Electrophilic Substitution of Heterocycles:
Quantitative Aspects

Advances in

Heterocyc 1ic
Chemistry
Volume 47

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Editorial Advisory Board
R. A . Abramovitch, Clemson, South Carolina
A. Albert, Canberra, Australia
A. T. Balaban, Bucharest, Romania
A. J. Boulton, Norwich, England
H . Dorn, Berlin, G.D.R.
J . Elguero, Madrid, Spain
S . Gronowitz, Lund, Sweden
T . Kametani, Tokyo, Japan
0. Meth-Cohn, South Africa
C. W. Rees, FRS, London, England
E. C. Taylor, Princeton, New Jersey
M. TiSler, Ljubljana, Yugoslavia
J. A . Zoltewicz, Gainesville, Florida

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Electrophilic Substitution of
Heterocycles:
Quantitative A spect s
Alan R. Katritzky, FRS
Department of Chemistry
University of Floridu
Gainesville. Floridu

Roger Taylor
School of Chemistry and Moleculur Sciences
The University qf Sussex
Falmer, Brighton
England

Advances in Heterocyclic Chemistry
Volume 47

ACADEMIC PRESS, INC.
Harcourt Brace Jovanovich, Publishers

San Diego New York

Boston

London Sydney Tokyo Toronto

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Contents

PREFACE
.... . . .. .... .......... . . ., . .. , , , . . . ., . .. ...... . . . . , . .. . .. , .. . , . . ....... . , . .... , ..... . . , . ....... . . .. ..
vii
DETAILED
TABLE
OF CONTENTS
. . . , _ . . _ _...
. __ ... _ . _ _.._. ..._. . ._ _ _. ..._, , _, . , .._.., . , . . . . _ _. ,_. , ._._ ix
CHAPTERI . Introduction ........... . .... . . .............. ,......... .........................._.........

i

Part I
Electrophilic Substitution Reactions
CHAFTER2.
CHAPTER3.
CHAFTEK4.
CHAFTER5.

Hydrogen Exchange .............................................................
Nitration ............ ._.............._
Other Reactions ..
Reactions lnvolvin

..............................
Side-Chain a-Posit

7
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59

77

Five-Membered Heterocyclic Rings
CHAFTER6. Reactivity of Five-Membered Rings Containing One Heteroatom .......
CHAPTER7 . Azoles .....................................................................................
CHAPTER8. Polycyclic Heteroaromatics Containing a Five-Membered Ring ..........

87
139
181

Part 111
Six-Membered Heterocyclic Rings
CHAPTER9. Heteroaromatics Containing One Six-Membered Ring ....._................
CHAFTER10. Six-Membered Rings: Electrophilic Substitution in the Azines .........
CHAPTERI I . Compounds Containing Two or More Six-Membered Rings .............
CHAPT'ER
12. Thiaazepines ............... . . ................ ........................... ...............

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353
399


REFERENCES
..............................................................................................

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Preface
Volume 47 of Advances in Heterocyclic Chemistry is, unlike most
volumes, a monograph and deals with the quantitative aspects of electrophilic substitution of heterocycles. It is written by Roger Taylor of the
University of Sussex, Brighton, England, and your editor with one
chapter contributed by Ross Grimmett of the University of Otago in New
Zealand. It is hoped that this survey of the whole area of electrophilic
substitution of heterocycles, covering as it does semiqualitative as well
as completely quantitative aspects, will be of considerable help to
workers in the field.
As is normal for volumes of our series, no subject index is included.
Instead, there is a very detailed contents from which we believe it will be
possible to track down most points. Of course, this volume will be
indexed in Volume 51, which will be the next “index volume” of the
series and will cover Volumes 46-50, just as Volume 46 covered Volumes
4 1 4 5 and Volume 40 covered Volumes 1-40.
ALANR. KATRITZKY


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Detailed Table of Contents
Chapter I . Introduction
I . General Objectives ...........................................
.......................
2 . Significance of Mechanism in the Electrophilic Sub
......................................
A . Rationahation of Experimental Results
B . Guidance in Future Experimental Work ........................
3. Scope and Organization of Review .............................................................

i

3

.

