Ring-Chain Tautomerism - Valters, Flitsch, 1985 PDF

RING-CHAIN
TA UT OM ER ISM
RING-CHAIN
TAUTOMERISM
Raimonds E. Valters
Faculty of Chemistry
A. Pelshe Riga Polytechnical Institute
Riga, USSR
and
Wilhelm Flitsch
Organisch-Chemisches Institut
der Westfalischen Wilhelms-Universitat
Munster, Federal Republic of Germany
Edited by
Alan R. Katritzky
University of Florida
Gainesville, Florida
PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data
Valter, Raimond Eduardovich.
Ring-chain tautomerism.
Includes bibliographies and index.
1. Tautomerism. 2. Ring formation (Chemistry) 3. Chemistry, Physical organic. I.
Flitsch, Wilhelm. II. Katritzky, Alan R. III. Title.
QD471.V26 1985 541.2'252 85-3447
ISBN-13: 978-1-4684-4885-6 e-ISBN-13: 978-1-4684-4883-2
DOl: 10.1007/978-1-4684-4883-2
© 1985 Plenum Press, New York

Softcover reprint of the hardcover 1st edition 1985
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted,
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Preface
After studying ring-chain tautomerism of keto ami des and related derivatives
of functionalized carboxylic acids for more than ten years, the authors
consider it useful to summarize available results on these prototropic
equilibria.
First attempts to systematize the material were published by Jones in
1963 (Chapter 1, ref. 11). Much, sometimes contradictory, experimental
data were scattered about the literature at that time; spectroscopic methods,
applied to this field during the last two decades, were needed to revise
several previous concepts.
In the following years special aspects of ring-chain tautomerism have
been discussed occasionally, but no attempt was previously made to cover
the whole field.
This review is designed to provide a comprehensive compilation of
ring-chain tautomerism with one exception: carbohydrates which have
already been treated repeatedly, have been omitted.
The book is based on a monograph published in Russian: R. E. Valters,
Ring-Chain Isomerism in Organic Chemistry. Zinatne. Riga, 1978. There-
fore, the arrangement and development of the theme is due mainly to one
of the authors (R.E.Y.). In the present work the literature has been covered
until the end of 1982.
Most of the processes reported here apply to prototropic tautomeric
equilibria. In addition, reversible conversions of open structured compounds
into cyclic isomers and vice versa have been considered. Contrary to simple
prototropy such as keto-enol tautomerism, ring-chain prototropic equilibra-
tions are more complicated processes: not only do migration of protons
and changes in electron distributions along the bonds of molecules occur,
but the formation or cleavage of C-X bonds (X = 0, N, S) also takes
place. Nonprototropic ring-chain equilibria will be considered only if they
contribute to a discussion of related prototropic processes.
This book has been organized along logical lines. An introduction into
the phenomenon of ring-chain tautomerism is given in the first chapter,
together with a critical discussion of applications of physical, mainly
spectroscopic, methods. Chapters 2-4 refer to particular tautomeric systems.
These have been arranged according to the interacting functional groups
to facilitate the location of individual cases. General rules concerning
structural as well as external influences have been discussed in Chapter 5,
vii
viii Preface
which should help to appraise unknown ring-chain tautomeric equilibria

and cyclization reactions.
Ring-chain tautomerism is of great significance both in the field of
synthesis of heterocyclic compounds and for a discussion of reaction
mechanisms, wherever ring closure, ring opening, recyclizations of
heterocycles, and migration of acyl and other functional groups are involved.
Therefore, this monograph is primarily addressed to chemists in academic
and industrial laboratories. It should also be useful for biochemists and
biologists since ring-chain tautomerism often plays a decisive role in bio-
chemistry.
The authors would like to express their thanks to everybody who has
rendered his help in writing the book. Professors O. Neilands, A. Strakovs,
and 1. Freimanis have read the whole of the manuscript published in Russian
and made valuable comments. Critical comments of Professors E.
Gudriniece, A. N. Kost, and Yu. N. Sheinker were taken into account.
Great help was rendered by A. Bace for the design work of the book and
by D. Murniece and L. Kundzina for the translation into English. The first
English version was extensively polished by one of the authors (W.F.).
R. E. Valters (Riga)
W. Flitsch (Munster)
Contents
1. Introduction ................................................. .
1.1. Ring-Chain Isomeric Interconversions. General Considerations .. .
1.2. Tautomerism or Isomerism? System Mobility and Equilibrium
Position... .............................. ........... ..... ... 5
1.3. Methods of Investigation of Ring-Chain Addition Tautomerism .. 8
1.3.1. Chemical Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.3.2. Visible and UV Spectroscopy. . . . . . . . . . . . . . . . . . . . . . . . . . . 10
1.3.3. I R Spectroscopy. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.3.4. Nuclear Magnetic Resonance. . . . . . . . . . . . . . . . . . . . . . . . . . . 11
1.3.5. Mass Spectrometry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.3.6. X-Ray Diffraction Analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.3.7. Polarography.......................................... 14
1.3.8. Other Physical Methods. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2. Intramolecular Reversible Addition Reactions to the

C=Q Group.................................................. 19
2.1. Aldehydo and Keto-carboxylic Acids and Their Derivatives
Modified at the Carboxylic Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.1.1. Aldehydo- and Keto-carboxylic Acids. . . . . . . . . . . . . . . . . . . . 20
2.1.2. Acyl Chlorides ........................................ 41
2.1.3. Amides, Hydrazides, and Amidines ....... ............... 49
2.1 .4. Esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
2.1.5. Mixed Anhydrides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
2.2. Hydroxy Aldehydes and Ketones and Related Compounds ...... 98
2.2.1. Derivatives Containing a Hydroxy Group at Carbon
(C-OH).............................................. 98
2.2.2. Derivatives Containing a Hydroxy Group at Nitrogen (N-
OH).................................................. 114
2.3. Amino Aldehydes and Ketones and Related Compounds. . . . . . . . 117
2.3.1. Covalent Hydration of Nitrogen-Containing Heterocycles .. 117
2.3.2. Derivatives Containing Amino Groups at Sp3_, Aromatic,
and sp2-Carbon Atoms...... .......................... 120
2.3.3. Urea and Thiourea Derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . 125
2.3.4. Dithiocarbamates...................................... 127
2.3.5. Sulfonamides and Sulfinamides......................... 127
2.3.6. Pyridones............................................. 129
2.3.7. 1,3-Diazaheterocycles . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
ix
x Contents
2.3.8. Triazenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

2.3.9. Miscellaneous......................................... 135
2.4. Intramolecular Migration of 0-, N-, and S-Acyl Groups......... 136
2.5. Oxa-, Aza-, and Thiacyclols .................................. 140
2.6. Mercapto Aldehydes and Ketones and Related Compounds. . . . . 146
2.7. Intramolecular Addition of C-H Groups. . . . . . . . . . . . . . . . . . . . . . . . 149
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
3. Intramolecular Reversible Addition Reactions to the

C=N Group.................................................. 169
3.1. OH-Derivatives of Imines, Hydrazones, Oximes, and Nitrones.... 169
3.1.1. N-(Hydroxyalkyl) and N-(hydroxyaryl) imines............. 169
3.1.2. N -Hydroxyalkylhydrazones ............................. 175
3.1.3. Hydroxyalkyl and Hydroxyiminoalkyl Nitrones . . . . . . . . . . . . . 180
3.1.4. Imines, Hydrazones, and Oximes of Hydroxyaldehydes and
Hydroxyketones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
3.1.5. Imines of Ketocarboxylic Acids ......................... 185
3.1.6. Fused Systems........................................ 187
3.2. N-H-Derivatives of Imines, Hydrazones, Oximes, and Nitrones ... 188
3.2.1. N-Aminoalkylimines.................................... 188
3.2.2. N-Aminoalkyl and N-Aminoacyl Hydrazones and Related
Compounds.......... ......... ............. ....... ... 190
3.2.3. 2-Benzimidoyl-benzamides and -benzenesulfonamides .... 193
3.2.4. N-(2- and 3-Hydroxyiminoalkyl)nitrones . . . . . . . . . . . . . . . . . . 196
3.2.5. Fused Systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
3.3. S-H-Derivatives of Imines and Hydrazones .................... 199
3.4. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
4. Intramolecular Reversible Addition Reactions to Other

Groups....................................................... 211
4.1. Addition to the C=N Group.................................. 211
4.2. Addition to C=C and C=C Groups.......................... . 219
4.3. Addition to the P=O Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
4.4. Addition to the P=N Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
4.5. Addition to the S=O Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
4.6. Addition to the Se=O Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
4.7. Addition to the 1=0 Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
5. Generalizations Concerning the Influence of Structural

and External Factors on the Relative Stability of Ring
and Chain Isomers .......................................... 241
Contents xi
5.1. Structural Influences ........................................ 243

5.1.1. Electronic Effects of Substituents at Interacting Groups .. . 243
5.1.2. Steric Effects of Substituents at Interacting Groups. . . . . . . 250
5.1.3. Structure of the Connecting Link. . . . . . . . . . . . . . . . . . . . . . . . 253
5.1.4. Steric Effects of the Substituents at the Connecting Link. . 257
5.1.5. Intramolecular Hydrogen Bonds. . . . . . . . . . . . . . . . . . . . . . . . . 261
5.2. Influence of External Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 262
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Index............................................................ 271
1
Introduction
1.1. RING-CHAIN ISOMERIC INTERCONVERSIONS. GENERAL

CONSIDERATIONS
The problem of ring-chain isomeric interconversions of organic com-

pounds had already aroused the interest of chemists at the end of the last
century. However, the use of chemical methods done for the investigation
of these interesting phenomena frequently gave erroneous results, even in
those cases when the type of structure (ring or chain) was to be determined.
Spectroscopic methods (electron and vibration spectroscopy, and nuclear
magnetic resonance) are much more efficient for this purpose. Since these
methods were developed only after the first active period of study of
ring-chain tautomerism, a new and extensive reexamination of the
phenomena was to be expected as Hammond had suggested in 1956 [1].
Indeed, this field of organic chemistry has had a real revival during the last
three decades.
Ring-chain isomeric interconversions of organic compounds can be
divided into two groups. The first group concerns interconversions where
a linear system forms a ring system (or vice versa) by means of electron
rearrangement without the migration of atoms or groups. Such interconver-
sions are generally called [2,3] valence isomerism. Woodward and
Hoffmann [4] have proposed rules governing "electrocyclic reactions",
i.e., the process of single bond formation (and its reverse) between the ends
of a conjugated linear system containing 0 7T-electrons:
C·
.
,
,
,
'.
~,
~.
ct'.
,
'
,
Ring systems which are formed in this way contain (0 - 2) 7T-electrons.

The equilibrium of benzofurazane oxide with o-dinitrosobenzene [2] and
tautomerism of azide and tetrazole [5-8] are given as examples:
2 Chapter 1
c~ "- + -
N=N=N
Many other examples of such valence isomerism are known [4,9,10].

In a second group of ring-chain isomeric interconversions, a linear
system transforms into a cyclic one by intramolecular addition of the
functional group to a polar multiple bond (1-4A) +:t (1-4B). Here and
subsequently the letter A refers to open isomers and the letter B to cyclic
ones. The molecular fragment connecting both mutually reacting functional
groups is designed by a semicircle.
The process of the interconversion of a linear isomer into a ring one
involves formally three operations: 1) Q-X bond cleavage, 2) Q- Y or Q-Z
bond formation (ring closure), and 3) Z-X or Y-X bond formation.
Q-X (Q
( •• I
Y=Z Y-Z-X
(1A) (18)
c Q- X
Y=Z
• • (Q"z
y/
"- X
(2A)
(28)
(Q-X
Y=Z
• • (f
Y~
(3A)
~Z-X
(38)
Introduction 3
C Q- X
Y_Z
(4A)
(48)
As in the case of electrocyclic reactions, a 1T-bond is transformed into a

O"-bond. However, simultaneously with the ring closure (or opening), the
migration of atom or group X occurs. Most commonly a proton is the
migrating particle (prototropy). These isomeric interconversions may be
precisely named "additive tautomerism" [10]. They are both widespread
and diverse in organic chemistry.
There are numerous polar multiple bonds Y=Z orY-Z, such as C=O,
C=N, N=C, C=C, C-N, C-C, a.o., and a great many functional groups
Q-X, such as O-H, N-H, S-H, CO-Hal, which are capable of intramolecular
addition to these bonds. The connecting fragment (designed by a semicircle)
can also possess various structures: however, it must comply with one
important condition, i.e., it must assure a favorable steric disposition of the
interacting functional groups Q-X and Y -Z for the realization of revers-
ible addition-cleavage reactions.
The present monograph deals with the study of the second type of
ring-chain isomerism of organic compounds. The immense variety of these
phenomena has made it impossible for the authors to present a thorough
examination of all possible cases of ring-chain tautomerism. The main
attention is paid to work published during the last three decades in which
modern spectroscopic and other physical methods have been widely used.
The results of earlier investigations will be discussed as necessary.
The first systematic study of the problem of ring-chain tautomerism of
organic compounds was by Jones [11] in 1963. A significant part of the
material covered in his review refers to the period when merely chemical
methods were used.
Earlier reviews of the present authors [12-15] and other investigators
[I, 16-19] were also useful in the writing of this monograph. Experimental
studies carried out by the authors refer to the ring-chain isomerism of amides
and other derivatives of keto-, imino-, and cyanocarboxylic acids [11-
15,20,21].
Reporting the literature data published on ring-chain isomeric intercon-
versions of organic compounds the main attention is paid to the following
aspects:
I) Structural influences such as the polarity of Q- X and Y =Z bonds,

electron and steric effects of the substituents at these bonds, the structure
4 Chapter 1
of the linking fragment and other structural (internal) factors on the relative
stability of isomers and the character of their interconversions (mobility of
the system and equilibrium position);
2) The influence of external factors (temperature, physical state of the
substance, properties of solvents, presence of catalysts) on the characteristics
of equilibrium systems;
3) A search for selective preparations of open and ring isomers;
4) The estimation of the potential of spectroscopic and other physical
methods for the identification of isomers and the determination of equili-
brium and rate constants.
These regularities of ring-chain tautomerism are of great significance

in the chemistry of heterocyclic compounds.
In many cases the estimation of the influence of structural factors on
intramolecular cyclization reactions allows prediction of the ease of forma-
tion of a heterocycle and its stability [1,14,22,23]. The reaction of
intramolecular additions are often followed by elimination of water, hydro-
chloric acid, etc., thus resulting in the stable heterocycles.
The structural factors favoring or preventing the cyclization act similarly
in many chemical reactions, including those which proceed through cyclic
transition states or intermediates. They relate to chemical interconversions
which proceed according to the following schemes:
chain - [ring] - chain
or
ring - [chain] - ring
Familiar examples of the first scheme comprise a) intramolecular catalysis

with the neighboring group participation [24-28], b) intramolecular migra-
tion of acyl and other groups [24,29-31] proceeded by the formation of
cyclic tetrahedral intermediates [32], and c) hydroxyacyl and amino acyl
incorporation into peptides and depsipeptides [33, 34].
The second scheme includes the majority of ring transformation re-
actions of heterocycles [35-37].
Study of these reactions necessitates estimation of the influence of the
molecular structure on the ability of the two atoms or functional groups to
mutually approach thus enabling their intramolecular reaction. Information
of that kind can be obtained from the ring-chain equilibrium constants in
systems in which the structure of the linking fragments are sequentially
modified.
Introduction 5
1.2. TAUTOMERISM OR ISOMERISM? SYSTEM MOBILITY

AND EQUILIBRIUM POSITION
Ring-chain isomeric interconversions are often referred to as ring-chain

tautomerisms [I, 11,38-40]. Strictly speaking this term should only be used
for certain cases of the phenomena because ring-chain equilibria can be of
very different mobility. Thus, solutions of 2-acylbenzoic acids in neutral
solvents at room temperature display a tautomeric equilibrium between
open and cyclic forms (SA) +:t (SB) [41]. Esters of these acids are usually
stable under these conditions, and acid or alkaline catalysis is necessary
[42] to achieve the equilibrium (6A) +:t (6B).
0~
1 COOH.
COR
• ~O
~
R OH
(5A) (58)
O
o
~O
COOMe
I 4 ~
~ COR
ROMe
(6A) (68)
There are cases where the equilibrium, reached only under drastic
conditions, is totally displaced toward one of the isomers. For example,
N -monosubstituted 2-cyanobenzamides, on heating or with base catalysis,
undergo isomerization into 3-iminoisoindolinones (7 A) -+ (7B) [43].
0 1
CONHR
~ ~
~ cr)
I
o
N-R
~ C=N ""
NH
(7A) (78)
Small modifications of the structure of substituents at interacting func-

tional groups can change the position of the equilibrium completely. For
instance, 2-(2,4-dimethylbenzoyl)benzoyl chloride is obtained only as the
6 Chapter 1
cyclic 3-aryl-3-chlorophthalide (8), whereas 2-(2,4,6-trimethylbenzoyl)ben-

zoylchloride exists as such (9) [44].
o
~COCI Me
~c0-O-MC
Me Me
(9)
(8)
Recently Zefirov and Trach [10], in considering general problems and

the classification of tautomerism, defined tautomeric transformation as: a
reversible dynamic process in a formally monomolecular system, proceeding
by the cleavage or formation of bonds between atoms (taking into account
individual atoms of the same type) on condition that both tautomeric forms
can be separately identified analytically.
The definition, while reflecting the generally accepted meaning of the
term "tautomerism"t, unfortunately does not differentiate clearly tautomer-
ism from isomerism.
Such differentiation was achieved in an alternative though less accepted
approach by Temnikova [17]. Following the ideas of Favorskii and Knorr,
Temnikova divides equilibration phenomena into tautomerism and isomer-
ism. Equilibrium interconversions are referred to as tautomerism if the
mobility of the system is high, i.e., when equilibration is observed in solutions
at room temperature. When the mobility of the system is very small and
isomeric transformation occurs only at elevated temperature or in the
presence of active catalysts, then such interconversions are examples of
isomerism. This approach, as with any other scientific classification, is not
unequivocal since properties change continuously giving any classification
an intermittent character.
However, the differentiation of equilibrium systems according to their
mobility proposed by Temnikova is of practical significance. Today the
structure of organic compounds is established by UV, IR, and NMR spectro-
scopic methods. It is indispensible for an interpretation of these spectra to
draw a strict borderline between the two cases of equilibrating systems: I)
the equilibrium is reached at room temperature in a neutral solvent; 2)
t A. Ihde, J. Chern. Educ. 1959, 36, 330.

Introduction 7
adjustment of the equilibrium affords more drastic conditions such as

heating and/or acidic or basic catalysis.
Minkin and coworkers [31, 45], using thermodynamic and kinetic
criteria, postulated a more rigorous definition of the term "tautomerism"
in the following way.
Let us consider the tautomeric system
and its energy profile (Fig. I).

The quantitative characteristic of the equilibrium (K or IlGO) and of
the rate (k or IlG"') must be considered in relation to experimental method
by which the equilibrium information was obtained. Hence, standard condi-
tions for the investigation of equilibrium systems and in particular the
sensitivity of the experimental methods must be considered. The choice of
the conditions is a matter of chemical experience: atmospheric pressure
and room temperature are taken as normal. The sensitivity of the most
precise methods of determination of small equilibrium constants establishes
constants with a lower limit 10-6 _10- 8 which corresponds to a free energy
difference IlGO = 8-9 kcal/mole.
As already mentioned above, it is rather difficult to draw a line between
a dynamic, rapidly attainable tautomeric equilibrium and a slow isomeriz-
ation. The barrier which, according to the general opinion of chemists,
separates a mobile system from a stable one, is the possibility of preparative
Figure 1. Energy profile of equilibrium A ~ B. The value of the free energy of the reaction
110° determines the equilibrium constant K, the values of the free energy of activation 110"
determine the rates of the reactions A --+ B "and B --+ A according to Eyring's equation.
8 Chapter 1
isolation under normal conditions. In terms of the rate constant and activa-
tion energy this corresponds approximately to kZ5 - 10- 5 S-l and .:lOi5 ==
20-25 kcal/mole.
Thus the approximate thermodynamic and kinetic line to be drawn
between tautomeric and isomeric systems is (under normal conditions);
.:l0;5 < 8 kcal/mole and .:lOi5 < 25 kcal/mole.
In discussing ring-chain tautomeric equilibria we shall try to give an
accurate characterization of the conditions under which the equilibrium is
observed to avoid difficulties caused by the uncertainty of the term
"tautomerism." If the equilibrium position within the possible limits of the
spectroscopic determination is totally displaced toward one of the isomers,
e.g., (B), we shall deal with the isomerization (A) -. (B).
It is not possible to consider all the investigations in which the isomers
have not been isolated, or in which the equilibrium has not been strictly
proven but postulated for the explanation of a mechanism of the formation
of reaction products. The intramolecular rearrangement (10) -. (12) is an
example which proceeds by the intramolecular migration of the acyl group
between two nucleophilic groups (OH, NH, SH) via the intermediate ring
isomers (11). Due to their limited stability these compounds have only rarely
been isolated or proven to be present in solutions [29,32,46-48].
R
[C:~<:H]
/
X H CX-C
C -
~o 4 ~ 4 ~ "0
Y-C Y-H
"R
(11) (12)
(101
X, Y=O,NR,S
1.3. METHODS OF INVESTIGATION OF RING-CHAIN

ADDITION TAUTOMERISM
Chemical and physical methods of the investigation of the tautomerism

of heterocycles have been considered in detail in an excellent monograph
[3]. We shall therefore briefly discuss only some specific aspects typical for
the ring-chain tautomeric systems.
1.3.1. Chemical Methods

As a rule the formation of derivatives is not admissible evidence for
the determination of the structure of ring-chain tautomeric compounds
Introduction 9
[1,3,11,49]. A solely chemical approach for this purpose is unreliable and

frequently leads to erroneous results.
Since such molecules of either open or ring structure contain at least
two reactive centers, ring isomers can form derivatives not only from cyclic
but also from the acyclic structure, depending on the nature of reagents.
On the other hand, cyclic derivatives may be obtained from open isomers.
This is demonstrated using the reactions of amines with 3-chloro-3-
phenylphthalide (13), as an example. The nucleophile according to its
nucleophilicity may attack C(l) or C(3) of the phthalide yielding derivatives
of either open and! or ring structure. Reaction of (13) with t-butylamine
gave the open-chain derivative N-(t-butyl)-2-benzoylbenzamide (14), [50]
while the less nucleophilic diphenylamine yielded the cyclic 3-(N,N-
diphenylamino)-3-phenylphthalide (15), [51].
~CONHBu-t
o
~COPh
~o Ph CI
(14)
(13)
When aniline is used as a nucleophile, the attack proceeds at both

reactive centers (C(l) and C(3) of phthalide (13) leading to a mixture of the
products of type (14) and (15) [51]. Sometimes, it is essential to take into
account possible isomerization of the starting material or products depend-
ing on the reaction conditions (acid or alkaline catalysis, heating). The
proportion of the ester isomers which result from Fischer-Speier esterifica-
tion of ketocarboxylic acids depends not only on the structure of the initial
acid and alcohol but also on the time of the reaction (kinetic or thermody-
namic control) [42, 52]. It is easily seen from this example that the chemical
method of synthesis of the compounds capable of the isomeric interconver-
sions cannot serve as a proof for the structure of the reaction product.
A spectroscopic determination of ring-chain (on any other) equilibrium
has the advantage in not affecting the equilibrium position or causing
isomerization during the course of the investigation.
10 Chapter 1
1.3.2. Visible and UV Spectroscopy

During the interconversion of a cyclic compound into the open isomer
(the isomerization (B) -+(A») a new multiple bond (i.e., a chromophore) is
formed which causes a corresponding change in the electronic spectrum.
If this chromophore (C=O, C=N) in the open isomer is a conjugated with
a 7T-electron system, then by interconversion (B) -+ (A) and an intensive
band appears in the experimentally accessible region of the UV spectrum.
However the ultraviolet or visible spectra of equilibrium mixtures cannot
be interpreted in such detail as the corresponding IR spectra which allows
unambiguous determination of the presence of a particular multiple bond.
Usually the spectra of model compounds with fixed open or ring
structure are used for a reliable interpretation of the electronic spectra of
the compounds capable of ring-chain tautomerism. Provided the absorption
of the model compound, in which the migrating hydrogen is substituted by
a methyl group, does not differ from that of the corresponding H-analogue,
it is possible to determine the quantitative proportion of the forms (A) and
(B) in tautomeric systems or mixtures of isomers.
Thus, 2-methoxycarbonylbenzophenone anils (17) were used as model
compounds in a quantitative study [53] of ring-chain tautomeric equilibria
of 3-arylamino-3-phenylphthalides (16A) ~ (16B). The UV spectra of these
anils have longwave absorption at 322-348 nm.
O
~I
COOH
C=NAr
~o O~I
COOMe
C=NAr
/ Ph NHAr /
Ph Ph
(16A) (16B) (17)
The second model compound, i.e., 3-(N,N-diphenylamino)-3-

phenylphthalide (15) shows no absorption in the above-mentioned region.
The proportion of the open form (16A) of the equilibrium mixture was
determined supposing the intensities of the longwave absorption bands in
the spectra of the. isomer (16A) and of the model compound (17) to be equal.
The UV spectroscopic method was used [54] to establish rate constants
for both the base and acid-catalyzed rearrangements of a series of ring
isomers of 8-benzoyl-I-naphthoates and 2-benzoylbenzoates to form the
chain isomers.
The simplest way is to use visible spectra for the identification of
isomers. Thus, all the open isomers or benzil-o-carboxylic acid derivatives
are yellow while ring isomers are colorless [55,56].
Introduction 11
1.3.3. IR Spectroscopy
IR spectroscopy provides valuable information concerning the
existence or absence of double or triple bonds in organic molecules. The
information obtained by an examination of the region of multiple bond
valence vibrations is the most important [57]. Additionally, absorption bands
of OH, NH, and SH bonds as well the complex bands (e.g., amide-H) may
be used to identify open and ring isomers.
Identification of the ring isomers of the derivatives of y-ketocarboxylic
acids utilizes the fact that the Vco band is shifted by 30-50 cm- 1 to higher
frequencies on cyclization, which is due to C=O group bond angle strain
in the five-membered ring [58]. This band usually appears in a region in
which the open chain isomers do not absorb. The band is therefore used
for quantitative measurements.
The identification of open and ring isomers by the IR method is
sometimes hampered by the formation of strong intermolecular (more rarely
intramolecular) hydrogen bonds. For example, in IR spectra of the crystal-
line ring isomers of keto carboxylic acid amides (hydroxylactams), the lactam
C=O band is greatly shifted to lower frequencies in comparison with
solution spectra and sometimes even split into doublets (see Table 7). Such
a shifting and splitting is caused by hydrogen bonds OH·· ·O=C in the
solid state. In these cases the spectra in the double bond region should be
recorded for solutions in proton acceptor solvents (e.g., in dioxan). Because
of the competitive formation of the intermolecular hydrogen bonds
OH·· ·solvent, it is possible to observe the absorption of free C=O groups
in such solutions.
The interpretation of IR spectra can also be hampered by the overlap
of bands, as in the spectra of some ketocarboxylic acids where the c=o
bands of carboxyl and ketone groups obscure each other, and in the spectra
of some amides of ketocarboxylic acids where the band of ketogroup is
overlapped by the amide-I band. In such cases, it is wise to measure the
integral intensity of the total band and to compare it with the sum of
intensities of both groups obtained from the spectra of the corresponding
model compounds [50,59,60].
A more detailed discussion on the problem of the application of IR
spectroscopy is given in the chapter concerning acylcarboxylic acids and
their amides (see Sections 2.1.1 and 2.1.3).
1.3.4. Nuclear Magnetic Resonance

In recent years IH-NMR spectroscopy has been used frequently for
the structure determination of open and cyclic isomers and for the quantita-
12 Chapter 1
tive determination of equilibrium mixtures. Commonly this method deals

with the differences in the chemical shifts of protons located at the carbon
atoms in a-positions to a polar multiple bond or directly attached to the
carbon atoms forming a double bond (aldehydes, aldimines).
Using the IH-NMR method for the analysis of ring-chain equilibrium
systems requires consideration of the rate of tautomeric interconversions:
two cases may be distinguished [61,62]:
1) If the tautomeric interconversion is slow on the IH-NMR time scale
the signals of protons of both tautomeric forms are observed separately and
the tautomeric composition is determined according to their relative
intensities;
2) In the case of a rapid tautomeric interconversion the signals of
protons of both forms coalesce and only averaged chemical shifts are
observed. For quantitative measurements, the ratio of the forms (A) and
(B) is assumed to be inversely proportional to the distances of this signal
from the corresponding signals in the spectra of model compounds of fixed
structure [41,63].
The replacement of a less polar solvent by a more polar one or the
addition of trace amounts of acids or bases can accelerate tautomeric
interconversions and substantially change the appearance of the IH-NMR
spectrum [41, 64, 65].
Thus, for example, in the IH-NMR spectrum of 2-acetylbenzoic acid
in DMSO-d 6 two signals for methyl groups of open (MeCO) and cyclic
(MeC(OH)O) tautomeric forms were observed. After the addition of
a trace of hydrochloric acid these signals coalesced into an averaged one
[66].
In studies of the kinetics of ring-chain tautomeric interconversions rate
constants were determined by full line-shape analysis of IH-NMR spectrum
[67,68] employing special programs for computers [69]. Only in the case
of slow tautomerizations (k ''is 10- 4 s-I) is it possible to determine the rate
constants following the intensity changes of the signals of both forms during
the approach to the equilibrium [70].
13C-NMR spectra were used for the identification of open and cyclic
isomers of 2-acylbenzoic acids [71], phthaloyldichloride and 2-acetoxyben-
zoylchloride [72].
Activation parameters (b.H", ilS") for the tautomerization of 3-oxo-
trans- bicyclo[ 4.4.0]decane-l-carboxylic acid (18A) --+ (18B) were estimated
by full line shape analysis of the 13C-NMR signals of the carboxyl and
lactone carbonyls at different temperatures. However, these results have
low reproducibility due to the presence of variable trace amounts of mineral
acid [73].
Introduction 13
OH
(18A) (18B)
In the estimation of ring-chain equilibrium constants of 2-hydroxy-

phenyliminosphoranes (19A) +:t (19B) by two independent methods, i.e.,
IH_ and 31p_NMR spectroscopy, precisely coincident results were obtained
(74].
1.3.5. Mass Spectrometry

In a mass spectrometer the substance is in the vapor phase at high
vacuum and collisions between molecules practically do not occur. These
conditions essentially differ from those in the condensed phase where UV,
IR, and NMR spectra are investigated. Therefore the results obtained by a
mass spectrometric investigation of ring-chain equilibria [75] can supple-
ment the information about this tautomerism acquired by other methods.
A few studies [76-79] of mass spectra of ring-chain equilibrium systems
show that the two isomers possess quite different fragmentation schemes.
Investigation of ring-chain tautomeric compounds in the gase phase
should allow for a separation of structural influences from solvation effects.
Differences of solvation of both isomers cannot be ruled out but the few
investigations which have been carried out so far do not point in this
direction (see Chapter 2, Ref. 297).
1.3.6. X-Ray Diffraction Analysis

X-Ray diffraction analysis may be used to establish the structure of
ring-chain isomers in the crystalline state. More important results, were
obtained by Chadwick and Dunitz [73] who studied the equilibrium of keto
acids such as (18A) +:t (18B). Their work was based on ideas of Burgi and
14 Chapter 1
Dunitz [80-82] who suggested that structural information, mainly obtained

by x-ray analysis of intentionally selected bifunctional compounds, could
be used for finding out the optimal geometry of approach of the interacting
groups during the reaction.
As a result of this work the optimal angle by which the nucleophilic
nitrogen approaches the carbonyl group was found to be approximately
107° and not 90° as was assumed previously. For oxygen, as a nucleophile,
the corresponding angle is in the limits of 100-110° [83].
1.3.7. Polarography
The use of polarography as an independent method for a structure
detection of open and ring isomers is rather limited and has sometimes led
to erroneous results. For example, the structure of 2-benzoylbenzanilide
was misinterpreted [84] using polarographic methods and later defined
exactly by spectroscopic methods [20, 51, 85]. It is useful to take into
consideration that the polarographic method possesses the same shortcom-
ings as the "pure" chemical methods since the molecular structure may be
modified at the electrode layer before reduction. Therefore polarographic
data on tautomerism require a careful explanation and the results should
be compared with those of spectroscopic investigations [86]. Combining
polarographic with spectroscopic methods an important problem can be
solved, i.e., the determination of rate constants of isomeric interconversions
[87].
1.3.8. Other Physical Methods

Optical activity has a direct relationship to ring-chain tautomerism
since in most instances a new asymmetric carbon atom is created during
the formation of a ring isomer. However, with the exception of studies of
the mutarotation of carbohydrates, optical activity measurements have rarely
been used for the investigation of ring-chain tautomerism [11].
Open and ring isomers differ in molar refractivity. This can be used
for quantitative investigations of ring-chain equilibria of pure liquids [88-
90]. However, the determination of the proportion of isomers in equilibrium
mixtures is hampered by the necessity to estimate accurately the molar
refractivity of both isomers which sometimes are difficult to isolate as pure
compounds. The results of molar refractivity measurements have been
compared with those obtained by NMR [88, 91, 92].
The use of chromatographic methods for an analysis, or for separation
of mixtures of open and ring isomers, not capable of equilibrium interconver-
sions in a neutral solvent, does not always yield reliable results. Initially,
Introduction 15
it should be shown that the adsorbent used (AI 2 0 3 , Si02 ) does not act as
a catalyst for the isomerization process. A case is known [75] where the
ring isomer of levulinic acid anilide was converted into the open isomer by
passing a methanolic solution through a column filled with silica gel.
Evidently for the same reason, gas-liquid chromatography is rarely
used for the analysis of mixtures of otherwise stable isomers. Nevertheless,
quantitative results concerning methyl 2-acylbenzoates, obtained by this
method, agree with the data obtained by IH-NMR spectroscopy [42].
Potentiometric titration and other methods of establishing protolytic
constants have been successfully used for a determination of the ring-chain
equilibrium constants of acylcarboxylic acids [93-97].
Studies of compounds capable of ring-chain isomeric interconversions
at or below the melting point should be regarded with caution. For example,
the real melting point of the ring isomers of some ketoamides cannot be
established [98, 99]. If the temperature of thermal isomerization of the cyclic
isomer into the open one (B) -+(A) is lower than the melting point of the
isomer (B) and if the isomerization process proceeds sufficiently rapidly,
the melting point of the open isomer(A) instead of the isomer(B) is observed.
In other words, the ring and the open isomers of these ketoamides show
identical melting points and they cannot be investigated by a mixed melting
points. If the temperature of the isomerization (B) -+(A) is above the melting
point of the ring isomer (B), double melting points can sometimes be
observed: the compound melts, the rising temperature results in crystalliz-
ation and subsequently again melting [98, 99].
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16 Chapter 1
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Introduction 17
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66. J. Finkelstein, T. Williams, V. Toome, and S. Traiman, J. Org. Chem. 1967, 32, 3229.
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Khim. Geterotsikl. Soedin. 1976, 676.
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18 Chapter 1
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2
Intramolecular Reversible Addition
Reactions to the C==O Group
2.1. ALDEHYDO- AND KETO-CARBOXYLIC ACIDS

AND THEIR DERIVATIVES MODIFIED AT THE
CARBOXYLIC GROUP
Ring-chain isomeric interconversions proceeding by intramolecular

reversible addition reactions to the double bond of the C=O· group have
been well studied, particularly as regards 'Y- and 8-aldehydo- and keto-
carboxylic acids (3- and 4-acylcarboxylic acids) and their derivatives (see
Refs. [1-3]).
Compounds possessing an open chain structure were originally termed
normal derivatives, ring (cyclic) isomers were designated pseudo or 1/1-
derivatives (pseudoacids, pseudo acid chlorides, pseudoesters, etc.).
Such terminology is not convenient, and now hardly ever is used, the
more current terms being ring and chain isomers or tautomers. Closed
(cyclic) and open structures will be applied in this book.
The structures of the most important derivatives (1)-(5) of the aldehydo
(R=H) or keto (R = alkyl, aryl) carboxylic acid isomers are depicted below.
o
C>
o II
\I
C>l
~O
C'-OH
(
/
C=O
/ "- /
R \ 0-
"-
R (1A) R OH
(10)
Acyl carboxylic
(18)
Open Cyclic (closed)
Hydroxylactone
acid anion anion
(Iactol)
o o
O II ~O \I
( C::CI
C,-
C'-o ( C'-NHR2 ( N-R2
(
C/ C/
"OH
C=O C=O
R
/ R/ "CI R
/ Rl /
(2A) (28) (3A) (38)
Acyl chloride Chlorolactone Amide Hydroxylactam
20 Chapter 2
-:;::-0 °II -:;::-0

(C, -:;::-0
°II
(C'OR 2 (C, O-C , 2 (C'O
C/O C/
C=O C=O R
R/ " O-C-:;::-0
R/ R/ "OR 2 /
R'
'R2
(4A) (48) (5A) (58)
Ester Alkoxylactone Mixed Acyloxy-
anhydride lactone
(
a b c
0,
e
0- ~
h
9
Some of the possible connections (a)-(h) of two mutually interacting

groups which enable the formation of cyclic isomers are given; they certainly
do not reflect all the cases suitable for cyclization.
Besides the above mentioned acy1carboxylic acid derivatives (1)-(5),
other derivatives of lesser importance, such as hydrazides, ami dines, ami-
drazones, etc., are capable of forming ring isomers.
2.1.1. Aldehydo- and Keto-carboxylic Acids

The intramolecular nucleophilic addition of the carboxylic group to
the C=O bond is a comparatively rapid reversible reaction [4-6] and the
ring-chain tautomerism (IA).,:t (1C).,:t (IB) does occur in the solutions of
3-acyl and some 4-acy1carboxylic acids. The carboxylate anion of these
acids always has an open structure (Ie) which does not depend on the
structure of the acid molecule and on the substituent R [5,7-18]. Since the
acidity of the cyclic form (IB) is considerably lower than that of the open
form (IA) [19] the cyclic anion (ID) does not appear in the equilibrium
mixture in any detectable concentration.
Intramolecular Reversible Addition to the C=O Group 21
Solutions of the methyl substituted levulinic acids in the solvents of

low polarity show [19] the equilibrium depicted below:
c<
O···H-O -?-O
~)
COO-
O-H"'O Y ( c . . . . OH 4 ~ 4 ~
,
4 ~
C=o O=C C=O (c=O

/ / /
R R R R
(1A)···(1A) (1A) (1e)
°II ~
c. . o/C)
HO, /R
4 ~ (cC/. . O 4 • ( c/ O
R
,OH
/
R
/
.... c
,
O-H"'O
II
(18) (18) .. ·(18)
The authors [19] suggested that the ring-chain equilibrium constantt

