Nucleophilic Aromatic Substitution of Hydrogen

372 Pages·1994·5.25 MB·English

by  Oleg N. Chupakhin

NUCLEOPHILIC
AROMATIC
SUBSTITUTION
OF HYDROGEN
Oleg N. Chupakhin Valery N. Charushin
Department of Organic Chemistry Department of Organic Chemistry
Urals State Technical University Urals State Technical University
Ekaterinburg, Russia Ekaterinburg, Russia
Henk C· van der Pias
Department of Organic Chemistry
Agricultural University
Wageningen, The Netherlands
Academic Press
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Library of Congress Cataloging-in-Publication Data
Chupakhin, O. N. (Oleg Nikolaevich)
Nucleophilic aromatic substitution of hydrogen / by Oleg N.
Chupakhin, Valery N. Charushin, Henk C. van der Pias.
p. cm.
Includes bibliographical references and index.
ISBN 0-12-174640-2
1. Substitution reactions. 2. Aromatic compounds. I. Charushin,
Valery N. II. Pias, H. C. van der. III. Title.
QD281.S6C48 1994
547'.604593-dc20 94-20812
CIP
PRINTED IN THE UNITED STATES OF AMERICA
94 95 96 97 98 99 BB 9 8 7 6 5 4 3 2 1
"Howfar it was and how cold..."
Dedicated to our wives Lyubov, Olga, and Mien
CONTENTS
PREFACE ix
1. INTRODUCTION 1
2. NUCLEOPfflLIC StmSTITUTION OF HYDROGEN IN ARENES 16
I. Unactivated arenes 16
II. Arene-metal complexes 18
III. Nitroarenes 31
A. Reactions with C-nucleophiles 33
B. Reactions with O-nucleophiles 52
C. Reactions with N-nucleophiles 59
D. Reactions with P-nucleophiles 66
v
PREFACE
Nucleophilic aromatic substitution in carbo- and heteroaromatic systems has been a sub­
ject of considerable interest to many chemists for many decades. In particular, the nucleo­
philic displacement reactions of halogens and other groups with nucleofugal properties have
attracted much attention. An overwhelming amount of information related to product for­
mation, kinetics, and mechanisms, supported by labeling techniques, UV, ESR, and NMR
spectroscopic studies, has been collected. In this respect, it is remarkable that textbook
treatment of the subject of nucleophilic aromatic substitution is sometimes very limited, in
contrast to the similarly important field of electrophilic substitution of aromatics.
Whereas investigations on the substitution of hydrogen in aromatics by use of electro-
philes have a long history, broad studies on nucleophilic displacement reactions of hydrogen
(S£) in ττ-deficient carboaromatics and heteroaromatics have a much shorter history. Early
examples of hydrogen substitution in ττ-deficient systems (the Chichibabin amination and
the hydroxylation reaction) showed that these nucleophilic displacements required very dras­
tic reaction conditions and oxidizing agents, a situation that did not stimulate chemists in
earlier days to enter this field of S£ substitutions. Today, this picture has completely changed.
Many new methodologies are being developed, making it possible to perform the replace­
ment reaction of hydrogen in ττ-deficient systems under mild conditions leading to C —C,
amm
C —Hal, C —U, C -0, C^—S, and C —P bond formation.
m m M m
It is the intention of the authors of this book to review the material on S£ substitution
reactions published in the literature up to 1993, to show the potential synthetic applications
of S£ substitutions, and to discuss the mechanisms involved in these reactions.
The authors will show that nucleophilic aromatic substitution of hydrogen is an advanced
field of chemistry. Electrophilic and nucleophilic substitutions of hydrogen in aromatics have
the common feature that, in the first step of the reaction, the aromatic system is destroyed
by addition of the attacking electrophile or nucleophile, respectively. However, whereas in
an electrophilic substitution the aromaticity is restored by loss of a proton, a nucleophilic
substitution requires an oxidizing agent, or an awio-aromatization to remove the formally
"hybride" ion. In this way, nucleophilic aromatic substitution is complementary to electro­
philic substitution of hydrogen in aromatics, both processes being of fundamental value in
the chemistry of (hetero)aromatic compounds.
