by oxidation of aldoximes. The cycloaddition of nitrile
oxide 246 obtained from tetrahydropyranyl derivative of 2-nitroethanol 245
provides heterocycle 247 (scheme-134)lo7.

+ -
THPOCH2-C=N-Q
246

/0
247

Scheme-134

Isoxazolines 250 have been obtained in good yields by the reaction of nitrile
oxide 249 with methyl vinyl ketone (scheme-135)108. The nitrile oxide 252 obtained

CsH11 - C= NOH
I
CI
248

250

Scheme-135
236 Heterocyclic Chemistry

from ro-nitroalkene 251 undergoes intramolecular cycloaddition to provide

heterocycle 253 (scheme-136)109. Reaction of (+)-(S)-isopropylidene-3-butene-l ,2-

ArNCO
.. [~C12H24C=N-O ]
252
O-N ~

~)
253

Seheme-136

diol254 and carbethoxyformonitrile oxide provides a 4:1 mixture of erythro- and

threo-isoxazolines 255 and 256 (scheme-137). As compared to intermolecular
addition, intramolecular cycloaddition is often achieved with an excellent selectivity
e.g. cycloaddition of nitro alkene 257 yields cycloadduct 258 in excellent yield
(scheme-138).

255
+
H3C
H3C~0~\~~
0-1 f" rC02C2Hs
O-N
256

Seheme-137
Heterocyclic Synthesis 237

60
OCOCH 3
N-O
'\\\\'OCOCH3
CH 3 '-" CH 3
:;i'H

257 258

Scheme-138

Cycloaddition reactions of nitrones with ethylenic and acetylenic dipolarophiles

yield isoxazolidines 260 and a2-isoxazolines 261, respectively (scheme-139)I10,

)c=~-6
I

260 261
Scheme-139

Cycloaddition of N-methyl-C-phenylnitrone 262 with acrylonitrile yields

predominantly trans-product 263, whereas with nitroethylene yields cis-isomer
265 as the main product (scheme-140)1ll, Cis-trans isomerisation of nitrone is ruled
out in case of cyclic nitrones and stereoselectivity is higher e,g. the cycloaddition
of 4-phenylbut-l-ene 268 yields only one adduct 269 via exo transition state
(scheme-141)1l2.
Intramolecular cycloaddition of C-alk-4-enylnitrone 271 yields exclusively cis-
fused cycloadduct 272 (scheme-142). However, C-alk-5-enylnitrone 274 yields a
mixture of cis- and trans-ring-fused products 275 due to the greater flexibility
allowed by the longer connecting chain. The bridged ring product 276 is also
formed by the attack of oxygen atom of nitrone at the end of the double bond
(scheme-l 43)J13.
238 Heterocyclic Chemistry

"<:
262

N0
2

CH3
I

5
H C• .. r
~N,~0

02 N

263 (trans) 265 (cis)

+ +

264 266

Scheme-140

o
N
I
+ C6H5~ __ A--I.~
o
H
267 268 269

Scheme-141
Heterocyclic Synthesis 239

~
CHO
270

Scheme-142

6,~
HgO,CHCI3
•
I
CH 3
273
274

,{
+

276

Scheme-143

Nitrones are generally prepared in situ by the oxidation of a disubstituted

hydroxylamine with yellow mercuric oxide or by the reaction of an aldehyde or
240 Heterocyclic Chemistry

ketone with a monosubstituted hydroxylamine. The cycloaddition reaction of

cyclic nitrone 278 (obtained by silver ion catalyzed cyclization of y- and 0-
oximinoallenes 277) with styrene yields heterocycle 279 (scheme-144).

QH=C=CH2
N
I
OH
277 278

279

Scheme-l44

[3 + 2] Cycloaddition of ethyl vinyl ether to optically active nitrone 281 yields

heterocycle 282 with excellent facial and endoselectivity (scheme-145)1l4.

282

Scheme-145
Heterocyclic Synthesis 241

An equimolecular mixture of heterocycles 284 and 285 is obtained from nitrone

283 having an opticaly active auxilIary (-)-menthyl group with trans- benzyl
crotonate (scheme-146)11S. Intramolecular cyclization of nitrone 286 yields
exclusively isoxazolidine 287 (scheme-147).

.::.

283
R =(-)-menthyl +
0 - - NCH 2 CaHs

,JV"IICOOR

COOCH 2 CaHS
285
Scheme-146

tert-amyl alcohol

/'...

H3c~~5
o 0
287
Scheme-147

Azides react with olefinic and acetylenic dipolarophiles to yield 4,5-dihydrotriazoles

and triazoles, respectively. In an intramolecular cycloaddition, 6-azide 288 yields
dihydrotriazole 289 (scheme-148). The olefinic azides 290 undergo thermal
decomposition yielding cyclic imines 292 and l-azabicyclo[3.1.0]hexane 293 via
the intermediate formation oflabile triazolines 291 (scheme-149)1l6. Azide 294 on
heating in a-dichlorobenzene yields imine 295 with complete regiospecificity
(scheme-150)1I7.
242 Heterocyclic Chemistry

Scheme-148

~ N3
290

292 293
Scheme-149

COOCH3

COOCH 3 Ll

294
Scheme-150
Heterocyclic Synthesis 243

Azomethine imine 297 (obtained in situ by the reaction of N-acyl-N'-

alkylhydrazines 296 with an aldehyde) reacts with alkenes to provide
pyrazolidines (scheme-151 )118.