KT should be derived from the equation:
K =
K'a
a 1 + KT
where Ka is the dissociation constant of the acylcarboxylic acid directly
measured by means of a potentiometric method and K~ means the "true"
(hypothetical) acid dissociation constant of the acyl carboxylic acid under
the condition that the formation of the ring isomer does not take place.
The necessity to estimate the K ~ constant, which can be done only indirectly,
limits the applicability of this method [5,19,20,21). To estimate K~ one
usually measures the dissociation constants for model compounds of similar
structure but incapable of ring isomer formation.
Using this method, Bowden and Henry [22] obtained ring-chain equili-
brium constants KT of a series of Z-3-acylacrylic acids. They estimated the
"true" K~ values comparing Ka values of Z- and E-3-acylacrylic acids. For
structural reasons the E-acids are incapable of cyclization.
Bell and co-workers derived the "true" constant K~ of levulinic acid
and its chain methylsubstituted derivatives [23], of 2-formylbenzoic acid
[5], of a series of 2-acylbenzoic, 3-acetyl-2-naphthoic, and 8-acetyl-l-naph-
thoic acids [24] measuring the catalytic effect of the respective anions on
the decomposition of nitramide and on the mutarotation of glucose [5,25).
For all of these well-established relations are known between the catalytic
t Here and elsewhere KT = [B]/[A].
22 Chapter 2
constants of carboxylate anions and the dissociation constants of the corre-

sponding acids. Using these K~ constants the authors have calculated KT
constants of the acylcarboxylic acids examined in the aqueous solution
(Table 3). Without d.oubt this method is more precise than that mentioned
above.
Bowden and co-workers [26,27] solved the reverse task: by using the
KT constants, determined by NMR method, and the Ka constants, deter-
mined by potentiometric method, they have calculated the "true" K~
constants for a series of 2-acylbenzoic and Z-3-acylacrylic acids in 80%
methoxyethanol-water solution.
There are many examples where the ring-chain equilibrium constants
of the acylcarboxylic acids have been measured using UV, IR, and NMR
methods (see Table 3).
The determination of KT constants by means of electronic spectroscopy
is supported on the assumption that position and extinction coefficients E
of the analytical bands in the spectra of the model compounds having a
fixed open structure (usually open ester (4A») and of the tautomeric forms
(IA) are equal [28-30]. Prior to these measurements the UV spectra of model
compounds having a closed structure (usually alkoxylactones (4B») had to
be studied to make sure that the ring form (IB) did not absorb in the region
of the analytical band.
The use of infrared spectroscopy in the determination of ring-chain
equilibrium constants is more useful for the 3-acylcarboxylic acids forming
a five-membered ring. Here, due to c=o group angle strain the C=O band
of five-membered hydroxylactones (IB) is shifted to higher frequencies
compared with the carboxylic or ketonic C=O band of the open form (IA)
and it usually appears in solution spectra at 1800-1770cm- I (Table 1). It
may also serve as analytical band for quantitative measurements of KT
constants.
The determination of KT constants for 2-aroyl [31,32], 2-acylbenzoic
[26] and Z-3-aroylacrylic acids [27] is based on the assumption that the
integrated intensities of c=o bands in the spectra of open and closed form
are equal to the intensities of the corresponding bands of fixed model
compounds, i.e., esters (4A), IICOOR 1740-1720 cm -I, IIC=O 1700-1670 cm- I )
and alkoxylactones (4B), IIC=O 1785-1770 cm -I) [26, 27, 36, 37]. The repro-
ducibility of determinations of tautomeric equilibria in solution is within
2-3% [26,32].
Lactone C=O bands in the spectra of 4-acylcarboxylic acids, which
form six-membered hydroxy1actones (lBd-g), are but little shifted to high
frequencies as compared with the carboxyl C=O band. These bands thus
overlap, which hampers analytical measurements. Nevertheless KT con-
stants have been determined 'for 8-aroyl-1-naphthoic acids by means of the
Table 1. C=O Band Frequencies in IR Spectra of 3-Acylcarboxylic Acids (la--c)

in Solution
0
-:;:-0 II
(C'OH ., . (C"o
C=O C/
/ /
R R "OH
(1A) (18)
c=o in (IA)
C R Solvent
Ketonic or
aldehydic Carboxylic
C=O in (18)
Lactonic Refs.
H CCI 4 1749 I7I I 1795 30

/'
CH 1 Me CCI 4 1726 1758 (free) 19
I 1714 (bonded)
CH,
,,- Ph dioxan 1690 1735 33
CCI 3 CHCI 3 1767 1724 1808 34
(JC
H dioxan 1699 1723 1778 26
Me dioxan 1706 1724 1776 26
Ph dioxan 1681 1726 1781 26
CCI 3 CHCI 3 1754sh 1721 1789 34
H, "" H (KBr) 1795,1761 35

C Me dioxan 1763 22
II Ph dioxan 1676 1713 1769 27
""C,
H CCI 3 CHCI 3 1786sh 1715 1812 34
IR method [38,39]: the ketonic band at 1670-1660 cm- 1 [39] was used as
the analytical one.
The qualitative and quantitative determination of the composition of
acylcarboxylic acid capable of ring-chain tautomerism by IH-NMR spec-
troscopy is most frequently accomplished using signals of alkyl (mostly
methyl) protons, located at the ketone group (AlkC=O in (IA) and
AlkC(OH)O in (18») [15, 19, 20, 26, 29, 40-42]. The signals of protons
located at the carbon atoms in the chain between ketone and carboxyl
groups are only rarely used [27,43]. The signals of aldehyde and methine
protons of aldehydrocarboxylic acids (HC=O in (IA) and HC(OH)O in
(18») are also suitable for analytical measurements [11,12,14,16-18,21,30].
The IH-NMR spectrum of 2-acetylbenzoic acid in DMSO-d 6 solution
shows signals at 2.45 ppm (CH 3 CO) and at 1.78 ppm (CH 3 C(OH)O),
the relative intensities of which indicated KT = 2. Addition of a trace of
24 Chapter 2
hydrochloric acid caused fast interconversion of the tautomers and the

collapse of these signals into one averaged signal at 2.02 ppm [42].
Most I H-NMR spectra of acylcarboxylic acids show a single averaged
signal, indicating tautomeric interconversions fast on the NMR time-scale
[19,20,26,29,41]. KT determination can be carried out in such cases using
lH-NMR spectra of fixed models «4A) and (4B») for calculation of the
positions of the averaged signals [26, 29].
The KT constant for 3-formylpropionic acid was obtained from the
ratio of the aldehyde (9.54-9.66 ppm) and methine (5.66-5.83 ppm) proton
signal intensities [30].
Rate constants for 2-formylbenzoic [5] and 2,3,3-trimethyl-Ievulinic [6]
acid tautomeric interconversions in aqueous solution were determined by
Bell and Cox by relaxation time measurements. Using the observed dissoci-
ation constants Ka, "true" dissociation constants K ~ and pH relaxation
times, measured by means of the temperature-jump method, the authors
calculated the rate constants for the equilibria (1) and (2), postulating them
as rate-determining proton transfer reactions (Table 2). The last equation
describes the ring-chain interconversion (K T = k 4 / k)).
0
II
c:>
R
/ ~
OH
+ H2O ~
k.
k2
'. (
COO-
COR
+ H)O+ (1)
0
II
COO- COO-
(C,o k3 (COOH
+ • k4 • (2)
C/ (COR (COR +
/ ~
COR
R OH
We now discuss the influence of the structure of acylcarboxylic acids
(la-h) on the ring-chain equilibrium constants given in Table 3. Cases are
considered in which either the open or the closed form predominates in
the solid state.
Table 2. Protolytic and Tautomeric Rate Constants of 3-Acylcarboxylic Acids

(I. mol-I. S-I) in Aqueous Solution [6]
Acid k2
2,2,3-Trimethyllevulinic 9 l.15 X 108 9.3 X 104 6.5 X 105 6.9

2-Formylbenzoic 23 2.5 X 107 2.2 X 105 3.2 X 106 14.8
Table 3. Ring-Chain Equilibrium Constants (KT = [B]/[A]) of Acy1carboxylic Acids
'i'0
C"-OH
°cII
( • I (~O
C=O
/ /C"
R R OH
c
(lA) (18)
R Refs.
Rl R2 R3 R4
H H H H H 0.82a 30
Rl Ob
H H H H Me 23
2 Ic/" Ob
R- Me H H H Me 23
R3_cI Me Me H H Me Ib 23
/ "- H H Me Me Me 0.2b 23
R4 Me Me Me H Me 6.9 b 23
H H H H t-Bu 0.2" 23
H H H H Ph Ob 23
H 14.8 b 5
6.7 c ; 4.6 d 26
Me 4.7c; 4:3 d 26
3.2 b 24
Et 4.3 c ; 3.5 d 26
i-Pr 4.8 c ; 2.2 d 26
5.6 b 24
t-Bu 5.3 c ; 5.7 d 26
PhCH 2 5S; 3.0 d 26
Ph O.07 c 26
0.033 c 32
4-MeC 6 H4 0.018 c 32
4-CIC 6 H4 0.034 c 32
4-BrC 6 H4 0.043 c 32
4-CNC 6 H4 O.078 c 32
4-N02C 6 H4 0.09Y 32
3-N02C 6 H 4 0.067 c 32
3-N02-4-MeC 6 H 3 0.057 c 32
3-N02-4-CIC 6 H 3 0.102 c 32
Rl Rl R2 R3 R4
R2¢ ,:71 MeH

H H
H
H
H
Me
Me
Me
16 b
0.52b
24
24
R3 :::::,... H Me Me H Me 2.9 b 24
R4 H MeO MeO H Me 5.1 b 24
CI CI CI CI Me 12 b 24
continued
26 Chapter 2
Table 3. ( cont.)
C R KT Refs.
ex)
:::::,.... .0
Me 6.3 b 24
H...... ,/
C I-Bu 94 e 22
II I-Adamantyl 70 e 22
,/C ...... Ph O.3 e 22
H
Me 34 e 22
Me ...... C ,/ 1.0' 27
4-MeOC 6 H4
II 4-MeC 6 H4 3.0' 27
/C ...... 4-BrC 6 H4 4.3' 27
H
4-CIC 6 H4 4.3 c 27
Ph 10.6 c ; 8 d 27
H ...... C / 4-MeOC 6 H4 I.7 c ; l.l d 27
II 4-MeC 6 H4 4.5 c ; 2.5 d 27
/C ...... 4-BrC 6 H4 7.6 c 27
Me 4-CIC 6 H4 6.6' 27
4-N02C 6 H4 26' 27
8
H 1200 e 38
Me 130 e ; 38
100h 24
Et 210 e 38
~ II i-Pr 420 e 38
I-Bu 1300 e 38
Ph 1.41 c; 38
2.34'; 1.56f 39
4-MeOC 6 H4 0.14'; 38
0.64'; 0.121 39
4-MeC 6 H4 0.43 c 38
4-BrC 6 H4 1.60' 38
4-CIC 6 H4 1.66' 38
3-MeC 6 H4 0.84c 38
3-CIC 6 H 4 2.63' 38
3-CF3 C 6 H 4 3.06 c 38
H 3000 e 38
3-Acylpropionic Acids and Substituted Derivatives (1a). The electrophi-

Ii city of the carbon atom in the group RCO decreases in the series R = H,
alkyl, aryl. As a consequence, the stability of the cyclic form of acylcarboxy-
lic acids is lowered in the same order. In solutions of 3-formylpropionic
acid, tautomeric equilibrium involves approximately equal amounts of both
forms [30]. Substitution in the chain shifts the equilibrium towards the ring
form [19,21,44-46].
In solutions of levulinic acid, the ring form is not observed [19,23].
Substitution of two or three methyl groups at the carbon atoms in the chain
forces the c=o and COOH groups into closer proximity and shifts the
equilibrium towards the cyclic form (see Table 3). The largest equilibrium
constant is found for 2,2,3-trimethyllevulinic acid (6.9 in aqueous solution
[6],7.7 in an 80% aqueous solution ofmethylcellosolve [19]). This has been
interpreted as a result of the Thorpe-Ingold effect, sometimes called the
gem-dimethyl or gem-dialkyl effect [47-51]. The most satisfactory explana-
tion was given by Allinger and Zalkov [52] who showed that branching of
the chain decreases the free energy of ring formation through more favorable
t..HO and T t..So terms and consequently shifts the equilibrium toward the
ring form. This effect plays an important role in many ring-chain equilibrium
systems, as will be shown later. It also increases the rates of cyclizations
and other reactions proceeding through cyclic transition states in the rate-
limiting step.
Recently it was shown experimentally [53], and corroborated by force
field calculations [54], that the dominant role of rate enhancement of
3-(2-hydroxyphenyl)propionic acid lactonization by methyl substituents in
the chain, and in the 3- and 6-positions of the benzene ring, is ground state
strain, i.e., an enthalpy effect. This work [53, 54] disproves the former
concept of stereopopulation control, suggested by Milstien and Cohen [55],
according to which the entropy effect dominates.
According to IR investigations, 3-aroylpropionic acids [33, 56-58], and
some of their more complicated derivatives [59], occur exclusively in the
open form in the solid state as well as in solution. It has been shown by
means of dissociation constant measurements [23] that an aqueous solution
of3-benzoylpropionic acid does not contain the cyclic form. 3-(3-Indolylcar-
bonyl)propionic acid also possesses the open structure as shown by IR and
UV spectra [60].
Footnotes to Table 3
The KT constants are determined by:
a UV method in dioxan;
b Dissociation constants measuring and true dissociation estimating in water;
, IR method in dioxan;
d IH-NMR method in dioxan:
, In the same way as b, but in 80% 2-methoxyethanol-water solution;
fIR method in OM SO.
28 Chapter 2
A series of 3-trichloroacetylcarboxylic acids based on 3-trichloro-

acetyl propionic acid shows a heightened tendency to form the cyclic
tautomers [13,34]' Obviously, the -I-effect of the trichloromethyl group
enhances the electrophilicity of the carbonyl carbon atom. The relatively
high stability of the ring form of bicyclic ketocarboxylic acids (6)-(9) is a
result of the fixed mutually eclipsed conformation of the COOH and C=O
groups providing the sterically most favorable condition for intramolecular
addition.
ctr,?O ctr,?o
C· O C/O
0
ctz-e~ ...--0
/C,
keo
~
0
/C
\
...--0
HO/I HO/I HO CCl 3 HO 'CCI 3
CCl] CCl]
(6) (7) (8) (9)
2-Acylbenzoic Acids (lb). The ring-chain tautomerism of 2-acylbenzoic

acids has been thoroughly studied [1,3]' Here the c=o and the COOH
groups are nearer to each other than in 2-acylpropionic acids. Furthermore,
rotation of the connecting C-C bond is impossible. Steric models show [61]
that the open tautomers (lOA) can exist only in a non-planar conformation,
which inhibits the conjugation ofC=O and COOH groups with the benzene
ring.
~COOH
~COR
4 '
~o R OH
(10A) (10B)
2-Formylbenzoic acid in the solid state exists as the cyclic

hydroxyphthalide (lOB, R = H) [62-64], and this form also predominates
in the solutions (see Table 3) [5,8, 12,26,65]. The same behavior applies
to solutions of 2-formyl-5,6-dimethoxybenzoic (opianic) acid [16, 18], but
for 2-formyl-3-hydroxy-2-methylpyridine-4-carboxylic acid the equilibrium
is shifted toward the open form [14, 18].
Many papers [29,41,62,64,66] present spectral evidence for the
existence of 2-acetylbenzoic acid in solid state as the 3-hydroxy-3-methyl-
phthalide (lOB, R = Me). However, the dependence of the solid state struc-
ture on the substituent R (10) is not straightforward. Some 2-acylbenzoic

acids with R = alkyl or a more complicated substituent crystallize in the
cyclic form [7,13,34,67], but others solidify in the open chain [68] or as
mixtures of both forms [68-73].
The isolation of one definite isomer as a solid substance does not
necessarily imply its prevalence in solution [29,68,71], since the minor
tautomer can possess the lower solubility [48]. The isomeric composition
of the solid acylcarboxylic acids isolated from solution depends not only
on the structural factors, but also on the method and conditions of the
isolation, such as crystallization or precipitation by acidification from alka-
line solutions, the temperature of the solution during crystallization or
precipitation, polarity and proton acceptor properties of the solvent, pH
value of aqueous solution after acidification, etc.
With variable or not clearly defined isolation conditions, little regularity
exists between the tautomeric composition of the isolated solid and the
structure of such acids (10).
Both isomers are observed [74, 75] for solid benzil-o-carboxylic acid: the
yellow form (l1A), lIc=o 1698, 1683 cm-\ lIOH 2632-2513 cm- I ; the colorless
form (118), lIc=o 1745, 1692 cm-\ lIOH 3268 cm- I [62]. The isomerization
(118) -+ (l1A) is accomplished by heating.
~COOH
0COCOPh« • ~o
PhCO OH
(11A) (118)
(XI
~
COOH
COCH~
Ph ~
~O /Ph
CH 2 CONHBu-t HO CH
"-
CH 2 CONHBu-f
(12A) (128)
3-(2-Carboxybenzoyl)-3-phenylpropionic N-(t-butyl)amide (12) was

isolated [73] in three crystalline modifications which differ from each other
concerning relative amounts of ring and chain forms (12A) and (128). This
is because there are various possibilities for intermolecular hydrogen bond-
ing in this molecule.
The acid (13) was obtained [76] in the lactone form (138) from acid
solution or as a betaine (13A) from alkaline solution.
30 Chapter 2
Korshak and co-workers [77] have isolated both forms of 2,5-diben-

zoylterephthalic acid (14A) and (14B). The open form, obtained by acidifica-
tion of a solution of the dis odium salt, is less stable and it is easily
transformed into the ring form (14B) by acids, by suspension in dioxan,
benzene, ether, methanol or acetic acid, and by recrystallization. The authors
[77] suggest that intermolecular hydrogen bonds
o Ph OH
HOOC
0 COPh
.' o~o
PhCO~COOH HO Ph 0
(14A) (14B)
O···HO
(-C ,f' '" C- orCOOH···O=C)
'" OH···O ,f'
stabilize the open form. Heating or the action of solvents breaks these bonds
and a C=O group protonation takes place which is followed by cyc1ization.
IR spectroscopy has been used [29, 62, 64] to determine the structures of
2-acylbenzoic acids in the solid state. Unfortunately, this method is ham-
pered by the presence of strong intramolecular hydrogen bonds OR-· ·O=C
(ring form), which cause splitting of the lactol vC=O band and shifting
toward the lower frequencies in comparison with solution spectra (see Table
1, Fig. 2). Concentrated solutions of 2-acylbenzoic acids and other ')'-
ketocarboxylic acids [19, 41, 68] in solvents oflow polarity show, in addition
80----,----,-----,----,--
60----+_---H~---1-----+--
40----+-++~~----+-----~-
~ 20----~r7~4_4r~~----_r-
<I>
o
C .-,-_ _-"""1
2
o
~ O~~+_~--~~~-r--~~-
L
o
CJl
~
o 60----+-----+-----t-----t--
40----~++~~--_+----~--
20----~~--+-~~~----t--
3
Figure 2. The IR spectra of 2-acylbenzoic acid ring isomers: 1-3-hydroxy-3-methylphthalide

in the solid state; 2-its solution in dioxan (A);;:2 (8); 3-3-bromomethyl-3-hydroxyphthalide
in solid state; 4---its solution in dioxan (c = 5 X 10- 2 mol/I).
to the free lactol band C=O group at 1770 cm-\ a band for the bonded
C=O group at 1750 cm- I (Fig. 3). The dilution of the solution decreases
the intensity of this band (1750 cm- I ) and such a change in the spectrum
makes it possible to distinguish the band of the bonded lactol C=O group
from the absorption of the free COOR group of the open isomer that usually
appears in the same range (-1750 cm -I).
The basic proof of the cyclic structure of acylcarboxylic acids in the
solid state is the presence of an intense broad band at 3350-3150 cm -I,
attributable to the bonded OR group (OR·· ·O=C) in their IR spectra.
Ketocarboxylic acids of the open structure (tA) show the OR-absorption
of dimeric COOR groups as a broad diffuse band at lower frequency (Fig. 4).
Tautomeric equilibria of 2-acylbenzoic acids (10, R = alkyl) [7, 24, 26,
29,41, 64, 68-71, 73] in solution are displaced in favor of the ring forms
(tOB) (see Table 3).
32 Chapter 2
o 40----.----.-----.----.--
0-
<11
()
§ 20 ---+-./----\-~\---+-----+--
.0
5
~ O-s~~~~~~~~~-
V,CM- 1
Figure 3. The IR spectra of 2-(2-phenylbutyryI)benzoic acid (A) +:!: (B) in CCl.: I-c =
5 X 10- 2 mol/I; 2-c = 10- 2 mol/I.
In the 2-aroylbenzoic acid molecule the electrophilicity of a keto group

is low owing to ketone group conjugation with two benzene rings. Hence,
2-aroylbenzoic acids both in the solid state and in solutions exist pre-
dominantly as the open form [26, 29, 64, 78-80], unless special structural
factor stabilize the ring form. Ring-chain equilibrium constants of 2-(3-X
or 4-X-benzoyl)benzoic acids, determined [26, 32] in dioxan by the IR
method, lie within the range of 0.03-0.10 (see Table 3). Higher values have
been observed for the acids possessing electron-withdrawing substituents
X. A satisfactory linear correlation connects KT and the O"-coefficients of
the substituents X.
The methyl groups in the 3- and 6-positions of 2-benzoylbenzoic acids
interfere sterically with the C=O and COOH groups, thus shifting the
equilibrium in favor of the ring form. The 6-methyl group has a greater
influence than the 3-methyl group [24]. Methyl groups in the 2'- and
·6'-positions of the benzoyl substituent sterically hamper the cyclization [28,
80----,----,----,,----.----,-----
V' 60--+--~H_--4_--_+_--__+_--
()
c
o
.D
t
(J)
40--1-~-_+~~~--~~--+_--
.0
o 2
20~~r---_+-----r----+-~~~~-
O~-~~-~~-~~~~~L-~~~-
3400 3200 3000 2800 2600 V, CM-1
Figure 4. The IR spectra of ring and chain isomers of 2-acylbenzoic acids in solid state at
3500-2500 em-I: 1-3-hydroxy-3-methylphthalide; 2-2-(2-phenylbutyryl)benzoic acid.
81, 82]. 2-Benzoyl-3,4,5,6-tetrachlorobenzoic acid reportedly [24, 29, 32]

exists preferentially in the cyclic form.
Reportedly [83], 2-acetyl-3-nitrobenzoic acid is cyclic, whereas 2-acetyl-
3-hydroxy- and 2-acetyl-3-amino-benzoic acids exist in open forms. This is
probably due to the ability of the last two acids to form intramolecular
hydrogen bonds as shown (15). Additionally, the electron-donor groups OH
and NH2 decrease the electrophilicity of the keto group and thus stabilize
the open structure.
Y~ I
X,
H
COOH
C ....
II
0
Me
(15)
Increasing the electron donating effect (X = N0 2 < H < OH < NH 2)

in a number of 2-acetyl-6-X-benzoic acids by contrast shifts the equilibrium
in favor of the ring form [42]. In this case the conjugation of the carboxylic
group with an electron-donating group increases the nucleophilicity of
COOH group oxygen atoms, thus stabilizing the ring form.
The introduction of nitro groups into the phthaloyl ring irrespective
of its position stabiiizes the open structure [29, 32, 78], which is difficult to
explain.
Some 2-heteroylbenzoic acids (lOA, R = 2-pyrrolyl, I-methyl- and 1-
benzyl-2-pyrrolyl [84], 2-pyridyl [85], 3-indolyl [60]) also possess the open
structure.
In contrast to 2-formylbenzoic acid (K T = 14.8 in aqueous solution
[5]), the ring form of its heterocyclic analogue 3-formylthiophene-2-
carboxylic acid is not observed in solution [86], perhaps due to the unfavor-
able bond angles of the five-membered thiophene ring.
Anthraquinone-l- (16A) [87] and fluorenone-l-carboxylic (16B) [26]
acids represent special cases among 2-aroylbenzoic acids. Their C=O group
is planar to the aromatic system and cannot rotate around the CO-Ar
bond (shown by arrows in formulae (16A) and (16B)). As a consequence,
the approach of the carboxyl group to the carbonyl group, which requires
strict stereoelectronic controlt, cannot take place and the cyclic isomers of
the acids (16A) and (16B) do not appear in solution.
t P. Deslonghamps, Stereoelectronic Effects in Organic Chemistry, Pergamon Press, Elmsford,

N.Y., 1983.
34 Chapter 2
o COOH
~
o
~
o COOH
(16A) (168)
Interestingly, the COOH group of anthraquinone-I-ylacetic acid, the

homologue of (16A), is capable of an intramolecular addition to the C=O
group. The cyclization is accompanied by 1,4-dehydration to the lactone
(17) [88-90]:
o
o
(17)
Z-3-Acylacrylic Acids (le). Z-3-Formylacrylic acid [2, 35, 91, 92], its
2-methyl [93], 3-methyl [94], 2,3-halogeno [11, 17, 95-98], and other 2,3-
substituted derivatives [99], and also Z-3-acetylacrylic acids [15, 20, 100-
103], exist in the solid state, as well as in solution, entirely in the ring form
(18B) as does penicillic (Z-3-methacryl-3-methoxyacrylic) acid [104, 105].
R'lj
RI , 0
/COOH HOOC, /RI
C C
II ~ ~
I 0 II
/C, R2 /C,
R2 COR R OH R2 COR
(18A) (188) (18C)
By means of acid ionization constant measurements [19], high ring-

chain equilibrium constants have been obtained [22] for Z-3-acylacrylic
acids in 80% aqueous 2-methoxyethanol solution (see Table 3).
Z-3-Aroylacrylic acids have been isolated in solid state in cyclic or
open form [9, 10, 106-109], but in solution the equilibrium is displaced in
favor of the ring form. In a number of Z-3-(4-X-benzoyl)-3-methylacrylic
acids, a good linear correlation has been obtained between KT constants

and inductive (O"[) and resonance (O"~) constants of the substituent X:
log KT/(KT)o = p[O"[ + PRO"~
Bowden and Henry [27] in a series of six compounds found: p[ = 0.374,
PR = 1.885 (standard deviation s = 0.072, correlation coefficient r = 0.990).
Polarography established a very low value of the ring-chain equilibrium
constant [110] for aqueous solutions of Z-3-formylacrylic acid (K T =
[(ISB)]/[(ISA)] = 1.82; R = R I = R2 = H). This differs greatly from the
results obtained for other Z-3-acylacrylic acids by potentiometric or spectro-
scopic methods (see Table 3). Unfortunately Z-3-formylacrylic acid has not
been investigated potentiometrically or spectroscopically.
In the study of 3-acylacrylic acid ring-chain tautomerism, it is sometimes
necessary to differentiate not only ring and chain forms (ISA) and (ISB)
but also Z- and E-isomers of the chain forms (ISA) and (ISC). This can be
achieved by I H-NMR spectroscopy using spin-spin coupling constants of
olefinic protons [15, 20, 102, 103], or by the I R technique utilizing the-out-of-
plane deformation C-H vibrational mode at 980 cm- I of the E-isomers
[43, Ill].
By the action of thionyl chloride on E-3-acetylacrylic acid, Scheffold
and Dubs [20] obtained the ring isomer of the acyl chloride, i.e., 5-chloro-5-
methyl-2,5-dihydro-2-furanone. Its careful hydrolysis led to the ring form
of Z-3-acetylacrylic acid (lSB, R = Me). Interconversion into the more
stable E-isomer took place during sublimation. The authors [20] did not
succeed in obtaining Z-3-acetylacrylic acid in the open form (1SA).
Sugiyama and co-workers [103] carried out the isomerization
(lSC)-+ (ISB) by irradiation of E-3-acetylacrylic acid with a mercury vapor
lamp. Attempts to obtain the open isomer by isomerization of E-3-pivaloyla-
crylic acid (lSC, R = t-Bu) were unsuccessful. These experiments confirm
the exceptionally high stability of the Z-3-acylacrylic acid ring form, which
is probably due to the steric proximity of the interacting groups in the open'
structure.
Kuchar [III] has obtained a mixture of three isomers (ISA), (ISB),
and (lSC) by acidification of an alkaline solution of 3-( l-adamanty1car-
bonyI)acrylic acids; however, the presence of the open Z-form (ISA) was
not strictly proven. An equilibrium between the open and closed forms was
observed in acidic and basic solutions of 3-{I -adamanty1carbonyI)-2-( or
3)-halogenoacrylic acids [43, 112]; however, the configuration of the open
isomers was not established.
Methyl substituents at the olefinic carbon atoms of Z-3-acylacrylic acids
stabilize the cyclic form (see Table 4), the methyl group at CD) exerting a
36 Chapter 2
Table 4. The influence of Methyl Substituents at Olefinic

Carbon Atoms on the Ring-Chain Equilibrium Constant of
Z-3-Acetylacrylic acids (18, R = Me)t [20]
R'. . . . /COOH Rlx)0

IT .' I 0
R2/C ....... COR R2
R OH
(18A) (18B)
pKa pK~
R' R2 determined estimated logKT
H H 6.7 5.5 1.2

Me H 7.60 5.7 1.9
H Me 9.14 5.5 3.6
Me Me 10.9 5.7 5.2
t Determined by means of potentiometric method in 80% aqueous methyl-

cellossolve.
greater influence than that at C(2) [20, 27]. An analogous phenomenon is

observed [43] for 3-(l-adamantylcarbonyl)-2-( or 3 )-halogenoacrylic acids.
The increasing stability of the ring form by a halogen atom at position
3 can be explained as the result of its -I-effect, which operates through
two bonds and increases the electrophilicity of the keto group. Simul-
taneously the +C-effect operating through the double bond increases the
nucleophilicity of carboxylic group oxygen atoms.
In the case of E-3-acyl-2-halogenoacrylic acids, the halogen atom has
a weaker influence on the ring stability, because its -I-effect operates on
the keto group through three bonds, but the +C-effect operating through
the double bond decreases the electrophilicity of the keto group.
Ring-chain and keto-enol tautomerism appear simultaneously in
maleiylacetone (19A) ~ (19B) [113, 114].
H H
H "C=C /
"C=C / "COOH
MeCO "OH
/
(19A) (19B)
4-Acylbutyric Acids (ld). Pentin and co-workers [57, 115-117] investi-

gated a number of 4-acylalkanecarboxylic acids. According to IR and UV
data these acids in the solid state and also in CHCl 3 and CCl 4 solutions
possess an open structure. Evidently, the great conformational mobility of
a chain having three Sp3 -carbon atoms does not favor the formation of the
six-membered hydroxylactone ring. Unfortunately, no data are available of
a spectroscopic examination of 4-acylbutyric acids possessing gem-dialkyl
substituents in the chain which could favor a ring closure by the Thorpe-
Ingold effect discussed on page 27.
Meerwein [118] found that the ionization constant decreases on going
from 4-formyl-4-methyl-3-phenylvaleric acid to its 2-methyl derivative. This
and some other differences in the physical and chemical properties of both
acids lead to a supposition that the introduction of a methyl or more
generally an alkyl group at C(2) favors the hydroxylactone formation. In
this case the chain between the interacting groups contains four substituents
including a gem-dimethyl group.
2-Acylmethylbenzoic and o-Acylphenylacetic Acids (Ie, If). In these acids
the chain containing two aromatic and one Sp3 -carbon atoms and possessing
therefore less conformational mobility than in the foregoing acids (ld) leads
to a greater stability of the ring form.
O:COOH
0
I
::::::.-..
R'
/
C
, RI
/
COR • •
oQ:H R' R'
(20A) (20B)
,
OC)0
R' R' R' R'
O:C
/
I 'COOH • • : : : .-. I 0
::::::.-.. COR
R OH
(21 A) (21B)
The structures of crystalline 2-acetonyl- and 2-phenacylbenzoic (20a-c),

and o-acylphenylacetic acids (2Ia-d) have been examined by IR (see Table
5) [1l9-122]. The position of the ring-chain equilibrium has only been
approximately determined from chemical reactions. Acids (20b, e) and (2Ie)
containing gem-dimethyl groups are cyclic in the solid state. The acid (2Id),
containing a keto group conjugated to two benzene rings, possesses an open
structure, regardless of the presence of a gem-dimethyl group. From these
acids only (20b) gives the cyclic 3-methoxy-3,4,4-trimethyl-l-isochromanone
38 Chapter 2
Table 5. The Structure of 2-Acylmethylbenzoic (20)

and o-Acylphenylacetic Acids (21) in the Solid State
[119, 120]
Isomeric structure
obtained in
Compound R Rl solid state
(20a) Ph H A
(20b) Me Me B
(20c) Ph Me B
(21a) Me H A
(21b) Ph H A
(21c) Me Me B
(21d) Ph Me A
in a reaction with diazomethane. The equilibrium of acid (20b) in solution

is shifted entirely in favor of the ring form due to the absence of a keto
group conjugation with the benzene ring and the presence of a gem-dimethyl
group [120].
Solid 2-formylmethyl-5,6-dimethoxybenzoic acid possesses an open
structure but a DMSO-d 6 solution shows a balanced equilibrium (K T = I)
[18].
8-Acyl-l-naphthoic Acids (lg). Among 4-acylcarboxylic acids, these
acids represent a special case. The interacting groups are rigidly fixed at
a shorter distance from one another than in 2-acylbenzoic acids.
Lansbury and Bieron [40] were the first to show, using 'H-NMR
spectroscopy, that the ring-chain equilibrium in a solution of 8-acetyl-l-
naphthoic acid is shifted toward the cyclic form. Additional indirect
chemical proof exists for a series of 8-acyl-I-naphthoic acids [81, 123-126].
A quantitative examination of these equilibria by IR [38,39J and
potentiometric [38] methods has clearly shown that KT values of 8-acyl-l-
naphthoic acids are about two orders higher than those of 2-acylbenzoic
acids having a corresponding substitution pattern (see Table 3). This differ-
ence is caused by a greater proximity of interacting groups in 8-acyl-l-
naphthoic acids, which can be confirmed using molecular diagrams. Figure
5 shows that the nucleophilic oxygen atom of a planar carboxyl group is
closer to the electrophilic carbonyl carbon atom in the naphthoic acid
derivative.
Increasing size of the alkyl substituent at the keto group in a series of
8-acyl-I-naphthoic acids (Me < Et < i-Pr < t-Bu) favors the cyclic form
[38]. A similar, but smaller effect has also been observed for the correspond-
ing 2-acylbenzoic [26] and Z-3-acylacrylic [22] acids.
o
o
~OH
l0Yo R
Figure 5. The molecular diagrams of 8-acylnaphthoic and 2-acylbenzoic acids demonstrating

the hypothetical planar conformations. The overlapping areas of circles with the effective radii
of a keto group carbon and of a carboxylic group oxygen atom are shaded.
Expanding the bulk of substituent R probably increases the steric strain

of the open structure much more than that of the cyclic one. Moreover,
sterically demanding substituents cause the keto group to turn out of the
plane of the aromatic ring or of the ethylene bond, which also favors
cyclization.
8-Benzoyl-l-naphthoic acid is certain to have at least two crystallinic
modifications and both possess cyclic structure [127]. By contrast, 8-(4-
methoxybenzoyl)-l-naphthoic acid exists as an open isomer in the solid
state [128].
The presence of increasingly electron-withdrawing substituents X in a
series of 8-(3-X- or 4-X-benzoyl)-I-naphthoic acids causes a displacement
of the equilibrium in favor of the ring form, as demonstrated by a linear
correlation [38]:
log KT/(KT)o = PP"I + PRO"~
A senes of eight compounds shows PI = 1.286; PR = 2.918 (s = 0.073;
r = 0.970).
Carboxylic Acids with Acyl Groups in Position 5. Unlike the 3- and
4-acylcarboxylic acids and their derivatives, often undergoing ring-chain
tautomerism, 5-acylcarboxylic acids show interconversions leading to the
seven-membered hydroxylactones very rarely.
Christiaens and Renson [81] did not succeed in an attempt to detect
the ring form of 2-acyldiphenyl-2'-carboxylic acids by chemical methods,
although the very type of structure might give the essential steric proximity
of COOH and C=O groups.
40 Chapter 2
A ring-chain equilibrium (22A) +:! (228) has been reported [129] for
solutions of N -pyruvoylanthranilic acid. However, later these data were
rejected [130].
The only 5-acyicarboxylic acid present in equilibrium with the seven-
membered hydroxylactone, which even predominates, is the 4-formyl-5-
phenanthroic acid (23A) +:! (238) [38, 81]. The interacting groups are rigidly
fixed at a short distance, which is shown by the high equilibrium constant
(KT = 3000) determined by the potentiometric method [38].
o
~COOH
~)OOH
0NHCOCOMe U .. _ Me
(22A)
~ 0
H
(228)
COOH
(23A) (238)
Bowden and Last [38] have suggested the following order of increas-
ing stability of the ring form provided that the substitution pattern at
the keto group is unchanged: 2-acylbenzoic < Z-3-acylacrylic <
8-acyl-I-naphthoic < 4-acyl-5-phenanthroic acids. Obviously, this order
reflects the distances between the interacting groups.
The Acylcarboxylic Acid Tautomeric Equilibrium Dependence on Solvents,
Temperature, and Other External Factors. The influence of solvent properties
on acylcarboxylic acid tautomeric equilibria has only rarely been studied.
Polar solvents favor the cyclic form [31,32,68]. The mechanism of solvent
effects on ring-chain equilibria (IA) +:! (18) is highly complex. Most impor-
tant is the stabilization of the ring or chain form by intermolecular hydrogen
bonds with the solvent molecules. There are some approaches which may
be helpful in special cases. A dilution of solutions [10, 30], a use of pyridine
or triethylamine as solvent or their addition to solutions [30] shifts the
equilibrium toward the open form. In acid media the equilibrium is shifted
in favor of the less acid cyclic form [10, 16-18]. Raising the temperature
favors the open form [65, 131].
2.1.2. Acyl Chlorides

Unlike the acylcarboxylic acids which form the ring tautomer as the
result of an intramolecular nucleophilic addition to the C=O bond, the
ring closure of acylcarboxyl chlorides takes place by intramolecular elec-
trophilic addition to the keto or aldehydo group:
~O
°II °II
CR; C C
c/"
-Cl-
---+ C +Cl-
---+ C
+/0
' '/0
C C
R
/ I / "-
R R CI
(2A) (28)
Structural factors, increasing electrophilicity of the COCl group and/ or

the nucleophilicity of the C=O group oxygen atom favor ring formation.
The stability of cyclic chlorides of acylcarboxylic acids is mainly due to the
high electrophilicity of the COCl group afforded by the -I-effect of the
chlorine atom, when the steric structure of the chain connecting the interact-
ing groups and the substituent R allow for a ring closure.
Bhatt and co-workers, investigating kinetically the solvolysis reactions
of levulinic and 2-benzoylbenzoic acid chlorides [132] and some of their
substituted derivatives [133], found no tautomeric equilibrium between the
ring and chain forms of these acid chlorides.
IR spectra of the cyclic isomers show an intense lactone C=O band.
Compared with a COCI band [134] it is slightly shifted toward high frequen-
cies for five-membered chlorolactones, but toward low frequencies for
six-membered analogues (see Table 6). Its frequency does not significantly
depend on the state of the substance (solid or solution). However, the most
important piece of evidence for the ring structure of acylcarboxylic acid
chlorides is the absence of the aldehydo or keto group absorption in the
range 1720-1660cm- 1 (Fig. 6).
A simple 13C-NMR spectroscopic method has been suggested [135] for
distinguishing between ring and chain isomers of ketocarboxylic acid
chlorides and dicarboxylic acid dichlorides (see the discussion on page 47).
3-Acylcarboxylic acid chlorides, with the exception of a few special
cases, have been obtained only as cyclic isomers (2B) [137], as has been
shown for the chlorides of 3-formyl [30, 138], 3-acetyl [139-141], and other
42 Chapter 2
Table 6. Chlorolactonic C=O Frequencies in the IR Spectra of