Part I Electrophilic Substitution Reactions
Chapter 2 . Hydrogen Exchange
I . Acid-catalyzed Exchange ..........................................................................

A . Mechanism .........................................................................................
B . Exchange Conditions
........................................
................................................
a . Aqueous Mineral A
b . Organic Acids ...................................................................................
C . Steric Effects ...............................................
D . Hydrogen Exchange in Heteroaromatics ..................................................
E . Experimental Techniques
.................................................
a . Deuteriation .....................................................................................
b . Detritiation ......................................................................................
F . Criteria for Defining the Reacting Species ..........
a . Species Variation .............................................................................
b . Use of Model Compounds ..................................................................
c . Consideration of Rate Profiles .............................................................
d . Other Criteria ...................................................................................
e . Examples of Rate Profiles
...........
......
G . Standard Conditions: Choice and Procedure .............................................
a . Acid-Catalyzed Hydrogen Exchange as a Quantitative Measure of
Reactivity ..........................................................
b . Justification for Selecting Standard Conditions ........
c . Procedure for Determining Standard Rates for Deuteriation ......................
d . Reliability of /iy Values ..............
e . Alternative Standard Conditions ..........................................................
2 . Base-Catalyzed Exchange .........................................................................
A . Mechanism ................................
B. Exchange Conditions ............................................................................

C . Steric Effects ....
.....................................................
cs ...........
D . Hydrogen Excha

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DETAILED TABLE OF CONTENTS

Chapter 3. Nitration
I. Nitration Conditions ....

......................................

2. Mechanism .....................................................
A. The Nitrating Species ...........................................................................
B. Encounter Control ...
C. Solvent Effects ....................................................................................
D. Electron-Transfer Mechanism ................................................................
E. Nitration of Bases ....
F. lpso Attack .........................................................................................
3. Experimental Techniques.. ........................................................................
A. The U V Technique ..

B. Calculation of Kinetics .........................................................................
C. Kinetic Complications
4. Criteria for Defining the Reacting Species ...................._....
...........................
A. Survey of Possible Criteria ....................................................................
B. High-Acidity Rate Profiles
C. Moodie-Schofield Plots ........ . ..... ... .. . ........
. .... .....
D. Modified Rate Profiles ..........................................................................
E. Other Types of Rate Profiles
F. Model Compound Studies .....................................................................
G. The Encounter Rate Criterio
...............
H. Thermodynamic Parameters ..........._................ ......................................
I. Summary of Mechanistic Criteria ...........................................................
5. Standard Conditions: Choice and Procedure
A. Selection of Standard Conditions
B. Determination of Standard Rates
C. Alternative Procedure ......................................................................... ..
D. Conclusions ............................................................................... .........

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Chapter 4. Other Reactions
A. Protiodemercuriation ............................................
B. Protiodeboronation ......... .
.........................................
C. Protiodesilylation ...........................................
...........................

..........................................
2. Metallation ............... ...
.................................
.........................

A. Lithiation .....
B. Magnesiation
.................................................
..............................................
C. Mercuriation ...............
.................................
D. Plumbylation ..............,.........................
3. Reactions Involving Carbon Electrophiles .................................
A. Alkylation .........................................
.........................................
..................
B. Haloalkylation and Hydroxyalkylation ...........
C. Aminoalkylation
.............................................................
D. Cyanoethylation ......................
.................................
E. Acylation .....................................................
b. Other Acylations ......
c. Alkoxycarbonylation ........................

................................................
...........................

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DETAILED TABLE OF CONTENTS
4. Reactions Involving Nitrogen and Phosphorus Electrophiles .............. . ......_.....
A. Nitrosation ............. .............. . . . .................... _ ....._..._
.
._._._
B. Diazonium Coupling
...................................
.. ..
C. Phosphonylation ..................................................................................
5. Reactions Involving Oxygen and Sulfur Electrophiles
A. Hydroxylation ................. ...................... ........... ...................................