IX
X PREFACE
This book was written through the close cooperation of three chemists: two from Russia
(Chupakhin and Charushin) and one from The Netherlands (van der Pias). This cooperation
made it possible to discuss the Russian literature, which is usually difficult to access. The
authors thank those colleagues who provided references, reviews, and other valuable infor­
mation. These colleagues also helped the authors in the selection of the material published
and encouraged them to prepare the manuscript.
O. N. Chupakhin
V. N. Charushin
H. C. van der Pias
Ekaterinburg-Moscow-Wageningen
January 1994
Introduction
Nucleophilic aromatic substitution of hydrogen comprises a large group of reactions
which have in common that through interaction of a π-deficient arene or hetarene with a
nucleophile the hydrogen in the aromatic ring is displaced (Scheme 1).
W W W
W - electron-withdrawing group
Scheme 1
The first examples of the displacement of hydrogen in the benzene ring by action of
nucleophiles were reported in the literature about one hundred years ago: reactions of
nitroaromatic compounds with the hydroxide anion in the presence of air oxygen,
yielding a mixture of ortho- and /7ara-nitrophenol (Scheme 2) [1882LA344;
1899CB3486].
N0 N0 N0
2 2 2
OH
Scheme 2
l
2 INTRODUCTION Chapter 1
A decisive role of an electron-withdrawing group activating the aromatic ring for a
nucleophilic displacement of hydrogen has been established by numerous studies. An
aromatic compound undergoing this kind of nucleophilic reaction usually needs
activation by either an electron-withdrawing substituent or heteroatom in the ring; it can
also be activated by annelation with the benzene ring or by forming an organometallic
complex (Scheme 3).
Φ_ 0_ ψ
Νθ2 Νθ2
ML
n
X = NR, O, S
O 0 O
X = NH, NR, NO, NOR,
NCOR, NF, O, S
Scheme 3. Activated aromatic and heteroaromatic compounds
undergoing nucleophilic displacement of hydrogen.
The reactions we are going to discuss in this book differ substantially from the
classical displacements of nucleofugal groups: by their reaction pathways, by the
specific mechanisms for departure of the hydride ion, by the conditions they do require,
by the nature of by-products, and so on. In order to underline the specific nature of the
reactions described formally in Scheme 1, the symbols S"(AE) [76RCR454; 88T1],
NASH (Nucleophilic Aromatic Substitution of Hydrogen), and S(Ar)H [91MI2] were
N
Chapter 1 INTOODUCTION 3
suggested. We prefer to leave the symbol Ar and to use the abbreviation SH
[76RCR454; 88T1]. To indicate by the symbol Ar that the substitution takes place in an
aromatic system is not necessary, since nucleophilic substitution of hydrogen is a
privilege of compounds of aromatic nature.
Reactions of electrophilic aromatic substitution of hydrogen (S Ar) have been
E
extensively studied and formed a solid basis for the development of theoretical
concepts, as well as for industrial use of aromatic raw materials (see, for example,
textbooks on organic chemistry [85MI2; 88MI2; 92MI1; 92MI2]). However, treatment
in textbooks of the subject nucleophilic aromatic substitution attracted less interest,
although it is evident that nucleophilic aromatic substitution of halogen or other
nucleofugal groups capable of forming stable anions (Hal", RO", RS", NO2"' etc.) is of
great synthetic importance for both laboratory use and wide industrial applications
[68MI1; 76MI2; 90MI6]. Even modern textbooks on organic chemistry [88MI2;
92MI1] limit discussions on these reactions to only a few pages, although one should
realize that about 30% of the organic compounds used in industry are of aromatic nature
[88MI3; 92MI3].
The monograph "Aromatic Nucleophilic Substitution" written by J. Miller [68MI1]
was the first and for a long time the only classical book on this subject till the beginning
of the nineties, when an excellent monograph of F. Terrier "Nucleophilic Aromatic
Displacement: The Influence of the Nitro Group" appeared, dealing with nucleophilic
aromatic substitution reactions in the series of nitroarenes [91MI2].