AcylcarboxyJic Acid Chloride Ring Isomers
-I
Formula R Solvent "c=ocm Refs.
Q
R CI
H CC\. 1812 30
(Go
0
H CC\. 1790 64
Me CC\. 1798 64
R CI Ph Dioxan 1792 80
(0
0
H CC\. 1818 35
Me CHCI, 1802,1785 20
R CI Ph CHCI, 1780 109
M'QO
Me
Ph CI
Nujol 1776-1754 136
0)
~ I
Me Me
CI
Ph
CC\. 1750 120
0)0
~I 0 CC\. 1770 119
Ph C\
8;i
~
-jPh :1
Dioxan 1731 128
80---.-----.----,-----,---
o 60--~-----r----+---~---
0-
Q)
g
o 40 ------It+-----t------+------j----
-£o
<Il
~ 20--H;r----hr+---+-----+---
1
0~~~~~~~~2~
V,CM- 1
Figure 6. IR spectra of open and ring isomers of 2-aroylbenzoylchlorides in dioxan solution
(c = 5 X 10- 2 mol/I): l-2-(2',4',6'-trimethylbenzoyl)benzoylchloride; 2-3-chloro-3-(2',4'-
dimethylphenyl)phthalide.
3-acylpropionic [142, 143], 2-formyl [64, 144], 2-ac)'1 (R = alkyl) [64, 145-
149], and 2-aroylbenzoic [78-80, 146-148, 150-152], Z-3-formyl [35], Z-3-
acyl (R = alkyl) [20, III], and Z-3-aroylacrylic [9, 10, 109, 153-155] acids.
2-(2',4',6'-Trimethylbenzoyl)benzoyl chloride (24) [78, 81, 156], an
exception among 2-acylbenzoyl chlorides, exists in an open structure due
to steric hindrance of the keto group by two o,o'-methyl groups [157].
0cp-Q-M'
~COCl Me
Me
(24)
1) "c=o 1797, 1732t
2) "c=o 1673
Attempts to synthesize 2-(9-anthroyl)benzoyl chloride from the acid

with thionyl chloride gave 9-chloro-9, 10-dihydroanthrylidenephthalide (26)
[158]. The phthalide C(3) atom in the intermediate carbocation (25) appears
to be shielded by two peri-protons of the anthryl group hindering the
chloride ion from adding to the cation at the C(9) atom. A similar shielding
effect of an anthryl substituent on a keto group was observed [159] for
t IR C=O frequencies for dioxan solutions.
44 Chapter 2
o o o
H II CI
(25) (26)
"c=o 1786 (6.8)
2-[o-(9-anthroyl)phenyl]-2-propanol, which exists exclusively as an open

tautomer.
The pentacyclic-4-pyridyl of compound (27) in comparison with an
anthryl substituent has a lesser influence on the keto group: the chloride
(27) exists in the ring form [160].
o
(27)
1) IJc=o 1801
2) "c=o 1726
OJ<
1
COCI 2 1
PhCO COCI
?
t§ S
~
I
2
CH,COCI
Ar
-
o
(28) (29) (30)
1) "c=o 1801 1) "c=o 1750 1) "c=o 1800-1770
2) "c=o 1726 2) IJc=o 1650 2) "c=o 1740, 1700
Besides the shielding influence of the substituent at the keto group,

the steric structure of the connecting link may prevent the chlorolactone ring
from closing. Thus, no cyclic isomers of the chlorides of anthraquinone-I-

carboxylic acid (28) [87], 4-benzoylthiophene-3-carboxylic (29) [161], and
W
(2-aryl-I,3-indanedione-2-yl)acetic (30) [59] acids have been observed.
o o o
(Y'9
CH2Ph
Me
o
I
0
~o ~Ph
C1
Me CI PhCO CI o
(31) (32) (33)
1) "c=o 1818 (4.0) 1) "c=o 1808 (4.6) 1) "c=o 1764 (3.6)
2) "c=o1720(1.7) 2) "c=o1694(1.2) 2) "c=o1726(1.7)
Attempts to prepare (2-benzyldimedone-2-yl)acetyl chloride have
led to 9-benzyl-8-chloro-6,6-dimethyl-2,4-dioxohexahydrocoumarane (31)
[162]. Here the five-membered chlorolactone ring is condensed with a
six-membered cyclohexane ring (instead of a five-membered ring in the
cyclic isomer of chloride (30»), which evidently favors the ring closure for
steric reasons. Moreover, the keto groups of chloride (30) are conjugated
with the aromatic ring. In a 1,3-cyclohexanedione derivative such conjuga-
tion is missing, which also favors the addition reaction to the C=O group
of the 1,3-cyclohexanedione.
Two competitive intramolecular additions are possible for the chloride
ofbenzil-o-carboxylic acid. Contrary to earlier studies [74] it was established
by IR comparison [163] that both isomeric cyclic chlorides, i.e., 3-benzoyl-3-
chlorophthalide (32) and 3-chloro-4-oxo-3-phenyl-3,4-dihydroisocoumarine
(33) were observed. The six-membered chlorolactone easily undergoes
isomerization involving ring contraction (33) -+ (32).
o o
CI
(34)
1) "c=o 1765 (35)
2) "c=o 1694 "c=o 1785 (Nujol)
It was recently shown [164] that the reaction of 2-(2-pyridylcar-

bonyl)benzoic acid with thionyl chloride leads to 4a-azoniaanthraquinone
chloride (34), which in polar solvents isomerizes into 3-chloro-3-(2-pyridyl-
carbonyl)phthalide (35).
46 Chapter 2
The chlorides of 4-acylcarboxylic acids have been comparatively rarely

studied [137,165]. By reaction of thionyl chloride and 4-benzoyl-4,4-
dimethylbutyric acid Newman [136] obtained a mixture of open and cyclic
isomeric chlorides. A similar mixture of isomers has been obtained for
4-benzoylbutyryl chloride [137].
It is impossible to obtain chlorides of 2-acylmethylbenzoic and 0-
acyl phenylacetic acids since the reaction is accompanied by dehydration,
leading to isocoumarines [120] and benzopyran-3-ones [1l9, 166, 167],
respectively. But on replacement of the methylene hydrogen atoms by two
methyl groups one succeeds in obtaining cyclic chlorides (for acids (20b, c)
[120] and (21e, d) [119]). 8-Acyl-I-naphthoyl chlorides possess a ring struc-
ture for reasons discussed earlier [81, 124, 127, 168].
The chloride of2'-benzoyldiphenyl-2-carboxylic acid was obtained only
as an open isomer [169]. Cyclic isomers of 5-acylcarboxylic acid chlorides
are not known.
0- BH
"
c:>"
/
-HCI
o ----+
II
C
( ~o +HB R/
o
Cl
(36)
C
R/ "CI -HCI
(
"
C"o
(28)
C/
R/ "B B = NR'R 2 , OR, SCN,
CN, N3
(37)
Reactions of chlorolactones (2B) with nucleophiles lead to open (36)

as well as cyclic (37) derivatives [9, 151, 168, 170, 171]. Since the absence
of tautomeric equilibria (2A) +:! (2B) in solutions is well-established [132],
the two reactions may be due to two electrophilic centers, i.e., the carbon
atoms of C=O and C-Cl groups. Strong nucleophiles add to the c=o
group, and the reaction is followed by ring opening yielding an open
structure derivative (36). The amides (36, B = NHR) formed in the reactions
with ammonia and primary amines may isomerize further to give hydroxylac-
tams (3B).
Weaker nucleophiles (aromatic amines, alcohols, urea, etc. [151])
replace the chlorine atom, leading to lactones (37). The direction of the
reaction depends not only on the nucleophilicity of the reagent HB [lSI],
but also on the structure of the chlorolactone (2B). Thus, substitution of
the chlorine atom of 3-chloro-3-phenylperinaphthalide takes place even

with aliphatic amines [168], which is quite unusual for a 3-chloro-3-
phenylphthalide [146].
Dicarboxylic Acid Chlorides and Some Related Compounds. The elec-
trophilic COCl group may intramolecularly add not only to the C=O bond
of aldehydes and ketones, but also to other carbonyl groups. For
example, some dicarboxylic acids may form two isomeric dichlorides of
open (38A) and cyclic (38B) structures. These isomers are sometimes named
as symmetrical and asymmetrical acid chlorides.
0 0
"..-:;0 + II II
cY'
~CI-
(c=o +CI-
( 'Cl •+CI-• • • ( C+ "0
C/
4: ~CI- •
(C"o
C-::::::: O C-:::::::O C/
"- "- I / "-
CI CI CI Cl CI
co
(38A) (388)
a b c
The most convenient way to identify sym- and asym-isomeric

dichlorides is by means of 13C_NMR [135]. Thus, for example, COCl carbon
signals appear at 8172.3 ppm in succinyl dichloride and at 8163.3 ppm in
sym-phthaloyl dichlor~de in CDCI 3. The 3,3-dichlorophthalide on the other
hand shows signals at 169.1 ppm (C=O) and at 104.6 ppm (CCI 2 ). In
addition three signals of benzene ring carbons appear in the spectrum of
sym-phthaloyl dichloride due to the symmetry of the molecule, whereas the
spectrum of 3,3-dichlorophthalide shows six benzene carbon peaks.
The isomerization of dicarboxylic acid dichlorides is an interesting
case of intramolecular· reaction between two identical functional groups
(COCl), one of them acting as electrophile, the other as nucleophile.
Evidently, a factor determining the stability of the cyclic isomers is the
structure of the linking fragment. By means of spectroscopic methods the
absence of a ring isomer in the solutions of succinic [135, 139, 142, 172]
and glutaric [165] acid dichlorides was established. Cyclic isomers are
formed from dichlorides of phthalic (38a) [135, 173], substituted maleic
(38b) [173, 174], and 1,8-naphthalic (38c) [126] acids.
48 Chapter 2
A condition for ring closure is the conformational rigidity of the linking

fragment, which ensures the essential proximity of the COC! groups. Both
isomers of phthalic acid dichloride have been obtained [175] and the
isomerization (38B) ...... (38A) proceeded on distillation. The reverse isomeri-
zation (38A) ...... (38B) takes place under the catalytic influence of Lewis
acids (e.g., AICU, which operate as chlorine anion transferrers.
The absence of a tautomeric equilibrium (38A) ~ (38B) for both isomers
of phthaloyldichloride was established [176] by means of a kinetic study
of their solvolysis in aqueous solutions of acetone, dioxan, and DMFA at
25-40°. Both isomeric phthaloyldibromides were also obtained [177].
The reactions of O-acetylsalicylic acid chloride (39A) with alcohols or
aromatic hydrocarbons in the presence of Lewis acids produces 2-alkoxy
or 2-aryl-2-methyl-I,3-benzodioxan-4-ones [178]. The authors [137] were
unable to provide spectroscopic evidence for the presence of the cyclic
isomer (39B). This is in accordance with a kinetic study [137] of the solvolysis
of (39A) in aqueous dioxan. The formation of cyclic products was attributed
[179] to the capability of O-acetylsalicylic acid chloride to form carbonium
ion (40), confirmed by the isolation of the hexachloroantimonate (40,
X = SbCI 6 ) [180]. A similar behavior was also observed for a-acyloxycar-
boxylic acid chlorides [180, 181].
OC'CI 0::0 eGoR

-:;::.-0 0 0
~ ../.:0
I ~CI I .- X
~ o
~
O-C Y 0 Me Me
"-
Me
(39A) (39B) (40)
An analogous intramolecular electrophilic addition to the C=O group

also involves S02C! and SOCI groups. Thus, both isomers (41A) and (41B)
of 2-formyl (R = H) [182] and 2-benzoylbenzenesulfochloride (R = Ph)
[183,184] were obtained. IR spectroscopy shows that both isomers (41A,
R = Ph) and (41B) are stable in solutions and do not tautomerize. The
mixture of isomers ([A]: [B] = 7: 3) was obtained from (41B) by heating to
220°.
CQ'0
~
I
S0 2
R CI
(41A) (41B)
Unlike the 2-formylbenzenesulfochloride isomers (41A, R = H) and

(41B) [182], which are stable in solutions, 2-formylbenzenesulfinylchlorides
(42A) are subject to a ring-chain equilibrium (KT - 0.25) in CD 2 Cl 2 solution
(XSOCI
as has been shown by IH-NMR investigations [185].
~ .-:/0
C"
H
4 I
CQ
~
1
H
'0
CI
(Xso,CI
(42A) (428)
~ COCI CQ''0
~
1
CI CI
(43A) (438)
Two isomeric 2-sulfobenzoic acid dichlorides (43A) and (43B) have

been described [186]. Distillation leads to the isomerization (43B)- (43A)
and the formation of the mixture of both isomers.
2-Sulfinobenzoic acid dichloride forms three isomers (44A), (44B) and
(44C) [187, 188]. The isomerization (44C) - (44A) was carried out at 130°C
in a vacuum.
0
Cl CI
"
(Xl
/'
~o
1 SOC I
~ COCI
Cl CI o
(44A) (448) (44C)
2.1.3. Amides, Hydrazides, and Amidines

Contrary to the acyl carboxylic acids, which equilibrate in solutions
(see Sec. 2.1.1.), N -unsubstituted and N -monosubstituted ami des of these
acids are more stable. In most cases the tautomeric equilibria (3A) ~(3B)
do not occur in neutral aprotic solvents at room temperature. The acidities
or basicities of amide groups, obviously, are insufficient for acidic or basic
catalysis. Assistance of a base especially seems indispensable for an
intramolecular addition to the keto group by a weak nuc1eophile such as
the amide nitrogen atom. Acid on the other hand increases the electrophilic-
ity of the keto group by protonation of the oxygen atom [189].
50 Chapter 2
(3A)
In protic solvents the interconversions of the keto ami des usually take
place at a measurable rate. Equilibria were obtained in methanol-d 4 [190]
(for rate constants see Table 13) and ethanol [191]. The reaction takes place
more rapidly in aqueous pyridine and a considerable acceleration may be
achieved by adding sodium bicarbonate to the solution [192] (for rate
constants see Table 10).
In aprotic solvents equilibration occurs after the addition of a proton
acceptor to the solution. Thus, for example, N-(t-alkyl)-2-aroylbenzamides
and their cyclic isomers, being stable in dioxan solution, equilibrate when
triethylamine is added [193]. The equilibrium position (generally reached
in 24-36 hours) is independent of the starting isomer (ring or chain).
In aprotic solvents ring-chain equilibria may be observed for
ketoamides, which contain additional amino groups, the latter providing
the basic catalyst. Ring-chain equilibria are described for N -unsubstituted,
N -methyl, N -ethyl, and N -phenyl-2-( 4-dimethylaminobenzoyl)benz-
ami des [191], and also for N-(t-alkyl)-2-(2-imidazolylcarbonyl)benzamides
[194] (see Table 14).
The mechanism of the base-catalyzed equilibration may be as follows:
By carrying out the isomerization in strongly basic solutions the anion

of the hydroxylactam (3C) is formed; hydroxylactams (38) possess a stronger
acidity (pKa - 12) than amides (3A) (pKa = 16-19). During acidification a
fast protonization (3C) -+ (38) takes place.
Since the energy of the hydrogen bond O-H···B is greater than that
of N - H· .. B, the proton acceptors not only act as catalysts in the reversible
isomerization, but, in greater concentration, also shift the equilibrium
toward the cyclic isomer.
A confirmation follows from IR investigations [195, 196] showing that

intramolecular hydrogen bonds 0 - H· .. N stabilize the cyclic isomers of
N-(~-dialkylaminoethyl)amides of (2-phenyl-l,3-indanedione-2-yl)- and
(2-benzyl-2-dimedonyl)acetic acids:
The IR method is most frequently used for a reliable determination of

open (3A) and closed (3B) structures (see generalized data in [33]). Proof
for the open structure of N -monosubstituted amides is the presence of an
amide-II band (VC-N + 8 N - H ) at 1570-1520 cm- I [33,146,189,197-200].
Since this band appears in the range which is usually transparent in the
spectra of hydroxylactams (3B) it can be used as an analytical band for
quantitative measurement of isomer proportions [146,193]. However, in the
spectra of nitro group-containing amides this band is useless since asym-
metrical vibrational bands of nitro groups (VN0 2 as) appear in the same
region (1550-1515 cm- I ).
In the solid-state IR spectra of open amides (3A) one can easily detect
the comparatively tight band of intermolecularly bonded N - H groups at
3400-3150 cm- I and distinguish it from the broad bands of bonded O-H
groups (O-H···O=C) appearing in the same range for cyclic isomers (3B)
(see Fig. 7) [146,200].
Open amides (3A) show C=O, amide-I, and amide-II bands in the
double bond region. In solid-state spectra lowering of the amide-I band
frequency and splitting of this band together with an increase of the amide- II
band frequency takes place [68,78, 146, 198] as contrasted with solution
spectra. This is due to the intermolecular hydrogen bonds
CONH .. ·O=CNH, usually characteristic of amides in the solid state.
Intramolecular hydrogen bonds N - H .. ·O=C(ketone) have been
detected [202, 203] by means of the IR method in a number of N -aryl-3-
acylpropionamides.
When interpreting the open isomer IR spectra difficulties sometimes
appear; these are due to an overlap of ketone C=O and amide-I bands
52 Chapter 2
60
~
0
Q) 40
0
c
.8t-
o<I) 20
.D
0
0
3400 3200 3000 2800
Figure 7. N-H and O-H bands in the IR spectra of ring and chain isomers of 2-acyl-
benzamides in solid state: l-N-(t-butyl}-2-(4-chlorobenzoyl}benzamide; 2-2-(t-butyl}-3-
(4-chlorophenyJ)-3-hydroxyisoiildolinone [201]'
[78,79, 146, 197, 199]. In such cases measuring the integrated intensity of
both band is recommended [204]. In this way the IRspectra of N-(t-butyl)-2-
benzoyl-x-nitrobenzamides (x = 3,4,5,6) were successfully interpreted
[79]; two overlapping bands were observed: IJc=o + amide-I at
1680-1670cm- 1 and (IJ N o 2Ls+amide-II at 1540-1530cm- 1 (in dioxan)
(see Fig. 8).
The lactam C=O band in the spectra of cyclic isomers of 3-acylcar-
boxylic acid amides (3Ba-c) in solution is shifted to high frequencies by
30-40 cm- I when compared with the amide-I band in the spectra of
open isomers, this is due to the angle strain in the five-membered ring (see
Table 7).
The use of C=O bands for the structure determination of acylcarboxylic
acid ami des is complicated because hydroxylactams (3B) can form inter-
molecular hydrogen bonds 0- H·· ·O=C(lactam) in the solid state
[20,78,146,147,162,163,170,196,198]. This causes a C=O band shift to
low frequencies as compared with solution spectra or even a C=O band
splitting due to the free and bonded C=O group absorption (see Table 7,
Fig. 9). The hydrogen bonded C=O group bands of crystalline 2-
benzoylbenzamides, strictly established as cyclic [33,80, 146, 170,205], have
sometimes been erroneously attributed to the overlapping bands (IJc=o
diarylketone + amide-I) of open isomers (3A). This led to an incorrect
conclusion [151, 191, 206] about the structure of these ami des in solid state,
the incorrectness of which is confirmed [207] by the absence of an amide-II
band and the presence of a broad OH band in the spectra. For this reason
the IR spectra of 2-phenylacetylbenzamides [208-210] and 2-a-(N-alkyl-
amino )phenylacetylbenzamides [208] were interpreted erroneously as
indicating an open structure. There is strong spectroscopic evidence
100
80
60
40
~,
hi"
0 20
0-
<l> \..2
0
C
0 -.--/ .V
0
.D
.t..
0
(f)
.D 80
0
~ Ni
60
1\
40
} \
V '1l 3
20
- ./
V Uvv 4
0
1800 1600
Figure 8. Partial IR spectra of 2-acylbenzamides: I-N-isopropyl-2-benzoylbenzamide in the
solid state; 2-its solution in dioxan; 3-N-(t-butyl)-2-benzoyl-4-nitrobenzamide in the solid
state; 4-its solution in dioxan (c = 5 X 10- 2 mol/I) [79, 146].
[147,211-213] for the cyclic structure of the above-mentioned amides in

the solid state.
It is recommended that frequencies and intensities of hydroxylactam
(3B) C=O bands in proton acceptor solvents be measured. Dioxan is most
suitable. As a result of the formation of intermolecular hydrogen bonds
with the solvent molecule (O-H·· ·dioxan) one can observe only the free
c=o group absorption. In solvents of low polarity the hydroxylactam
54 Chapter 2
Table 7. C=O and OH Band Frequencies in IR Spectra of Hydroxylactams (3B)

o
il
C C"N- R 2
C/
R' / "OH
Solution in
Solid state dioxan
Ring R' Refs.
Me H 1670 3280 1705 33

Me Me 1660 3250 1695 33
Ph Me 1680 3220 1698 33
Ph H 1703, 1661 3275 1720 5.5 146

Ph Me 1673 3259 1707 5.1 146
Ph i-Pr 1678, 1666 3169 1697 4.3 146
4-C1C 6 H4 I-Bu 1674 3311 1700 201
Ph Ph 1675, 1660 3181 1707 4.7 170,205
1695,1661 3390,3344, 9
3279
1698,1658 3289 9
Me 1638 3327 1661 214
H 1640 3300 1667 171

Me 1621 3317 1649 171
Ph 1633 3295 1648 171
Ph Pr 1637 3278 1651 168

Ph Ph 1661sh 3281 1663 3.0 128
1634
t Integrated intensities are given in units 104 1. mol-I. cm- 2 (In).
c=o band shifts toward lower frequencies, increasing its intensity, and
sometimes splitting .simultaneously [198,205]. These phenomena were
erroneously said to indicate an equilibrium (3A) ~ (3B) [199].
80
60
40
~
20 \ \ 1
0 d '0t---J
- 2
80
...!!
0
. 60
CI>
()
c::
0
.D
t. 40 n
V
0
(J)
.D
0 1/
20 /r-...
-3
0
-.J V _____ 4
60
r'1
40
5
~ !'----V
20 I
'~
0 ~ 6
1800 1600
Figure 9. The splitting and the shift toward lower frequencies of the hydroxylactam C=O
band in the IR spectra of ketoamide ring isomers in the solid state as compared with solution
spectra: 1-2,3( CO }-benzoylen-I-ethyl-2-hydroxy-3-phenyl-5-pyrrolidone in the solid state;
2-its solution in dioxan; 3-3-hydroxy-3-phenylisoindolinone in the solid state; 4--its solution
in dioxan; 5-3-hydroxy-2-isopropyl-3-phenylisoindolinone in the solid state; 6-its solution
in dioxan [146, 198].
56 Chapter 2
The hydroxylactam association was quantitatively evaluated [215] by

means of an association constant
K _ [(3B)·· ·(3B)]
d - [(3B)f
and hydrogen bond enthalpy (IlH) measurements (Table 8). The concentra-
tions of the associated form and of the free hydroxylactam were deduced
from the intensities of free and bonded OH group bands in CCl 4 solution.
(3B)···(3B)
Table 8. Dimeric Association Constants and Intermolecular Hydrogen Bond

Enthalpies in CCI 4 Solutions of Some Hydroxylactams [215]
Kd -!:J.H
Hydroxylactam (1/ mol) (kcal/ mol)
458
d$!
:
pr"N
HO
I Ph
0
319
o;N-.'
Ph Pr 96 5.14
o Ph i-Pr 27 4.63
Ph Ph 169
4-CIC 6 H4 PhCH 2 177
4-CIC 6 H4 Pr 126 5.33
R' OH 4-CIC 6 H4 i-Pr 63 4.74
3-N0 2 C 6 H 4 Pr 145 5.36
In comparison with hydroxypyrrolidones, hydroxyisoindolinones (see

Table 8) are less capable of association, which may account for the decrease
of C=O group proton acceptor ability due to its conjugation with the
benzene ring. Electron-withdrawing substituents R I, which increase OH-
acidity, favor association, while an increase in the steric bulk of substituent
R2 decreases the association constant.
IR spectroscopy has been applied to structure determination of
ketoamide ring and chain isomers. Due to the association phenomena, many
contradictory results have been published.
Apart from IR methods UV [9,80,194,199,216,217], IH-NMR
[33, 189, 190, 192, 199,218-222], and mass spectrometric [189] methods were
successfully applied to ketoamides. A detailed discussion of IH-NMR
application is given by Flitsch [33].
We now consider the influence of the structure of the connecting link
of a molecule and of substituents R I and R2 on the stability of acylcarboxylic
acid amide isomers (3Aa-h) and (3B) in the solid state and in solution, and
also on their mutual interconversions.
3-Acylpropionarnides. The isomeric structures (45A), (45B), and (46) of
levulinic acid amide, obtained by Wolf from a-angelicalactone [223], were
first suggested in Beilstein's handbook [224].
Lukes and Prelog [225-228] have systematically examined levulinic
and 3-benzoylpropionic acid ami des. However, due to the lack of a spectro-
scopic method they were unable to assign correctly the structure of these
amides. A product obtained from the reaction of aniline and a-angelicalac-
tone was reported to possess the open structure (45A, RI = Me, R2 = Ph),
/CONHR 2 0 0
CH 2
I
CH J
"'C- OR I
QN-R'
RI
Qo
RI NHR2
OH
(45A) (458) (46)
while a reaction of N-phenylsuccinimide with phenyl magnesium bromide

was said to give the cyclic isomer (45B). Later Walton [229] ascertained
that both reactions lead to the same product, to which he erroneously
ascribed the ring structure (45B). Lukes [230], thirty years after his first
investigations, using IR spectra, was able to show that the product formed
in both reactions possesses the open structure (45A). The history of the
investigations shows clearly that chemical methods, e.g., the synthesis of a
compound, cannot be taken as an evidence of its structure, if the compound
is capable of the isomeric interconversion.
58 Chapter 2
Flitsch isolated [33,231] both isomers (45A, R I = Me, R2 = H) and

(45B) of levulinic amide. The isomerization (45B) -+ (45A) was accom-
plished at 100°. A similar occurrence of equilibrium displacement toward
the open form by heating a number of levulinic and 3,3-dimethyllevulinic
amides was observed by other investigators [219,232].
Keller and Prelog [189] isolated both levulinic anilide isomers and
carried out the isomerization (45A) -+ (45B) by passing CHCI 3 solution
through a column filled with acidic ion exchange resin. The reverse isomeriz-
ation (45B) -+(45A) proceeds when a methanolic solution is treated with
silica gel. Both isomers are stable in the solid state and in neutral solvents.
Over 10 days the formation of an equilibrium was observed in CDCl 3
solution in the presence of acidic (CF3 COOH) or basic (pyridine) catalysts.
Cromwell and Cook [197] comparing the IR spectra of a number of
3-benzoylpropionamides (45, Rl = Ph, R2 = H, Me, Ph, a.o.) with those of
N,N -disubstituted ami des found that in the solid state these ami des with
the exception of the N-methylamide possess an open structure. In the IR
spectra of dioxan solutions of open forms the ketone C=O and the amide-I
bands overlap leading authors [197] to propose incorrectly equilibrium
(45A) ~ (45B) [199].
As a result of systematic IR comparisons of a large number of 3-
acylpropionamides Chiron and co-workers [199,200,202,203,233] showed
that all these ami des exist as open isomers in the solid state as well as in
solution. In some cases the open structure is stabilized by an intramolecular
hydrogen bond N-H· ··O=C(ketone).
Only N-methylamides of 3-acylpropionic acids possess a cyclic struc-
ture, an exception being some 3-aroylpropionamides having an electron-
donating substituent in the aroyl group.
The + I-effect of substituent R2 in (45) increases the nucleophilicity of
the nitrogen atom. Therefore the cyclic structure is stabilized. The + I and
+C-effects of substituent Rl at the keto group in (45) act in the reverse
direction: the electrophilicity of the keto group decreases. This leads to the
decrease in the ability of the keto group to add the nucleophilic nitrogen.
The increased stability of the cyclic isomer of N -methyl ami des may
arise from hyperconjugation [199].
Another interpretation, however, has been suggested [214]. +I-Effect
increases in a series of substituents: H < Me < Et < i-Pr; therefore in the
same order substituents at a nitrogen atom should increase the stability of
the cyclic form. However, since steric hindrance by a substituent at nitrogen
destabilizes the cyclic structure [3, 70, 146, 198], the stability of the ring
form must be lowered in the same order as that of the substituents. Both
opposing effects may explain the increased stability of the ring isomer for
N-methylamides only.
Table 9. The Isomeric Structure of Some 3-Acylpropionamides in the Solid State
R3 R 3R4
,,/ \
/
R4
R 1CO-C-C-CONHR2
RlfiR'
HO N 0
(A)
I
R2
(B)
The structure ami des,

when R2 =
R3 R4 H Me Ph PhCH 2 Refs.
H H H B B 239,240
Me H H A,B B A,B A,B 33,189,218,220
Ph H H A B A A 33,197,199
Me Me H B B B 231
Ph H Me B B 200
Ph
"-
J~
Me H Me B A,B 238
A great number oflevulinic [33,189,199,218,220,230,231,234,235],

other 3-acylpropionic (R 1 = alkyl) [199, 220, 236, 237], 3-aroylpropionic
[33, 197, 199,202,203], and methylsubstituted acylpropionic [141, 200, 221,
231, 237, 238] ami des were synthesized and their structures strictl,Y proven
by means of spectroscopic methods. But one rarely succeeded in obtaining
both individual isomers. This was the case for the N-unsubstituted amide
[33], the N-benzylamide [218, 220], and the anilide [189] of levulinic acid,
as well as for the N-benzylamide of 2,2-dimethyl-3-(3-methyl-l-phenyl-
pyrazolyl-4-carbonyl)propionic acid [238] (see Table 9).
The N -monosubstituted ami des of 3-formylpropionic [239-245] and
3-formyl-3-R-butyric [246,247] acids were obtained in the ring form irre-
spective of the structure of the substituent at the nitrogen atom. Evidently
this is due to the greater electrophilicity of the aldehyde group as compared
with the ketone group.
3-Acylpropionic amides, bearing methyl groups in the chain, pre-
dominantly, also possess a cyclic structure [141,200,221,231,237,238].
The data concerning tautomeric equilibria of solutions of 3-
acylpropionic amides are contradictory. Again, conclusions stating the
60 Chapter 2
presence of equilibria (4SA) ~ (4SB) were sometimes based on incorrect

interpretations of IR spectra [197, 199].
Both isomers oflevulinic anilide [189] and N-benzylamide [220], which
were isolated, are stable in neutral aprotic solvents at room temperature
and do not form equilibrating mixtures. Using IH-NMR spectroscopy the
presence of both isomers of levulinic anilide was demonstrated [33] in
DMSO-d6 solution.
Sheiman, Denisova, and Berezovskii [231, 248, 249] using the IH-NMR
method have observed the tautomeric equilibria (47A) ~ (47B) which are
displaced toward the cyclic tautomer in the case of N -unsubstituted and
N-arylamides of 3,3,dimethyllevulinic acid. The situation is complicated
by a dehydration of (47B) to give methylenepyrrolidone (48) which takes
place under the condition of ring-chain equilibration in non-aqueous sol-
utions.
Me
:~~o __ Mh
Me Me
'-./
Me-CO-C-CH 2 -CONHR -H 0
2 CH 2 N 0
(47A)
I I
R=H,-Q-X
R R
(478) (48)
x= NEt2, OMe, H, CI, Br, COOH, CDOMe, CN, ND2
Equilibrium constants were determined [249] using 50% aqueous

pyridine. Table 10 shows that electron-withdrawing substituents X in the
benzene ring destabilize the cyclic form and shift the equilibrium toward
(47 A) (see also [231]). The thermodynamic data tJ.H and tJ.S were calculated
from the KT temperature dependence.
Due to an increase of conformational freedom ring opening is accom-
panied by rising entropy. For most of the amides investigated tJ.S values,
being in the range 11-12 e. u., slightly depend on the substituent.
The introduction of strong electron-withdrawing substituents X into
the benzene ring causes a simultaneous decrease of tJ.H and tJ.S values.
The decrease in entropy is explained [249] as a decrease of conformational
freedom of the open isomers (47A). This should be due to the formation
of stronger intramolecular hydrogen bonds N-H .. ·O=C caused by elec-
tron-withdrawing substituents, increasing N - H acidity.
A good linear correlation log KT/(KT)o = -1.38u+(r = 0.96; s = 0.18)
was found.
Solvents exert only a slight influence on the equilibrium position of
(47A) ~ (47B). However, the rate of isomeric interconversion strongly
:::l
:i
Q)
3
o
(0
(")
c
.,Qi
:0
CD
Table 10. 3,3-Dimethyllevulinic N-{4-X-Phenyl)amide Ring-Chain Equilibrium (47 A) ~ (47B) and Rate Constants, <
Thermodynamic and Activation Parameters, Determined by IH-NMR [192,249] ~
!!!.
c-
(0
(A)-+ (8) (8)-+ (A)
»
0.
0.
X KT = [B]/[A] -I:J..H -I:J..S kl I:J..H" I:J..S" k2 I:J..H" I:J..S" ;:j:
(R = 4-XC 6 H4) (34°C) (kcaljrnol) (e.u.) (s-I,500) (kcal/rnol) (e.u.) (s-I,500) (kcaljrnol) (e.u.) o·
:::l
r+
o
(R = H) 14.7 5.3 11.9 r+
:::r
NEt2 16.4 5.2 11.2 0.31 25.7 18.7 0.031 30.1 27.6 CD
OMe 17.2 5.1 11.1 2.34 19.3 2.7 0.19 24.6 14.2 n
H 5.85 4.7 11.8 54.6 19.1 8.7 14.2 23.9 20.9 II
12.4 75.9 18.7 7.8 18.0 24.7 23.5
o
CI 5.26 4.8 G)
Br 5.0 3.9 9.6 77.6 15.3 -2.4 23.4 19.6 8.1 (3
22.9 5.1 27.2 C
COOH 4.37 4.5 12.1 0.03 0.013 8.6 "0
COOMe 2.13 3.2 9.3 195.0 14.6 -2.7 148.4 17.7 6.1
CN 1.66 3.1 9.5 512.9 17.9 11.3 478.6 21.1 18.9
N0 2 1.62 2.4 7.0
~
62 Chapter 2
depends on the properties of solvents. In the aprotic polar solvents

(chloroform, pyridine, DMSO) the equilibrium is reached very slowly
(usually in 11-26 days), in protic solvents the process proceeds more rapidly
(-0.3-0.8 h). The addition of basic catalysts to the aqueous solution acceler-
ates the equilibration even more. It may be possible that the reaction in
aprotic solvents is catalyzed by traces of water, arisen from dehydration.
At elevated temperatures the equilibrium shifts toward the open form
[192] (see also [219, 231]). The kinetics of equilibration was examined [192]
by means of dynamic 'H-NMR spectroscopy and the activation parameters
of the tautomeric interconversions were determined (Table 10) using 50%
aqueous pyridine containing 0.032 mol/liter sodium bicarbonate. The bicar-
bonate was added to bring the rates into an experimentally convenient range
for all substituted derivatives. A linear correlation is observed between k,
and k2 and the concentration of bicarbonate.
Going from the electron-donating to electron-withdrawing substituents
X rate constants k, and k2 increase very strongly (Table 10). A good linear
correlation is found between log k/ ko and u or even better u + coefficients
of substituents X:
log k,/(k,)o = 3.56u+, r = 0.997
log kd(k 2 )o = 4.68u+, r = 0.993
A large rate enhancement brought about by addition of bases led
Sheiman and co-workers [250] to suppose that deprotonation is the rate-
limiting step. This suggestion is in accordance with an acceleration of
tautomeric interconversions by electron-withdrawing substituents X (p > 0).
On the basis of kinetic and thermodynamic data the authors [251]
suppose that the conversion (47 A) ~ (47B) proceeds via an open structure
intermediate anion.
This conclusion contradicts the above-mentioned conjecture [251], that
based on the larger acidity of hydroxylactams compared with open keto
ami des anions of ketoamides should possess a cyclic structure.
3-Cycloalkanonecarboxarnides. 2-Decalone-9-carboxamides [252,253]
and analogous compounds of steroidic structure [254-256] possess cyclic
HOC
structure (49) or (50). Spectroscopic methods did not succeed in detecting
the open isomers in solutions of these compounds.
HO, ~
./
N----<:-...
0 ./ N---<::::'0
'
H H
(49) (SO)
Both isomers (51A) and (51B) of N -homoveratrylamide of 3-cyclohep-

tanonecarboxylic acid were isolated [257]; however, their stability and the
conditions or their interconversions were not studied.
The cyclic structure (52) was established [258] for trans-bicyclo[5.3.0]-6-
decanone-l-carboxamide.
0=00
NHR
cW
/
(51A) (518) (52)
R=CH CH
22
~OMe
Y
OMe
(2-Phenyl-I,3-indanedione-2-yl)acetamides and Hydrazides. Either open

amides (54A) or their cyclic isomers (54B) were formed, depending on the
reaction conditions and on the structure of substituent R, by acylation of
primary amines with the (2-phenyl-l ,3-indanedione-2-yI)acetyl chloride (53)
[198]. The probability of intramolecular cyclization decreases with increas-
ing steric bulk of the substituents.
o
n--\v CH ,CONHR
~Ph-
W<
o
o (54A)
CH'COCI
I· - RNH,
~ Ph
o
(53) _ _U o
o
(548)
64 Chapter 2
Cyclic isomers (54B, R = Et, Pr, Bu) show two melting points: the
substance crystallizes after the melting and melts again at the higher tem-
perature, which corresponds to the melting point of the open isomer (54A).
This ring opening of hydroxylactams (54B) occurs at 200-220° and is the
first reported example of a thermal ring opening of hydroxylactams.
Similar double melting points, indicating thermal isomerizations
(54B) -+ (54A), were later observed [259] for some esters of (2-phenyl-l,3-
indanedione-2-yl)acetylaminoacids, e.g., for (54, R = CH 2 COOEt).
The increase of the steric bulk of substituents at the nitrogen atom
decreases the stability of (54 B), which is confirmed by a noticeable lowering
of the isomerization temperature. The lower melting point of N -butylderiva-
tive (54B, R = Bu) is poorly defined. It is impossible to detect the true
melting point of the N -benzyl derivative (54B, R = PhCH 2 ) because the
isomerization proceeds before the hydroxypyrrolidone melts. Therefore both
isomers show the same experimental melting point and are indistinguishable
by the method of mixed melting points.
Amides (54A, R = n-alkyl) under conditions of alkaline catalysis
isomerize into hydroxypyrrolidones (54 B), which is generally characteristic
for addition reactions of weak nucleophiles to the C=O group.
Both series of isomers are stable in neutral aprotic solvents. Ring-chain
equilibration is not observed even after 10 days at room temperature in
dioxan or dichloroethane solutions.
Bulky substituents at the nitrogen atom prevent cyclization: ami des
(54A) with R = i-Pr, cyclo-Hexyl, t-Bu, and l-Adamantyl do not undergo
the isomerization. Sodium hydroxide in aqueous dioxan does not isomerize
these amides. A hydrolytic opening of indanedione ring takes place,
yielding N -(sec- or t-alkyl)amides of 3-(2-hydroxycarbonylbenzoyl)-3-
phenylpropionic acid, which as a 2-acylbenzoic acid, form tautomeric
equilibria (55A) +::t (55B) [71, 73].
(55A)
Either the open isomers of hydrazides (56A) or the mixtures of bo~h

isomers (56 A) + (56B) are formed in the reactions of chloride (53) with
N, N -dialkylhydrazines [217]. The recrystallization of hydrazides (56A) from
alcohols results in an isomerization (56A) -+ (56B), obviously due to the
presence of an NRR group in the molecule, which in boiling alcohol acts
o R
~CH2CONHN/ OH
~Ph ~R • -220'C
o o
(56A) (568)
o
(578) (57A)
as a catalyst for the intramolecular nucleophilic addition of the NH group

to the keto group.
True melting points of cyclic isomers (56B) cannot be obtained because
of a thermal isomerization into open hydrazides.
On protonation of the NRR group of compounds (56B) ring opening
occurs, which obviously is due to the action of a strong -I-effect of the
+
substituent -NHRR, destabilizing the ring form. One may assume that
protonation favors the ionization of the OH bond in (57 B) shifting the
electron density in the C- N bond toward the nitrogen atom simultaneously
and finally promotes the heterolytic breaking of this bond and subsequent
isomerization (57B) --+ (57 A). The deprotonation of hydrochlorides (57 A)
results in a complete or partial isomerization to the initial hydroxypyrro-
lidones (56B).
Hydrazides and their cyclic isomers in solution slowly form equi-
librating mixtures (56A) ~ (56B). Equilibrium is attained from both sides
within 5-10 days. Isomeric interconversions are apparently facilitated by
catalytic influences of the NRR group being able to transfer protons. The
equilibrium of the hydrazide (56, R = Me) in dioxan (KT = 9.1) and
acetonitrile is shifted toward the ring form; in CHC1 3 (KT = 0.54) and
nitromethane, however, the open form is more favored. Proton acceptor
solvents (dioxan, acetonitrile) form intermolecular hydrogen bonds with
the pyrrolidone hydroxy group (58) thus stabilizing the ring form. In proton
66 Chapter 2
R
R-N
"-
CXr
1\ "-N_~/O
o O···H-O o R
"---I -:;/ CH CONHN:.'.H-CCI
I 2 " 3
Ph ~ Ph R
o o
(58) (59)
donating solvents (chloroform, nitro methane ) intermolecular hydrogen

bonds of type (59) may appear strengthening the -I-effect of the NRR group;
hence, the nucleophilicity of the hydrazide a-nitrogen atom is lowered and
the open isomer stabilized [251].
(2-Benzyldimedone-2-yl)acetamides and Hydrazides. The reactions of
cyclic (2-benzyldimedone-2-yl)acetyl chloride (31) with amines were carried
out in dioxan. Subsequently the reaction mixture was diluted with water
[162,196]'
(fl
Me
0CH2Ph
Me
)j50 CH2Ph
N 0 o 0
Me HO I Me CI
N '\. 0
R/ 'R (31)
Me~CH2CONHR
(62)
Me~CH2Ph
~ 0
~ (60A)
200°C
-H 2 0
(61) (60B)
The n-alkylamines gave the cyclic isomers (60B); isopropyl and t-

butylamines, however, gave open amides (60A), which do not isomerize
[(60A) - (60B)] under the influence of alkaline catalysts. This happens
in a reaction of chlorolactone (31) with ammonia and propylamine in
benzene yielding open isomers of amides (60A, R = H, Pr), which isomerize
to hydroxylactams (60B) under basic conditions.
On heating, cyclic isomers (60B) dehydrate forming l-alkyl-9-benzyl-
6,6-dimethyl-2,4-dioxo-2,3,4,5,6,9-hexahydroindoles (61), and this conver-
sion excludes the thermal isomerization (60B) - (60A).
N,N -Dialkylhydrazides (62) are obtained only as ring isomers. Proton-
ation of the dialkylamino group opens the ring of hydroxypyrrolidone
(62) - (63); deprotonation gives rise to the reverse conversion.
Contrary to indanediones, the keto groups of cyclohexanedione are
not conjugated with the benzene ring and are therefore more electrophilic.
Amides (60) as compared to the (2-phenyl-1 ,3-indanedione-2-yl)acetamides
(54) display a greater capability of forming cyclic isomers: N -unsubstituted
amide forms ring isomer, N-methyl and N-ethylamides are obtained as
ring isomers even if their synthesis is carried out in benzene solution;
N,N-dialkylhydrazides exist only in the cyclic form.
2-Acylbenzamides. In the first investigations published in the last century
[260-263] the open structure (64A) was erroneously ascribed to the 2-
acylbenzamides.
However, in 1896 Graebe and Ullmann [264] proposed that 2-
benzoylbenzamide (64, RI = Ph, R2 = H) represents a mixture of isomers
(64A) and (64B). Later Sachs and Ludwig [265] obtained a number of
2-acylbenzamides by the action of alkyl and phenyl magnesium bromides
on the N -ethylphthalimide. They concluded that these compounds possess
cyclic structure (64B).
o
0CONHR2
~N-R'
~CORI RI OH
(64A) (648)
o
~COOH
0C=NPh
/
~o Ph NHPh
Ph
(65A) (658)
68 Chapter 2
The history of the determination of the structure of the products

obtained from 2-benzoylbenzoic acid and its chloride with aniline provides
an instructive example of the insufficiency of chemical methods for an
elucidation of the structure of ring-chain isomers. Meyer [266] obtained
two products with m.ps. of 195 and 221 to which on the basis of chemical
0
,
properties he assigned the structures (64A) and (64B).