C. Chlorosulfonation
D. Sulfenylation .....................................

.___....
.....................

........, ...........

....................
..........................................................
....................................................
C. Other Reactions ..................................................................................

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Chapter 5. Reactions Involving Formation of Carbocations at

Side-Chain a-Positions
Experimental Technique
B. Kinetic Method ..

..........................................................
..............................
..............................
..............................
.......................................................................

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Part 11. Five-Membered Heterocyclic Rings
Chapter 6. Reactivity of Five-Membered Rings Containing One
Heteroatom
I . Acid-Catalyzed Hydrogen Exchange
A. Thiophenes .........................................................................................
B. Selenophene ................. .............. ................... ... ......... .......... ...............
C. Furan ...........
D. Pyrrole ..............................................................................................
2. Base-Catalyzed Hydrogen Exchange.. ......... .. ..............................................
Furan. Thiophene, and Selenophene ... . ......... .......
3. Nitration ................................................................................................
A. Thiophenes ....
B. Pyrrole ..............................................................................................
4. Halogenation ........................................... ............................................ ...

A. Thiophene and Selenophene
..................................................
B. Furan and Pyrrole ....................................................................
5. Alkylation ..............................................................................................
............................
Pyrrole. N-Methylpyrrole. Furan, and Thiophene
6. Chloroalkylation .......................... ... ........... .................................
Thiophene ......................................... . . .............................. ........... ...........
7. Acylation ............................
A. Thiophenes ......................
B. Selenophene and Tellurophene .. ...................... .......... .. . ............ ........ ......
C. Furans ...................................
D. Pyrroles .............................................................................................

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DETAILED TABLE O F CONTENTS

8. Other Electrophilic Substitutions ..............................
A. Thiophenes .........................................................................................
B. Selenophene and Tellurophene
C. Furans ...............................................................................................
D. Pyrroles .............................................................................................
9. Side-Chain Reactions ............
A. Thiophene ..........................................................................................
B. Selenophene and Tellurophene .... ................ ...........................................

I I3
I I3
120

D. Pyrroles .............................................................................................

10. Conclusions
A. Aromaticit
........................................................
B. Summary of Relative Rates ...................................................................
C. Sensitivity of the Five-Membered Heterocycles
to Substituent Effects ...........................................................................

125
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122

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132

Chapter 7. Azoles
1, Introduction

.....................................
...........................................
atoms ...... .......................

b. Neutral Five-Membered Rings with Three Heteroatorns

c. Neutral Five-Membered Rings with Four Heteroatoms ....................
d. Monocationic Azoles

........

.............................................
2. Acid-Catalyzed Hydrogen Exchange

.....................

A. Mechanism ................................................................
B. Reaction at the 4-Position .....................................................................
....................
C. Effect of Ring Nitrogen Atom on Rate
D. Effect of Methyl Substitution on Rate .....................................................
E. Reactivity of Cations versus Free Bases .................................................
3. Base-Catalyzed Hydrogen Exchange .......
A. Introduction .................................
.................... ..................................
B. Positional Reactivity Order ........................................................... . ........
C. Substituent Effects
......................
4. Nitration ...................................................................
A. Oxazoles, Thiazoles Selenazoles and Imidazoles ................................. ... ..
b. Thiazoles ..........................................................
c. Selenazoles ....................................... ...................................... . ........
d. lmidazoles ..
.....................
a. lsoxazoles ........................................................................................
b. Isothiazoles

.............................................................
d. Dithioliurn Ions ...... ..........................
.......................................
C. Oxadiazoles, Thiadiazoles. Triazoles. and Derivatives ......