o
H5C6 Jl NHNHCH:3

296
" HCHO
toluene, ~ ' "

297

!H5C6~
o CH 3

H5C.~~
H5 C6

299(65%) 298(68%)
+

300(7%)

Scheme-lSI

Intramolecular cycloaddition reaction of N-alkenoyl-N'-alkylhydrazine 301 with

benzaldehyde provides bicyclic pyrazolidine 303 (scheme-152)1l9.
244 Heterocyclic Chemistry

301

303
Scheme-152

N-Imide of pyridine generated in situ by deprotonation of N-amino salt reacts

with acetylenic dipolarophiles to yield adduct 305 which subsequently on
dehydrogenation provides heterocycle 306 (scheme-153)120.

Scheme-153
Heterocyclic Synthesis 245

Cycloaddition reaction of diazoalkanes with olefinic and acetylenic dipolarophiles

yields pyrazolines and pyrazoles, respectively, The reaction of methyl acrylate with
diazomethane yields heterocycle 308 (scheme-154),

riCOOCH3
CH 2 =CHCOOCH 3
+ (. ~N
N
307

~COOCH'
(. ,\N
N
H
308

Scheme-154

Cycloaddition of methyl diazoacetate to N-(1-propenyl)pyrrolidine provides

pyrrolidinopyrazoline 311 which on elimination ofpyrrolidine gives pyrazole 312
(scheme-155)l2l, Intramolecular cycloaddition of diazo compound 313 yields
pyrazoline 314 (scheme-156)122,

CH-N=N
I
COOCH3
+
+ C N-CH=CHCH3

309
310 \

CH3 ~ CH3

CH30OC-dH ........!---CH300c
N
~H
N
312 311

Scheme-155
246 Heterocyclic Chemistry

313 314
Scheme-156

Cyclization of tosylhydrazone 315 with sodium hydride yields pyrazoline 316

(scheme-I 57).

H~
NNHOS0 2 -CsH4 -CH 3 -p
NaH
q) H

H
315 316

Scheme-157

2.2.2 [2 + 2~4] Cycloadditions

Four-membered heterocycles can be prepared by concerted or non-concerted [2 + 2]

cycloadditions 123 . These reactions often compete with the side reactions. The
important processes are cycloreversion either to starting materials (a) or
cycloreversion with dismutation (b), and the expansion to yield six-membered rings
(c) as shown in Fig. II. The alkenes undergo thermal [2 + 2] cycloadditions mostly
via a step-wise pathway involving diradical or zwitterionic intermediates 124 . The
widely employed reactions involve ketenes and heterocumulenes such as
isocyanates, isothiocyanates etc. The reaction of ketenes with imines has been
used for the synthesis of p-Iactams 319 (scheme-I 58)12s. The reaction of
oxazolidone 320 with benzyl imines 321 in the presence of triethylamine is almost
completely diastereoselective yielding heterocycles 322a and 322b (scheme-I 59)126 .
Ketene 324 reacts with optically active imine 323 providing p-Iactam 325 with high
diastereoselectivity (scheme-160). The addition of alkenes to diformylmethyl
Heterocyclic Synthesis 247

A=B
+ <
a .. A-B
I I
C-D
C=D

;V ~
B+
A B
K A=B K B. . . A
C
II
" + 0 I
C, _ • I
C, ".B
I
0 0

Fig. 11

±to
R N ....
R
1

317 318 319

Scheme-158

320 321

322a
Scheme-159
248 Heterocyclic Chemistry

H CHa

H)'l(j-Oi'
CH3OCH2COCl
N(~Hs)3' CH2C12
[CH3OCH=C=O]
NC sH4 -OCH a-p
324
323

H
H HL-O CHa
CHaOIl~'~Lo><CHa
NC sH4 -OCH a-p
o
325

Scheme-160

acetate constitutes an important application for the synthesis of pyran ring system
328 (scheme-161)l27. Paterno-Biichl photochemical cycloaddition of olefins to

~OCHa

) n,OiO
CHaOOCxCHO
+ I hv ~
H OH OH

I
326 327

COOCHa

o
OH
328

Scheme-161
Heterocyclic Synthesis 249

aldehydes and ketones yields oxetanes. A stepwise radical mechanism is

suggested (scheme-162)128. The photochemical cycloaddition of aldehydes to
furans provides head to head exo-products 330 with high regio- and
stereoselectivity (scheme-163)129.

329

Scheme-162

hv
RCHO ----..

Scheme-163

2.2.3 Hetero-Diels-Alder Reactions: [4 + 2~6] Cycloaditions

The cycloaddition of a conjugated diene to a dienophile (a double or triple bond)

to fonn an adduct with a six-membered carbocyclic or heterocyclic ring is known
as Diels-Alder reaction. The fonnation of two new a-bonds takes place in the
cycloadduct at the expense of two 1t-bonds in the starting compound. The reaction
is depicted in Fig. 12. It is known as [4 + 2] cycloaddition reaction, since it involves
interaction of a four 1t-electrons system with a two 1t-electrons system. According
to the Woodward-Hoffmann rules, it is thennally allowed process. Its synthetic
usefulness arises from its versatility and high regio- and stereo selectivity. Both