Later it was concluded from polarographic data [267] that the com-
pound having m.p. 195 possesses structure (64A, R 1 = R2 = Ph) but that
0
the other one with m.p. 221 should be a mixture of both 2-benzoylbenzoic
0
acid anil (6SA) and 3-phenylamino-3-phenylphthalide (6SB).

These results were refuted by IR spectroscopy [33, 170, 205] demon-
strating that the compound with m.p. 195 possesses a cyclic structure (64B)
0
in the solid state as well as in solutions. The amide-II band does not appear,
but the isoindolinone C=O band does at 1710-1699 cm -I in solutions. The
frequency lowering and the splitting of the latter band in the solid state
spectra, as well as the band splitting in dichloroethane solution spectra are
caused by intermolecular hydrogen bonds O-H···O=C. The absorption
of the bonded OH group in the solid state spectra appears as a broad band
at 3180cm- l .
It was confirmed [170] that the compound with m.p. 221 really rep-
0
resents a mixture of (6SA) and (6SB) with a considerable predominance of

the latter.
For the first time the IR method was used by Graf and coauthors [80]
for establishing the structure of 2-acylbenzamides. All ami des examined by
these authors exist in the ring form (64B, RI = aryl, R2 = alkyl).
It has been shown subsequently by many investigators that almost all
the 2-acylbenzamides exist as 3-hydroxyisoindolinones in the solid state as
well in solutions (see Table 11).
2-Aroylbenzamides, really existing as open ami des, were first obtained
[146] from 3-aryl-3-chlorophthalide and t-alkylamines (Table 12). These
amides are not capable of ring closure on account of the steric hindrance
of the bulky t-alkyl group at the nitrogen atom.
Note that 2-formylbenzamides having t-alkyl substituents at the
nitrogen atom are stable as cyclic isomers (64B, RI = H, R2 = t-Bu, 1-
adamantyl, Me3CCH2Me2C) and do not undergo a thermal isomerization
into open amides [222].
Introducing electron-withdrawing substituents into the benzoyl group
of N -( t-alkyl)-2-benzoylbenzamides one can observe an interesting com-
bined influence of the steric effect of the substituent R2 and the electronic
effect of the substituent RI (64) [193,201]. Only cyclic isomers (64B) were
obtained from 3-chloro-3-(X-phenyl)phthalides (where X = 3-N02' 4-N02'
4-Cl) with t-butylamine, when the reaction was carried out in dioxan with
Table 11. References for the Proof of Cyclic Structure (648) for
2-Acylbenzamides
o
~N-R'
R' OH
R2 = H, Me, Ph, etc.
R' References
H 33,148,220,222,248,268-270
Me 33,271-274
cydo-Pr 275
PhCH 2 147,211,212,276,277
t-Bu 148
Other alkyls and substituents of more 33,146,213,236,276,278-284
complicated structure
Ph and other aryls 33,78-80,146,148,170,201,220,277,285-291
PhCO 163
R'R 2 NCO 292
e>-N
I
33
[~
N
293
I
H
a subsequent dilution of the reaction mixture with water. A reaction of

strictly equimolar quantities of reagents (chlorophthalide, t-butylamine,
triethylamine) in benzene afforded an open isomer when R' = 4-CIC6 H 4 ,
but the ring isomer when R' = 4- N0 2 C 6 H 4 • Hence, an increasing electron-
CI
x
70 Chapter 2
Table 12. N-Monosubstituted 2-Acylbenzamides Possessing Open

Structure (64A)
~CONHR2
VCORI
X
Isomeric structure
R2 in solid state Refs.
i-Pr A,B
t-Bu A
Ph 146
Me3CCH2Me2C A
I-adamantyl A
i-Pr A,B
78
t-Bu A
PhCH 2 t-Bu A 147
t-Bu A
PhCH 2(Ph)CH Me3CCH2Me2C A 146
I-adamantyl A
I-adamantyl A 290
t-Bu A,B
Me3CCH2Me2C A 201
I-adamantyl A
t-Bu A,B 201
t-Bu A,B
Me3CCH2Me2C A 201
I-adamantyl A
t-Bu A,B
Me3CCH2Me2C A 193
I-adamantyl A
t-Bu A,B
I-adamantyl A,B 193
Me 3CCH 2Me 2C A
Ph t-Bu A 79
(X = 3-N02' 4-N02'
5-N0 2,6-N0 2 )
continued
Table 12. (cont.)
Isomeric structure
R2 in solid state Refs.
Ph t-Bu A,B
(X = 3-Cl) I-adamantyl A,B 193
Me 3 CCH 2 Me 2 C A
Ph t-Bu A 193
(X = 4-Cl)
M'-Q-
Me
H, Me, Pr, i-Pr, A 78
PhCH 2 , Ph
Me
H, Me, Pr, i-Pr, A 158

t-Bu, PhCH 2 , Ph
H, Et A 160
cJ(
N
t-Bu
I-adamantyl
A
A 293
I Me,CCH 2 Me 2 C A
H
t When X is not noted then X ~ H.
withdrawing effect of substituents R I may favor the cyclic isomer (64B)

even in the presence of such a sterically bulky substituent at the nitrogen
atom as t-butyl. However, additional enhancement of the steric bulk of
substituent R2 (64) prevents the cyclization: N -(1,1 ,3,3-tetramethylbutyl)-
and N -(1 -adamantyl)amides of 2-( 4-chloro or 3-nitrobenzoyl)benzoic acids
72 Chapter 2
exist exclusively in the open form. Nevertheless, an accumulation of two

electron-withdrawing substituents in the benzoyl group (R I =
3-NOr4-CIC6H3 in (64») permits isolation of the cyclic isomer of N-(l-
adamantyl)-amide.
~CONHR
R = t-Bu. 1-adamantyl
YCOPh
CI
Cyclic isomers have also been obtained for N-(t-butyl) and N-(l-
adamantyl)-2-benzoyl-3-chlorobenzamides. In addition to the -I-effect of
the chlorine atom increasing the C=O group electrophilicity, most probably
a considerable role is played by a steric effect [28] of the chloro atom on
the C=O group in the open structure which brings the C=O group near
to the amide group. This is corroborated by the fact that the N-(t-butyl)-2-
benzoyl-4-chlorobenzamide exists exclusively as the open isomer. The shift
of the chlorine atom from position 3 to position 4 cancels the steric influence
leaving the electronic effect nearly unchanged.
The melting points of 2-( t-alkyl)-3-aryl-3-hydroxyisoindolinones are
poorly defined since these compounds thermally isomerize into open ami des
(64B) -+ (64A).
Ring and chain isomers of N-(t-alkyl)-2-aroylbenzamides differ in
reactivity: thionyl chloride transforms the open isomers into 2-cyanobenzo-
phenones [294]; the cyclic isomers, however, into 2-( t-alkyl)-3-chloro-3-
arylisoindolinones under the same conditions [295].
Treating 2-( t -butyl)-3-( 4-chlorophenyl)-3-hydroxyisoindolinone with
CF3COOH at room temperature makes it possible to carry out the isomeriz-
ation (64B) -+ (64A). In concentrated sulfuric acid the open as well as the
cyclic isomers of N- (t-alkyl)-2-aroylbenzamides undergo N -dealkylation
forming the corresponding 3-aryl-3-hydroxyisoindolinones [296].
The reverse isomerization (64A) -+ (64B) is carried out in an aqueous
dioxan solution of potassium hydroxide or by boiling in ethanolic triethyl-
amine. The last method is more convenient preparatively.
Both series of isomers are stable in dioxan at room temperature.
Equilibration occurs on addition of triethylamine to a dioxan solution [193]
and also in methanol [190].
The signals of the t-butyl protons in IH-NMR spectra of CD30D
solutions differ for ring and chain isomers. Consequently, the time depen-
dence of the intensity ratio and rate constants for the isomeric interconver-
sions have been determined (Table 13).
Intramolecular Reversible Addition to the C=Q Group 73
Table 13. Ring-Chain Equilibrium and Rate Constants of

N-(t-Butyl)-2-acylbenzamides in CD 3 0D Solution as Determined by
IH-NMR Method [190]
CXI
o
. ~
CONHBU-I
• kl, I N-Bu-t
~ COR k, ~
R OH
(A) (8)
I-Bu protons
8, ppm
Temperature
R (A) (8) Ky kl x 10' S-I k2 X 10'S-1 (OC)
PhCH 2 1.40 1.76 0.72 2.0 2.8 24

Ph 1.19 1.50 0.56 2.9 5.2 27
4-CIC 6 H. 1.12 1.43 0.92 4.5 4.9 28
4-BrC 6 H. 1.12 1.43 0.98 5.9 6.3 23
4-CI-3-N02C 6 H 3 1.22 1.52 3.55 260 73 24
Table 13 shows that the introduction of electron-withdrawing sub-

stituents into the aryl group not only shifts the equilibrium towards the
cyclic form but also accelerates tautomerization.
In aprotic solvents ring-chain equilibria were observed for 2-acylbenz-
ami des containing a proton acceptor group in the acyl substituent. Thus,
for example, by means of the UV method ring-chain equilibrium constants
were measured [194] for N- (t-alkyl)-2-(2-imidazolylcarbonyl)benzamides
in various solvents (Table 14). For a discussion of a dependence of these
equilibria on the substitution pattern see p. 76.
Table 14 shows that in proton donating solvents the equilibrium is
shifted to the cyclic form. One may suppose that the ring form is stabilized
by intermolecular hydrogen bonds ROH···N (imidazole) thus increasing
the electron withdrawing effect of the imidazole group. An analogous solvent
shift of the equilibrium in ethanol is observed for N -unsubstituted, N-
methyl, N -ethyl, and N -phenyl-2-( 4-dimethylaminobenzoyl)benzamides
[191].
Heating transforms 2-isopropyl-3-hydroxy-3-phenylisoindolinone into
N-isopropyl-2-benzoylbenzamide [196]. On cooling slowly a mixture is
obtained in which the cyclic form predominates. The bulky N -isopropyl
substituent stabilizes the open structure; hence, it is possible to freeze the
equilibrium, which is shifted in favor of the open form by an increase in
the temperature. On rapid cooling a mixture is obtained which contains a
considerable proportion of the open isomer. Attempts to carry out an
74 Chapter 2
Table 14. Ring-Chain Equilibrium Constants for

N- ( t- Alkyl) -2-( 2-imidazoly1carbonyl) benzamides
Determined by a UV Method [194]
o
0co-{J . . ~I
~CONHR
N-R
::::::....
N OH
(
H
/ ~ ~
N"
H
KT with R =
Solvent t-Bu I-Adamantyl Me3CCH2Me2C
Ethanol 1.13 0.65 0.30

Methanol 0.79 0.75 0.23
Chloroform 0.20 0.16 0.15
Dioxan 0.18 0.16 0.15
Acetonitrile 0.08 0.06 0.03
analogous isomerization of 2-(n-alkyl or phenyl)-3-hydroxy-3-phenyliso-

indolinones failed.
Recently Sheinker, Anisimova, and Valters [297] have reported the
results of a mass spectrometric investigation of 2-acylbenzamides and their
cyclic isomers. The open isomer is characterized by a fragment ion [M-
NHR2t (see formula (64» the fragmentation of the ring isomer yields
mainly the ion [M-OHt and, to a lesser degree [M-Rlt (see also [189]).
The proportions of the intensities of peaks
I[M.oH] d I[M.R']
an
I[M.NHR 2 ] I[M.NHR 2 ]
quickly fall in a series of compounds (64, R I = Ph, R2 = H > Me > Et >

Pr> Ph> t-Bu). The proportions of the cyclic form accordingly decrease
in gaseous phase (at 180°). An examination of the intensities of the frag-
mentation peaks at various temperatures (40-140°) showed that the amount
of the cyclic form decreases with increasing temperature.
The intensities of the fragmentation peaks do not give completely
correct quantitative data concerning the proportion of the tautomeric forms
in the gas phase because the intensity of any peak depends not only on the
concentration of a specific isomer, but also on the ease of bond breaking
leading to the formation of fragments and also on the further break up of
these fragments [297].
Irrespective of the substituent at the nitrogen atom, 2-mesityloyl [78]

and 2-{9-anthroyl)benzamides [158] exist only in the open form (see Table
12]. The two ortho-methyl groups or two peri-protons in these amides hinder
the intramolecular attack of the nucleophilic nitrogen at the C=O group
perpendicular to its plane. Evidently for the same reason the open structure
of 2-[2,3( CO),6,5( CO)-dibenzoylenisonicotinoyl]-benzamides is more
stable [160] (Table 12).
Summarizing, stable open isomers of2-acylbenzamides can be obtained
only by an introduction of bulky substituents either at the nitrogen atom
or at the keto group.
Valters and Karlivans [290,293,298] presented two examples studying
the influence of a protonation of an amino group which is involved in the
ring-chain interconversion process of 2-acylbenzamides.
Using IR, UV, and IH-NMR methods they were able to show [290, 298]
that contrary to earlier results of Indian chemists [191] N -unsubstituted
and N -monosubstituted 2-( 4-dimethylaminobenzoyl)benzamides in the
solid state possess a cyclic structure (648, RI = 4-Me2NC6H4; R2 = H, Me,
Et, PhCH 2, Ph), N-{I-adamantyl)amide (66) being an exception.
o
(XI -0- CONHR
Me
4
+H+
-H+
~
~ f_~ N~Me
CO
(66) +
Me-N
/1
Me H
(67) -H'~
o
N+
/ "-
Me Me
(68)
76 Chapter 2
The protonation of the dimethylamino group in the amide (66) leads

to a cyclization giving (67). Due to the electron-withdrawing influence of
the NHMe2 group the electrophilicity of a c=o carbon atom is increased
+
so much that an intramolecular addition of an amide group bearing a bulky

l-adamantyl substituent becomes possible. According to IH-NMR
spectroscopy the hydroxyisoindolinone (67) dehydrates in CF3COOH
forming the quinoide compound (68) [290].
The reaction of ammonia and primary amines with imidazolo[I,2-
b ]isoquinoline-5, I O-dione gives 2-(2-imidazolylcarbonyl)benzamides (69A)
[299]. A more detailed spectroscopic examination showed [293] that these
amides, except N-(t-alkyl)substituted, exist in the cyclic form (698, R = H,
Me, Et, Pr, i-Pr, PhCH 2, Ph, 4-MeC 6 H4) in the solid state and in DMSO
solution.
~CONHR o
0co-{J ='
/
H
(69A) (R = t - Bu)
(698)
o
N-t-Bu
OH
(70)
N-(t-Alkyl)amides (69, R = t-Bu, I-adamantyl, Me3CCH2Me2C)

possess an open structure in the solid state, but in solution the equilibrium
(69A) ~ (698) is observed (see Table 14 and the discussion on p. 73). The
protonation of the imidazole ring of N-(t-alkyl)amides (69A) promotes
cyclization to (70); deprotonation reverses the process. Evidently, the cycliz-
ation (69A) - (70) occurs for reasons similar to those for the interconversion
(66)- (67).
2-Acylbenzhydrazides. An analogous but contrary influence of proton-

ation on cyclization takes place in 2-dialkylamino-3-hydroxy-3-phenyliso-
indolinones (71, RI = Ph, R2 = R3 = Alkyl) [162]. Protonation of the
dialkylamino group gives rise to ring opening (71) - (72). Deprotonation
reverses the transformation.
The N -phenylhydrazide of 2-phenylacetylbenzoic acid also possesses
a cyclic structure (71, RI = PhCH 2 , R2 = Ph, R3 = H) [300].
In the case of N,N'-dimethyl-2-acylbenzhydrazides, ring closure is

possible owing to the intramolecular addition of the hydrazide ,a-nitrogen
to the keto group.
N,l\I'-Dimethylhydrazides of 2-benzoyl and 2-(2,4-dimethylben-
zoyl)benzoic acids exist as 4-aryl-4-hydroxy-2,3-dimethyl-3,4-dihydro-
phthalazones (73) [301], but the 2-mesityloylbenzoic acid derivative has
open structure (74), presumably due to steric hindrance of the mesityl group.
0; ~ I
~
Ar
01
'I-
~:
N~
OH
Me
Me
a~
%
I Me
/
Me
CON-NHMe
co~ )-Me
(73) Me
1~1__________~~N~CO~ _________ (7~4\
C¢
~
~
I
0
Ph
1+
N
.&N.......
/Me
Me
~~/Me
vyN
Ph
a~
I
CON
COAr
(n)
/
"N/
Me
Me
"CONHPh
(75) (76)
78 Chapter 2
Compounds of open (74) or cyclic (73) structure in a reaction with

phenylisocyanate form identical products (77). The formation of the open-
structured (77) (but not the corresponding N-phenylurethane) from (73)
may be explained by the presence of rapidly equilibrating ring and open
tautomers with an open form reacting faster with phenylisocyanate than
the cyclic form. Alternatively, a hydroxyphthalazone ring opening may
occur in the course of the reaction with an initial attack of phenyl isocyanate
on the N(3) of (73).
4-Hydroxy-2,3-dimethyl-4-phenyl-3,4-dihydrophthalazone and elec-
trophile agents under mild conditions gives 2-methyl-4-phenylphthalazone
(76). This unexpectedly easily accomplished N(3)-demethylation, apparently,
proceeds via an intermediate immonium ion (75). The elimination of
methanol (73) -+ (76) also takes place by heating compound (73). An attempt
to thermally isomerize compounds (73) into the open hydrazides failed.
Benzil-o-carboxamides. Benzil-o-carboxylic acid represents an interest-
ing example to study the dependance of ring isomer stability on ring size.
N-Monosubstituted ami des of this acid are expected to form three isomeric
structures: open ami des (78A), five-membered hydroxylactams (78B) and
six-membered hydroxylactams (78C). Both chlorides of benzil-o-carboxylic
o
1
--+
l ~CONHR
0CO-COPh
~~N-R
PhCO OH
(78A) (78B)
acid, i.e., the five-membered (32) and the six-membered (33) chlorolactones
in reactions with primary amines form exclusively 3-benzoyl-3-hydroxy-2-R-
isoindolinones (78B, R = alkyl, Ph) irrespective of the substituent at the
nitrogen atom [153]. Hydroxyisoindolinones (788) are formed in the reac-
tions of chlorolactones (32) or (33) even with t-butyl or l-adamantylamines.
This indicates that the ring closure of benzil-o-carboxamides is favored
compared with that of other 2-acylbenzamides which may account for an
increased electrophilicity of the C=O group due to the -1- and -C-effects
of the neighboring benzoyl group. Attempts to obtain the open isomers
(78A) of benzil-o-carboxamides failed.
A reaction of chlorolactone (32) with propyl amine gave in addition to
compound (788, R = Pr) its six-membered isomer (78C), which at 200°C
or in boiling ethanol isomerized under ring contraction to the 3-hydroxy-
isoindolinone (788).
This rearrangement corroborates the greater stability of a five-

membered hydroxylactam ring compared with that of a six-membered
isomer (see also [302]).
An analogous ring contraction of a six-membered hydroxylactam has
been reported [303] for the more complicated 8,13-dioxo-14-hydroxy-
canadine (79C) -+ (79B).
o
<o
OMe
OMe
(79C)
o
~
(798)
Similar regularities have been observed investigating monoimines of

benzil-o-carboxylic acid. Usov and Freimanis [269] prepared 3-aryl-3-
hydroxy - I - oxo - 2 - phenyl - 4 - phenylimino - 1,2,3,4 - tetrahydroisoquino-
lines (80C) and showed that in polar solvents these compounds isomerize
rapidly and irreversibly into isoindolinones (80B). Here ring contraction
also takes place although the CONHR group adds to a C=N rather than
to a carbonyl group.
o
~
o /Ph
~~N-Ph
~ N ~CONHPh
I OH---+
~
Ar
~C-C-Ar
II II PhNH COAr
NPh NPh 0
(80C) (808)
Anthraquinone-l-carboxamides, Amidines, and Hydrazides. For

stereoelectronic control of an intramolecular nucleophilic addition of an
NH group to a keto group it is necessary for the latter to rotate around the
CO-Ar bond and to take a conformation which allows the nitrogen atom
to approach the C=O group nearly perpendicular to its plane. In derivatives
80 Chapter 2
of anthraquinone-I-carboxylic acid (81A) this possibility is lacking and

therefore they do not form cyclic isomers (81B) [87,304].
For the same reason N-butylamide (82) exists only in the open form
[305]. Here, due to the bond angles in the five-membered ring CONHBu
and C=O groups are still more removed from each as in the ami des (8IA).
o o
(81A) x=o, NR (818)
(82) o
(83)
X= 0, NPh
o
HO
~~
~N
o
(84)
An exception among anthraquinone-I-carboxylic acid derivatives is

N,N'-dimethylhydrazide and N,N'-dimethyl-N"-phenylamidrazone exist-
ing only in the cyclic form (83, X = 0, NPh) [87, 304]. N-(Anthraquinone-l-
carbonyl)tetrahydrophthalazine also possesses ring structure (84) [306]. The
formation of stable cyclic isomers (83) is favored by the greater nucleophilic-
ity of the f3-nitrogen atom of hydrazides as compared with the a-nitrogen
or with the amide nitrogen atoms of compounds (81). This is confirmed by
the fact that N'-acylhydrazides of anthraquinone-I-carboxylic acid do not

cyclize [307].
Another very important factor favoring cyclization may be the enhanced
conformational mobility of the chain -CX-N-NH as compared with
-CX - NH giving rise to conformations which are more favorable
stereo electronically for an intramolecular attack of the nitrogen atom on
the C=O group.
Z-3-Acylacrylamides. Following spectroscopic investigations amides of
Z-3-formyl [240], Z-3-acetyl [20,308-310], Z-3-acyl (R 1 = alkyl) [311-314],
and Z-3-aroylacrylic [9, 10, 109,216,308,315-317] acids are cyclic (85B)
irrespective of the substituents at the nitrogen atom and at the ethylene bond.
Using the example of Z-3-(4-bromobenzoyl)-3-methylacrylic acid Lutz
and coauthors [9] have shown that cyclic amides (85B, R2 = H, Me, Ph)
are formed: a) by the action of ammonia or primary amines on the corre-
sponding chi oro lactone; b) by the action of ammonia or amines on the
cyclic as well on the open methyl ester of these acids; c) by the sunlight
irradiation (E-Z-isomerization) of E-3-( 4-bromobenzoyl)-3-methylacryl-
amides. These data confirm the extraordinary great tendency of Z-3-acyl-
acrylamides to form cyclic isomerst. Communications [312, 318, 319] which
claim the existence of open Z-3-acylacrylamides should be revised (see
[207]).
Recently Japanese authors [320] using IH-NMR spectroscopy were
able to show that the introduction of a benzyloxycarbonyl group at the
nitrogen atom of Z-3-aroylacrylamides (85, R2 = PhCH 2 0CO) results in
ring-chain equilibria which depend on the substituent in the aroyl group
(85, R I = XC 6 H 4): electron-donating substituents stabilize the open form.
Evidently, here the electron-withdrawing PhCH 2 0CO group at the nitrogen
atom decreases its nucleophilicity thus favoring the stability of the open
form. Moreover, it was shown [321] by IR and IH-NMR methods that
E-3-bromo-3-(4-pentoxybenzoyl)acrylamides (85, Rl = 4-C s H 11 0C 6 H4'
R2 = ""-- , ~ , R3 = H, R4 = Br)
U"COOEt ~OOEt
with bulky l-ethoxycarbonyl-I-cyclopentyl and -l-cyclohexyl substituents
at the nitrogen atom possess an open structure.
Z-3-Benzoyl-2,3-diphenylacrylhydrazide having cyclic structure (86B)
dehydrates upon heating and transforms into the pyridazone (87) [109].
This transformation suggests the presence of equilibrium (86B) ~(86A) in
the course of the reaction.
t See also A. A. Jakubowski, F. S. Guziec, Jr., M. Sugiura, C. Ch. Tam, and M. Tishler, 1.
Org. Chern. 1982, 47, 1221.
82 Chapter 2
Ph:Q°
I N-NH2
Ph Ph OH
(868)
4-Acylbutyramides. Lukes and coauthors [322,323] have obtained N-

methyl ami des of 4-acylbutyric acids by the action of Grignard reagent on
N -methylglutarimide (88). They erroneously suggested that the compounds
possess cyclic structure (89B). It was shown later by IR spectroscopy [324]
that these compounds exist in open form (89A).
RMgBr
R rl -- RCO(CH2hCONHMe
~NAo
HO I
Me
(898) (89A)
This seems to be the case more generally [200, 325, 326]. Evidently the
chain between CONHR and C=O groups containing three sp3- carbon
atoms does not create favorable steric conditions for the cyclization.
3-(2-Phenyl-I,3-indanedione-2-yl)propionamides also exist only in an
open form [68, 195, 198].
Some 4-formylbutyramides [244] and their chain substituted derivatives
[327, 328] possess a cyclic structure, probably due to an increased electro-
philicity of the formyl group as compared with the keto group.
4-Aroyldimethylbutyramides (90) [200] and (91) [329] are cyclic. In this
case the cyclization is favored by the Thorpe-Ingold effect [47-49] (see p.
27 for a discussion).
2-Acylmethylbenzamides. N- Monosubstituted 2-phenacyl and 2-(4-
methyoxyphenacyl)benzamides are obtained by the interaction of 3-
arylisocoumarines with primary amines [214,330,331]. This reaction was

first carried out by Gabriel [332], who erroneously suggested that all the
£00Ph ~
H
(91)
product amides are open structured. However, IR shows [214, 330, 331] that
2-phenacylbenzamides having N-(n-alkyl) substituents exist in the cyclic
form (92B), but N -isopropylamides possess an open structure (92A) in the
solid state as well as in solution. N -Monosubstituted 2-( 4-
methoxyphenacyl)benzamides, with the exception of N-methylamide (92B,
R' = 4-MeOC 6 H4' R2 = Me), are open structured (92A).
(X CONHR 2 ~N/R2
~ I CH 2 COR' VJRl
(92A) (928) (93)
The reduced tendency of 2-(4-methoxyphenacyl)benzamides to form

the cyclic isomer is mainly due to a decreased electrophilicity of the keto
group brought about by the electron-donating methoxy group.
The cyclic isomers (92B, R' = aryl) very easily dehydrate forming
l-isoquinolones (93) [333]. It is therefore impossible to carry out thermal
isomerization (92B) - (92A).
Unlike aryl substituted ring isomers (92B, R 1 = aryl) the corresponding
methylderivatives (R 1 = Me) cannot be obtained from a reaction of 3-
methylisocoumarine with n-alkylamines since they spontaneously dehydrate
yielding only l-isoquinolones (93). The dehydration is favored by +I-effect
of the methyl gr~up.
N-Isopropyl-2-acetonylbenzamide, however, has an open structure
(92a, R' = Me, R2 = i-Pr) and does not undergo spontaneous dehydration
[334].
Generally N -alkyl-2-acylmethylbenzamides as compared to 4-acyl-
butyramides show an increased tendency to form the cyclic isomers.
o-Acylphenylacetamides. By action of ammonia on methyI2-acylphenyl-
acetates Jones [335] obtained 3-isoquinolones (95) instead of the expected
84 Chapter 2
amides (94A), which, obviously, are formed as a result of a dehydration of

the cyclic amide isomers (948). For the majority of the known N -unsub-
stituted and N -monosubstituted o-acylphenylacetamides the open structure
O
R3 R3 R3
M: C'tr:
I
CH
?'" I 'CONHR2
~ CORI ~N'R2 ~N'R2
RI OH RI
(94A) (948) (95)
(94A) was established [166, 336]. A rare exception is the cyclic l-hydroxy-6,7-
dimethoxy-2-methyl-I-veratryl-1 ,4-dihydro-3-isoquinolone (96) [336].
However, all these amides in an acidic medium or on heating very easily
dehydrate and transform into 3-isoquinolones (95) [166,336-338], which
hampered the investigation of isomeric interconversions (94A) ~ (948). For
MeoW
this reason 2-benzoylphenyl-a,a-dimethylacetamides (97) were investigated
O
I N
MeO ~ 'Me
HO C~
\={ OMe
OMe
(96)
W:R
Me Me
~CONHR
VCOPh
Ph OH
(97A) (978)
[171], since a 1,4-dehydration of the cyclic isomers is impossible. Under

the influence of the Thorpe-Ingold effect these amides exist exclusively as
cyclic isomers (978, R = H, Me, Pr, i-Pr, Ph) which do not undergo thermal
isomerization into open forms. The reverse is true only for N-(t-butyl)amide
which, possessing an open structure, does not isomerize (97 A, R =
t-8u) -+ (978) even under conditions of alkaline catalysis.
On the whole o-acylphenylacetamides display a low tendency to form

cyclic isomers compared with 2-acylmethylbenzamides.
8-Acyl-1-naphthamides. 8-Aroyl-l-naphthamides, obtained by the inter-
action of 3-chloro-3-phenylperinaphthalide with amines or by the isomeriz-
ation of 3-alkyl( or aryl)amino-3-arylperinaphthalides, possess the cyclic
structure (98B) [128, 168,339].
~ ~CONHR
~ j COPh
(98A)
All attempts to carry out the thermal isomerization of (98B, R = i-Pr,

Ar = Ph) to (98A) failed. Hence it follows the cyclic form of N-alkyl-8-
benzoyl-l-naphthamides is more stable than that of N -alkyl-2-benzoyl-
benzamides.
The only amide of 8-benzoyl-I-naphthoic acid obtained as an open
isomer is the N-(t-butyl)amide (98A, R = t-Bu), which is formed in the
reaction of the methyl ester of this acid with an excess of t-butylamine in
an autoclave at 230°. The alkaline isomerization (98A, R = t-Bu) -+ (98B)
does not take place.
2-Benzoyldiphenyl-2'-carboxamides possess the open structure (99) and
do not ring close even under alkaline catalysis [81, 169].
CONHR
COPh
(99)
Summary of Structural Influences on the Relative Stability of Open and

Cyclic Isomers of Acylcarboxamides. The structural factors on which the
relative stability of ring or chain isomers depends may be divided into three
groups.
1. The influence of the structure of the chain connecting the groups
CONHR and C=O. Increasing the rigidity of the chain favors the proximity
of mutually interacting groups and, hence, the stability of cyclic form rises.
86 Chapter 2
Table 15. Influence of Keto Amide Structure and of Steric Bulk of a

Substituent at Nitrogen on the Existence of Open (A) and Closed (8)
Isomers
Favored isomer when R =

Keto amide
structure H Me n-Alkyl sec-Alkyl t-Bu
PhCH 2 CH 2 CONHR A B A A
M">(j<CH'CONHR
0
Me CH 2 Ph A,B B A,B A A
0
o=(CH ,CON
0
HR
~ I Ph A A,B A,B A A
0
OCONHR
B B B A,B A
~ COPh
OCONHR
B B B B B
~ I COCOPh
PhCOCH 2 CH 2 CH 2 CONHR A A A A
O C H 2CONHR
A A
~ COPh
OCONHR
B B A
~ I CH 2 COPh
"
Me Me
/
(J(C'-CONHR B B B B A
~ COPh
SCONHR
B B B B A
~ ;/ COPh
The formation of a five-membered ring is favored over that of a six-

membered one. As an example anthraquinone-l-carboxamides having a
rigid arrangement of the keto group in a conformation, which does not
allow for a stereoelectronically favored nearly perpendicular approach of
the nitrogen atom to the c=o group, does not undergo cyclization.
2. The steric influence of substituents at a nitrogen atom and/ or keto
group. The ring form is destabilized as the bulk (branching) of the substituent
at the nitrogen increases in a series: Me < n-alkyl < sec-alkyl < t-alkyl.
Substituents (mesityl, 9-anthryl) at the keto group which hinder the approach
of the amide group act similarly.
3. The electronic influence of substituents. The electron-withdrawing
effect of substituents at a keto group increases its electrophilicity thus
increasing the stability of the cyclic form; electron-donating substituents
operate in the opposite direction. Electron-withdrawing substituents at the
nitrogen atom decrease its nucleophilicity and stabilize the open form.
It is shown in Table 15 that as the rigidity of the chain connecting the
groups CONHR and C=O increases keto amides form cyclic isomers with
very bulky substituents at the nitrogen atom.
Numerous examples of electronic influences on ring-chain equilibria
have been discussed in the preceding chapters. In addition to 2-acylbenz-
amides, discussed on p. 68, N-(t-alkyl)-2-acylbenzamides [193,201] may
be cited as an example where the increasing electrophilicity of a keto group
by an electron-withdrawing substituent outweighs the steric hindrance of
an N-(t-alkyl) substituent. Thus, N-(t-butyl)-2-acylbenzamides having
alkyl or phenyl substituents at the keto group exist only in the open form
and are not capable of hydroxyisoindolinone ring closure even under
alkaline catalysis. However, the introduction of electron-withdrawing sub-
stituents X into a benzoyl group allows cyclization of N-(t-butyl) and even
N-( l-adamantyl)-2-(X-benzoyl)benzamides into hydroxyisoindolinones.
2.1.4. Esters
The esters of 3-acylpropionic [21, 30, 139, 140,340], 2-acylbenzoic [28,

29,32,36, 74, 80-83, 151,341-345], Z-3-acylacrylic [9, 10, 15,22,27, 101,
(4A)
88 Chapter 2
108, 109, 346-348], and 4-acy1carboxylic [40, 119, 120, 345, 349-355] acids
were obtained in an open (4A) as well as in a cyclic (4B) form. Both isomers
are stable in neutral solvents at room temperature. The equilibrium
(4A) ~ (4B) may be. observed only under the conditions of acid or alkaline
catalysis [28, 36, 108, 140, 356] or by heating [346].
The determination of the structures of the isomers was carried out by
UV [10,29,30,82,216,346], IR [10,27,36,40,62,82, 109, 151,346,357],
and IH-NMR methods [27,29,30,36,38,40,346]. Quantitative measure-
ments were made by gas-liquid chromatography (GLC) [36], UV [30,356],
IR [82] and IH-NMR spectroscopy [28, 29, 36, 38].
In the IR spectra of five-membered lactones (4Ba-c) the bands of the
lactonic C=O group appear in the range of 1790-1760 cm- I (see Table 16),
which is transparent for the open isomers (4A). This band can be used as
an analytical tool for quantitative measurements. It is not applicable for
Table 16. Frequencies of C=O Bands in the IR Spectra of Open (4A) and
Cyclic (4B) Acylcarboxylic Acid Esters in Solution (cm- I )
Open isomer Cyclic

Structure of isomer
open isomers R Solvent COR COOMe C=O Refs.
/COOMe
CH 2
I H CCl. 1717 1750 1790 30
CH 2
"-COR
OCOOMe H Dioxan 1700 1727 1782 26

Me Dioxan 1706 1727 1777 26
~ COR Pha Dioxan 1680 1727 1783 26
X Y
H H H Pure liquid 1695 1733 1795,1661 35

X, /COOMe H
C Me Me CHCI 3 1695 1724 1761 101
\I H Me Ph Dioxan 1676 1727 1777 27
y./C'COR CI CI H CHCI 3 1706 1732 1795 346
Br Br H CHCI 3 1714 1731 1796 346
SeDOM, H CCl. 1704 1734 1742 38

~ II COR
Me CCl.
Ph CCl.
1693
1669
1722
1739,1726
1730
1737
38
38
a For the IR spectra of 2-aroylbenzoic acid esters substituted in phthaloyl group see [37].
esters of 4-acylcarboxylic acids because the C=O bands of six-membered

alkoxylactone and of ester groups differ only slightly.
In the IH-NMR spectra of open structured acylcarboxylic esters the
signals of alkyl substituents at the keto group (R 1 in formula (4A») and the
alkoxygroup (R2) are shifted toward lower fields as compared with those
of cyclic isomers (4B) (see Table 17). This characteristic has been used for
quantitative experiments. For a structure determination of aroylcarboxylic
acid esters the IH-NMR method is of little use.
Esterification methods of acylcarboxylic acid6 generally lead to one
specific isomer [1]. The open derivatives are formed by the action of alkyl
halides on the silver salt of acylcarboxylic acids [10, 35, 101], and by
esterification of acylcarboxylic acids with ethyl orthoformate or with
diazomethane [10, 30, 40, 82, 101, 109, 119, 346], but there are some
exceptions to the last reaction [83, 120].
Table 17. Chemical Shifts of Protons in IH-NMR Spectra of Open (4A) and
Cyclic (48) Isomers of Acylcarboxylic Acid Esters
Open isomer Cyclic isomer

Structure of open isomer
(solvent) Ra il(R) il(OMe) il(R) il(OMe) Refs.
H 9.63 3.60 5.90 3.7 30

RCOCH 2 CH 2 COOMe
CH 3 2.11 3.60 1.54 3.29 139
CH 3 2.55 3.87 1.82 3.06 36

aCOOMe CH 2 CH 3 1.18 3.88 0.83 3.04
CH(CH 3 )2 1.17 3.87 0.81 2.99
~ COR C(CH 3 h 1.24 3.90 1.03 2.99
CH 2 Ph 4.07 3.97 3.35 2.99
(in CD 3 OD) Ph 3.44 3.16
X y
X, /COOMe
C
II H H CH 3 2.27 3.72 102
H H Ph 3.58 3.27 102
y./C'COR
Me H CH 3 2.22 3.79 1.60 3.20 101
(in CDCI 3 ) CI CI H 10.02 3.93 5.76 3.54 346
SeOOM'
~ II COR
H
CH 3
CH 2 CH 3
CH(CH 3 h
10.21
2.62
1.23
1.25
3.87
3.83
3.85
3.80
6.32
1.87
0.82
0.88
3.65
3.20
3.20
3.16
38
(in CCl 4 ) Ph 3.32 3.28
a The chemical shifts of protons printed in bold are given in the columns O(R)'
90 Chapter 2
Beska, Rapos and Winternitz [346] have observed that esterification of