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DETAILED TABLE O F CONTENTS

........., ,, ............ ......
a. Oxadiazoles .............
b. Thiadiazoles .................
c. Triazoles ................................................................................
5. Halogenation ..._............
. .................... . . ........ . ......... . . . . .......... ...._........, , ._..
A. Oxazole. Thiazole. and lmidazole ..........................................
B. Isoxazole. Isothiazole. and
.........................
C. Thiadiazoles and Triazoles

.....................
6. Alkylation. Chloro(hydroxy)al
7. Sulfonation, Sulfenylation, and Diazonium Coupling ........
8. Metallation ...... .... . _ . _ _,_
, ...
___,
A. Mercuriation ......... .................. . ......... ... . ......... .............. ..........._

...

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... .. . ........... . . ......... .. .................... , . ....... ........ .
173
A. Determination of Positional

9. Transmission of Substituent Effects ........ .. ...... ............... ................., , ...... 177
10. Theoretical Calculations of Reactivity ........ . . . ............................. . . .......__.... 178

Chapter 8. Polycyclic Heteroarornatics Containing a Five-Membered
Ring
1. General Introduction ................................................................................
181
2. Compounds with One Five- and One Six-Membered Ring ..............................
IXI
A. Molecules Containing One Heteroatom: BenLo[h]furan. Benro[h]thiophene.
Benzo[b]selenophene, Benzo[h]tellurophene. and lndole .. ............. ............... 182
a. Positional Reactivity Order
............... 182
184
b. Reactions .........................................................................................
... 213
c. Quantitative Aspects of the
B. Molecules Containing One H
and lndolizine ................ . . , .. ........... . . .. . ......... .............. ......... . ............... .. 216
a. Reactions
..............
.. .......
.... 216
218
b. Quantitative Aspects of the Reactivity Data ...........................................
C. Molecules with More Than One Heteroatom in the Five-Membered Ring ...... 220
a. Positional Reactivity Order
............ 221
222
b. Reactions .........................................................................................

228
D. Molecules with Heteroatoms in Each Ring ...............................................
a. Positional Reactivity Order
..............
............... 229
230
b. Reactions .........................................................................................
... 239
3. Compounds with One Five- and Two Six-Membered Rings .............._
A. Molecules Containing One Heteroatom ... . . ..._.
.......................... . .....___.__.
.. 239
r . . .. ............................... .. ............. ............. .. 239
242
......
248
e Re
...........................................
B. Molecules Containing Two or More Heteroatoms . . ............ ....... .. ............... 25 I
253
4. Compounds with Two Five- and One Six-Membered Ring .......
255
A. Acid-Catalyzed Hydrogen Exchange . ......... .
257
B. Other Reactions ..................................................................................
262
5. Compounds with Two Five-Membered Rings ...
A. Acid-Catalyzed Hydrogen Exchange ...... .............................. ....... .. .......... 265
268
.......... . ........................

269
C. Other Reactions
...........
s ................... ......., ...... 272
6. Compounds with T
Acid-Catalyzed Hydrogen Exchange of Dithienothiophenes ..... ....... . . . ... . .......... 272

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D E T A I L E D T A B L E OF CONTENTS

xiv

.

Part 111 Six-Membered Heterocyclic Rings

.

Chapter 9 Heteroaromatics Containing One Six-Membered Ring

...........................................................................................
........................................................................
...............................................................................
.........................................................................................
....................................................................
...................................................................................
......................................................................................
..................................................................................

...................................................................................
...............................................................................

I. Introduction
A Compounds Considered
B . Reactivity Patterns
a Pyridines
b Pyridine N-oxides .............................................................................
c Pyrones and Thiapyrones
d Pyrylium Ions
e Arsabenzene .....................................................................................
f. Phosphorins
2 . Acid-Catalyzed Hydrogen Exchange ...........................................................
A Methylpyridines
B . Aminopyridines
C . Pyridones and Hydroxypyridines ............................................................
D Pyridine N-Oxides
E. Pyrones and Thiapyrones ......................................................................
F Pyrylium Ions .....................................................................................
G Arsabenzene
H Summary of Kinetic Data .....................................................................
3 Base-Catalyzed Hydrogen Exchange
4 Nitration ................................................................................................
A . Pyridines ............................................................................................
B Pyridones and Hydroxypyridines ............................................................
C . Pyridine N-Oxides ...............................................................................
D 2-Pyrone ............................................................................................
E Arsabenzene
F Summary o f Kinetic Data ......................................................................
5 Halogenation ..........................................................................................