S" Reactions have been unnoticed for a long period of time, since the σ-adducts
derived from the addition of nucleophiles to an unsubstituted ring carbon (aH-adducts)
cannot easily lose the hydride anion. Although a few examples of the S" reactions were
reported at the end of the last century it was not until 1976 when the first review on
nucleophilic substitution of hydrogen appeared [76RCR454]. For many organic
chemists S" reactions have long been associated with the Chichibabin animation, a
4 INTRODUCTION Chapter 1
reaction which is known to require rather severe conditions [71MI4; 88AHC2]. Reviews
appeared dedicated to particular S" reactions such as nucleophilic substitution of
hydrogen in azines [88T1], and the so-called vicarious nucleophilic substitution
[83MI2; 87ACR282; 89RCR747; 90MI4; 92PJC3]. Also, some aspects of the S"
reactions are reflected in review articles: on nucleophilic substitution of nucleofugal
groups [51CRV273; 60AG294; 76MI2; 90MI5], on the formation and structural
elucidation of the anionic σ-adducts [84MI1; 82CRV77; 82CRV427], on the chemistry
of nitroarenes [69MI1; 91 Mil], and on reactions of electron-deficient heteroaromatics
[67MI1; 71MI3; 88H2659; 88AHC2; 88AHC199; 90AHC117]. In the book of F.
Terrier a whole chapter of over 60 pages is dedicated to substitution of hydrogen in
nitroarenes [91MI2]. A similar chapter is presented in the book by Russian authors V.L.
Rusinov and O.N. Chupakhin on the chemistry of nitroazines [91MI1]. The reactions of
nucleophilic aromatic substitution of hydrogen have been discussed briefly by J. March
in his book "Advanced Organic Chemistry" containing a chapter on nucleophilic
aromatic substitution with a subsection "Hydrogen as Leaving Group" [92MI2]. In
accordance with common terminology J. March suggested to phrase these reactions by
first naming the substituent which is introduced followed by ending with
"dehydrogenation reaction." For instance, the displacement of hydrogen by the amino
group is defined as the "amino-dehydrogenation" reaction [92MI2].
Since the displacement of hydrogen proceeds with various aromatic compounds and
through different reaction pathways, they are considered in different sections of chemical
literature with a variety of terminology, which, of course, does not stimulate progress in
this field. Sometimes the S" reactions are defined by mistake as addition reactions, even
if the intermediate adduct has not been registered at all (for instance, see [74TL1361]). In
other cases the S" reactions are rationalized as carbenic [71JOC2907], electrophilic
[73UK1416], or radical ones [86MI1; 89MI1; 90T2525; 92TL3057]. In the chemistry of
arene-metal complexes they are simply interpreted as functionalization of an aromatic
Chapter 1 INTRODUCTION 5
ligand [76MI1; 77MI2]. In a number of papers the S" processes are described as
"unexpected," "abnormal," and "unusual" reactions [73UK1416; 64JCS2806;
64JOC3381;90TL3217].
The huge amount of data on direct nucleophilic amination, hydroxylation,
halogenation, alkylation, arylation, and heteroarylation of π-deficient aromatic
compounds being accumulated in the literature during the last two decades prompted us
to undertake a systematic analysis of the vast range of reactions which can formally be
regarded as nucleophilic substitution of aromatic hydrogen (S"). We have tried to
provide a comprehensive and coherent concept of both theoretical and practical aspects
of nucleophilic displacement of hydrogen occurring in different types of aromatics
(nitroarenes, arene-metal complexes), and heteroaromatic substrates (pyridines, their
aza and benzo analogs, as well as quaternary N-alkyl, N-acyl, N-alkoxy, N-amino,
and N-fluoroazinium salts, N-oxides, pyrylium cations, five-membered heterocycles,
etc.). It is our purpose to pay in this book considerable attention to synthetic aspects of
the S" reactions and the scope of their applications, to discuss mechanisms for the
displacement of hydrogen, to define terminology, and finally to show the common
features of S" reactions, which at first glance seem to be very different. At the same
time, the book does not pretend to be an exhaustive compilation of all data on SjJ
reactions. The emphasis lies on reactions of arenes and hetarenes with typical C-, N-,
O-, S-, and P-nucleophiles; less attention is paid to nonbenzenoid systems and other
heteroatomic nucleophiles. Quinones are omitted as not being aromatic systems,
although quinones react in S " reactions in a manner very similar to that of nitroarenes.
Also photochemical reactions are not discussed in the book due to their specific nature.
One of the aims of this book is also to show the common character of S " reactions
N
in the series of arenes, hetarenes, arene-metal complexes, carbo and heteroaromatic
cations, and other π-deficient aromatics (Scheme 3), and to stress their features and
specific traits. In this book we do not discuss in detail the aryne S (EA) mechanism
N