3-formyl-2,3-dihalogenoacrylic acids with diazomethane at 0° yields open
isomers but with an increasing proportion of ring isomers at higher tem-
peratures. The open isomers of these acid esters undergo thermal isomeriz-
ation into the cyclic ones.
The 2-formyl and 2-acetylbenzoates of open structure were obtained
[343,358] by the esterification of the acids with methyl iodide in the presence
of potassium carbonate.
Alkoxylactones have been formed mainly by the alcoholysis of
chlorolactones (2B) usually in the presence of pyridine [9,10,81,109,151,
350]. Urea has also been used instead of pyridine [359]. The cyclic isomers
oflevulinic ester were obtained [340] by the alcoholysis of a-angelicalactone.
The esterification of acylcarboxylic acids with alcohols in the presence
of hydrogen chloride (Fischer-Speier method) or other acidic catalysts
usually leads to a mixture of isomers (4A) and (4B), the proportion of which
depends not only on the structures of the acid and the alcohol, but also on
the reaction time (kinetic or thermodynamic control). The ratio of products
is determined by the following equilibria [28, 29, 36, 360] (intermediates
are not shown):
(COOH (COOMe
•b •
a
C=O C=O
/ /
R R
(1A) (4A)
n ~
b~
k.jlk2
0 0
II II
CC,-O • • CC,-O
C/ C/
R/ "OH R/ "OMe
(18) (48)
a +MeOH, -H 2 O
b +H 2 O, -MeOH
The scheme reflects the possibility of a nucleophilic attack of MeOH

at both electrophile centers of tautomers (lA) and (lB).
A number of kinetic investigations have been published [342, 343,
351-354,361-367] proving that the neighboring C=O group accelerates the
hydrolysis of aldehydo or keto carboxylic acid esters by intramolecular
catalysis with neighboring group participation [49,368]. In this case the

reaction is initiated by an addition of the nuc1eophile to the keto group.
The mechanism of the alkaline hydrolysis may be given as an example:
MeO 0-
(COOMe
. +ow
-ow
~
(CDDM'
C/
0- ---+
(C, "- /
/0 ---+
C=O C
R
/
R
/ "- OH R
/ "- OH
(4A)
(c, .
II
(COOH
---+ ~
/0
c C=O
R
/ "-OH /
R
(18) (1A)
The result of thermodynamically controlled Fischer-Speier esterifica-

tions is determined by the equilibrium (4A) ~ (4B).
Using GLC and 'H-NMR methods Bowden and Taylor [36] have
measured equilibrium and rate (k , and k2 ) constants (see Table 18) for
ring-chain interconversions (100A) ~ (100B) of methyl 2-acylbenzoates in
Table 18. Equilibrium and Rate Constants for Ring-Chain Interconversions of

Methyl 2-Acylbenzoates (IOOA) ~ (IOOB) in the Presence of Acid or Alkaline
Catalysts [36] in Methanol
Equilibrium constants KT = [8J/[AJ Rate constants

I· mol-I. S-I
'H-NMR method, 36° OLC method, 40° OLC method, 40°C
acid-catalyzed
Acid
R catalyzed Alkaline Acid Alkaline k, x 103 k2 X 103
Me 1.9 2.2 1.7 1.8 1.03

Et 2.2 2.1 2.6 2.3 1.43 0.560
i-Pr 3.0 3.5 4.5 4.9 1.10 0.242
I-Bu 8.1 6.1 8.1 8.1 a 0.273 0.0337
PhCH 2 2.8 2.6
Ph 0.02 0.02
a The rate constants under alkaline catalysis at 200 e are k, x 103 = 3.08; k2 x 103 = 0.380.
92 Chapter 2
methanol in the presence of acidic (hydrochloric acid) or alkaline (sodium

methoxide) catalysts.
~COOMe :.oH=k~=rH:" ~o
~COR k, Vl)
ROMe
(100A) (1008)
Table 18 shows that the equilibrium constants for acid catalyzed and
base catalyzed equilibrations are equal within the limits of experimental
error. KT increases with an increase in the bulk of substituents R: Me < Et <
i-Pr < t-Bu. The open form is destabilized by bulky substituents turning
the C=O group out of the plane of the benzene ring (see [61]). Equilibrium
constants correlate roughly with Taft's steric substituent coefficients Es:
log KT/(KT)o = BE" B = -0.35 ± 0.05 [36].
The rate constants k, and k2 for acid catalyzed isomerizations were
obtained from GLC experiments. They decrease with increasing steric bulk
of substituents R, k2 being affected more (B = 0.9 in log k2/ (k 2)o = BEs)
than k, (B = 0.5).
Bowden and EI-Kaissi [356] have suggested the following mechanisms
of isomeric interconversions:
1) acid catalyzed:
0
0 0 0
II II II
c- oMe +H+ O C -oMe +MeOH C- OMe
O I •- w' I ===~ 1
OH
,,+0 /Me
+=.
~ C-R ~ C- R -MeOH ~ C-
II . II /
o +OH R
"H
(100A)
+OH
II
~C-OMe 4 '
~C-OH
/
ROMe "
Intramolecular Reversible Addition to the C=Q Group 93
~
-MeOH
+MeOH 03: ROMe

~O;o
ROMe
(1ooB)
o
2) methoxide catalyzed:
o o
(XI
II II
:;..- C-OMe ~=~ 0 ' C - oMe
+MeO-
~ 4 •
~ C- R
-MeO-
~C_O-
II / "-
o ROMe
(1ooA)
4 ~
0)
~
I
0- OMe
0
-MeO-
+MeO
~o
o
ROMe ROMe
(100B)
The authors [356] carried out a kinetic investigation of base and acid
catalyzed isomerization of the cyclic isomers of methyl 2-aroylbenzoates
r
(100B, R = 3 or 4-XC 6 H4) to (100A) and 8-aroylnaphthoates substituted in
aroyl group (101B) to (lOlA).
~COOMe ,
CO-O~ .~
~ j - X OMe
(101A)
(101B)
The isomerizations proceed according to the depicted mechanisms. In

the rate-limiting step of the methoxide catalyzed isomerization a tetrahedral
intermediate forms (for (100B») or decomposes (for (101B»).
94 Chapter 2
The equilibria (lOOA) ~ (lOOB) and (lOlA) ~ (lOlB) are almost fully
displaced in favor of the open isomer (KT < 0.02). The isomerization
(lOOB) -+ (lOOA) proceeds more rapidly than (lOlB) -+ (lOlA). Especially
in the case of methoxide catalysis this difference arises from the lower
enthalpy of activation (see Table 19) which is due to the greater strain in
the five-membered ring. For these isomerizations (methoxide catalysis) a
good linear correlation with (T or even better with (Tn values of substituents
X has been obtained.
In acid catalyzed isomerizations substituents X exhibit an insignificant
influence on the rate constants. Based on substituent, solvent, and solvent
isotopic effects it has been concluded [356] that the rate-limiting step of the
reaction sequence given on page 92 is a nucleophilic attack of methanol
at the protonated C=O group of alkoxylactones or the subsequent proton
transfer.
Generally ring-chain equilibrium constants of acylcarboxylic esters are
governed by the same structural factors as equilibria of the corresponding
free acylcarboxylic acids. Thus, there is a good correspondence between
the tautomeric equilibria of acylcarboxylic acids and the isomer distribution
of products of Fischer-Speier esterification reactions carried out under
thermodynamic control [29], as has been shown in the case of esterifications
Table 19. Rate Constants, Correlation a , and Activation Parameters of Acid- and
Base-Catalyzed Isomerizations (1008, R = XC 6 H 4 ) to (lOOA) and (1018) to
(lOlA) in Methanol [356]
X = H, at 30°C
k2 0"
Initial I. mol-I. S-l or flH" flS"
compound (X = H, at 60°C) 0"" P s (kcaljmol) (e.u.)
Methoxide catalyzed
(lOOB), 4.05 0" 0.952 0.996 0.074 9.4 -28
R = XC 6 H 4 0"" 1.087 0.996 0.062
(lOlB) 0.125 0" 2.041 0.996 0.112 12.6 -25
0"" 2.108 0.999 0.060
Acid catalyzed
(lOOB), 2.74 x 10- 3 0" -0.172 0.771 0.054 11.3 -36
R = XC 6 H 4 0"" -0.182 0.731 0.064
(lOlB) 3.25 x 10-4 0" -0.123 0.878 0.Q30 12.2 -38
0"" -0.125 0.878 0.032
a For (100) n = 9, X = H, 4·Me, Me2CH, Me3C, Mea, F, Cl, I, 3-N0 2 ; for (101) n = 7, X = H, 4-Me, CI,
Br, 3-Me, Cl, CF3.
oflevulinic [140, 340], 2-aroylbenzoic [28, 29, 81, 82, 342], Z-3-aroylacrylic
[27, 348], and 4-benzoylbutyric [350] acids mainly yielding open isomers.
2-Acylbenzoic (lb, R = H, alkyl) [26, 29, 36], Z-3-acylacrylic (Ie,
R = H, alkyl) [96, 101, 346], and 8-acyl-1-naphthoic [40] acids for which
the ring-chain equilibrium is shifted toward a cyclic form (see Table 3) in
the esterification mainly form cyclic esters. The isomerizations (rearrange-
ments) (4B) to (4A) (levulinic [140, 340], 2-aroylbenzoic [80, 356], Z-3-
aroylacrylic [10, 108], and 8-aroyl-1-naphthoic [356] esters) proceeding in
the presence of acid or alkaline catalysts are reflecting the thermodynami-
cally more stable isomer of the equilibrium (4A) +:t (4B).
2.1.5. Mixed Anhydrides

The identification of acylcarboxylic acid mixed anhydrides (5A) or
their more widespread cyclic isomers, the acyloxylactones (5B), may be
o
II
C~o c
c 0
RI / "0 - C-?
(5A) (58) 'R2
easily carried out using IR comparisons. In the IR spectra of open isomers
(5A) anhydride C=O bands appear at 1820 and 1750 cm-\ being clearly
separated from the vibrational modes of the aldehydic or ketonic C=O
groups at 1725-1660 cm -I. Hence, absence of any absorption in the range
of 1725-1660 cm -I is good evidence for the cyclic structure (5B). Acyloxy-
60
0
0-
Q)
- 40
u
c
0
.D
t.
0 20
(J)
1)
0
0
1800 1600 v,eM-'
Figure 10. C=O Bands in IR spectra of 3·acetoxyphthalides in the solid state: 1-3·acetoxy-3-
(I ,2·diphenylethyl}phthalide; 2-3·acetoxy·3·( I·phenylpropyl}phthalide [68].
96 Chapter 2
o 0 o
II II
( Co
II
COOH _C_I-_t_o_M-+e~ C-O-X-OMe ---+
( (
C=O N.R-N C=O c/' 0
/ "----l / /" II
R R R O-X-OMe
(1A) (102A,X=C, S) (1028)
,/,C /'
( ,I
/,C, /'
/,C,
a b d
(R=Me (140)) (R=Ph, [150,370]) (R=Ph (350))
e f
(R = Ph (349)) (R=Ph (349))
(
COOMe ( C : o
o
II
Oj
~
I CX·
o ~
C
~
C
X)
~
0
~ I
-------0 ----
/
C=O
/
C
"-
Ph 0 C'iO O"'C I ~
R R OMc
(4A) (48) (X
~
~ I
~ ""0
Ph
Me¢MC M e l ) M e
~
I I
--?
C/
II Me Me
o
(103) (105)
lactones (5B) obtained from 3-acylpropionic [30], 2-acylbenzoic [66, 68],

and Z-3-acylacrylic [10, 35, 101, 109] acids show the C=O band of the
lactone at 1810-1775 cm -I and that of the acyloxygroup at 1770-1745 cm -I.
Sometimes these bands overlap [68] (see Fig. 10).
Acylation of 3-formy1propionic [30], 2-acylbenzoic [66-68, 81, 369],
Z-3-acylacrylic [10, 35, 96, 101, 109], and 2-(2-benzoylphenyl)-2-methyl-
propionic [121] acids with acetic anhydride [30, 67, 96, 101,369], a mixture
of acetic anhydride and pyridine [66, 68, 81, 109, 121] or sodium acetate
[66], acetic acid in the presence of sulfuric acid [10] or acetyl and benzoyl
chlorides [35], gave acyloxylactones (5B). A more specific synthesis is the
reaction of chlorolactones (2B) with silver acetate [10,369]. Mixed anhy-
drides of open structure (5A) were obtained by action of ketene on
3-formylpropionic acid [30], by acetylation of 3-benzoyl-2,3-
diphenylpropionic acid with acetic anhydride [109], and by the action of
acetylchloride on the silver salt of benzil-o-carboxylic acid [369].
Newmnan and others [140, 150, 156, 350, 370] have obtained mixed
anhydrides of 3- and 4-acylcarboxylic acids from methylchlorocarbonate
or methylchlorosulfite in the presence of base, e.g., 1,4-diazabicyclo[2.2.2]-
octane or by using the sodium salts of these acids.
Heating transforms mixed anhydrides (102A) into cyclic isomers (102B),
which were not isolated in every case. These cyclic isomers on pyrolysis at
higher temperature fragmented yielding mixtures of open (4A) and cyclic
(4B) esters. Pyrolysis of mixed anhydride (l02Ab, X = C, R = Ph), obtained
from 2-benzoylbenzoic acid, gave in addition to esters (4A) and (4B) 2-
benzoyl benzoic acid anhydride (103), a compound consisting of one open-
structured acid moiety and a second cyclic part.
The anhydride (103) has been obtained also by the action of
ethoxyacetylene on 2-benzoylbenzoic acid, of 3-chloro-3-phenylphthalide
on 2-benzoylbenzoic acid in the presence of pyridine [150] and of 3-chloro-3-
phenylphthalide on sodium nitrate [151].
o 0
II II
~C" /C~
0 c -:: :-o 0 o~c~
I I
Ph Ph
(104)
On the basis of UV spectroscopic [369] and polarographic [371] data

the structure (104) was first erroneously assigned to the anhydride (103).
The pyrolysis of 2-mesityloylbenzoic acid mixed anhydride (l02Ab,
X = C, R = 2,4,6-Me 3 C 6 H 2 ) gives the anhydride (l05) as the only product,
but from the mixed anhydrides of 4-benzoylbutyric acid (102Ad, R = Ph)
and some gem-dimethyl derivatives unsaturated lactones (106) are obtained
in addition to the esters (4B) [350].
Schmid and co-workers [369] have shown that 3-acetoxy-3-
phenylphthalide (107) thermally isomerizes into mixed anhydride (108), i.e.,
a thermal isomerization takes place which is the reverse of the above-
mentioned (102A) -+ (102B»).
98 Chapter 2
o 0
o II II
~o
C"'-O/C",-
---..... ((
~
I ....:;0
Me
,-..... C/"
Ph OCOMe I
Ph
(107) (108)
The available investigations do not allow conclusions to be reached

concerning the influence of the structure of the acyl group (R2 in formula
(5» on the stability of open and cyclic isomers of mixed anhydrides and
on the conditions of their interconversions.
2.2. HYDROXY ALDEHYDES AND KETONES AND RELATED

COMPOUNDS
2.2.1. Derivatives Containing a Hydroxy Group at Carbon

(C-OH)
Ring-chain tautomerism in which a ring forms by intramolecular addi-
tion of a hydroxy group to a c=o bond occurs widely in organic chemistry.
The structures are sometimes called ketolo-lactolic (as well as keto-lactolic)
or oxo-cyclotautomeric [I]; ring isomers are sometimes named hemiacetals
or hemiketals [372]. Commonly it is possible to isolate one of the isomers,
but in solutions equilibration occurs. Both isomers have been isolated only
rarely.
Mutarotation of aldoses and ketoses is a very important example of
ring-chain interconversion of hydroxyaldehydes and hydroxyketones. Since
a series of reviews [373-377] is dedicated to this problem we shall not
discuss it here. Significant progress has been made recently in the study of
the kinetics of tautomeric interconversions of sugars [378].
Here we shall discuss ring-chain isomeric interconversions of
hydroxyaldehydes and hydroxyketones where the hydroxy group is located
at an aliphatic, aromatic, or unsaturated (enols) carbon atom. Mainly those
tautomeric systems will be considered which allow one to draw more general
conclusions about the influence of structure on the relative stability of
isomers and on the positions of equilibria in solutions. Unfortunately,
precise quantitative data concerning tautomeric systems are rarely available.
In most cases the influence of structural modifications on the relative stability
of isomers was discussed only qualitatively.
Aliphatic hydroxyaldehydes and hydroxyketones provide the simplest

examples for a study of ring-chain interconversions (109A) ~ (109B). 4-
Hydroxybutanal and 5-hydroxypentanal (109, R = H, n = 3, 4) forming
five- and six-membered rings on cyclization possess the ring structure of
hemiacetals (109B). In the neat state [379-381], and in their solutions the
equilibrium is strongly displaced toward the cyclic form (see Table 20). In
larger rings the equilibrium shifts to the open form [382, 383].
/OH
(CH 2 )n
" 4 ~
C=O
/
R
(109A) (109B)
There is a striking difference between hydroxyaldehydes and hydroxy-

ketones: in solutions of 5-hydroxy-2-pentanone (109, R = Me, n = 3) and
6-hydroxy-2-hexanone (109, R = Me, n = 4) the equilibrium is shifted
toward the open form though five- and six-membered rings are formed [379,
384-386]. Equilibrium constants were determined [387] using the intensities
of the signals of the methyl group in both tautomeric forms (slow equilibra-
tion on the IH-NMR time-scale), as well as by measurement of band
intensities at 265-280 nm.
Table 20. Ring-Chain Equilibrium Constants of

Hydroxyaldehydes (l09A, R = H) ~ (109B) in
Solutions [382, 383]
KT = [B]/[A]
75% Aqueous dioxan a Toluene-d 8 b

n [382] [383]
3 7.8
4 15.4 9
5 0.18 0.17
6 0.19
7 0.25 0.43
8 0.19
9 0.10 0.69
10 0.47
12 0.33
14 0.54
aat 25"C by a UV method

bat 70"C by an 'H-NMR method
100 Chapter 2
Table 21. Ring-Chain Equilibrium Constants in Solutions of

5-Hydroxy-2-pentanone and 6-Hydroxy-2-hexanone
(109A, R = Me, n = 3, 4) ~ (1098) [387]
KT = [B]/[A]
IH-NMR method at 37°C UV method at 25°C
Solvent n=3 n=4 n=3 n=4
Pure liquid 0.83 0.85

Cyclohexane a 0.81 0.95 0.78 0.87
Dioxan 0.83 0.74
Carbon tetrachloride 0.73 0.95 0.75 0.96
Chloroform a 0.82 0.85 0.75 0.81
Acetone a 0.82 0.82
Ethanol a 0.83 0.62 0.80 0.54
Methanol a 0.81 0.51
Acetonitrile a 0.82 0.79 0.79 0.61
DMSO a 0.64 0.81 0.56 0.77
Water" 0 0 0 0
a J H-NMR measurements are made in de ute rated solvents.
Increasing temperature [386, 387] and solvent polarity displaces the

equilibria in favor of the open form. Equilibrium constants in various
solvents, except water, differ only slightly (see Table 20. This can be
explained by the presence of similar proton-donating groups (0- H) in
both forms.
In aqueous solution the cyclic form is absent. Addition of water to
solutions of hydroxyketones in dioxan, ethanol or DMSO abruptly shifts
the equilibrium toward the open form. This was explained [387] by a
hydration effect on the carbonyl group. Thermodynamic characteristics of
the equilibrium (l09A, R = Me, n = 3, 4) ~ (109B) have been determined
in different solvents.
"X
R /"-
S/ Me
S X
Rl-CO-CH -C-C
2
,,/
I"
/
4 ~ R1QMe
HO Me HO 0 Me
(110A) (1108)
R1=-f) , -f);
s
X=O,s; R=-CH 2 CH 2 - , (JC
°
Curiously, the ring-chain equilibrium of more complicated compounds

(110A) ~ (110B) shows a reverse solvent effect. Increasing the solvent polar-
ity results in a shift of the equilibrium toward (110B) and equilibrium
constants vary within larger limits [388]. Addition of sodium bicarbonate
to an aqueous pyridine solution accelerates equilibration. The investigation
of equilibria in aprotic solvents is complicated by the dehydration of the
ring (110B).
The greatest stability of a six-membered ring isomer was observed
a(e,
[389,390] in the series of 2-(w-hydroxyalkyl)cyclohexanones: 2-(3-
hydroxypropyl)cyclohexanone possesses hemiketal structure (I11B, n = 3),
but its homologues (I11A, n = 4,5) are not capable of cyclization.
HO 0
(111A) (1118)
Compared with cyclohexanones the corresponding 2-(2-hydroxyethyl)

and 2-(2 or 3-hydroxypropyl)cyclopentanones are less prone to form cyclic
hemiketals [390].
c&~HO
OH
(1128) (112A)
ct5>
o OH
(1128')
5-0xo-3,5-seco-A-norcholestan-3-o1 forms an equilibrium mixture

(112B) ~ (112A) ~ (112B') in carbon tetrachloride and chloroform. The
equilibrium is displaced in favor of the epimeric cyclic forms (K T =
[(112B)J + [(112B')}/[(112A)J > 9) [391].
(113A) (1138)
The equilibrium (I13A) ~ (I13B) of 7-hydroxymethyl-

bicyclo[3.3.1]nonan-3-one in CDC1 3 is in favor of the lactol [392].
102 Chapter 2
Sterically interacting groups in the open form shift the equilibrium to

cyclic isomers. Thus, for a series of N-(2-hydroxyalkyl)-N -(2-
oxoalkyl)amines 014A) +=! (114B) [393-398] the introduction of a third
substituent at nitrogen (R 3 = alkyl) and in particular the protonation of the
nitrogen atom [399] stabilizes the cyclic structure. Electron-donating sub-
stituents at the keto group (R I = 4-MeOC 6 H 4 ) displace the equilibrium
(114A) +=! (114B) toward the open form; electron-withdrawing substituents
(R I = 4-CIC 6 H 4 ) act in the reverse direction. Esterification in acidic media
led to 2-alkoxymorpholines (115).
R3
I
R2 ./
N
,./ R4
'CH CH
I I
C0.- CH 2 0H
Rl./ ~O
(114A) (1148) (115)
The ring-chain equilibrium is also observed in the series of S-(2-

hydroxyethyl)-S-(2-oxoalkyl)mercaptans [400] and two enantiomeric cyclic
isomers have been detected.
Thermochromy, piezochromy, solvatochromy, fluorescence, and
amphoteric properties as well as a double-step curve of polarographic
reduction of 2-[N-(2-hydroxyethyl)-N-alkyl]aminobenzoquinones were
explained [401-404] on the basis of the ring-chain tautomerism
(116A) +=! (116B). On heating solutions the equilibrium is displaced toward
the colored quinonoid form (116A) [402,403]' Equilibrium constants were
Table 22. Ring-Chain Equilibrium, Rate Constants, and Thermodynamic

Parameters for 2-[N -(2-Hydroxyethyl)-N -alkyl]aminobenzoquinone
(116A) ~ (1168) at 25°C a [402]
Phosphate buffer (pH = 7)-

Methanol methanol (5: I)
KT = -/lH -/lS KT =
R R' R2 [B]/[A] (kcal/mol) (e.u.) [B]/[A] k, (5-') k2 (5-')
Me Me Me l.l 2.9 9 2.0

Me H Me 2.9 4.5 13 5.3
Me H H 22 5.7 12.8 39 95 2.5
Et H H 53 6.1 12 83 76 0.9
Pr H H 67 6.3 12.5 100 73 0.7
a The measurements are carried out at concentrations 2.5 x 10-4 _1.5 x 10- 3 mol/I.
deduced from UV spectra of methanolic solutions and the rate constants

of isomeric interconversions were determined polarographically (see Table
22). Thermodynamic parameters were calculated.
(116A)
(1168)
N,N -Disubstituted derivatives (116, R = H) are not at all capable of

cyclization, and in N,N,N-trisubstituted derivatives (116, R = alkyl) the
equilibrium shifts toward the cyclic form as the volume of the alkyl sub-
stituent at the nitrogen atom increases (Me < Et < Pr, see Table 22). The
reason for this is the approach of the interacting groups due to a decreasing
C- N -C bond angle and a hindering of the free rotation as a result of an
increased steric bulk of substituent (R in (116») at the nitrogen atom. In
the benzoquinone ring, methyl groups (R 1 and R2 in (116») lower the
electrophilicity of the C=O group thus shifting the equilibrium toward the
open form. Isomeric interconversions proceed comparatively slowly.
Summarizing, one can state that a decreasing conformational mobility
of the chain connecting the OH and C=O groups stabilizes the cyclic
structure.
The ring-chain equilibrium (117A) +:t (117B) constants for 2-hydroxy-
methyl and 2-(2-hydroxyethyl)benzaldehydes in aqueous solution have been
established by the UV method (n = 1, KT = 6.7; n = 2, KT = 20). The
pertinent rate constants were measured by a pH jump method between pH
W'0
1 and 8 [405].
(CH 2 )n
~
I
H OH
(1178)
o-Acylphenylcarbinols with methyl or phenyl substituents in the

methylene group (R 2 in formula (118») exist in a stable cyclic form as
3-hydroxyphthalanes (118B) [159, 406-409].
The equilibrium (118A) +:t (118B) of a solution of 5-chloro-l-hydroxy-l-
methyl-3, 3-diphenylphthalane in CDC1 3 (K T = 2.4) was investigated [274].
104 Chapter 2
R2 R2
~o Rl OH
(118A) (1188)
By introducing a mesityl [408, 410] or 9-anthryl [159] substituent to

the ketogroup (R 1 in (118») one succeeds in obtaining stable open isomers
(118A, R2 = Me, Ph). In this case the steric shielding of the keto group by
the substituents (mesityl o,o'-methyl groups, anthryl peri-protons) prevents
addition of the OH group. An analogous effect of these two substituents
was noted also for 2-acylbenzoic acid derivatives [28, 78, 81, 82, 158].
a,{3- Unsaturated y-hydroxyketones possess mostly the ring structure
of2-hydroxy-2,5-dihydrofurans [406,411]. 8-Acyl-l-naphthylcarbinols [126]
also exist in a stable cyclic form (119).
Cy(
ru-jR':H
(119)
There are many examples of intramolecular additions of a phenolic

hydroxyl group to aldehyde or ketone groups including the closure of a
five-membered as well as a six-membered ring.
A preference of five-membered cyclic isomers was observed in the case
of 2-hydroxyphenylglyoxal (t20B, X = 0) [412], 2-(2-hydroxy-
phenyl)isobutyric aldehyde (120B, X = Me 2 ) [413], and ketones of similar
structure [414, 415].
OI
~
OH
C/C,
-:::-0
~O\(OH
V--{"H
II H X
X
(120A) (1208)
Six-membered cyclic isomers of 2-(2-hydroxybenzyl)cyclohexanone

(12IB, X = Y = H 2 ) [416,417], 4-(2-hydroxybenzoyl)-1 ,3-cyclohexanedione
(t21B, X = Y = 0) [418]), a series of the derivatives of 1-(2-
hydroxyphenyl)-I,3-propanedione (122) [419-422], and similar compounds
[423] have been obtained. For (i22, Rl = Ph, R2 = Br, OH, PhCOO) in
chloroform equilibria (122A) ~ (122B) were observed (R2 = Br: KT = 3.7;
R2 = OH: KT = 0.5) [419, 420]. Apparently, substitution of the hydroxyl
group by a bromine atom increases the electrophilicity of the keto group,
and the equilibrium is displaced toward the ring form. The compounds
(i22, Rl = H, R2 = H, Me) [421] and (i22, Rl = CF3 , R2 = H) [422] exist
exclusively in the cyclic form. Solutions of (122, R I = H, R2 = Me) in
acetone in the presence of a trace of t-BuONa show equilibria
(122A) ~ (122B), the ring isomer (122B) existing as a mixture of cis- and
trans-isomers, the interconversions of which proceed via the open form
(122A).
H
((:~( •• C
II X
X (1218)
(121A)
O(H
~ I COCHCOR 1
• • O((H
I
~
Rl
R2
I 0
R2
(122A) (1228)
Me Me
(J(H~o • •
CH
Me Me Me Me
(123A) (1238)
Korobitsyna and co-workers [424] isolated both isomeric 4-(2-hydroxy-

benzylidene)-2,2,5,5-tetramethyl-3-furanidones (123A) and (123B). The
isomerization (123A) --+ (123B) proceeded on saturation of the ethereal
solution of (123A) with dry hydrogen chloride. By dissolution of the hemi-
ketal (123B) in sodium hydroxide solution and subsequent neutralization
the isomerization was accomplished in the reverse direction
(123B) --+ (123A). Evidently, under basic conditions the phenolate anion of
(123A) is formed. The hemiketal (123B) can also be obtained by the addition
106 Chapter 2
of water to the corresponding furanidinobenzopyrylium salt which is formed

by the action of strong acids on the hydroxyketone (123A).
The condensation of ninhydrin with 2-amino-phenol and -thiophenol
gives the ring structure (124, X = 0, S) as shown by [425, 426] means of
IR, IH-NMR, and 13C-NMR spectroscopy, thus correcting incorrect struc-
ture assignments [427]. The introduction of substituents R 1 and R4 into
molecules of ninhydrin condensation products with polyphenols shifts the
equilibrium (125A) ~ (125B) in favor of the cyclic isomer [428].
o o
R2 • •
(125A) (125B)
0:yOH~ OMe
R2 -(JC
I
~ N ~ 0
I C
H 0-:::/ . . . . R1
(126B)
Schafer and co-workers [429-431] have observed the equilibria

(126A) ~ (126B) in solutions of substituted 2-(2-hydroxyphenylamino )-1,4-
benzoquinones. The ring isomer is formed as a result of an intramolecular
addition of the phenolic hydroxyl group to the benzoquinone carbonyl
group. Previously a similar equilibrium was detected in solutions of 2-(2-
hydroxyphenylamino )-1 ,4-naphthoquinones by the authors [432], who had
established the ratio of tautomers by UV spectroscopy. In the spectra of
model compounds having a fixed open structure the long wave band appears
at 470 nm; however, in the spectra of fixed cyclic model compounds the
corresponding absorption was found at 394 nm [430].
Me 0
'C'l ···H
Jyb:y~OMe
~N ~ 0
I /.:C,
H oy Me
(127)
In an ethanolic solution of 3-acetyl-2-(2-hydroxy-3-acetylphenyl-

amino)-5-methoxy-I,4-benzoquinone (126, Rl = Me, R2 = 3-MeCO) the
cyclic form predominates but in solvents of lower polarity the equilibrium
is shifted toward the open form. The authors [430] assume that the open
form is stabilized by an intramolecular hydrogen bond between the hydroxyl
Table 23. Isomeric Structures of bis-(Cyclohexanone-2-yl)methanes and

Their Derivatives (128)-(131) Obtained in the Solid State [433-437]
Isomeric structure
R n X Y in solid state
(128), H H2 H2 A
Ph H2 H2 A,Ba
4-MeOC 6 H4 H2 H2 A,B
2-Furyl H2 H2 Bb
H 0 H2 B
Ph 0 H2 B
Ph 0 PhCH B
Ph PhCH H2 B
4-MeOC 6 H4 4-MeOC 6 H4 H2 B
Ph PhCH PhCH B
(129), H A
H 2 A
Ph Be
Ph 2 A
(130) A
(131) A
2 Be
a KT = [B]![A] = 0.25 (in CDCI 3 ).

b KT = 0.11 (in CDCI 3 ).
C In solutions equilibrium (A) +" (8) is detected.
108 Chapter 2
group and the 3-acetyl group (127). Both isomers have been isolated: the
open quinone as a black powder (after crystallization from benzene), the
ring isomer as yellow crystals (from methanol). Obviously, in a proton-
donating solvent the cleavage of intramolecular hydrogen bonds proceeds
due to the competitive formation of intermolecular hydrogen bonds
MeC=O···H-O (solvent), and the liberated phenolic hydroxyl group
intramolecularly adds to the C=O group of quinone. UV spectra of solutions
of both isomers are identical showing that equilibrium mixtures are formed
independently of the structure of the starting compound.
Visotskii, Vershinina, and Tilichenko [433-436] investigated the
intramolecular addition of an enolic hydroxyl group to a keto group in the
series of bis-(cyclohexanonyl-2)methanes and of some their analogues
(128)-(131) (see Table 23). In some cases the authors [437] succeeded in
obtaining both isomers: (128A, R = Ph, 4-MeOC 6 H4' X = Y = H 2 ) and
(128B). In solutions equilibria (128A) i2 (128B) are reached only slowly
(during 70 h). The isomeric interconversion (128A) i2 (128B) involves an
enolization.
R R
I I
C;CCHX) =' 0(:01) ='

X Y X Y
(128A)
(128B)
OX
R
I R
CH)::)CH')"
~ I 0 0 o OH
~
(129A) (129B)
Ph
a D~:
1
CH
(jr'0
(130)
(131A) (1318)
The presence of substituents R at the bridgehead carbon atom stabilizes

the cyclic isomer (128B) (see Table 23). The presence of one or two arylidene
groups in conjugation with the keto groups (X, Y = PhCH) or of a second
conjugated keto group in the cyclohexanone ring (X = 0) acts in the same
direction. In the last case the cyclic isomer is formed even in the absence
of a substituent at the bridgehead carbon atom (R = H), which is impossible
for the other compounds in this series.
In the series of compounds (129) and (131) it was determined that
contrary to the C=O group of cyclohexanone the keto group of cyclopen-
tan one does not intramoleculariy add the hydroxyl group and the cyclic
isomers of compounds (129) and (131), when n = I, were not detected. This
has been explained assuming [436] that in the five-membered fing the
transformation of a planar carbonyl carbon to a tetrahedral configuration
is energetically disfavored because of the formation of more eclipsed confor-
mations.
A ring-chain equilibrium (132A) +:! (132B) was observed [438] for 1,5-
cDR
diketones bearing one keto group in the open chain.
a
Ph Ph
I
CH " CH R
~
/'
~ I
o.A.ph OH 0 Ph
(132A) (1328)
110 Chapter 2
Ph
e't;(CHoJ::fMe
M I Ph
PhCH PhCH
(133A) (1338)
R3
O .. \H-O
R~CH~Rl~
RZy VR Z
O-H···O
(134A) (1348)
By a condensation of l-methyl-4-piperidone with benzaldehyde

heterocyclic derivatives of open (133A) and cyclic (133B) structure were
obtained [439]; these are analogous to compounds (128).
Bis-( 1,3-cyclohexanedione-2-yl)methanes, which can be obtained from
condensation reactions of 1,3-cyclohexanediones with aldehydes, can exist
in two isomeric forms: the open chelate (134A) stabilized by two
intramolecular hydrogen bonds [440-442] and the cyclic hemiketalic
decahydro-l,8-xanthenedione (134B) [443].
Gudriniece, Lielbriedis, and Lemba systematically studied the structure
and behavior of the large group of bis- (1 ,3-cyclohexanedione-2-yl)methanes
[444-446]. In two cases both isomers were isolated (134A, R 1 = R2 = Me,
R 3 = 4-(ClCH2CH2)2NC6H4, 4-(NCCH2CH2)2NC6H4) and (134B) [443,
447, 448]. These compounds were isomerized in both directions:
(134A) -+ (134B) in boiling ethanol or by recrystallization from acetic acid
and (134B) -+ (134A) by slow crystallization from dioxan.
Other compounds of this series were isolated either as a chelate (134A)
or a chemiketal (134B). However, no simple correlation is perceptible
between the structure of substituents (R 1, R2, R 3 ) and the favored isomer
in the solid state. This is obviously not surprising since the substituents R \
R2, and R3 are rather removed from the reacting groups. Moreover, it is
difficult to estimate steric effects of the substituents in conformationally
flexible molecules (134A).
Bis-(dimedone-2-yl)methanes mostly possess the chelate structure
(134A, Rl = R2 = Me) except for the condensation products of dimedone
with 2-substituted benzaldehydes existing as hemiketals. The majority of
condensation products of unsubstituted 1,3-cyclohexanedione and its 5-
methyl and 5-aryl-derivatives with aldehydes are hemiketals (134B).
As a general rule open isomers of bis-(I,3-cyclohexane-dione-2-

yl)methanes (134, R3 = H) being un substituted at the bridgehead carbon
are favored. Electron-donating substituents in the aryl group of (134, R3 =
aryl) stabilize the open structure (I34A), electron-withdrawing groups show
the opposite effect.
Leaving out unsubstituted derivatives (134A, R3 = H) bis-(I,3-cyclo-
hexanedione-2-yl)methanes, irrespective of their isomeric structure in the
solid state, slowly give in solution tautomeric equilibria (I34A) ~ (I34B)
which are shifted toward the open form [445]. The methylation of com-
pounds (134) with diazomethane led to O-methylderivatives only of the
cyclic structure [449].
Diacylformoines (135) provide interesting examples of ring-chain
tautomerism, an enolic hydroxyl and a keto group participating [450-457].
The enolization can proceed in two directions. The symmetric enediol has
an open structure (E-I ,2-diacyl-l ,2-dihydroxyethylene (135A») stabilized by
two intramolecular hydrogen bonds. The asymmetric enediol exists as the
cyclic 2,5-dialkyl( or diaryl)-2,4-dihydroxy-3-furanone (135B). Both isomers
have been identified by IR (135A), IIC=O 1630-1620 cm- I ; (135B), IIC=O
1705-1695 cm- I ) and UV spectra [455].
OH
I
R-COCHCOCO-R
(135)
R r
1. j 1
H.
-R
4 •
HO
R
liOH
0 R
0
"H (1358)
(135A)
R=Me(A)t, i-Pr(B), t-Bu (B),4-XC s H4,X=H (B), Me (B), MeO (A), t-Bu (B), Me2N (A),CI (A,B),
Br (A, B), N0 2 (B). 2,4,6-Me3CsH2 (A), 1-naphthyl (A), 2-naphthyl (A, B)
Both isomeric 4-chloro and 4-bromobenzoyl [455], and 2-naphthoylfor-

moines [457] have been obtained in the solid state. The open isomers (135A)
crystallize as red crystals from benzene after extended heating of the
solution. The cyclic isomers (135B) were isolated as yellow crystals from
ethanol. Heating of the cyclic (135B) results in a thermal isomerization into
the open isomer (135A).
t In parentheses the isomeric structure of compounds in the solid state is noted.
112 Chapter 2
In other cases either open or ring isomers are formed depending on

the structure of the substituent R. The introduction of electron-donating
substituents in the aromatic ring of aroylformoines decreases the electrophil-
icity of the carbonyl carbon and stabilizes the open structure (135A) while
electron-withdrawing substituents act in the reverse direction. Branching of
the aliphatic substituent R stabilizes the cyclic structure [456]. Mesityloylfor-
moin is not capable offorming the ring isomer because of the steric shielding
of the keto group.
In proton acceptor solvents (ethanol, tetrahydrofuran) the equilibrium
(135A) ~ (135B) is shifted to the cyclic form which is stabilized by inter-
molecular hydrogen bonds O-H·· ·solvent [453]. In aprotic solvents the
equilibrium is displaced in favor of the open form [455,456].
R l-COCH 2COCOCH 2CO- R2

(136)
.H.
~
O:P
" .. ,: _. R2
Rl ," ,
'
, '
O. .0
H
(136A)
o o
IDOH DOH
R 0 CH 2 COR 2 R2 0 CH2COR1
(136B) (136B')
When R'=R 2, B=B', R'=R 2=t-Bu, Ph, 4-CIC s H., 4-Br-C s H.; R'=Ph, R2=Me.
A similar type of ring-chain tautomerism was observed [458] in the

series of 1,6-disubstituted 1,3,4,6-hexanetetrones (136A) ~ (136B). Both
forms of the diphenyl derivative (136, R I = R2 = Ph) have been isolated:
a yellow chelate (136A) and a colorless cyclic 2-hydroxy-2-phenacyl-5-
phenyl-3(2H)furanone (136B). At room temperature (136A) slowly trans-
forms into (136B). Both isomers were easily identified by means of their IR
(136A), a broad chelate absorption band at 1600-1490 cm- 1; (136B), IIC=O
furanone 1717cm-\ acyl group IIC=O 1688cm- 1), UV (136A), 364nm;
(136B), 320 and 248 nm in methanol) and IH-NMR spectra (equivalence
of methine and substituent R protons in the open isomer). An equilibrium
involving 2,2,9,9-tetramethyldecane-3,5,6,8-tetrone (136, Rl = R2 = t-Bu)
in DMSO-d6 was observed (K T = 5.7, IH-NMR method). Apart from 16%

of the open form two cyclic forms ([(136B)]/[(136B/)] = 6) have been found
in the case of Rl # R2 (136, Rl = Ph, R2 = Me). In nonpolar solvents the
equilibrium is totally shifted toward the chelate (136A), while in polar
solvents the content of (136B) is increased.
It is characteristic for the cases of ring-chain tautomerism discussed
so far (134)-(136) that the open form, being stabilized by one or two
intramolecular hydrogen bonds, is predominant in apolar solvents and that
on going to polar solvents acting as a proton acceptor the equilibrium is
displaced in favor of the cyclic form.
An intramolecular reversible addition of gem-diolic hydroxyl groups
to aldehydo or keto groups (137) ~ (138A) ~ (138B) proceeds by the hydra-
tion of aliphatic 1,4 or I ,5-dialdehydes [459,460], phthalic dialdehyde [461],
or diketones [462],
OH
/OH I
CH ........ CH,O
( OH (
~O CH/
c"
H I
OH
(137) (138A) (138B)
OH
o OH
1/ I
r
X
C""",
y 4 ~
rY""",
X 0 Y
'---CJ
/, '---C J
I
HO R R
(139A) (139B) (140)
A related intramolecular transannular addition yields bicyclic hemi-

ketals (139A) ~ (139B). The hemiketals 5-hydroxycyclooctanone (139B,
X = Y = (CH 2)3, R = H) [463] and a series of the derivatives of I ,8-{I ,8-
naphthalyl)naphthalene (140, R = H, Me, OH, NHNH 2 ) [464] are given
as examples. A transannular addition is also observed in more complicated
systems (erythronolide B, erythromycins [465], a.o. [466]).
114 Chapter 2
2.2.2. Derivatives Containing a Hydroxy Group at Nitrogen