A Pyridines ............................................................................................
B. Pyridones and Hydroxypyridines ............................................................
C . Pyridine N-Oxides ...............................................................................
6 Other Reactions ......................................................................................
A . Metallation
B. Alkylation and Acylation
C. Diazonium Coupling .............................................................................
D Sulfonation and Sulfenylation ................................................................
E Demetallation ......................................................................................
7 . Side-Chain Reactions ...............................................................................
A Pyrolysis of Esters ...............................................................................
a Pyridine ...........................................................................................
b. Pyridine N-Oxide
B. Solvolysis of I-Aryl- I-Methylethyl Chlorides ............................................
a Pyridine ...........................................................................................
b Pyridine N-Oxide
8 Transmission of Substituent Effects in Pyridine ............................................
9. Comparison of Theoretical Calculations of the Reactivity of Pyridine and
Pyridine N-oxide with Observed Data

.

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DETAILED TABLE OF CONTENTS

A . Pyridine Free Base ..............................................................................
B Hydrogen-Bonded Pyridine ...................................................................
C. Pyridinium Cation ................................................................................
D. Pyridine N-Oxide Free Base ..................................................................
E Hydrogen-Bonded Pyridine N.Oxides ......................................................
F Protonated Pyridine N-Oxides................................................................
G. Pyrylium and Thiopyrylium Ions ............................................................
H Methyl-Substituted2-Pyridones .............................................................
1 Comparison of Standard Data for Nitration and Hydrogen Exchange............

.

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Chapter 10. Six-Membered Rings: Electrophilic Substitution in the
Azines
by M . Ross Grimmer;

I. Reactivity of the Monocyclic Azines ...........................................................
2 Acid-Catalyzed Hydrogen Exchange...........................................................
A . Pyridazines .........................................................................................
B. Pyrimidines ........................................................
............................
C. Pyrazines ...........................................................................................
D. Triazines .............................
...........................................................
3 . Base-Catalyzed Hydrogen Exchange...........................................................
A . Pyridazines .........................................................................................
B. Pyrimidines ........................................................................................
C . Pyrazines ...........................................................................................
D. 1.2.4-Triazines. .....................................................................................
4. Nitration ................................................................................................
A . Pyridazines .........................................................................................
B Pyrimidines .........................................................................................
C Pyrazines ...........................................................................................
D Triazines ............................................................................................
E Borazapyridines ............................
.................................................
5 Halogenation..........................................................................................

A Pyridazines .........................................................................................
B. Pyrimidines ........................................................................................
C. Pyrazines ...........................................................................................
D. Triazines ............................................................................................
6. Other Electrophilic Substitutions................................................................
A Diazo Coupling ...................................................................................
B. Nitrosation .........................................................................................
C . Sulfonation .........................................................................................
D. Acylation ............................................
...........................................
E Alkylalion ...........................................
...........................................
F. Metallation .........................................................................................

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.

Chapter I I Compounds Containing Two or More Six-Membered Rings

I . Introduction ...........................................................................................

A . Survey of Heterocycles Considered ........................................................
a Compounds Containing One Nitrogen Atom ...........................................
b. Compounds Containing Two Nitrogen Atoms .........................................
c Compounds Containing Three Nitrogen Atoms .......................................

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d Compounds with Four or More Nitrogen Atoms .....................................
e . Hydroxy Derivatives "Ones" of Compounds 11.1-11.39 with Hydroxy
Group Conjugated with Nitrogen...........................................................
f. N-Oxide Derivatives of Compounds 11.1-1 1.39 .......................................
g. Compounds Containing Other Group VB Elements

h. Compounds Containing Boron and Nitrogen ..........................................
i Benzo-AnnelatedPyrylium Ions ...........................................................
j Benzo-Annelated Pyrones....................................................................
B Reactivity Patterns...............................................................................
2 Acid-Catalyzed Hydrogen Exchange ...........................................................
A . Quinolines and lsoquinolines
B Quinoline and Hydrogen lsoquinoline N-Oxides ........................................
C . Chromone and Thiachromone ................................................................
3 Base-Catalyzed Hydrogen Exchange...........................................................
4 . Nitration ................................................................................................
A Compounds Containing One Nitrogen Atom .............................................
B Compounds Containing More than One Nitrogen Atom ..............................
C Xanthylium Salts .................................................................................
D Boraza Compounds..............................................................................
E. Summary of Kinetic Data......................................................................
5 Halogenation
A Compounds Containing One Nitrogen Atom .............................................
B. Compounds Containing More than One Nitrogen Atom
C Boraza Compounds..............................................................................
6 . Other Electrophilic Substitutions
A Mercuriation .......................................................................................
B. Sulfonation
C. Miscellaneous Electrophilic Substitution
7 Side-Chain Reactions: Pyrolysis of I-Arylethyl Acetates
8 . Theoretical Calculations of Reactivity
A . Summary of General Methods ...............................................................
B Quinoline and lsoquinoline

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.

Chapter 12 Thiaazepines
Thiaazepines ...........................................................................................
References

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CHAPTER
1

Introduction
1. General Objectives
A large and important part of the preparative chemistry of heteroaromatic compounds has been concerned with their electrophilic substitution

reactions. Similarities between the chemistry of heteroaromatic compounds and benzenoid derivatives were recognized early, and reactions
discovered initially in the benzene series were then applied to various
heterocycles.
The classical investigations of the mechanism of aromatic electrophilic
substitutions concentrated on benzenoid derivatives; thus the 1266 pages
of the second edition of Ingold’s definitive Structure and Mechanism in
Organic Chemistry, written in 1969, while describing in great detail the
mechanism of electrophilic substitution, barely mentioned heterocyclic
chemistry. However, over the last 20 years the position has changed dramatically and several schools have made considerable headway in the
detailed study of mechanism and reactivity in heteroaromatic electrophilic substitution, notably at the Universities of East Anglia, Exeter,
Florida, Perugia, and Sussex, and at University College London.
The objectives of this work can be illustrated by reference to the program at the University of East Anglia over the years 1965-1980.
(1) It was first necessary to define the species of the heterocycle entering into reaction under any particular set of conditions. For example, basic molecules such as pyridine could react as free base or conjugate acid,
whereas a potentially tautomeric compound such as 4-pyridone could react as such, or in the other tautomeric form (Chydroxypyridine), or as
the conjugate acid or base.
(2) Having defined the species reacting, the quantitative effect of the
heteratom(s) on reactivity had to be determined. This entailed a kinetic
investigation which, for purposes of comparison, often needed extrapolation to standard conditions of the kinetic results (which had to be obtained
under a wide variety of conditions because of the very large differences
in reactivity encountered).
(3) With information available regarding the quantitative effects of the
heteroatoms on the reactivity of various systems, the correlation of the
effects of heteroatoms on different reactions and different substrates
could be examined. Mutual interactions with substituents and other hetI

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2


1. INTRODUCTION

[Sec. 2.A

eroatoms, and interactions of heteroatoms with the reagent in the transition state, were to be investigated and, if possible, explained by linear
free-energy relationships (LFER), valence bond, molecular orbital (MO),
or other theoretical methods.
(4) The experimental program at the University of Sussex (1970-present) of reactivity in the gas phase (involving formation of side-chain carbocations) has, in addition to the points already mentioned, demonstrated
the need to take hydrogen bonding into account for both n-deficient and
n-excessive heteroaromatics, showing that this can in some cases markedly alter the reactivity.
( 5 ) Many other studies have encompassed all or some of the aspects
discussed below.