(N-OH)
Ring-chain tautomerism of hydroxyderivatives of this type was sys-
tematically studied·[467-471] in a series of monooximes of 1,3-diketones.
In the solutions of these compounds three tautomers were detected: syn
and anti-isomers of 3-hydroxyiminoketones (141A) and (141A') and 5-
hydroxy-a 2-isoxazolines (141B):
R4 R4
"
OH
C=N / R3 "C=N
"/\
R3
C/ ---.
...s.-
"C! "OH
/ \
R2 C=O R2 C=O
/ /
R' RI
(141A') (141A) (1418)
The equilibrium (141A') <=! (141A) is shifted toward the syn-isomer

(K , > I), which is explained by the formation of an intramolecular hydrogen
bond NOH·· ·O=C in (141A). The ring-chain equilibrium constants K2 as
well as the pertinent thermodynamic parameters were established by 'H-
NMR spectroscopy in pyridine-ds at different temperatures [471].
Introduction of methyl (or phenyl) groups in positions R2, R 3, or R4
of the isoxazoline ring shifts the equilibrium toward the cyclic form. In the
doubly substituted (141, R2 = R3 = Me) the open form could not be
detected.
Two possible reasons for this gem-dimethyl effect were already pro-
posed by Ingold [472]: (i) decrease of the bond angle Me2C::: and (ii)
restricted rotation as a result of the introduction of two methyl groups. The
authors [471] prefer the second alternative which is supported by the
observation that in solutions of 5-hydroxy-3-methyl-5-phenyl-4-
spiropropane-a 2-isoxazoline (142) and the corresponding gem-dimethyl
derivative (143) open tautomers could not be detected by IR and 'H-NMR
spectroscopic methods. In the open isomer of (142) the bond angle
(CH2)2C::: is not reduced but rather is increased by the cyclopropane ring
J;o
Me Me
Me,j=N
o
MeAx
Ph OH Ph OH
(142) (143)
Table 24. Ring-Chain Equilibrium Constants of 5-Aryl (or alkyl)-5-

hydroxy-.l2-isoxazolines (141A, R2 = R3 = R4 = H) ~ (1418) in
Pyridine -d5 Solutions Determined by IN-NMR at 34°C [471]
RI = 4-XC 6H4
X KT = [8]j[A] RI KT = [8]j[A]
Me 2 N 0.01 Me >100
MeO 0.33 Pr 12.8
Me 0.83 Me 2 CHCH 2 3.77
F 1.48 Me 3 CCH 2 0.97
H 1.68 i-Pr 35.7
Ph 2.54 Ph 2 CH 10.1
CI 2.83 I-Bu 30.3
Br 3.18
N0 2 40.0
even compared with the tetrahedral angle H 2C::::, which should stabilize
the open isomer. The absence of the open form is therefore explained by
a restricted free rotation in the open isomer of isoxazoline (142) as compared
with the 4,4-unsubstituted derivative.
In the series of 5-hydroxy-5-( 4-X-phenyl)-il2 -isoxazolines a good linear
correlation between the ring-chain equilibrium constants K2 and the (J" +
coefficients of Brown-Okamoto was detected [471]: log K 2 /(K 2 )o = 1.26 (J"+,
r = 0.993.
A similar correlation with the inductive and steric coefficients ((J" + and
Es) of alkyl substituents does not exist for 5-alkyl-5-hydroxy-il 2-isoxazolines
(141, R I = alkyl) (see Table 24), which is explained by the fact that alkyl
substituents at the keto group affect the tautomeric equilibrium not only by
their electron and steric effects on the reactivity of the keto group but that
they also exert a steric influence on the conformational mobility of the
whole molecule of the open isomer.
The formation of a five- or six-membered ring by participation of a
hydroxyimino group was observed in a series of monooximes of 2-benzoyl
[473] and 2-phenacyl-2-aryl-1 ,3-indanediones [474] which in the solid state
are cyclic (144B, n = 0, I). This happens to be the case also for solutions
(144A) (1448)
116 Chapter 2
of monooximes of 2-benzoyl-2-phenyl-l ,3-indanedione (144B, n = 0, Ar =

Ph) in acetonitrile. The monooximes of 2-aryl-2-phenacyl-l ,3-indanediones,
however, form equilibrium mixtures (144A, n = I, Ar = Ph, 4-MeOC 6H4'
4-Me2NC6H4) ~ (144B) in dichloroethane.
RI
I
O~/N'OH
,
R2 I
/C, ~O
R2 CY
I
R3
(145A)
Equilibria are also obtained in solutions of hydroxamic acids, 5-

hydroxy-4,4-diisopropyl-3-isoxazolidinone is an example (145A, R I = R3 =
H, R2 = i-Pr) ~ (145B) [475]. Spontaneous isomerization (145A, R = Me,
aryl, R2 = H, R3 = Me) --+ (145B) takes place by the interaction of N-
monosubstituted hydroxylamines with diketene [476].
MeCOCH 2CH 2CH(N0 2)2

(146A)
00
Ph M
I e
CH-C/
"'NO,- Na'
(147)
Only one case is known of an intramolecular addition of a nitronic

acid hydroxy group to a keto group. Nielsen and Archibald [477] using IR,
UV, and IH-NMR spectroscopic evidence were able to show that contrary
to results of previous investigations [478] the cyclic form (146B) was absent
in solutions of 5,5-dinitro-2-pentanone (146B). 8a-Hydroxy-3-methyl-4-
phenyl-4a,5,6,7 ,8a-hexahydro-4H-l ,2-benzoxazine-2-oxide (148), the only
cyclic ketonitronic acid which has been observed so far, was obtained [479]
by acidification of an alkaline solution of the condensation product of
cyclohexanone with 2-nitro-l-phenyl-l-propene. In alkaline medium, com-
pound (148) forms the sodium salt of oxonitronic acid (147). The structure
(148) was supported by IH-NMR spectroscopy [477].
Spectroscopic investigations of other I-nitro-3(or 4)-oxoalkanes and

1,I-dinitro-3-oxoalkanes confirm their open structure. No data are available
on the ring-chain tautomeric equilibrium in solutions of 3 or 4-oxonitronic
acids.
2.3. AMINO ALDEHYDES AND KETONES AND RELATED

COMPOUNDS
In this section ring-chain isomeric interconversions are described which

are brought about by intramolecular addition of N - H groups to a c=o
bond. Examples of this kind have already been discussed in the sections
on amides and hydrazides of acylcarboxylic acids (see Sec. 2.1.3). The cases
treated here comprise amino derivatives of aldehydes and ketones containing
primary or secondary amino groups (NH2 or NHR) located at saturated,
ethylene or aromatic carbon atoms. Reactions of covalently hydrated
nitrogen-containing heterocycles are an unusual source of aminoaldehydes
and amino ketones capable of ring-chain tautomerism. Equilibria are also
discussed in which an intramolecular addition of N - H groups of imines,
hydroxylamines, hydrazines, triazenes, amidines, ureides, thioureides,
guanidines, dithiocarbamines, sulphamides and other functional groups to
a C=O bond occurs. Unfortunately, not all these cases have been
throroughly investigated.
The closure of a five- or six-membered (rarely a seven-membered) ring,
i.e., 1,4 or 1,5 (l,6)-positioned interacting N-H and c=o groups, is a
necessary condition for the formation of cyclic isomers. In spite of numerous
investigations by different authors it is rather difficult to obtain a general
picture of additional structural influences on the relative stability bf ring
or chain isomers.
2.3.1. Covalent Hydration of Nitrogen-Containing Heterocycles

The tautomeric amino aldehydes (more rarely aminoketones) vs. car-
binolamines (149A) i2 (149B) can be formed by covalent hydration of
heterocycles containing immonium (N -protonated, N -alkyl, N -aryl)
groups. A series of reviews [480-484] have appeared which mainly treat the
equilibrium between ionic and covalent forms of the cyclic immonium bases
(149C) i2 (149B).
Beke and Szantay [485,486], investigating carbinolamines, obtained by
the addition of alkali to solutions of 2-substituted isoquinoline or 3,4-
dihydroisoquinoline salts, draw the conclusion that a weak basicity of the
118 Chapter 2
nitrogen atom of the carbinolamine (1498) would favor the formation of

the open form (149A).
Rl Rl
+/
N
/
NHRI
C~
OH~
4 '
CLOH Cc=o 4 '
"
(149C)
R R
I
(149B)
R
/
(149A)
- H20 11+ H 20
Rl Rl
"
CI 1)
/
R/ ~o/ "R
(150)
Four cases have been discussed [485]:

I. Strong bases (2-alkyl-3,4-dihydroisoquinolines). In the solid state
and in nonpolar solvents they exist as carbinolamines (1498), while in polar
solvents only immonium ions (149C) are detectable. No evidence was found
by chemical or physical methods for the presence of an open form (149A).
2. Moderate bases (2-aryl-3,4-dihydroisoquinolines). In the crystalline
state as well as in nonpolar solvents they show structure (1498). In aqueous
solution equilibria (149C) ~ (1498) ~ (150) were observed. The open form
(149A) is absent.
3. Carbinolamines not capable of forming immonium ions (149C)
isomerize into the open form (149A). Both forms can be detected in solution
and even have been isolated occasionally [486].
4. Compounds showing no pseudobasic properties exist exclusively in
the open form (149A). Carbinolamines (1498) formed in alkaline solutions
of immonium salts of heterocycles are not stable and spontaneously trans-
form into the open isomer (149A).
Hence, it appears that equilibria (149C) ~ (1498) and (1498) ~ (149A)
can not be observed simultaneously. Carbinolamines capable of forming
the ionic form (149B) do not transform into the open isomer (149A) and
vice versa.
Products of covalent hydration of l-arylpyridinium salts [487] have the
open structure of monoaniles of glutaconic aldehyde. An interesting
rearrangement of 3-cyano-l-methylpyridinium iodide into 2-methylamino-

3-formylpyridine by the action of alkali involves covalent hydration and
opening of the pyridine ring with subsequent cyclization [488].
Many examples of the recyclizations of pyridine derivatives proceeding
via covalent hydration, ring opening, and subsequent ring closure have been
thoroughly reviewed [489].
Hydration of 2-(2,4-dinitrophenyl)isoquinolinium ion [486] gave both
isomers (ISlA) and (151B) which were isolated. A study [486] of etherifica-
tion reaction kinetics «151B) with alcohols in presence of basic catalysts)
showed that under the reaction conditions the equilibrium (ISlA) ~ (151B)
': :
took place.
0)
I
~ N~
N0 2
H OH~
N0 2
(151A) (1518)
~
~
I N,
I;I
NHCOR
c:;
X~
I
~J<R
N
NOH
X I II
N I II
N-N N-N
(152A) (1528)
In formula (152)
Isomeric structure
X R in solid state References
H H A,B 490
H Me B 491
COOH Ph B 492
Br Me A 493,494
Br Ph A 493,494
Postovskii and coauthors [490-494] demonstrated that the covalent

hydrates of 5-R-9-X-tetrazolo[1,5-c]quinazolines, depending on the struc-
ture of the substituents R and X in the solid state, possess either the open
(l52A) or the cyclic (152B) structure. Both isomers of the parent compound
120 Chapter 2
(152, X = R = H) were isolated [490]. Using the example of the methyl-

derivative (152, X = H, R = Me) it was shown [492] that acidification
stabilizes the less acidic cyclic form. In pyridine, however, isomerization
(152B) -+ (152A) proceeds.
Covalent hydrates of pteridines (153) [482,483,495,496] as well as of
I ,3,6-triazanaphthalenes [497] in acidic medium rapidly transform into open
isomers (I54A). Neutralization leads to the reverse reaction. Evidently, the
isomerization (154B) -+ (154A) is favored by the addition of a proton to
N(ll decreasing the basicity of N(3).
N N
(Y-1, ~
N~ H
H OH
(153)
2.3.2. Derivatives Containing Amino Groups at Sp3, Aromatic, and

sp2-Carbon Atoms
The high nucleophilicity of a nitrogen atom causes the great stability
of cyclic isomers of the aliphatic 4- or 5-aminoderivatives of aldehydes and
ketones. Besides, these compounds often undergo a dehydration reaction
resulting in cyclic enamines. It is possible to isolate open isomers or to
observe the equilibria only if the stability of the cyclic form is lowered
because of an unfavorable structure of the linking fragment or of a sub-
stituent at the amino group thus lowering the nucleophilicity of the nitrogen
atom, e.g., by the introduction of an acyl group.
A ring-chain tautomeric equilibrium was observed [498,499] in
solutions of the N -methyl amide of 5-acetamino-2-oxovaleric acid
(155A) <2 (155B). In chloroform the equilibrium constant is nearly one, in
r--lOH
/ \ ,OH 4 •
~ ~ (R~MeCOl "~~o
N
I
CONHMe
01
-/XN, Me
CO
I HO Me
R
(155A, R = Me) (1558, R = Me) (1568)
(156A, R = MeCO) (156A', R = MeCO)
0 20 it is 1.5, and in pyridine the equilibrium is strongly displaced toward

the open form (155A). Only the open isomer (155A) was isolated. Surpris-
ingly, the N-methylamide of 2-oxo-5-pyruvoylaminovaleric acid (156A) is
stable in chloroform solution [498]. A double cyclization (156A) -+ (156B)
proceeds in a solution of hydrochloric acid. Analogues of (156B) were also
obtained [500].
Vanags and Oregeris [501] obtained both isomers of 2-[2-(N-cyclo-
hexyI)aminoethyl]-2-phenyl-l,3-indanedione (157 A, R 1 = H, R2 = cyclo-
C 6 Hl h R3 = Ph) and (157B). Isomerization with ring closure proceeds in
the presence of bases. Perekalin and co-workers [502] obtained cyclic
isomers of aminoketones (157B) by the reduction of 2-(2-nitroethyI)-2-
substituted 1,3-indanediones. Protonation of the nitrogen atom is accom-
panied by ring opening (157B) -+ (158), while deprotonation involves the
reverse process [501,502].
(157A) +~w (1578)
0)<
~
-::;:?' I
0 f +
CHCHzNHzR z
R3
°
(158)
4-Aminomethyl- and 4-(2-amino-2-propyI)-cyclohexanones are not

capable of forming carbinolamines [503,504].
For endo-7-amino-3-bicyclo[3.3.I]nonanone the cyclic structure of
I-hydroxy-2-azaadamantane (159B) has been determined [505]. The
homologue endo-7 -aminomethyl-3-bicyclo[3.3.1 J-nonanone also possesses
the ring structure (160B) in the solid state. In solution, however, an equili-
brium (160A) ~ (160B) containing the open isomer was detected
[504,506,507). The absence of a C=O absorption in the IR spectrum of
the hydrochloride led to the conclusion that the protonated form is cyclic
(161). The influence of protonation of the nitrogen atom on the stability of
the cyclic isomer strongly depends on the steric structure of the aminoketone
122 Chapter 2
as may be seen from a comparison with the above-mentioned transformation

(157B) --+ (158).
(1598)
NH2
(159A)
°
6 (1608) (161)
The formation of tricyclic carbinolamines from 9-acyl-2-azabi-

cyclo[5.4.0]undecanes was reported [504].
2-Acylbenzylamines having an alkyl substituent at a nitrogen atom exist
as stable cyclic isomers of l-hydroxyisoindolines (162B) [508-511]. This is
also the case for 2-(2-oxoalkyl or 2-oxoacyl)anilines (163, R I = alkyl, X =
CO, CR2 ) [512,513] which easily undergo ring closure forming 2-hydroxy-
indolines (163B).
It is possible to observe the equilibrium (163A) ~ (163B) by lowering

the nucleophilicity of the nitrogen atom by means of N -acyl substituents.
This was detected [514-517] for solutions of N -acyl-2-(2-oxoalkyl)anilines

(163, X = CH 2 , CHMe, Rl = COR), the ring form predominating for
aldehydes (R2 = H) and the open form for ketones (R2 = Me). Mass spec-
trometric analysis presented evidence that the equilibrium in the gaseous
phase is totally displaced in favor of the open form [518].
2-Acetaminobenzile (163, X = CO, R I = COMe, R2 = Ph) in solid state
possesses the cyclic structure (163B), but solutions slowly equilibrate
(163A) ~ (163B) [519].
The tautomeric equilibrium (I64A) ~ (I64B) was observed [520] in
solutions of Z-I-amino-2-(2-oxoacyl)ethylenes, which possess a ring struc-
ture (I64B) in the solid state.
The introduction of electron-donating substituents at the keto group (R 3 =

4-MeOC 6 H4' 4-MeC 6 H4) destabilizes the ring form. Using the lH-NMR
method equilibrium constants were determined from solutions kept at room
temperature for 20 days (see Table 25). Increasing proton acceptor proper-
ties of the solvent shift the equilibrium toward the cyclic tautomer.
Table 25. Ring-Chain Equilibrium Constants of Z-l-Amino-

2-(2-oxoacyl)ethylenes (I64A) ~ (I64B) Determined by
lH-NMR [520]
Ky = [B]/[A]
R I = Me, R2 = H, R I = Ph, R2 = H,
Solvent Q
R3 = 4.MeC 6 H. R3 = 4-MeOC 6 H.
Acetonitrile 0.56 0.45

Acetone 0.52 0.6\
Methanol 5.7 3.3
DMSO 19 >19
Q All the solvents are fully deuterated.

124 Chapter 2
Other examples [521-523] of the formation of stable cyclic isomers of

amino ketones are also known where molecules contain unsaturated frag-
ments:
R R
I I
-C=C-CO- and
Safonova and co-workers thoroughly studied intramolecular addition
of aromatic amino groups to keto groups in a series of o-acylmethylmercap-
tohetarylamines. Thus, by interaction of o-aminomercaptoderivatives of
pyridine (165a) [524-528], pyrimidine (165b) [529-533], and pyrazine (165c)
[534,535] with a-halogenocarbonyl compounds only one, i.e., the most
stable isomer (either (166A) or (166B») and its dehydration products were
obtained in the majority of cases.
Rl
Ix NsHHR1_R_~ _/R3_
HaiCCOR
•
4
- I(~i:: S R2
(165) (1668)
(166A)
Ix )0(. Rl~' :X~j(, :o:::x

R'
a b c d
Electron-withdrawing substituents at keto group (R4) and electron-

donating substituents (R, R') in the heterocycle stabilize the cyclic structure
[525, 530, 533-535]' Phenacyl derivatives prove to be less disposed to the
formation of the cyclic form (I66B) than aliphatic analogues.
In the reactions of 5-amino-4-chloro-6-mercaptopyrimidine (165b, R =
Rl = H, R' = Cl) with phenacyl bromides (R 4 = C 6 H 4 X, X = H, 4-Br, 3-
NO z, 4-NO z) [529,532] and of 3-amino-6-chloro-2-mercaptopyridine (165a,
Rl = R' = H, R = Cl) with o-substituted phenacyl halogenides [528], the
authors succeeded in isolating both series of isomers. In a nearly neutral
medium 5-amino-4-chloro-6-phenacylthiopyrimidines (166Ab) were for-
med. Their cyclization proceeded under the conditions of base catalysis.
This method failed, however, when methyl groups were attached to the
amino group (R 1 = Me) [532].
Attempts to detect tautomeric equilibria in solutions of 4-chloro-6-alkyl-

6-hydroxy-5,6-dihydropyrimido[4,5-b] [1,4]-thiazines (I66Bb, R = RI =
R2 = R3 = H, R' = CI, R4 = Me, CH 2 CI, CH 2 COOEt) by means of IR and
IH-NMR spectroscopy failed [533]. Derivatives, however, bearing a methyl
group at the nitrogen atom (R I = Me), form equilibrium mixtures in so-
lutions. In CDCl 3 the equilibrium of 6-methylderivatives (166b, R I = R4 =
Me, R' = CI) is displaced toward the open form, but in the solutions of
6-chloromethyl and 6-ethoxycarbonylmethylderivatives (166b, R I = Me,
R' = CI, R4 = CH 2 CI, CH 2COOEt) the cyclic form prevails. The addition
of a proton acceptor solvent, e.g., pyridine-d s to the solutions shifts the
equilibria toward the cyclic form.
The destabilizing effect of an N-methyl group (R 1 = Me) on the ring
structure cannot be explained by electronic effects since the methyl group
raises the nucleophilicity of the nitrogen atom and, hence, should act in
the reverse direction. The experimentally observable effect of the methyl
group is explained [533] by a steric interaction of peri-substituents in the
cyclic form (166B, R' = CI, RI = Me) which destabilizes the 1,4-thiazine
ring.
Compared with 6-acylalkylthio-5-aminopyrimidines (166b) the equili-
brium (166Ad) ~ (166Bd) is displaced toward the open form in a higher
degree [536]. The introduction of two methyl groups into the quinoxaline
ring (166d, R = Me) stabilizes the cyclic form. N - Methylaminoquinoxalines
(166d, R I = Me) have exclusively the open structure. This is explained [536]
by a steric nonbonded interaction between the substituents R I = Me and
R4 or OH of the dihydrothiazine ring which destabilizes the cyclic structure
(166Bd). Probably steric interactions of this type take place also in the series
(166Bb, R I = Me). The stabilization of the open form brought about by a
phenyl substituent at the keto group (R 4 = Ph) is stronger than that of
methyl and chloromethyl substituents, respectively. The introduction of a
bulky t-butyl group as R4 hinders the closure of the dihydrothiazine ring.
For the tautomeric system (166Ad) ~ (166Bd) it was demonstrated that the
cyclic form predominates in the solid state and in pyridine solution as
compared to a solution in chloroform, probably due to a stabilizing action
of intermolecular hydrogen bonds O-H···N:::.
2.3.3. Urea and Thiourea Derivatives

Unkovskii and co-workers [537-539] investigated N-(3-oxo-alkyl)-N'-
substituted thioureas (167). In the solid state these compounds possess, with
one exception [538], the cyclic structure of 4-hydroxyhexahydropyrimidine-
2-thiones (167B), but in solutions they form equilibrium mixtures
(167 A) ~ (167B). Equilibria were reached after 6-15 days. The equilibrium
126 Chapter 2
s
II
/C-NHRs
HN 0
RI I II
:::C, /C,
R2 CH R4
I
R3
(167A) (1678)
constants were determined [539] from the intensities of c=o bands in IR

spectra of solutions. The introduction of methyl groups as R I and R2 (always
R4 = Me) stabilizes the cyclic form as indicated by the arrow showing the
direction in which the stability of the cyclic form (167B) increases:
RI= H H Me Me Me
R2= H H H H Me
R 3 = Me H Me H H
Increasing the bulk of the substituent at the nitrogen atom (R 5 = Me,

Et, Pr) gives rise to an increased rate of ring opening thus shifting the
equilibrium toward the open form (167 A). One cannot agree with the
statement of the authors [539] that increasing electron-donating properties
of the substituent (R 5 ) at the nitrogen atom works in the same direction.
Aldehyde derivatives (167, R4 = H) unlike keto derivatives (R4 = Me) exist
totally in the cyclic form in solution.
A similar phenomenon was also observed in a series of N -(3-oxoalkyl)-
S-methylthioureas [540, 541], where the compounds possess a ring structure
in the solid state but form ring-chain equilibrium mixtures in solution.
N-(2-Acylphenyl)-ureas and -thioureas [542-545] have a ring structure,
being 4-hydroxy-l ,2,3,4-tetrahydro-3-quinazolinones (or thiones) (168, X =
0, S). Ring-chain equilibria in their solutions have not been detected.
N-(Anthraquinone-l-yl)-N'-phenylurea possesses the open structure in the
solid state and in solution [307].
RI
~
o'NIX
I
-::?' N,
R2
~ R3
o
(169)
2-Ureido [546,547], 2-thioureido [548,549] and 2-guanidino-2-

substituted 1,3-indanediones [547] are cyclic (169, X = 0, S, NR).
2.3.4. Dithiocarbamates
Ratios of tautomeric forms of S-(2-oxoalkyl)dithiocarbamates in so-
lution have been determined by IR spectroscopy [550]. The open isomer
(170A, R 1 = Ph, R2 = R3 = H, R4 = t-Bu) was isolated by crystallization
from methylene chloride and the cyclic isomer was obtained from methanol-
water. The introduction of alkyl groups R2 and R3 displaces the equilibrium
toward the ring form. Increasing electron-donating properties of the sub-
stituents at the keto group (R4) as well as increasing steric bulk of sub-
stituents at the nitrogen atom and keto group (R 1 and R4 in the compound
(170» stabilize the open form [550,551].
S
\\
C-NHRI
/
S 0 4 •
\ I;
C-C
/ \ \
R2 R3 R4
(170A) (170B)
S-(3-0xoalkyl)dithiocarbamates [552, 553] show less of a trend to form

six-membered 4-hydroxytetrahydro-l,3-thiazine-2-thiones (171B). Deriva-
tives containing a gem-dimethyl group (l71B, R2 = R3 = Me) are cyclic in
the solid state, but in solution the equilibrium is shifted to the open form
[553].
(171 B)
2.3.5. Sulfonamides and Sulfinamides

Contradictory data are available concerning the structure of 2-acylben-
zenesulfonamides. The preparation of 3-alkyl (or phenyl)-3-hydroxy-l,2-
128 Chapter 2
benzisothiazoline-l,l-dioxides (172B, R' = alkyl, Ph, R2 = H) from ben-

zisothiazoline-3-one-l, I-dioxide with Grignard reagents has been reported
[554, 555]. However, a repeated investigation [556] accomplished using IR
and 'H-NMR spectroscopic methods failed to support the formation of
compounds (I72B).
2-Phenyl-3-R-3-hydroxybenzisothiazolines obtained [557] from reac-
tions of 2-phenylbenzisothiazoline-3-one with RMgBr were oxidized by
hydrogen peroxide to their dioxides (172B, R' = Me, Ph, R2 = Ph), but no
a;
spectroscopic evidence for the structure (I72B) was given.
~
I
S?2
N-R2 0-.;,(N-M,
~S\2
R' OH Ph OEt
(172A) (1728) (173)
Hauser and co-workers [558] assume the existence of equilibria

(172A) ~ (I72B) strongly shifted toward the open form. The only basis of
such a suggestion is the formation of a cyclic O-ethylether (173) in a reaction
of N -methyl-2-benzoylbenzenesulfonamide with ethanol.
The cyclic structure (I72B, R' = 4-MeC 6 H 4S0 2 0CH 2 , R2 = Ph) was
supported by spectroscopic methods [559].
The structure of the open 2-aroylbenzenesulfonamides (I72A, R' = Ph,
4-CIC 6 H4' R2 = Me, PhCH 2, Ph) was confirmed by IR spectroscopy [184].
The formation of the cyclic form (I72B) could not be detected in dioxan
and in the presence of triethylamine or other basic as well as acidic catalysts.
Obviously, the S02 group decreases the nucleophilicity of the nitrogen atom
to such a degree that contrary to 2-aroylbenzamides the isomerization
(I72A) -+ (I72B) is prevented.
Unlike 2-benzoylbenzenesulfonamides (I72A), 2-benzoylbenzenesul-
finamides in the solid state and in solution exist as stable cyclic isomers
(173B, R' = Ph, R2 = Me, i-Pr, PhCH 2, Ph) [560]. It is possible only to
obtain open isomers of N-(t-alkyl) derivatives (173A, R' = Ph, 4-CIC 6 H4'
R2 = t-Bu, l-adamantyl). Equilibria (173A) ~ (173B) in dioxan solution
even in the presence of triethylamine have never been observed.
((}-R' R' OH
(173A) (1738) (174)
During oxidation of 2-benzyl-3-hydroxy-3-phenylbenzisothiazoline-l-

oxide (173B, R' = Ph, R2 = PhCH 2 ) with hydrogen peroxide ring opening
occurs and the sulfonamide (174) is formed instead of the expected 3-
hydroxybenzisothiazoline-I, I-dioxide (I72B).
The existence of stable cyclic N -monosubstituted 2-benzoylbenzenesul-
finamides (173B) as well as the oxidative transformation (173B) -+ (174)
provide conclusive evidence that the sulfinamide group, due to a higher
nucleophilicity of the nitrogen atom of SO NHR, is capable of intramolecular
nucleophilic addition to a c=o bond but the sulfonamide group is not.
2.3.6. Pyridones
We now discuss more thoroughly investigated examples of the
intramolecular addition of an NH group, which is part of a heterocyclic
system, to C=O bonds.
The intramolecular nucleophilic addition of lactam N - H groups to a
keto group has been demonstrated [561] for 5-carboxy-6-(2/-oxocyclo-
hexyl)methyl-2( I H)-pyridone (175A) existing in the cyclic form (175B). This
phenomenon was studied in detail [562,563] by means of IR and 'H-NMR
methods using 6-(3/ -oxoalkyl) and 6-(2/ -oxocycloalkyl)methyl-3-hydroxy-
2(lH)-pyridones (176, R' = alkyl, R2 = alkyl; R', R2 = (CH 2 )n). In the
solid state and in DMSO-d 6 solution the open form predominates for
ketoderivatives (176, R' = Me, R2 = Et; R' = Et, R2 = Me), whereas the
COOH
o o
(175A) (175B)
(176A) (176B)
ring form predominates for the corresponding aldehydes (176, R' = H,

R2 = Me, Et, Pr, i-Pr, Bu). Curiously, aldehydes with R2 = CsH" and larger
alkyl groups are open structured in the solid state but in DMSO-d 6 solution
the cyclic form predominates. In the series of crystalline cycloalkanones
130 Chapter 2
(176, RI, R2 = (CH 2 )m n = 3, 4, 5, 6) only the derivative with n = 4 exists

as a cyclic isomer. In DMSO-d 6 solution the tautomeric equilibrium
(176A)? (1768) (K T = 4) is observed. Higher temperature shifts the equili-
brium toward the open form.
2.3.7. 1,3-Diazaheterocycles
An intramolecular addition of an amidine nitrogen atom, part of an

imidazoline ring, to a keto group was reported [564] in the case of 2-(2-
benzoylphenyl)imidazoline. In the solid state this compound possesses the
open structure (177 A, Ar = Ph), but in solution the equilibrium
(177A)? (1778) is observed.
An analogous equilibrium is observed also for 2-(2-aroylphenyl)imi-
dazolines substituted in the aroyl group [565,566].
cG
I
~
l~
N
Ar OH
(1nA) (1nB)
Many investigations carried out by several groups (Alper, Kochergin,