2. Significance of Mechanism in the Electrophilic Substitution
of Heterocycles
In addition to their own intrinsic scientific interest, the studies outlined
above are of great importance in several respects.

A. RATIONALIZATION
OF EXPERIMENTAL
RESULTS
The recognition of the species which is undergoing reaction, of the
quantitative effects of heteroatoms, of interactions between heteroatoms
and substituents, and of the importance of hydrogen bonding have made
possible, for the first time, a rational, quantitative, overall treatment of
heteroaromatic reactivity pat terns.
The heterocyclic literature is enormous, and a significant fraction deals
with electrophilic substitution reactions of heteroaromatics. A great many
authors have provided quantitative data, but the data are scattered
through the literature, rarely reviewed comprehensively, and still less interpreted. Indeed, a proper interpretation is possible only by taking the

wider view. This is what this book is intended to provide. It has been
found possible not only to give interpretations of all of these quantitative
data-in many cases for the first time-but to consider, additionally,
much of the semiquantitative and qualitative work on the electrophilic
substitution of heterocycles.
In our rationalization, we have relied heavily on the classical concept
of aromaticity with particular emphasis on bond order and bond fixation.
These concepts, together with acid-base and tautomeric equilibria and
hydrogen bonding, are capable of explaining nearly all of the quantitative

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Sec. 31

SCOPE A N D ORGANIZATION

3

results. We have found MO methods less helpful: Electrophilic substitution reactions are usually carried out in condensed phases involving very
strong solvent-substrate and solvent-reagent interactions, which vary
considerably from ground to transition states. MO methods are still unable to cope effectively with this behavior, although this is changing
rapidly.

B. GUIDANCE
IN FUTURE
EXPERIMENTAL
WORK
The rationalizations just discussed can be used in extrapolation. Study
of this book should be of considerable assistance in the optimization of

experimental conditions, whether it be to improve overall yields, or to
maximize the yield of one particular orientation or substitution.
The reactivity patterns disclosed in this book will be of greatest help in
assessing the probability of success for new reactions, and in choosing
experimental conditions likely to render such reactions successful.

3. Scope and Organization of Review
In this review we have gathered the important work on quantitative and
mechanistic aspects of electrophilic aromatic reactivity of heterocycles.
We have concentrated in particular on acid-catalyzed hydrogen excharzge, nitration, and gas-phase elimination, these being the major efforts
of our own research groups. However all other electrophilic substitution
reactions are covered for completeness.
The book is divided into two parts: Part 1 (Chapters 2-5) is concerned
with individual reactions, and Parts I1 and 111 (Chapters 6-12) with groups
of related compounds.
Part I commences with hydrogen exchange, both because this is the
simplest electrophilic substitution, and because the studies can be and
have been extended over a far wider range of experimental conditions,
and substrates, than any other electrophilic substitution. Chapter 3 deals
with nitration, and Chapter 4 with other electrophilic substitutions. Chapter 5 is devoted to a study of the formation of side-chain carbocations,
the results of which are of great importance in the interpretation of heteroaromatic reactivity .
Parts 11 (Five-Membered Heterocyclic Rings) and 111 (Six-Membered
Heterocyclic Rings) are organized along classical lines: Monocyclic fivemembered rings with one heteroatom (Chapter 6), monocyclic five-membered rings with two or more heteroatoms (Chapter 71, polycyclic com-

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4

1. INTRODUCTION


[Sec. 3

pounds with five-membered rings (Chapter 8), monocyclic six-membered
rings with one heteroatom (Chapter 9), monocyclic six-membered rings
with two heteroatoms (Chapter 101, and polycyclic six-membered rings
(Chapter 1 1 ) . Little quantitative work has been reported on seven-membered or larger rings. Some of this is considered in Chapter 12.

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Part I
Electrophilic Substitution
Reactions

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CHAPTER
2

Hydrogen Exchange
Hydrogen exchange can occur under either acid- or base-catalyzed
conditions. Both can be considered electrophilic aromatic substitutions,
the latter involving attack of the electrophile upon an aromatic anion,

zwitterion, or ylide. The former reaction is aided by electron supply, the
latter by electron withdrawal (particularly by - I effects) as the ratedetermining step is the initial proton loss. Steric hindrance, negligible in
virtually all cases under acid-catalyzed conditions, appears to be of
slightly greater importance under base-catalyzed conditions.

1. Acid-Catalyzed Exchange

A. MECHANISM
The mechanism of acid-catalyzed exchange has been described in very
great detail elsewhere [72MI2(194)], so that only a summary of the main
features together with more recent material is given here.
The reaction (in the form of deuteriation) was first shown to be an electrophilic substitution by Ingold, Wilson, and their co-workers some 50
years ago [34N(L)347; 36JCS915,1637; 38JCS281. These workers found
the order of reactivity of electrophiles to be D,SO, > D,O+ > DOPh >
D,O. Shortly thereafter, Koizumi and Titani examined the reactivity of
additional aromatics, including heterocycles (38BCJ95,681 ; 39BCJ353).
Both these and subsequent studies have concentrated on two main areas,
namely the determination of the mechanism of the reaction, and use of it
to determine quantitative electrophilic reactivities' of aromatics. In this
latter respect the reaction has great advantages over other electrophilic
substitutions, including (i) absence of steric hindrance; (ii) the ability to
carry out studies on very small quantities of aromatic; (iii) very high kinetic accuracy; and (iv) a large rate spread due to the range of electrophiles available, including those of fairly low reactivity, which provide a
reaction of quite high p factor.
The mechanism of the reaction was shown by Eaborn and Taylor to
be (6OJCS3301) an acid-catalyzed version of the S,2 mechanism (A-S,2),
which applies to most electrophilic substitutions (Scheme 2. I). This involves a bimolecular reaction between an acid (HA) and the aromatic to
give a Wheland intermediate, which then loses a hydrogen ion to give
7

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2. HYDROGEN EXCHANGE

8

[Sec. 1.A

SCHEME 2. I . The A 4 2 mechanism for acid-catalyzed hydrogen exchange.

A - . The reaction is reversible and the profile is symmetrical about the
intermediate (2.1) apart from small differences arising only from the nature of the isotopes. Bond breaking and bond making take place in essentially identical and rate-determining steps (56ACS879; 59JA5509;
6OJCS3301; 61JA2877); it is this near symmetry of the reaction pathway
that contributes to the low steric requirement of the reaction. The existence of a Wheland intermediate was first demonstrated by Gold and Tye,
who found that anthracene in sulfuric acid gave a yellow species, attributed to 9-protonated anthracene (2.2) (52JCS2172,2184). More recently,
nuclear magnetic resonance (NMR) methods have confirmed the existence of such structures in a number of cases, and even shown that the
charge distribution in the benzenonium ion is as shown in structure
2.3 (58MP247; 60RTC737; 70JA2546; 71JOU 1232; 72JOU 1685,1808;
73JOC3212; 74BAU232, 74JA6908).
H

0.30
(2.3)

(2.2)

Early kinetic work had led to the proposal of the A-1 mechanism, i.e.,
one in which .rr-complexesare formed in a rapid pre-equilibrium, followed
by rate-determining intramolecular exchange of (one form of) the intermediate into the other (55JCS3609,3619,3622; 56JCS391 I). However, this
was based on a linear correlation of log exchange-rate coefficient versus

the acidity function - Hn , which was found subsequently not to hold over
wider acid ranges, the slopes increasing with increasing acidity
(6OJCS3301); similarly, there was no correlation of exchange rates between different acids of the same Hn value (55JCS3609). The implication
drawn from the supposedly linear log k versus - H , plots was that exchange was catalyzed by specific acids (i.e., by H,O' only), but later
work showed that catalysis is effected by a variety of other proton-donor
acidic species (general-acid catalysis). The A- 1 mechanism was further

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