Singh, a.o.) have considered the ring-chain tautomerism of2-acylmethylthio-
1,3-diazaheterocycles. These comprise S-acylalkylderivatives of 2-mercap-
toimidazole (178) [567-572], 2-mercaptoimidazoline (179) [569,571-574],
2-mercapto-I-methylimidazolinium (180) [575], 3-mercapto-I,2,4-triazole
(181) [571], 2-mercapto-3,4,5,6-tetrahydropyrimidine (182) [571], 2-mercap-
tobenzimidazole (183) [572-574,576-583], 2-mercaptonaphtho[I,2-d]imid-
azole (184) [572, 584, 585], 8-mercaptopurine (185) [572,586], 8-mercap-
totheophilline (186) [572,586,587], 2-mercaptoperimidine (187) [588], 5-
mercapto-4-nitroimidazole (188) [589, 590] and 3-mercapto-6-methyl-2,5-
dihydro-I,2,4-triazine-5-one (189) [591]. In most cases these compounds
were isolated as intermediates of syntheses of imidazo[2,I-b]thiazoles and
their derivatives.
On studying the influence of structure and state of aggregation on the
stability of tautomers and ring-chain equilibrium positions 2-formylmethyl-
thioimidazoles and their condensed analogues were found [572,582, 588]
to have a cyclic structure in the solid state as well as in solution. Passing
from aldehydes to aliphatic (RI = Me) and aromatic (RI = Ph) ketones the
stability of the open tautomers increases.
A B
C:tH
R3
N -:;::::-""
R4
):NH
N
A'
(NH
N
)r.., C+)r..
N
NH
I
(178) (179) R
(180)
N-NH ~NH
(A'
N
~~'
N
(181) (182)
L A,
(184)
Njr--NH
~~~'
N
(185)
N
Me "N
°~NI
O
Me
I
N
NH
c2:r, N
(187)
(186)
R6
)-NH Me:(N
/'" . . . NH
N~' o A
NO z
(188) (189)
Varying the structure of substituents R I of 2-acylmethylmercaptoben-

zimidazoles (183, R Z = R S = H) it was shown that the open form is stabilized
by bulky substituents at keto group (R I) as well as by decreasing electrophi-
licity of the keto group brought about by conjugation with aromatic rings,
ethoxycarbonyl or cyclopropyl groups. Compounds (183, R I = 4-XC 6 H4'
COOEt, cyclo-C3 Hs, R2 = R S = H) in the solid state and in solution exist
exclusively in the open form (183A).
132 Chapter 2
Table 26. Ring-Chain Equilibrium Constants of

2-Acylmethylmercaptobenzimidazoles (183)
and -perimidines (187) Determined by
'H-NMR in DMSO-d 6 [588]
KT = [B]/[A]
(183A) <2 (1838) (187 A) <2 (1878)

R' (R 2 = R 5 = H) (R2 = H)
Me 0.54 2.0
Et 0.41 1.5
i-Pr 0.11 0.54
Surprisingly, the introduction of electron-withdrawing substituents in

the para-position of the aromatic ring (R I = 4- N0 2 C 6 H 4 ) does not affect
[581] the stability of the open form, though, as was shown using the
trifluoromethylderivative (183, R I = CF3 , R2 = R 5 = H), the presence of
the substituent R I having a strong -I-effect shifts the equilibrium totally
toward the cyclic form. The introduction of a nitro group into the ben-
zimidazole ring (183, R 5 = N0 2 ) decreases the nucleophilicity of the
nitrogen atom and displaces the equilibrium toward the open form as
compared with the unsubstituted compound.
Alper and Lipschutz [588] comparing equilibrium constants of solutions
of 2-acylmethylmercapto-benzimidazoles and -perimidines (see Table 26)
revealed the influence of the basicity of a nitrogen atom on the equilibrium
position. Higher equilibrium constants, i.e., a greater stability of the cyclic
form of 2-acylmethylmercaptoperimidines, were explained by a greater
basicity of perimidine (pKa = 6.39) compared with benzimidazole (pKa =
5.53).
In the solid state the ring form is more stabilized [572], which, obviously,
is caused by a favorable influence of intermolecular hydrogen bonds. If
imidazole acylmethylmercaptoderivatives have an open structure in solid
state, then in solution the equilibrium is totally displaced toward the open
tautomer. Crystallinic cyclic isomers in solution either possess a cyclic
structure or form ring-chain equilibrium mixtures [582]. Dilution of so-
lutions in nonpolar solvents as well as increasing the temperature of the
solutions shifts the equilibrium toward the open form [592].
Mass spectroscopic investigations [592] of the ring-chain tautomerism
of 2-acylmethylthiobenzimidazoles (183) revealed that in the gaseous phase
these compounds exist in the open form. Fragmentation proceeds from the
open form of the molecular ion with a predominant bond cleavage in the
side chain.
Investigation of the equilibrium (183A) ~ (183B) is suggested to be a

simple experiment in the field of ring-chain tautomerism for an undergradu-
ate organic laboratory course [593].
On studying the influence of ring size on the stability of the cyclic form
of imidazoline (190, n = 1,2) or benzimidazole derivatives (191, n = 0, I;
m = 1,2), it was established [573, 574] that cyclic forms are obtained only
if five-membered ring closure is possible (190, n = I; 191, n = 0, m = I).
R
/
/
O=C
CC
H \
(CH 2 )m
I
~ ~ \
~ 0 /
N (CH 2 )n
(190) (191)
rr ----+
o 0
BrCH,COMe
•
UN~S)
N OH
+ rr~
UN~S
(193) HO I I
Me
(194)
In the reaction of tetrahydroquinazoline-2-thione-4-one (192) with

bromoacetone a mixture of the products (193) and (194) was obtained [594]
in ratio 9: I. This may be explained assuming that formation of the ring
occurs at the sterically less hindered nitrogen atom even if the competitive
nitrogen atom is more basic.
2.3.8. Triazenes
An intramolecular addition of a triazene nitrogen atom to the keto
group in 1-(2-oxoalkyl)triazenes (195A) leads to the formation of 5-hydroxy-
£12 -I ,2,3-triazolines (195B) [595-600].
(1958) (195A) (1958')

134 Chapter 2
In the solid state and in solution N -alkyl derivatives exist exclusively

in the cyclic form (195B, R I = alkyl). An introduction of various substituents
R2 and R3 results in an equilibrium between two diastereoisomers (195B)
and (195B') [597,598].
In solutions of 1-{2-oxoalkyl)-3-aryltriazenes bearing a bulky alkyl
substituent at the keto group the equilibrium (195A) ~ (195B) is adjusted
within a few seconds. In the solid state these compounds, except for (195A,
Rl = Ph, R2 = R3 = Me, R4 = t-Bu), possess a cyclic structure (195B).
Bases, e.g., potassium hydroxyde in DMSO-d 6 , accelerate equilibration
which then is fast on the IH-NMR time-scale [598].
From Table 27 it can be seen that decreasing the nucleophilicity of the
nitrogen atom by means of electron-withdrawing substituents in the aryl
group displaces the equilibrium in favor of the open form. Electron-donating
substituents act in the reverse direction.
When substituents R I, R2, and R3 remain unchanged a change of R4
from isopropyl to t-butyl causes a drastic decrease of K T • The introduction
of a second methyl group (195, R2 = R3 = Me) to the fourth carbon atom
of the triazoline ring considerably shifts the equilibrium toward the open
form. The destabilization of a cyclic isomer is a most remarkable exception
since generally the introduction of two geminal methyl groups into the chain
between interacting groups stabilizes the cyclic structure (Thorpe-Ingold
effect). It is possible that the cyclization of 1-{2-oxoalkyl)triazenes is kineti-
cally impeded by two methyl substituents in a-position to the keto group
for steric reasons.
Proton acceptor solvents stabilize the ring form due to the formation
of intermolecular hydrogen bonds O-H···solvent. Passing from solutions
Table 27. Ring-Chain Equilibrium Constants in Solutions of

1-(2-0xoalkyl)-3-aryltriazenes (195A, R3 = Me) ~ (195B)
Determined by IH-NMR [598]
KT = [B]/[A]
R' R2 R4 CDCl 3 Pyridine
4-NH 2 C 6 H4 H I-Bu 8.09 >49

Ph H I-Bu 3.17 >19
4-N02C 6 H4 H I-Bu 1.14
4-NH 2 C 6 H4 Me i-Pr 1.94 19
4-MeOC 6 H4 Me i-Pr 1.70 19
Ph Me i-Pr 0.89 11.5
Ph Me I-Bu 0.10 0.41
4-BrC 6 H4 Me i-Pr 0.79 8.1
4-N02C 6 H4 Me i-Pr 0.43
in chloroform to solutions in pyridine or DMSO shifts the equilibrium

towards the cyclic form.
2.3.9. Miscellaneous
In addition to examples of a ring-chain tautomerism mentioned above
proceeding by a formation of carbinolamines the tautomerism of
monoimines of 1,5-diketones [601,602], O-(3-oxoalkyl)hydroxylamines
(196A) ~ (196B) [603,604], monohydrazones of 1,3-dicarbony1compounds
(197A) ~ (197B) [605-613], 2-(2-formylbenzoyl)-I-hydrazono-I,2-dihy-
drophthalazine (198A) ~ (198B) [614], N -(2-pyridyl)aminoacetaldehydes
(199A) ~ (199B) [615] is reported.
R2
I
R i COCH 2 CONHR
I
R3
(l96A) R = H, CONH 2
(197A)
er
~
I
~O
C........
CO-N:U
H
NH
I
........2
N
I
0------+
+---'-
N~ .,.-::;
(l98A)
C(I :::""'N NHCH 2 CHO

~a~R
N ~N
(l99A) HO-i--J
H (1998)
R= COOH, CONH 2
136 Chapter 2
Ring-chain equilibria were repeatedly discussed in connection with

investigations of mechanisms of nitrogen-containing heterocycles (see, for
example [612,616]). However, it has rarely been possible to isolate the
carbinolamine intermediates.
Investigating the mechanism of Hantzsch's thiazole synthesis from
a-haloketone and thioamide intermediates (200A) and (200B) were isolated
[616]. The cyclic structure of 4-hydroxythiazolinium ion (200B) is stabilized
by the introduction of the substituents R 3 , whereas bulky substituents at
the nitrogen atom (R') and at the keto group (R4) stabilize the open
structure.
An interesting case of a formation of a carbinolamine structure was

recently detected [617] for a cobalt(III) amine complex (201A) -+ (20lB).
2.4. INTRAMOLECULAR MIGRATION OF 0-, N-,

AND S-ACYL GROUPS
The intramolecular migration of acyl functions between two

nucleophilic groups (202) ~ (204) is an example of chemical transformations
which proceed via heterocycles oflow stability (cyclic tetrahedral intermedi-
ates). The close relationship of these reactions with ring-chain tautomerism
under consideration is best demonstrated by the fact that both reactions
proceed by an intramolecular nucleophilic addition to an acyl carbonyl
group (R-CO-O, R-CO-N, R-CO-S) [618-623].
-.:/0
(X-H-.:/O~ [CX:C~O-H] ~ (X~C"R
Y-C" Y R Y-H
(202) R (203) (204)
X, Y=O, NR, S
Migration of acyl groups is observed in acylated aminophenols,
aminoalcohols, polyalcohols, polyphenols, diamines, thioglycols, amino-
thiophenols, aminothiols, etc. Not only acyl but also other groups accessible
to nucleophilic attack are subjects of migration between two nucleophilic
centers (OH, NH, SH).
Many examples using kinetic methods show [620] that acyl group
migration (0 -+ N, N -+ 0, 0 -+ 0', N -+ N', S -+ 0, S -+ N, N -+ S e.o.)
proceeds along the general mechanism via cyclic tetrahedral intermediates.
Following an intramolecular nucleophilic addition of the X-H group (X =
0, N R, S) to the acyl C=O group the cyclic tetrahedral intermediate (203)
depending on the pH value of the medium opens along the most easily
polarizable bond (C-X or C- Y). Cyclic intermediates (203) rarely are
isolated because they are of low stability [624].
Both isomers (205A) and (205B) of a rearrangement of 2-benzoyloxy-
a
benzyl alcohol have been isolated [625], and their interconversions in both
directions were accomplished.
CH20H
~9_0H
L MeONa
I 2. H 2 S0 4 •
~
~ OCOPh CHCI 3 ~OAph
(205A) (205B)
Me Me
Met5<OH
Me 0 CF3
(206A) (206B)
The ring-chain equilibrium (206A) i2 (206B) has been observed in so-

lutions of pinacol trifiuoroacetate using IH-NMR spectroscopy [626]. In
this case the cyclic form is stabilized by two gem-dimethyl groups and a
strong electron-withdrawing substituent (CF 3 ) at the keto group. Analogous
Me, MeAo
M- ~0
HoN";-"~~Me
HO ~
I
~ SO-
3
(207)
138 Chapter 2
structural factors, i.e., a protonated imidazole as an electron-withdrawing

group and a gem-dimethyl group stabilize the tetrahedral intermediate (207)
which was isolated also [627,628].
The acidity of the medium exerts a great influence on the rates and
direction of acyl group migration. Thus, an 0 -+ N migration of acyl groups
proceeds only in alkaline solution while in acidic medium the reverse N -+ 0
migration occurs. This is explained by the greater basicity of the nitrogen
atom compared with that of the oxygen atom.
The formation of the cyclic tetrahedral intermediate (203) is supported
by experiments concerning the influence of the steric proximity of both
nucleophilic centers on the migration rate.
In a series of S-acetylmercaptoalkylamines of general formula
MeCOS(CH2)nNH2 it has been demonstrated [629] that the transacetylation
rate of S-acetylmercaptoethylamine (n = 2) is higher by two orders than
that of 3-S-acetylmercaptopropylamine (n = 3). If the chain between the
nucleophilic centers amounts to more than three carbon atoms, the trans-
acetylation does not take place at all. The formation of a five-membered
cyclic tetrahedral intermediate proceeds considerably more rapidly [630]
than that of a six-membered analogue. The greatest rate of transacylation
including cyclic five-membered intermediates was observed in a series of
acetylthioalkanols [631] and similar compounds [620].
Differing rates of acyl group migration are observed for
diastereoisomers of acylated aminoalcohols. For cis- or threo-forms of
1,2-aminoalcohols the transacylation proceeds rapidly but for analogous
compounds with trans- or erythro-configuration the migration proceeds
extremely slowly and requires severe conditions. In the last case products
with the reversed configuration are obtained indicating a different migration
mechanism (intramolecular electrophilic addition to a carbonyl group)
[620,632-634]:
The migration rate increases with rising acyl group electrophilicity. For
this reason an acetyl group migrates more rapidly than a benzoyl group.
Thus, for example, the rate of S-acetylmercaptoethylamine transformation
into the corresponding thiol is higher by an order of magnitude than that
of the rearrangement of S-benzoylmercaptoethylamine [635]. The acceler-
ation of the migration of a trichloroacetyl group is even greater.
Though structural factors favoring the formation of the cyclic tetrahe-
dral intermediate (203) in general affect positively the migration of acyl
groups, the total rate of the process depends as well on the ring opening
(203) -+ (204). For example, it was determined that for S -+ N migration
the rate is greater than 0 -+ N. However, in the case of O-acylaminoa1cohols
the formation of an intermediate cyclic compound proceeds more rapidly
by two orders of magnitude than in the case of S-acylaminothiols. This is
caused by a greater electrophilicity of the -CO-O- group carbon atom
compared to that of the -CO-S- group. Considering this one should
expect that the rate of migration of an acyl group from 0 -+ N could be
greater than that of the migration S -+ N. Actually the subsequent opening
of a hydroxythiazoline ring, leading to the formation of N-acylaminothiol,
in alkaline medium proceeds significantly more rapidly than hydroxy-
oxazolidine ring opening, and as a result the rate of S -+ N transacylation
appears to be greater [620,636].
Minkin, Olekhnovich, and Zhdanov [637-639] detected and thoroughly
investigated the migration of acyl and nitro aryl groups in the systems
(208) ~ (210), (211) ~ (213), and similar ones [638,640-642] proceeding
through bipolar cyclic intermediates (209) or (212).
Contrary to the prototropic migration processes for acyl groups dis-
cussed so far, which proceed with a simultaneous proton migration, these
transformations relate to acylotropic or arylotropic (carbonotropic) rear-
rangements.
Electronic and steric effects of substituents and the structure of
molecules favoring or disfavoring the formation of cyclic intermediates and
thus controlling the migration rate have the same influence as those in the
prototropic ring-chain equilibrium systems already discussed.
Thus, for example, increasing the electron-withdrawing properties of
the substituent R in (208) accelerates the migration of acyl groups, electron-
withdrawing properties of the substituents R I and R3 on the other hand
retard it. The migration process is accelerated as well by a steric interaction
of the reacting groups, e.g., by passing from (208) to (211).
The introduction of three electron-withdrawing substituents in the
migrating aryl group (211, R = 2,4,6-trinitrophenyi), the introduction of
methyl groups in positions 3 and 7 of tropolone ring (211, R I = R2 = Me),
sterically favoring the approaching of interacting groups, and also increasing
140 Chapter 2
o
II
C
VR2
R/ ' 0 0
R1 R3
(208) (209) (210)
/
R / ,
R- R
\
X Y X Y X Y
Rl(JR2
I
~ RI@"---'R2
~
' ~RDR' ',-,:
+ ,
(211) (212) (213)
>(}
----- (NOJn
n = 1, 2,3
the nucleophilicity of the centers X and Y in the series 0 < NR' < S stabilize
the bipolar intermediate (212). It does not matter if centers X and Y differ
greatly in nucleophilicity as indicated by arylthiotropones (211, X = 0,
Y = S, R 1 = R2 = H) where the equilibrium is totally displaced toward
(213).
It is not within the scope of this book to discuss in detail intramolecular
migrations of acyl and similar groups (see reviews [618-624]). We only want
to show that structural factors, governing intramolecular additions of XH
groups to C=O bonds in ring-chain tautomeric systems, also rule
intramolecular acyl migrations and similar reactions which proceed via
cyclic tetrahedral intermediates.
2.5. OXA-, AZA-, AND THIACYCLOLS
The insertion of a hydroxy-, amino- or mercapto-carboxylic acid moiety

into the ring of a lactone, or a cyclic peptide or depsipeptide, represents a
particular case of intramolecular transacylation. These reactions proceed
according to the scheme given below, "cyclols" (215), i.e.: oxacyclols (X =
0), azacyclols (X = NR) and thiacyclols (X = S) being intermediates of
the reactions. Finally peptide (216, X = NH), depsipeptide (216, X = 0)
or thiadepsipeptide (216, X = S) macro cycles (see Table 28) are formed.
Wrinch [646-648] was the first to discuss the possibilities of the forma-
tion of cyclols from peptide molecules. The scheme of interconversions
(214)-(216) was proposed by Shemyakin [649,650]. Hofman's synthesis
of ergotamine [651-654] was based on this principle.
0 OH 0
II I II
,r-- X - He""" ,r--X-C~ ,r--X-C~
Y
"--C--N./
I z 4 ~
Y I z
"--C-N~
4 ~ Y
"--C-N./
Z
II II II I
0 0 0 H
(214) (215) (216)
X= O. NR.S
Shemyakin, Antonov, Shkrob [649,650,655-658] investigating these

reactions systematically showed that the reaction sequence (214) - (216)
represents a new way of inserting hydroxy and amino acids into peptide
chains or rings. The formation of stable cyclols (215) is a particular case
of these reactions requiring definite structural and steric conditions.
The investigation of N -hydroxyacyllactams (214, X = 0) showed [643,
644, 656, 659-661] that depending on the size of the cycle (Z) and on the
structure of hydroxyacylchain (Y) either a spontaneous isomerization
(214) - (216) proceeds or oxacyclols (215, X = 0) are isolated, not being
capable of isomerization into macrocycles (216).
Table 28. Isomeric Structures of

N -Hydroxyacyllactams (214, X=O,
Z=(CH 2 )n) [643-645]
y n Structure
CH 2 3 (214)
MeCH:::: 3 (214)
CH 2 CH 2 3 (214)
CH 2 4 (214) <2 (215)
MeCH:::: 4 (214) <2 (215)
Me2C:::: 4 (215)
CH 2 CH 2 4 (216)
CH 2 5 (214) <2 (215)
MeCH:::: 5 (215)
CH 2CH 2 5 (216)
CH 2 11 (216)
o-C 6 H4 3 (214)
o-C 6 H4 4 (215)
o-C 6 H. 5 (215)
142 Chapter 2
N-Glycolyl- and N-(3-hydroxypropionyl)butyrolactams (214, X = 0,

Y = (CH 2 ) and (CH 2 )2, Z = (CH 2 h) do not isomerize into cyclols (215).
For N -glycolyl- and N -(2-hydroxypropionyl)-valerolactams (214, X = 0,
Y = CH 2, CHMe, Z = (CH 2)4) a tautomeric equilibrium (214) ~ (215) is
observed in solution. If macrocycles containing eleven or more atoms are
formed, cyclodepsipeptides (216, X = 0) emerge in high yields. Sometimes
even ten-membered rings are obtained (216, X = 0, Y = (CH 2)2, Z =
(CH 2)4) (see Table 28).
Unlike N -salicyloylbutyrolactam, N -salicyloylvalero- and -caprolac-
tams form stable cyclols. The latter are not capable of isomerization into
the corresponding cyclodepsipeptides, the formation of which is prevented
by the presence of a benzene ring which flattens the macrocycle (216) thus
favoring the intramolecular transannular addition reaction between the
amide N - H group and the ester c=o group.
In solutions of N-(a-hydroxyacyl)diketopiperazines an equilibrium
(214) +:! (215) is observed [662]. On heating the equilibrium shifts toward
N-hydroxyacyllactams (214). The rate of the equilibration in solutions
(dioxan, tetrahydrofuran) appreciably increases in the presence of trace
amounts of water.
Isomeric interconversions (214) +:! (215) +:! (216) were observed also in
a series of azacyclols. However, azacyclols (215, X = NR) have only rarely
been isolated since in most cases they dehydrate yielding cyclic acylamidines
(217). Alternatively, they may isomerize into cyclodipeptides (216, X = NH)
[656,657,663-665].
H OH
I I
/N-C~ /N=C~
Y I Z Y I Z
"'--C-N~ "'--C-N~
II \I
o o
(215, X = NH) (217)
The isomerization of azacyclols into cyclopeptides (215, X =

NH) --. (216) proceeds more rapidly than the analogous conversion of
oxacyclols [656,665]. It has been assumed that cyclopeptides are less prone
to a reverse transannular reaction between two amide groups (216, X =
NH) --. (215) than cyclodepsipeptides in a similar reaction between amide
and ester groups (216, X = 0) --. (215).
An azacyclol was isolated from N-(2-methylaminobenzoyl)butyrolac-
tam (215, X = NMe, Y = o-C6 H4' Z = (CH 2 h) [666].
Italian scientists [667] obtained azacyclols (218) substituted at the
nitrogen atom and therefore not capable of dehydration by cyclization
~iR
M~\-~;lo
o H 'CH 2 Ph
(218) R = PhCH 2 0CO. 4-BrC 6 H.OCO
of N -benzyloxycarbonyl- and N -4-bromobenzyloxycarbonyl-L-alanyl- L-

phenylalanyl-L-proline-4-nitrophenyl esters in aqueous alkaline solution.
Other azacyclols [668,669] as well as oxacyclol [670] of tripeptide structure
have also been obtained by them.
A stable azacyclol, 7 -hydroxy-2-oxo-l-azabicyclo[5.3.0]decane (220), is
formed by a trans annular addition of the amide N - H group to the keto
group in l-azacyclodecane-2,7 -dione (219) [671].
c!) --rt\
01
~N-/
H o
(219) (220)
n
Me~Sfr'~/
9H
H' N H 10
I X_~'
o CH 'H
,,2
Ph
(221)
In solutions of N -( thiosalicyloyl)lactams (214, X = S Y = o-C 6 H4'

Z = (CH 2 )m n = 3-5), tautomeric equilibria (214) ~ (215) ~ (216) have
been detected [672-674]' Increasing the size of the lactam ring as well as
increasing the dielectric constant of the solvent displaces the equilibrium
toward the macrocycle (216).
A stable thiacyclol (221) was obtained [675] by the cyclization of
[( RS)-2-tritylthiopropionyl]- L-phenylalanyl-L-proline.
Additional analogous formations of heterocycles via intermediate
cyclols are known. The isomerization of 3-( N -ethylaminocarbonylmethyl)-
144 Chapter 2
1,3-benzoxazine-2,4-dione (222) into I-salicyloyl-3-ethylhydantoin (224)

proceeds most likely via an intermediate cyclol (223) [676].
o
~N)=O
VO+N OH\
(223) Et
(224)
t( SOlCI
_HX_-_Z_-Y_H--.. t( , SO -X-Z-YH
(225) (226)
t NHSOlCI
C-Y-Z-XH
o
II
(228)
~ ~NH-SO"l
~C--Y/
II
o
(229)
X, Y=O,NR;
Z = O-C S H4' (CH 2 b
A synthesis of macrocycles (229) from N -sulphochlorides of f3-lactams

(225) and bis-functional nucleophiles HX-Z- YH was recently reported [677].
The mechanism was thought to proceed via intermediate cyclols (227).

However, an alternative mechanism as well is under discussion, based on
the assumption of an initial attack of the nucleophile at the carbonyl group
followed by opening of the lactam ring and repeated cyclization
(225) -+ (228) -+ (229). .
Hesse and co-workers proposed [678-684] a convenient method for
the synthesis of macro cyclic polyaminolactams (231) by an alkaline
isomerization of N-3-aminopropyllactams (230, m = 0, n = 6,7,9,11). The
KAPA reagent (I ,3-propanediamine/ potassium 3-aminopropylamide) was
used as a catalyst for the isomerization.
C:H,) "-[NH(CH,),]:)
II I
o H
(231)
The reaction works also when the chain at the lactam nitrogen contains
several aminopropyl residues (230, n = II, m = 1,2,4,9). Using this route
[679] even a 53-membered polyaminolactam was obtained. The authors
suppose [683] that the introduction of aminopropyl residues into the ring
proceeds stepwise via intermediate cyclol anions:
---
-H+
KAPA
146 Chapter 2
In analogy to a zip-fastener this reaction is called a "zip-reaction."

Reimschuessel [685] proposed a cyclol mechanism for an isomerizing
polymerization of ,B-carboxy- and ,B-carboxymethyllactams, e.g., for the
polymerization of ,B-carboxymethyl caprolactam:
rN~
C _ o~ -- H,o
COOH
The examples reported so far convincingly demonstrate that cyclols

are of great importance as intermediates in the formation of many macro-
cyclic systems, particularly of cyclopeptides and cyclodepsipeptides.
Unfortunately, the information available from the literature does not allow
a more detailed discussion of the influence of molecular structure on the
relative stabilities of cyclols (215) and their isomers (214) and (216), probably
with the exception of oxacyclols (see Table 28).
The transformation (216) -+ (215) is a transannular isomerization. Use-
ful information about trans annular interaction and reactions of type
(232) -+ (233) and other similar reactions has been given in reviews by
Leonard [686,687].
The transformations of type (232) -+ (233) not being isomerizations will
not be discussed in detail here.
o OH
cb
II
C~)
I I
R R
(232) (233)
2.6. MERCAPTO ALDEHYDES AND KETONES AND

RELATED COMPOUNDS
The ring-chain isomeric interconversions of this type have been com-

paratively rarely investigated. As generally known sulfur possesses a higher
nucleophilicity than oxygen. Thus, if the structure of the linking chain does
not hinder intramolecular addition, ring isomers (234B) predominate. They
are often subjected to dehydration reactions or to more complicated transfor-
mations.
(S~H S S-
/
C=O
4 •
(LoH I
~
(c=O/
R R R
(234A) (2348) (235)
Since an SH group has a greater acidity than an OH group [688], anions

can be expected to possess the open structure (235) as discussed below.
N -(2-0xo-l, l-dimethylalkyl)- and N -(2-oxo-l, I-diphenyl)alkyl-
dithiocarbaminic acids (236A, R 1 = Me, Ph, R2 = Me, Ph) in the solid state
and in solution are cyclic 5-hydroxythiazolidine-2-thiones (236B), but the
anion possesses the open structure (237).
R~jlH~
HO S S
(236A) (2368) (237)
Me Me
"- /
M><M~H
C
H C/ "NH
2 I I..
Me>l~l
Me ./' ~
C
OHS
/ ~S
C
HO S S
(238A) (2388)
/COR
/COR S 0
N-N 0 II II
N-N OH -H+ II \ ~
II \/ ~ C C PhC-NHNH-C-R
~A /\ "-
Ph S H Ph S- H
(239) (240) (241)
5-(t-Butyl)-5-hydroxythiazolidine-2-thione (236B, Rl = t-Bu, R2 = H)

in solution transforms into the open form (236A). In CDCl r DMSO-d 6 at
-40°C, however, signals of cyclic (236B) are only observed by IH-NMR
148 Chapter 2
spectroscopy. Heating the solution above O°C results in ring opening

(236B) - (236A). Analogous reactions were observed in solutions of 5-
hydroxy-5-phenylthiazolidine-2-thione (236B, R I = Ph, R2 = H) and 6-
hydroxy-4,4,6-trimethyl-l,3-thiazine-2-thione (238B) [689, 690].
The products of the covalent hydration of 3-acyl-5-phenyl-l,4,5-
thiadiazolium salts are cyclic 3-acyl-2-hydroxy-5-phenyl-l,4,5-thiadiazo-
lines (239) [691,692]. The anion (240) has the open structure, and N -acyl-N'-
thiobenzoylhydrazines (241) have been isolated by acidification of alkaline
solutions. Reactions of compounds (239) with diazomethane gave S-methyl-
derivatives of open structure while with diazoethane a mixture of S- and
O-derivatives was formed.
In acidic aqueous solution O'-thiosemicarbazones, dithiocarboxyhy-
drazones, and thiobenzoylhydrazones of isatin are in equilibrium with
9b-hydroxy-l,3,4-thiadiazino[5,6-b]indoles (242A) ~ (242B) [693,694].
Increasing medium acidity displaces the equilibrium toward the cyclic
(242B) which apparently is more basic.
(2428)
Rl = H; R2 = NH 2, NHMe, NMe2' SH (only B), SMe, Ph, 4-MeOC sH4' 3-CIC sH4.
R2 = Me; R2 = NH 2, NMe2' NHPh, 4-EtOOCC sH4NH.
Electron-donating substituents R2 shift the equilibrium toward (242B).

With the exception of (242B, R I = H, R2 = SH) both isomers were isolated,
the open isomers being red, the cyclic yellow. It can be deduced from kinetic
measurements carried out by the UV spectroscopic method that increasing
the acidity of the solution raises the cyclization rate. In the rate-limiting
step of cyclization a proton participates. Obviously, the protonation of the
keto group precedes the cyclization. In acidic solution the reaction
(242A) - (242B) is accelerated by electron-donating substituents R2.
CC( Oct
OH
O S NHR
l SrNR
,\--/4
I
~ N ~ /N~
1 3
~ ~ /N,
N N Me
I ~ Me I
H H
(243A) (2438)
However, under neutral conditions the influence of substituents R2 on the

rate of cyclization could not be evaluated.
The introduction of a methyl group at N(2) of isatin a-thiosemicar-
bazone and its 4-methylderivative (243A, R = H, Me) significantly acceler-
ates cyclization (243A, R = H, Me) -+ (243B) compared with N(2) unsub-
stituted derivatives (242A, RI = H, R2 = NH 2 , NHMe).
2.7. INTRAMOLECULAR ADDITION OF C-H GROUPS
Intramolecular addition of C- H groups to a C=O bond occurs rather

frequently. However, these as well as the reverse reactions generally are
practical only in the presence of alkali, acids, or other catalysts. The need
to use severe reaction conditions often results in a dehydration of the
products of intramolecular addition yielding unsaturated compounds.
An important condition for the above-mentioned reactions is the pres-
ence of electron-withdrawing substituents at a carbon atom, which increase
the acidity of the C- H bond, thus favoring either the formation of a
carbanion (basic catalysis) or an electrophilic substitution of hydrogen atom
(acidic catalysis).
o
II RI
C <i~CH/ R2
2 I
C-COOH
II
o
(244A)
OC
~
I 5
II
Cc,c-....
I /'
/'
7 C H.. . .
C-COOH
--+
~
II HO COOH
o
(245A) (2458)
Shemyakin and Shchukina [695] summarized a large amount of the

information concerning the formation of hydroxycarboxylic acids in cycli-
zation reactions (244A) -+ (244B) and (245A) -+ (245B). They came to the
150 Chapter 2
conclusion that a comparatively important influence on both reactions is

exerted by the carboxylic group increasing the electrophilicity of the adjacent
keto group.
In (244A) the keto group in position 5 as well as substituents R I and
R2 (CI, OH, NCsHs a.o.) [695-697] possessing a -I-effect raise the C-H
acidity and favor cyclization. The same is true for substituents at the atoms
C(6) and C(7) in (245). Hydroxycarboxylic acids (245B) under conditions of
their formation are often subjected to dehydration or subsequent oxidative
decarboxylation to quinones.
Transformations of this kind are important for a discussion of a·mecha-
nism of oxidative-hydrolytic transformations of quinones and particularly
of the Hooker-reaction [697-699]. Unfortunately, no spectroscopic investi-
gation of this type of equilibrium has been carried out. This is obviously
caused by difficulties which result from the severe reaction conditions
necessary to carry out an intramolecular addition of C- H groups to the
c=o bond.
Unlike the nucleophilic addition of O-H, N-H, and S-H groups
to the C=O bond which is due to a participation of p-electrons of these
heteroatoms and a final migration of the proton, a nucleophilic addition of
a C- H group cannot take place before the proton has been removed
forming a carbanion in alkaline solution. In strongly acidic media, where
the keto group is protonated, reactions can proceed as electrophilic substitu-
tion of the hydrogen atom (C-H).
Thorpe [700-705] quantitatively investigated ring-chain equilibria of
2-oxo-3,3-disubstituted glutaric acids (246A) ~ (246B).
Rl CH 2 COOH Rl
, / »[COOH
C • •
R2/ 'C-COOH R2 COOH
II HO
o
(246A) (2468)
Et Et Et Et
H>0<H HOOC>0<H
HOOC " 0 "COOH H 0 COOH
(247) (248)
These studies gave rise to the very useful hypothesis [472] of the
gem-dimethyl or gem-dialkyl effect which has been called the Thorpe-Ingold
effect. This effect was discussed earlier in this book and used repeatedly to
explain the stabilizing influence of the gem-dialkyl substituents in a chain
on cyclic tautomers as well as the accelerating influence on the cyclization

reactions. The effect was experimentally supported by many cyclization
reactions [47-55, 706-708] and was theoretically substantiated [52-54].
OH
O I
CH-COOH
CH-COOH
I
OH
(249)
Curiously, the structures of the compounds (246A) and (246B), the

investigation of which initiated the conceptualization of the Thorpe- Ingold
effect, are incorrect. After it was stated that the first experiments gave no
strict evidence [48] a reinvestigation [709] using 'H-NMR spectroscopy
revealed that the compounds described by Thorpe as (246A, R' = R2 = Et)
and (246B) were actually oxethanes (247) and (248). According to other
work [710] the compound (246B, R', R2 = (CH 2 )s) really possesses structure
(249).
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257. A. Mondon, G. Aumann, and E. Oelrich, Chern. Ber. 1972, /05,2025.
258. E. W. Warnhoff, W. T. Tai, and Y. C. Toong, Can. J. Chern. 1978, 56, 93.
259. S. Mincev and B. V. Aleksiev, Compt. Rend. Acad. Bulg. Sci. 1976,29,363.
260. S. Gabriel, Ber. Dtsch. Chern. Ges. 1885, 18, 1251.
261. S. Gabriel, Ber. Dtsch. Chern. Ges. 1885, 18,2433.
262. S. Gabriel, Ber. Dtsch. Chern. Ges. 1885, 18,2451.
263. A. Ruhemann, Ber. Dtsch. Chern. Ges. 1891, 24, 3964.
264. C. Graebe and F. Ullmann, Justus Liebigs Ann. Chern. 1896, 291, 8.
265. F. Sachs and A. Ludwig, Ber. Dtsch. Chern. Ges. 1904, 37, 385.
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266. H. Meyer, Monatsh. Chern. 1907,28, 1211.

267. S. Wawzonek, H. A. Laitinen, and S. J. Kwiatkowski, J. Am. Chern. Soc. 1944, 66,830.
268. Z.-l. Horii, Ch. Iwata, and Y. Tamura, J. Org. Chern. 1961, 26, 2273.
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270. Y. Kubota and T. Tasuno, Chern. Pharrn. Bull. Tokyo 1971, 19, 1226.
271. C. Broquet and J. P. Genet, Cornpt. Rend. Acad. Sci., Ser. C 1967,265,117.
272. H.-R. Muller and M. Seefelder, Justus Liebigs Ann. Chern. 1969, 728, 88.
273. H. Fritz and S. Schenk, Justus Liebigs Ann. Chern. 1975, 255.
274. L. Barsky, H. W. Gschwend, J. McKenna, and H. R. Rodriguez, J. Org. Chern. 1976, 41,
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275. E. Breuer and S. Zbaida, Tetrahedron 1975, 31,499.
276. M. Sekiya and Y. Terao, Chern. Pharrn. Bull. Tokyo 1970, 18, 947.
277. A. M. Islam and Y. M. EI-Gharby, Egypt. 1. Chern. 1973, 16, I.
278. F. Micheel and W. Flitsch, Chern. Ber. 1961, 94, 1749.
279. W. Flitsch, Justus Liebigs Ann. Chern. 1965, 684, 141.
280. M. Sekiya and Y. Terao, J. Pharrnac. Soc. Jpn. 1968, 88, 1085.
281. L. Sh. Arsenievich and D. B. Stefanovich, Glasn. Khern. Drushtva 1970,35,209.
282. W. S. Ang and B. Halton, Austr. J. Chern. 1971, 24, 851.
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285. W. Metiesics, T. Anton, and L. H. Sternbach, J. Org. Chern. 1967,32,2185.
286. P. Aeberli and W. J. Houlihan, J. Org. Chern. 1969, 34, 165.
287. H. Bredereck and H. W. Vollmann, Chern. Ber. 1972, 105,2271.
288. H.-J. W. Vollmann, K. Bredereck, and H. Bredereck, Chern. Ber. 1972, 105, 2933.
289. T. W. M. Spence and G. Tennant, J. Chern. Soc., Perkin Trans 1 1972, 835.
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291. A. R. Katritzky, S. Rahimi-rastgoo, and N. K. Ponkshe, Synthesis, 1981, 127.
292. S. Petersen and H. Heitzer, Justus Liebigs Ann. Chern. 1978, 283.
293. G. A. Karlivans and R. E. Valters, Khirn. Geterotsikl. Soedin. 1980, 335.
294. R. E. Valters and G. A. Karlivans, Latv. PSR Zinat. Akad. Vestis, Kim. Ser. 1976,61.
295. R. E. Valters and G. A. Karlivans, Khirn. Geterotsikl. Soedin. 1976, 1207.
296. G. A. Karlivans, R. E. Valters, and V. P. Ciekure, Khirn. Geterotsikl. Soedin. 1977, 763.
297. O. S. Anisimova, Yu. N. Sheinker, and R. E. Valters, Khirn. Geterotsikl. Soedin. 1982,666.
298. G. A. Karlivans and R. E. Valters, Zh. Org. Khirn. 1978, 14, 890.
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307. J. R. Mednis and R. E. Valters, Latv. PSR Zinat. Akad. Vestis, Kim. Ser. 1977,74.
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310. G. B. Quistad and D. A. Lightner, Tetrahedron Lett. 1971,4417.
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315. A. Queen and A. Reipas, 1. Chern. Soc., Sect. C 1967,245.
316. H. Junek, B. Hornisher, and H. Hambiick, Monatsh. Chern. 1969, 100,503.
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318. M. Semonsky, A. Cerny, B. Kakac, and A. Subrt, Collect. Czech. Chern. Cornrnun. 1963,
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322. R. Lukes and J. Gorocholinskij, Collect. Czech. Chern. Cornrnun. 1936, 8, 223.
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325. E. J. Cragoe, Jr. and A. M. Pietruszkiewicz, f. Org. Chern. 1957, 22, 1338.
326. E. Winterfeldt, Chern. Ber. 1964, 97, 2436.
327. E. Tagmann, E. Sury, and K. Hoffmann, He/v. Chirn. Acta 1954,37, 185.
328. A. Warshawsky and D. Ben·Ishai, f. Heterocycl. Chern. 1970, 7,917.
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331. L. Kronberg and B. Danielson, Acta Pharrn. Suec. 1971, 8,373.
332. S. Gabriel, Ber. Dtsch. Chern. Ges. 1887, 20, 2863.
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335. D. W. Jones, f. Chern. Soc., Sect. C 1969, 1729.
336. W. E. Kreighbaum, W. F. Kavanaugh, and W. T. Comer, f. Heterocycl. Chern. 1973, 10,
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338. R. Nowicki and A. Fabrycy, Khirn. Geterotsikl. Soedin. 1976, 1103.
339. A. Warshawsky and D. Ben-Ishai, f. Heterocycl. Chern. 1969, 6,681.
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343. K. Bowden and G. R. Taylor, f. Chern. Soc., Sect. B 1971, 149.
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348. K. Bowden and M. P. Henry, f. Chern. Soc., Sect. B 1971, 156.
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350. M. S. Newman and S. S. Gupte, f. Org. Chern. 1970,35,4176.
351. K. Bowden and A. M. Last, f. Chern. Soc., Chern. Cornrnun. 1970, 1315.
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353. K. Bowden and A. M. Last, f. Chern. Soc., Perkin Trans. 2 1973, 351.
355. K. Bowden and F. A. EI-Kaissi, f. Chern. Soc., Perkin Trans. 2 1977, 526.
356. K. Bowden and F. A. El-Kaissi, f. Chern. Soc., Perkin Trans. 2 1977, 1927.
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358. M. S. Newman and K. Naiki, f. Org. Chern. 1962, 27, 863.
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360. M. S. Newman and C. Courduvelis, f. Arn. Chern. Soc. 1964, 86, 1893.
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362. M. L. Bender, J. A. Reinstein, M. S. Silver, and R. Mikulak, f. Arn. Chern. Soc. 1965, 87,
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363. K. Bowden and G. R. Taylor, f. Chern. Soc., Chern. Cornrnun. 1967, 1112.
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366. K. C. Kemp and M. L. Mieth, f. Chern. Soc., Chern. Cornrnun. 1969, 1260.
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368. B. Capon, Quart. Rev. Chern. Soc. 1964, 18,45.
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371. S. Wawzonek and J. H. Fossum, f. Electrochern. Soc. 1949, 96,234.
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380. H. Kosmol, K. Kieslich, and H. Gibian, fustus Liebigs Ann. Chern. 1968, 711,42.
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386. H. Sterk, Monatsh. Chern. 1968, 99, 2107.
387. J. E. Whitting and J. T. Edward, Can. f. Chern. 1971, 49, 3799.
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392. J. A. Zalikowski, K. E. Gilbert, and W. T. Borden, f. Org. Chern. 1980, 45, 346.
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398. B. M. Mikhailov and A. N. Makarova, Zh. Obshch. Khirn. 1957, 27, 2526.
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684. U. Kramer, H. Schmid, A. Guggisberg, and M. Hesse, Helv. Chirn. Acta 1979, 62,811.
685. H. K. Reimschuessel, Angew. Chern. 1975, 87, 43.
686. N. J. Leonard, Rec. Chern. Progr., 1956, 17,243.
687. N. J. Leonard, Acc. Chern. Res. 1979, 12,423.
688. A. Ohno and S. Oae, In: Organic Chemistry of Sulfur, Ed. S. Oae, Plenum Press, New
York-London, 1977, 119.
689. J. C. Jochims, Chern. Ber. 1975, 108, 2320.
690. J. C. Jochims and A. Abu-Taha, Chern. Ber. 1976, 109, 139.
691. A. Alemagna and T. Bacchetti, Gazz. Chirn. Ital. 1972, 102, 1068.
692. A. Alemagna and T. Bacchetti, Gazz. Chirn. Ital. 1972, 102, 1077.
693. A. B. Tomchin and G. A. Shirokii, Zh. Org. Khirn. 1977, 13,404.
694. A. B. Tomchin and G. A. Shirokii, Zh. Org. Khirn. 1979, 15, 855.
695. M. M. Shemyakin and L. A. Shchukina, Zh. Obshch. Khirn. 1948, 18, 1925.
696. D. P. Vitkovskii and M. M. Shemyakin, Zh. Obshch. Khirn. 1951,21,547.
697. L. A. Shchukina and M. M. Shemyakin, Zh. Obshch. Khirn. 1956,26, 1708.
698. L. A. Shchukina, Yu. B. Shvetsov, and M. M. Shemyakin, Zh. Obshch. Khirn. 1951,21,346.
699. L. F. Fieser and M. Fieser, J. Arn. Chern. Soc. 1948, 70,3215.
700. G. A. R. Kon, A. Stevenson, and J. F. Thorpe, 1. Chern. Soc. 1922, 121,650.
701. S. S. Deshapande and J. F. Thorpe, J. Chern. Soc. 1922, 121, 1430.
702. B. Singh and J. F. Thorpe, J. Chern. Soc. 1923, 123, 113.
703. L. .Bains and J. F. Thorpe, J. Chern. Soc. 1923, 123, 1206.
704. E. W. Lanfear and J. F. Thorpe, J. Chern. Soc. 1923, 1683.
705. E. W. Lanfear and J. F. Thorpe, 1. Chern. Soc. 1923, 123,2865.
706. I. B. Blagoeva, B. J. Kurtev, and I. G. Pojarlieff, J. Chern. Soc., Perkin Trans. 2 1979, 1115.
707. G. Illuminati and L. Mandolini, Acc. Chern. Res. 1981, 14, 95.
708. A. J. Kirby, Adv. Phys. Org. Chern. 1980, 17, 183.
709. K. B. Wiberg and H. W. Holmquist, 1. Org. Chern. 1959, 24, 578.
710. H. O. Larson and G. S. K. Sung, Austr. J. Chern. 1962, 15,261.
Additions in proof: References to some more important papers published in 1983 and 1984
are added below. They supplement with new data the main list references marked with an
asterisk.
*471. For ring-chain tautomerism of monooximes of 1,4-diketones see A. Maccioni, P. P. Piras,
A. Plumitallo, and G. Podda, Gazz. Chirn. Ital. 1983, 113,91.
*473. K. N. Sawhney and Th. L. Lemke, 1. Org. Chern. 1983, 48,4326.
*486. For NMR study in solid state of both these isomers «ISlA) and (15IB), page 119) see
H. Kessler, H. Oschkinat, G. Zimmermann, H. Mohrle, M. Biegholdt, W. An, and H.
Forster, Chern. Ber. 1984, 117, 702.
*500. For ring-chain tautomerism of 4-methylamino-I-(phenyl or 3-pyridyl)-I-butanones see
S. Brandiinge, L. Lindblom, A. Pilotti, and B. Rodriguez, Acta Chern. Scand. 1983, B 37,
617.
*611. S. I. Yakimovich, V. N. Nikolaev, and S. A. Blohtina, Zh. Qrg. Khirn. 1984,20,1371.
*613. S. I. Selivanov, K. G. Golodova, Ya. A. Abbasov, and B. A. Ershov, Zh. Org. Khirn.
1984, 20, 1494.
3
Reactions to the C==N Group
Despite the lower reactivity of azomethine groups compared to carbonyl

groups, intramolecular reversible nucleophilic additions of OH, NH, and
SH groups often proceed. Moreover, equilibria of these systems are
frequently shifted toward the ring isomers to a considerably greater extent
than in cases of corresponding c=o analogues. Evidently the higher
basicity of the nitrogen atom favors the formation of the protonated
+
C=NHR group, to which the nucleophilic part of the molecule is easily
added [I].
C X H
-
N=C
/
RI . ex'~
N
/C
/R'
"R2
" R2 I
H
(1A) (1B)
C X H
eLNHR'
- • I
C=NR2
/ I
RI RI
(2A) x=o, NR,S (2B)
The intramolecular addition of nucleophilic groups XH to a C=N

group can proceed in two ways (1 and 2) that differ in the orientation of
the azomethine group.
3.1. OH-DERIVATIVES OF IMINES, HYDRAZONES, OXIMES,

AND NITRONES
3.1.1. N -(Hydroxyalkyl)- and N -(hydroxyaryl)-imines
In solutions of N -hydroxyethylimines of aldehydes and ketones the

equilibrium involving Schiff's base and 1,3-oxazolidine (3A) ~ (3B) is
observed [2-7].
170 Chapter 3
Using I H- NMR, a quantitative investigation of a series of 4,4-dimethyl-

2-(3- or 4-X-phenyl)oxazolidines (3, R = Me, R I = H, R2 = 3- or 4-XC 6 H4)
was carried out. The equilibrium constants were deduced from the intensities
of the signals of the proton adjacent to the aryl groups (R I = H) of both
tautomeric forms [4, 5, 7,8].
Increasing the electron-withdrawing effect of substituents X in the aryl
group shifts the equilibrium toward the cyclic form (see Table 29). A linear
correlation was detected for the ring-chain equilibrium constants and a or,
better, a + -coefficients of the substituents X in the aryl group [5]:
19 KT/(KT)o = 0.86a, r = 0.973;
19 KT/(KT)o = 0.54a+, r = 0.999.
Table 29. The Influence of the Polar Properties of

Substituent X on Ring-Chain Equilibrium Constants in
Solutions of 4,4-Dimethyl-2-(3- or 4-X-phenyl)oxazolidines
[5] and 2-( 4-X-Phenyl)-3,4-dihydro-2H-l ,3-benzoxazines [9]
as Determined by IH-NMR
KT = [B]/[A]
(3A) +2 (38)
R = Me, RI = H (5A) +2 (58)
Substituent X R2 = XC 6 H 4 RI = H, R2 = XC 6 H 4
in aryl group (in CCl 4 ) (inCDCI 3 )
4-Me 2N 0.21
4-M~O 0.66
4-i-Pr 0.11
4-Me 1.18
H 1.71 0.19
3-MeO 1.96
4-CI 2.16
4-8r 0.25
3-CI 2.72
3-N0 2 4.0 0.96
4-N02 1.04
Intramolecular Reversible Addition to the C=N Group 171
Alper with co-workers [8] determined a ring-chain equilibrium con-

stant for a solution of 4,4-dimethyl-2-( 4-tolyl)oxazolidine, the toluene ring
of which was complexed with chromium tricarbonyl (3, R = Me, R' = H,
R2 = Me .~ , KT = 4.3 in CCI 4 ). The high value of the

~- Cr(COh
equilibrium constant can be explained by the strong electron-withdrawing
effect of the aryl group involved in the complex.
Condensation reactions of 3-aminopropanol with carbonyl compounds
gave either Schiff's bases or tetrahydro-I,3-oxazines or mixtures of both
isomers [10, II].
4-Aminobutanol in a reaction with formaldehyde formed hexahydro-
1,3-oxazepine while condensation products with benzaldehyde or acetoph-
enone have been reported to possess the open structure [10].
A study of condensation reactions of substituted 2-aminoethanols and
3-aminopropanols with carbonyl compounds revealed [3, 10] that an elonga-
tion and branching of alkyl substituents at the carbon atom of the azomethine
group (R' and R2 in the formula (3)) stabilize the open form. Branching
at the chain between the interacting functional groups on the other hand
stabilizes the cyclic isomer.
Condensation of 2-aminophenols with substituted glyoxals yielded
2-substituted 2,2'-bis-benzoxazolines (4B) which form tautomeric equilibria
(4A) ~ (4B) in solution [12, 13].
H R H
ryN0NAJ
I I I R o~y
ryN)<C~N ~
Y~O HIYOH y~O
14A, Y H
148,
I
H
R= -Ox, X=H, Me,el, N0 2 ; Y=H;
R=-f),
o
-f),
S
0; S
Y=H,N0 2 •
UV as well as 'H-NMR investigations rendered possible a determina-

tion of the contents of the open isomer (4B) in solutions of arylderivatives
(4, R = 4-XC 6 H4) [12]. As can be expected electron-withdrawing sub-
172 Chapter 3
stituents X shift the equilibrium toward the ring form. However, an introduc-
tion of a nitro group into the aryl ring of the 2-aminophenol (Y = N0 2 )
stabilizes the open form. The additions of bases to solutions of (4) displaces
the equilibrium toward the more acidic open form.
N-(2-Hydroxybenzyl)imines of aromatic aldehydes have an open struc-
ture in the solid state (SA, R' = H, R2 = 4-XC 6 H4)' In solutions the equili-
brium (SA) ~ (5B) occurs [9, 14] (see Table 29). In this case also a linear
free energy relationship with u or, better, u + -coefficients of the substituents
X of the phenyl group was found [5,9]:
Ig KT/(KT)o = 0.76u, r = 0.993;
Ig KT/(KT)o = 0.68u+, r = 0.999.
The open isomers (SA) are stabilized by the intramolecular hydrogen

bonds between the phenolic hydroxyl and the azomethine nitrogen atom.
This has been confirmed by a linear correlation between the chemical shifts
of the hydroxyl protons and u-coefficients of the substituents X (R 2 =
4-XC 6 H4)'
N-(2-Hydroxybenzyl)imines of aliphatic aldehydes and ketones are
cyclic 2-substituted 3,4-dihydro-2H-l,3-benzoxazines (5B) in the solid state
and the equilibrium in solution is almost totally shifted toward the cyclic
form.
Condensation of 2-hydroxybenzylamine with glyoxal and some 1,2-
diketones gave 2,2'-bis-benz-l,3-oxazines (6B, R' = R2 = H; R' = H, R2 =
Me; R', R2 = (CH 2 )4) [15], which in solvents of low polarity (CCI 4, CDCI 3 ,
PhCl) maintain the cyclic structure. An equilibrium (6A, R' = R2 =
Me) ~ (6B) was detected in pyridine (KT = 0.25) as well as in chloroben-
zene at 120°C.
<(OH Hoi>
CH 2 -N N-CH
\\ II 2
C-C
/ \
R' R2
(6A) (68)
2,4-Diaryl-2,3-dihydro-l H-naphth[ 1,2-e]-1 ,3-oxazines obtained from 1-

(a-aminobenzyl)-2-naphthol with aromatic aldehydes possess the ring struc-
ture in the solid state, but in solution they equilibrate [16]. Equilibration
of protonated open and cyclic isomers were observed in trifluoroacetic acid.
As has been shown before an introduction of electron-withdrawing sub-
stituents in the aryl group of the initial benzaldehydes displaces the equili-
brium in solutions toward the cyclic form.
In different solvents the equilibrium constants (3A) ~ (3B) and
(SA) ~ (SB) vary considerably. However no correlation either with the
dipole moment, the dielectric constant, or Kosower's Z-constants [17] was
observed [9]. Paukstelis and Hammaker [4] showed that the ability of the
solvent to form intermolecular hydrogen bonds with the hydroxyl group of
the open isomer (3A) decisively influences the equilibrium position. In fact
a good correlation was observed between the di-tert-butylcarbinol OH band
frequency shifts (dVo_H, assuming dVO_H = 0 in CCI 4 ) in IR spectra of
di-tert-butylcarbinol solutions in different solvents and the enthalpies of
ring-chain tautomeric interconversions of 4,4-dimethyl-2-phenyloxazolidine
(3A, R = Me, R 1 = H, R Z = Ph) ~ (3B) in the same solvents. In this case
the frequency shift dVo_H is caused by the formation of intermolecular
hydrogen bonds t-BuzCHO- H·· ·solvent and therefore utilized as a measure
of solvent proton accepting ability. Increasing proton accepting ability of
the solvent displaces the equilibrium toward the open form (3A) (see Table
30).
Several examples of the influence of N -protonation on ring-chain
equilibria of N-hydroxyalkylimines were studied. Thus, using UV spectros-
Table 30. Influence of Solvent Proton Accepting Properties on Ring-Chain

Equilibrium in Solutions of 4,4-Dimethyl-2-phenyloxazolidine (3A, R = Me,
RI = H, R2 = Ph) +±(3B) [4]
tiVO_H a -tiH -tiS

Solvent (em-I) KT = [B]j[A] b (kcal/mol) (e.u.)
Carbon tetrachloride 0 1.89 1.154 2.7

Chloroform 8 1.72 1.269 3.0
Oimethylcarbonate 69 0.80 0.675 2.7
Acetonitrile 87 0.62 1.145 4.7
Acetone 110 0.42 0.097 2.0
Tetrahydrofuran 156 0.51 -0.425 0.0
Oimethylacetamide 193 0.12 -0.967 1.2
OM SO 224 0.10 -1.2\3 0.7
a Hydroxyl band shift in IR spectra of di-tert-butylcarbinol solution as the reference of solvent proton
accepting ability.
b Determined by 'H-NMR method at 38°C.
174 Chapter 3
copy it was shown [18] that a protonation of oxazolidines (CH 2 CI 2 solution

in the presence of a great excess of CF3 COOH) leads to ring opening and
formation of immonium salts (7 A). Using equimolar amounts of CF3 COOH
oxazolidine salts (7B) were isolated.
(7A) (7B)
Following 'H-NMR investigations [19] N-methylated 1,3-

oxazaheterocycles (8. n = 1,2) in CC1 4 solution at room temperature do
not equilibrate with open forms. In CF3 COOH solution, however, an equili-
brium (9A) <2 (9B) has been observed (-10% (9A) at room temperature).
In the 'H-NMR spectrum of the protonated N-methyloxazolidine, two
singlets were observed in the CH 2 = region which led the authors to propose
the presence of a second open tautomer (9A', n = I). However, the formation
of the diprotonated form (9A") seems to be more likely.
Me H Me
/ +1/
(CH 2 )n-N (CH 2 )n-N
H+
(0) CF,COOH (0) 4 ~
(8) (SB)
CH 2 CH 2
+11 ~+
/N,
HO(CH 2 )n+l Me "-(CH 2 )n+,NHMe
(SA) (SA')
CH 2
+"o
" (CH 2 ),,+,NH
+ 2 Me
(SA")
'H-NMR investigations also showed that protonating the compounds

(5, R'= H, R2 = alkyl, aryl; R' = R2 = alkyl) in CF3 COOH yielded the
immonium ions of open structure. Protonated ring isomers form only from
formaldehyde and trichloroacetaldehyde imines [20].
Yakimovich and co-workers [21,22] gave an interesting example of

ring-chain tautomerism in the series of the N-hydroxyalkylimines of f3-
ketoesters. Here, two equilibria, i.e., (lOA) +:t (lOB) and (lOA) +:t (10C) have
been observed. The situation is even more complicated by the possibility
of forming configurational isomers, i.e., syn-(lOA), anti-(lOA), E-(lOC),
Z-(lOC), as well as two stereoisomers for (lOB).
Me R
\ /
C=C
/ \
HO(CHz)nN C-OMe
\ II
H··O
Z-(10C) (10A)
R
I
Me" /CHCOOMe
"
C
• ~HN / 0
"(CHz)n
/
(108)
It has been shown by IH-NMR spectroscopy that compounds (10,

R = H, n = 2 or 3) exist in the enamine forms Z-(10C, n = 2) and Z- and
E-(lOC, n = 3). Imine (lOA) and cyclic (lOB) were observed only in deriva-
tives containing alkyl substituents (R = Me, Et, i-Pr). Going from N-(2-
hydroxyethyl)imines (10, n = 2) to N-(3-hydroxypropyl)imines (10, n = 3),
the proportion of the cyclic form decreases.
3.1.2. N -Hydroxyalkylhydrazones
Yoffe and Potekhin [23, 24] simultaneously with Dorman [25] observed
ring-chain tautomerism of N-(2-hydroxyalkyl)hydroazones of aldehydes
and ketones. In this case the cyclic isomer is formed as a result of an
intramolecular addition of a hydroxyl group to the hydrazone C=N bond
[26].
A series of papers published by Potekhin et al. [27-34] are related to
this tautomerism (llA) +:t (llB), the results being compiled in a monograph
[35]. The composition of the equilibrium mixtures was deduced from
molecular refraction data and IH-NMR spectra.
176 Chapter 3
N-(2-Hydroxyalkyl)hydrazones of aldehydes and ketones mono-

substituted at the nitrogen atom (11, R3 = H) [27, 28, 32] as well as products
of a condensation of lactic acid hydrazide with carbonyl compounds [30]
possess open structure (ttA) and are not capable of cyclization.
Freshly distilled condensation products of N -alkyl-N -(2-
hydroxyalkyl)hydrazines with aldehydes and ketones in most cases are
cyclic perhydro-l,3,4-oxadiazines (I1B). On standing as well as in solution
equilibrium mixtures (I1A) ~ (I1B) are formed.
The introduction of one or two methyl groups (R 4 = R 5 = Me) in the
hydroxyethyl group as well as increasing the steric bulk of the alkyl sub-
stituent at the nitrogen atom (R 3 = Me < Et < Pr < i-Pr < t-Bu) displaces
the equilibrium toward the cyclic form [28,32]. It has been said [33] that
introduction of alkyl substituents at the nitrogen atom weakens the
intramolecular hydrogen bond between the hydroxyl group and nitrogen
atom in (ttA), thus destabilizing the open isomer. The decrease of open
isomer rotation entropy brought about by the substituent at the nitrogen
atom may also be of significance.
Pinacoline N-aryl-N-(2-hydroxyethyl)hydrazones (11, Rl = Me, R2 =
t-Bu, R3 = 4-XC 6 H 4 , R4 = R 5 = H) show [31] equilibrium displacement
toward the ring form corresponding to an increase in the electron-with-
drawing effect of the substituents X in the aryl group (see Table 31).
A greater tendency of hydrazones of aliphatic aldehydes compared to
that of ketones to form the cyclic (ttB) has been explained [27] assuming
that perhydro-l ,3-4-oxadiazines with two alkyl substituents at C(2) possess
an increased conformational energy. A greater electrophilicity of C=N
bond carbon atom in aldehyde derivatives compared to the ketoanalogues
[36,37] may also be an important factor favoring intramolecular cyclization.
The condensation products of N-methyl-N-(2-hydroxy-2-methyl-l-
propyl)hydrazine with isobutyric aldehyde have found special interest since
for the first time both isomers, i.e., (I1A, R I = H, R2 = i-Pr, R3 = R4 = R 5 =
Me) and (I1B) have been isolated [32]. A rapid distillation of the reaction
mixture gave first the low boiling 2-isopropyl-4,6,6-trimethylperhydro-l ,3,4-
oxadiazine (I1B) and then the high boiling open isomer (I1A). A slow
distillation gave exclusively the ring isomer. The same investigators found
:::l
..,....
III
3
o
CD
C')
c:
Table 31. Ring-Chain Equilibrium Constants of N-(2-Hydroxyalkyl)hydrazones of Aldehydes and Ketones ..,III
(l1A) ~ (l1B), Determined by IH-NMR for Neat Liquids at 25°C [27-29, 31-33] :xJ
CD
<
CD
..,
KT = [B]/[A] when R3 = !!!.
0-
CD
Rl R2 R4 R5 H Mo Et Pr i-Pr I-Bu Ph 4-MeC 6 H4 4-N02C 6 H4 :t>
Q.
Q.
H Me H H 0 1.0 13.3 7.3 8.1 32 a 19 b 19 b 19 b ;:;"
0"
H Et H H 0 9.0 :::l
H i-Pr H H 0.49 4.6 ....
o
Me Me H H 0 2.3 1.4 1.8 2.7 13.3 a 5.7 b 4.3 b 9b ....
:::T
Me I-Bu H H 0.11 0.32 b 0.15 b 0.67 b CD
(")
Et I-Bu H H 0.05
H Me H Me 0 7.3 50 24 a II
z
Me Me H Me 0 3.2 4 G>
H i-Pr H Me 0.67
..,
o
H I-Bu H Me 0.05 0.1 c:
"0
H Me Me Me 0 5.7 24 a
H i-Pr Me Me 0.79
Me Me Me Me 0 0.05
a Determined by a refractometric method.

h Determined for 15-20% solution in chloroform.
-..j
-..j
178 Chapter 3
conditions for a conversion of the perhydro-l ,3,4-oxadiazine into the open

isomer by keeping the cyclic isomer at about 100° for several hours, leading
to the enrichment in the open isomer in the equilibrium mixture. This is
followed by a subsequent rapid distillation. Thus, it appears that increasing
temperature displaces the equilibrium (l1A) ~ (l1B) toward the open
isomer (see also [28]).
The thermodynamic parameters of the equilibrium (l1A) ~ (l1B) have
been determined by a refraction method. The value -~H =
2.2 ± 0.2 kcal/mol turned out to be near to that found for the product of
isobutyric aldehyde condensation with N-aminoephedrine (2.41 ±
0.11 kcal/ mol) [25], but the value - ~S = 7.6 ± 0.5 e. u. was significantly
lower (9.15 ± 0.35 e.u.). However, it is rather difficult to compare these
results because of essential differences in the structure of the initial
hydrazinoaIcohols.
Dorman [25] by condensation of N-methyl-N-(l-hydroxy-l-phenyl-2-
propyl)hydrazine (N-amino-l-ephedrine) with aliphatic aldehydes obtained
equilibrium mixtures of hydrazones (12A) and cyclic isomers 2-alkyl-4,5-
dimethyl-6-phenyl-I,3,4-oxadiazines (12B).
Me Me
Me I R
'/N" N=C /
H·--C
Mex~,
H-- N
/H
H---C
I
I "H « • H-- J:H
"O-H Ph 0 R
Ph
(12A) (128)
Equilibrium constants for (12A) ~ (12B) in tetrachloroethylene were

measured by I H-NMR spectroscopy at different temperatures; 0.1 % of
CF3 COOH was added to the solutions to increase the rate oftautomerization.
Increasing the dielectric constant of the solvent, raising the solution tem-
perature, as well as extending the steric bulk of the alkyl substituent R
shifts the equilibrium in favor of the open isomer (see Table 32).
Potekhin and Safronov [34] obtained a very interesting and unexpected
result studying the N -benzyl-N-(2-hydroxyethyl- or 2-hydroxypropyl)hy-
drazones of benzaldehydes and acetophenones (13, R I = H, Me; R2 = H,
Me).
Unlike the hydrazones of aliphatic aldehydes and ketones (see Table
31) discussed so far, hydrazones of the benzaldehyde (13, R I = H) are less
prone to form cyclic isomers than derivatives of acetophenone (13, R = Me).
Thus, benzaldehyde N -benzyl-N -(2-hydroxyethyl- and 2-hydroxy-
propyl)hydrazones and their derivatives substituted in the aryl group
Table 32. Ring-Chain Equilibrium (12A) ~ (12B) Constants and

Thermodynamic Parameters, Determined by IH-NMR in a
Solution of Tetrachloroethylene and 0.1 % CF 3COOH [25]
KT = [B]/[A] at t, °C
-/:1H -/:1S
R 22.5 35 50 82 (kcal/mol) (e.u.)
H 0.67
Me 1.61 1.39 1.13 0.70 2.93 8.94
Et 1.23 1.00 0.76 0.55 2.88 9.31
i-Pr 0.59 0.53 0.43 0.30 2.41 9.15
t-Bu 0.26 0.23 0.18 0.15 2.05 9.62
exist exclusively as open isomers (13A, R I = H, R2 = H, Me) in the solid

state and in tetrachloroethylene solution. The stabilization of (13A) was
thought to be due to a conjugation which includes the benzene ring [34].
(13A) (138)
Table 33. Ring-Chain Equilibrium (13A, RI = Me,

R2 = H) ~ (13B) Constants and Thermodynamic
Parameters Determined by IH-NMR using
Tetrachloroethylene [34]
KT[B]/[A] -!l.H -!l.S

X at 30°C (kcal/moI) (e.u.)
3·N0 2 2.92 3.04 7.89

3-Br 2.09 4.47 13.4
4-Br 1.29 3.56 11.2
4-CI 1.14 3.68 12.0
H 0.752 4.49 10.8
4-Me 0.472 3.39 12.8
4-MeO 0.287 3.15 12.9
3-NHAc u 0.192
4-NHAc u 0.10
u In solution of acetone.d6 •
180 Chapter 3
An equilibrium (13A) +:t (13B) is observed in the case of derivatives of

acetophenone (R I = Me). A twisting of the benzene ring out of the plane
of the azomethine group, probably due to the methyl group, disturb the
conjugation and favors the cyclic structure (13B).
Equilibrium constants for hydrazones (13, R I = Me, R2 = H) in tetra-
chloroethylene have been determined at different temperatures (30, 50, 70,
and 90°C) by IH-NMR spectroscopy; thermodynamic parameters were
deduced. As is easily seen from Table 33, electron-withdrawing substituents
in the benzene ring shift the equilibrium toward the cyclic form, a good
correlation being observed with (T or (T + coefficients of the substituents X:
19 KT/(KT)o = 1.03(T, r = 0.980, s = 0.08;
19 KT/(KT)o = 0.74(T+, r = 0.986, s = 0.06.
3.1.3. Hydroxyalkyl and Hydroxyiminoalkyl Nitrones

Several examples of ring-chain tautomerism are known where the cyclic
isomer is formed as a result of an intramolecular addition of a hydroxyl
group to the C=N bond of nitrones, yielding hydroxylamine derivatives.
No cyclic isomers of aryl-N-(2-hydroxyalkyl)nitrones (14A, R = Ar)
could be observed by IR and IH-NMR spectroscopy in the solutions [38].
However, solutions of alkylderivatives (14, R = Me, C 6 H II) showed an
equilibrium (14A) +:t (14B) which is strongly displaced in favor of the open
form [39]. Chemical reactions, as for example acylation, gave derivatives
of the open form as well as those of the cyclic isomer.
\ / \ /
C-C /OH
~\R
/ \+
0 H N-O- 4 ~
\ \ij'
H C
1
R
(14A) (148)
0- OH
1+ 1
ro
/N=CHR NiR
CH z 4 ~
0
OH
~ ~
(15A) (158)
An analogous ring-chain equilibrium was detected [40] in solutions of

N-(2-hydroxy-l-naphthyl)methylnitrones (15A) ~ (15B) in DMSO-d 6 and
methanol-d 4. 'H-NMR investigations showed that the equilibrium depends
on the substituent R. An introduction of an aryl substituent (15, R = Ar)
instead of hydrogen or a methyl group (15, R = H, Me) stabilizes the open
structure. No cyclic isomers of compounds (15, R = 4-XC 6 H4' X = N0 2 ,
NMe 2 ) have been detected in solutions (see also [41]).
Volodarskii and co-workers using 'H-NMR spectroscopy have been
able to show that products of condensation of syn-a-hydroxylaminooximes
with aliphatic aldehydes [42] and acetone [43] in alcoholic solution form
an equilibrium mixture of N -(syn-2-hydroxyiminoalkyl)nitrones and 5-
hydroxydihydro-4H-l,2,5-oxadiazines (16A) ~ (16B). Derivatives of for-
maldehyde, however, are exclusively cyclic (16B R3 = R4 = H). The equili-
brium position also depends on the structure of the substituents R I and
R2. If the oxadiazine ring is condensed with the five-membered indane ring
(16, R', R2 = -o-C 6 H 4CH r , R3 = H, R4 = Me) the open form predomi-
nates, but in the case of a six-membered tetraline ring (16, R I, R2 =
-o-C 6 H 4CH 2 CH r , R3 = H, R4 = Me) the 'equilibrium is shifted toward the
cyclic form (see Table 34).
R2
I
0- CH I
.... + / . . . . . . . . /R
N C
II II. ~
C N
R3/ ........R 4 HO/
(16A) (168)
Increasing the temperature shifts the equilibrium toward the open
form. It has been shown by UV spectroscopy that aqueous alkaline
solutions contain the anion of the open isomer.
Table 34. Isomeric Composition of N-(2-hydroxyiminoalkyl)nitrones

(16A) ~ (168) in Ethanol [42,43]
Rl R2 R' R4 Composition
Ph Me H H B
-o-C 6H 4CH 2 CH 2- H H B
Ph Me H Me A ~ B (27% A at 28°C)
-o-C 6H 4CH 2- H Me A~ B,A> B
-o-C6H4CH2CHz- H Me A~B,A< B
Ph H Me Me A~ B,37% A
Ph Me Me Me A~ B,20% A
-o-C 6H 4CH 2CH 2- Me Me A~ B,24% A
182 Chapter 3
The intramolecular addition of a hydroxyl group to a nitrone C=N

bond has been observed also in the case of nitrone C-hydroxyalkylderiva-
tives.
Thus, N -methyl- N- (tetcahydro-2-pyranyl)hydroxylamine (17B) at
room temperature is stable, but during vacuum distillation (150°C,
0.3 mm Hg) it is partially converted into the a-(4-hydroxybutyl)-N-
methylnitrone (17 A) [44, 45].
O/Me
o N
I
OH
(17B) (17A)
OI
0-
+/ I
NH-CO-CH=N
~NyO
~Ar
~ OH ~ o A /N,
Ar
OH
(18A) (18B)
The intramolecular addition of a phenolic hydroxyl to a nitrone C=N

bond in (18A) leads to the formation of 2-(N-arylhydroxylamino)-3-
benzo( e ]morpholinone (18B) [46]. The isomerization (18A) -+ (18B) pro-
ceeds in different solvents at 20°e. The reverse isomerization is carried out
by heating to 165° or by an action of trace amounts of an acid.
3.1.4. Imines, Hydrazones, and Oximes of Hydroxyaldehydes and

Hyd roxyketones
The ring-chain tautomerism of the N -hydroxyalkyl- or N -hydroxyary-
lalkylimines and hydrazones of aldehydes and ketones (type (IA) ~ (IB»)
has been studied rather thoroughly but little attention has been paid so far
to the series of imines and hydrazones of hydroxyketones and hydroxyal-
dehydes (type (2A) ~ (2B»).
/OH ~
(CHZ)n (CHz)n 0
~ ~ /
C=NRz C
/ / ~
Rl Rl NHR2
(19A) (19B)
Table 35. Ring-Chain Equilibrium (19A) ~ (19B) Constants,

Determined by IH-NMR at 30°C [50]
KT = [B]/[A]
Rl R2 n Neat liquid Solution in CCI.
H Me 3 0.91 6.25
H t-Bu 3 0.28 2.0
H Me 4 12.5 >100
H Et 4 11.1 >100
H i-Pr 4 6.3 >100
H t-Bu 4 5.6 >100
Me Me 3 0.50 4.0
Me Et 3 0.48 3.55
Me i-Pr 3 0.06 0.39
Me Me 4 1.27 7.2
Me i-Pr 4 0.08 0.67
Potekhin, Zhdanov, and coauthors recently reported on a series of

investigations [47 - 51] th us eliminating this lack of information. They investi-
gated a large number of N-alkyl and N-arylimines of 4-hydroxybutanal
(19, Rl = H, n = 3), 5-hydroxypentanal (19, Rl = H, n = 4), 5-hydroxy-2-
pentanone (19, Rl = Me, n = 3), and 6-hydroxy-2-hexanone (19, Rl = Me,
n = 4) which were obtained as equilibrium mixtures (19A) ~ (l9B) (see
Table 35).
Analogous to hydroxyaldehydes and hydroxyketones the six-membered
cyclic isomers of the corresponding imines are more stable. Sterically
demanding alkyl substituents at the nitrogen atom shift the equilibria toward
the open form. The ring form of imines of hydroxyaldehydes is more stable
than that of imines of hydroxyketones.
It has been pointed out [50] that steric peculiarities of the five- and
six-membered ring exercise a strong influence on the stability of the cyclic
form. A displacement of the equilibria toward the open form, passing from
the imines of hydroxyaldehydes (19, R 1 = H) to those of hydroxy ketones
(19, R 1 = Me), was explained by an increased destabilizing repulsion
between the 1,3-diaxial groups in the tetrahydropyrane ring or by a cis-l ,2-
interaction in the tetrahydrofuran ring. Differences in the electrophilicity
of the C=N bond in aldehyde and ketone derivatives have already been
discussed.
In the solid state as well as in solution N -arylimines of 5-
hydroxypentanal exist exclusively as cyclic 2-arylaminotetrahydropyranes
(19B, Rl = H, R2 = 4-XC 6 H 4 , n = 3) [48]. Even heating solutions to 90°C
does not lead to the formation of open isomers (19A). The unexpected
184 Chapter 3
stability of the cyclic form of N -arylimines as compared with that of

N -alkylimines was attributed to a conjugation of the lone pair of the nitrogen
atom and the benzene ring in the cyclic form (19B, R2 = Ar). Conjugation
in the open form is disturbed because of the noncoplanarity of the system
C=N-Ar.
One may also suggest that during the transformation (19B) -+ (19A) a
heterolytic rupture of the C-O bond occurs simultaneously forming a
C=NHR2 group in the intermediate (20). The lone pair of the nitrogen
atom that is involved in this transformation may be hindered by conjugation
with the benzene ring (R2 = Ar) and thus disfavors the ring opening.
RI
- 1.+ 2
(19B) ~ O(CH2)nC=NHR ~ (19A)
(20)
Solvents have a significant influence on the position of the equilibria

of these N -alkylimines. In nonpolar solvents the equilibrium is strongly
displaced in favor of the cyclic form. Thus, the equilibrium constant of
5-hydroxy-2-pentanone N-methylimine (19, RI = R2 = Me, n = 3) changes
from 5.6 to 0.66 on passing from benzene to nitromethane. Increasing the
temperature shifts the equilibrium toward the open form [50].
Whitting and Edvard [37] were the first to investigate the structure of
2,4-dinitrophenylhydrazones of 5-hydroxy-2-pentanone and 6-hydroxy-2-
hexanone (19, RI = Me, R2 = 2,4-(N02)2C6H3NH, n = 3,4). Using spectro-
scopic methods they were able to show that these compounds are exclusively
open structured in the solid state and also in ethanol, acetone, or DMSO.
Systematic studies of a large number of alkyl, dialkyl, and arylhy-
drazones of 4-hydroxybutanal, 5-hydroxypentanal [48,51], 5-hydroxy-2-
pentanone, and 6-hydroxy-2-hexanone [47] showed that they possess exclus-
ively the open structure independently of the substitution pattern of the
hydroxycarbonyl compound, the substituent at the nitrogen atom, the
properties of the solvent, and the temperature. Using IR, UV, and IH-NMR
spectroscopy no indication of the presence of cyclic isomers was obtained
in spite of an extensive variation of the solvent (acetonitrile, benzene,
dimethylformamide, dioxane, pyridine, deuterium oxide) and the tem-
perature (30-90°C). The authors suggest [47] that the stability of the open
isomers may possibly be caused, first, by a destabilization of the cyclic form
due to the nonbonded interactions and, second, by the stabilization of the
open form by means of hydrogen bonds involving the hydroxyl group.
Similar to 5-hydroxypentanal hydrazones, arylhydrazones of D-glucose
also possess an open structure in ethanol or in DMSO [51]. Nitroarylhy-
drazones of D-glucose, however, in DMSO show equilibria with the cyclic
pyranozic form which according to the authors [51] is caused by the nitro
group of the benzene ring stabilizing the cyclic structure by the increase of
conjugation in the system -NH-Ar.
Similar to the hydrazones oximes of 5-hydroxypentanal [48], 5-hydroxy-
2-pentanone, and 6-hydroxy-2-hexanone [47] neat and in solutions exist
exclusively as the open isomers (19A, R I = H, R2 = OH, n = 3; R I = Me,
R2 = OH, n = 3, 4).
3.1.5. Imines of Ketocarboxylic Acids

There are well-known examples of intramolecular reversible addition
of the carboxylic group to the C=N bond. Indications of a ring-chain
tautomerism of N benzylideneanthranilic acid (21A) ~ (21B) have been
given [52]; however, no spectroscopic evidence is available.
(JeCOOH
0
I ~
~O
I
~ N=CHPh ~ N~Ph
I
H
:-6 .
(21A)
CCOOH
(21S)
/C=NQI . C:/
0
~ ~
Ph Ph
~ I
~ ~
X X
A C
CC,
0
II
Q ~C:O:Q
c/o
/ 'NH
/ I
• I
Ph ~
Ph
~
X X
B D
186 Chapter 3
c
(22) (23)
(X
~ I
COOMe
C=NC H X
/64
Ph
(24)
3-Arylamino-3-phenylphthalides [53-56] are cyclic (22B) in the solid

state and in solution the equilibrium (22A) ~ (22B) is displaced toward the
ring form (see Table 36). Equilibrium constants were determined [56,57]
by UV spectroscopy on the basis of the assumption that the intensity of the
long-wave band (322-348 nm) in the spectra of open isomers (22A) is equal
to that of the corresponding model compounds, i.e., anils of 2-methoxycar-
bonylbenzophenone (24).
Electron-withdrawing substituents X in the benzene ring increase the
electrophilicity of the azomethine carbon atom, thus stabilizing the cyclic
form. The equilibrium constants approximately correlate with u-coefficients
of the substituents X:
r = 0.94
Table 36. Ring-Chain

Equilibrium Constants of 3-
Arylamino-3-phenylphthalides
(22A) ~ (22B) in Dioxan
Solution as Determined by
UV at 20°C [57]
X KT = [B]j[A]
4-MeO 2.69
4-Me 3.83
3-Me 5.21
H 4.78
4-1 4.67
4-EtOOC 7.94
4-MeCO 9.61
Table 37. Solvent Influence on Ring-

Chain Equilibrium of 3-Phenylamino-3-
phenylphthalide (22A, X = H) ~ (22B)
[56]
Solvent KT = [B]/[A]
Dichloroethane >100
Tetrahydrofuran 5.26
Dioxan 4.78
Ethanol 1.64
DMSO 1.15
A better correlation was observed with (J" + coefficients [57]:

r = 0.97
This observation (found in various reversible intramolecular additions
to the azomethine bond [5,9]) was explained assuming that the equilibrium
(22A) ~ (228) goes through bipolar intermediate (22C) in which the elec-
tron-donating substituent X exerts a direct interaction on the nitrogen atom
bearing the positive charge.
Increasing proton acceptor properties of the solvent shifts the equili-
brium (22A) ~ (228) toward the open form (see Table 37). A similar
regularity was already discussed for 4,4-dimethyl-2-phenyloxazolidine [4]
(see Table 30). The stabilization of the open isomer in proton acceptor
solvents is brought about by a formation ofintermolecualr hydrogen bonds,
COO H· . ·solvent.
3-Arylamino and 3-alkylamino-3-phenylperinaphthalides (238) are
cyclic in the solid state as well as in solutions OR and UV evidence) [58, 59].
The reason for the stability of the cyclic form (238) is similar to that already
discussed for 8-acyl-l-naphthoic and 2-acylbenzoic acids (see p. 39, Fig. 5).
Bases convert aminolactones (228) and (238) to anions of open struc-
ture (22D) and (23D).
3.1.6. Fused Systems

Grandberg, Dashkevich, and Ivanova [60,61] investigating analogues
of the alkaloid physovenin demonstrated by means of UV and 'H-NMR
spectroscopic data that substituted 2,3,3a,8a-tetrahydrofuro[2,3-b ]indols in
acidic media open the furanidine ring (258) -+ (26).
Electron-donating substituents, especially at nitrogen atom (R 5 ),
increasing the basicity of nitrogen atom and decreasing the electrophilicity
of the atom C(8a) in the molecule (258), facilitate this ring opening, thus
188 Chapter 3
•(R'=H)
')r-----j----,3
N
8a
0
2
.
+H+
-H+
~
I Rl
R5
(25A) (258)
affording a less acidic medium. The introduction of alkoxygroups at C(5)

of the aryl ring (25, R I = R2 = Me, R3 = MeO, PhCH 2 0, R4 = R 5 = H)
permits observation of the equilibrium (25A) ~ (25B) in neutral, hydroxyl-
containing solvents. Apparently, the electron-donating alkoxy group
decreases the electrophilicity of the atom C(8a) and polarizes the C(8a)-O
bond sufficiently for a furanidine ring opening without a preliminary proton-
ation of the nitrogen atom. Electron-withdrawing substituents in the aryl
ring (R 3 or R4 = Br) or at the nitrogen atom (R 5 = Ph) stabilize the cyclic
structure, and the equilibrium (25B) ~ (26) is obtained at lower pH values.
3.2. N-H-DERIVATIVES OF IMINES, HYDRAZONES, OXIMES,

AND NITRONES
3.2.1. N-Aminoalkylimines
In the reactions of ethylenediamines with aldehydes and ketones mix-
tures of Schiff's bases (27 A) and isomeric imidazolidines (27B) are formed.
However, it was not possible to confirm the existence of a tautomeric
equilibrium (27 A) ~ (27B) in solution [62]. A IH-NMR study proved that
the amount of the cyclic isomer in the reaction mixture decreases with
increasing steric demand of the alkyl substituent R I (when R = H) or if
RI = Ph.
Condensation of N -methylethylenediamine with aromatic aldehydes
gave a mixture of the open and cyclic isomers (27 A, R = R3 = H, R I =
4-XC 6 H4' R2 = Me) and (27B) [63]. The amount of the cyclic isomer
(27A)
increases with increasing electron-withdrawing properties of the substituent

X: when X = NMe2 the mixture contains 50% of the cyclic isomer, X =
NHAc: 62%, X = H: 80%, X = N0 2: 100%. However, 'H-NMR spectra
in different solvents (CCI 4 , DMSO) gave no evidence for an equilibrium
(27 A) +± (27B) displacement. Obviously, one can conclude that isomers
(27 A) and (27B) in the usual solvents at room temperature do not undergo
interconversion.
Products of condensation of 1,3-diaminopropane and its alkylsub-
stituted derivatives with formaldehyde have been shown to be cyclic hexahy-
dropyrimidines (28B, R2 = R3 = H) by IR and 'H-NMR technique [64].
The ring structure is destabilized in the condensation product of 1,3-
diaminopropane with acetone. 1-Benzylideneamino-3- tert- butylamino-
propane exists in the open form (28A, R' = t-Bu, R2 = Ph, R3 = H).
H
CN~'
N)( 2
I R
(28A)
RI
(28B)
Products of condensation of 2,4-diamino-2-methylpentane and 4-

amino-2-methylamino-2-methylpentane with aldehydes have been shown
to be hexahydropyrimidines. An analogous condensation with ketones led
to the open or cyclic isomers or their mixtures depending on the structure
of the ketone [65].
Reactions of 4-amino-5-aminomethyl-2-methyl (or phenyl) pyrimidine
with benzaldehydes yield open (29A) or cyclic (29B) products or mixtures
(X = F) [66]. However, no correlation has been found between the structure
of the products (i.e., substituents X) and the isomer preferentially formed.
I H-NMR investigations showed [19, 67] that 1,3-dimethylimidazolidine
(30, n = I) and 1,3-dimethylperhydropyrimidine (30, n = 2) in CF3COOH

form equilibrium mixtures of protonated isomers (31A) +± (31B) (when
n = 1, KT = 4.5).
190 Chapter 3
Q
Mey:xN NH z
N N=CH I
~ CH/
z ~
~I
(29A) X (29B)
X = 4-CI, 4-Br, 4-F X = 4-F, 4-MeO, 4-N02'
2,4-CI 2 ,3,4-CI 2
CF,COOH
(31A)
The rate of tautomerization is highest for the five-membered system

which disagrees with Baldwin's rules [68-70]. The coalescence temperature
of the equilibrium (3IA, n = 1) <2 (3IB) is found to be 90°C which corre-
sponds to a free activation energy of 16.9 kcal/ mol.
A study of the IH-NMR spectra of 5-nitro-l,2,3,4-tetrahy-
dropyrimidines in CF3 COOH established [71] that the 2-unsubstituted
derivatives (32, R2 = H) are stable in acid but the 2-alkyl and 2-arylderiva-
tives (32, R2 = alkyl, aryl) transform into diprotonated open isomers E-(33)
and Z-(33). The authors suggest [71] that in CF3 COOH an equilibrium exists
between a N-monoprotonated ring form, a diprotonated pyrimidine of little
stability, and two more stable diprotonated open isomers E-(33) and Z-(33).
Thus, the equilibrium is strongly shifted toward (33).
R3 R3
NOzH 1+ NOzH 1+
OzN'CN/R3 _ _ _ H~NyRz H, A - /NyH
I I +
/N,
H + 11+
N
"" 2
N AR2 RI/ "H RI/ 'H
R
1
RI
(32) E-(33) Z-(33)
3.2.2. N -Aminoalkyl and N -Aminoacyl Hydrazones and Related

Compounds
Ring-chain tautomerism caused by an intramolecular addition of an
amino group to the hydrazone C= N bond of the general type (34A) <2 (34B)
was investigated for a rather large number of compounds of different

structure, and as a rule the formation of five- and six-membered rings is
observed.
2-Phenylsemicarbazones of acetone and acetophenone are obtained
[72], both in the open form (35A, R I = Me, R2 = Me, Ph, R3 = Ph) and as
the cyclic 1,2,4-triazolidin-3-one (358). The isomerization (35A) -+ (358) is
sensitive to acidic catalysis as are the isomerizations of 4-alkyl-2-phenyl-
semicarbazones of aliphatic and alicyclic ketones [73]. Introduction of a
t-butyl group at the terminal nitrogen atom (R 4 = t-Bu) prevents cyclization.
I H-NMR investigations revealed [74] that unsubstituted semicar-
bazones (35, R3 = R4 = H), as well as 2- or 4-methylsemicarbazones of

aromatic aldehydes in DMSO-d 6 and CF 3 COOD solutions, exist in the open
form. Some 2,4-dimethylsemicarbazones (35, R I = H, R2 = Ar, R3 = R4 =
Me), however, show equilibria between open and cyclic protonated isomers
in CF3 COOD. Electron-withdrawing substituents in the aryl group stabilize
the cyclic form.
An equilibration being effected only after protonation of a nitrogen
atom was detected recently [75] for 1-(2-propylidene)benzamidrazone. An
analogous equilibrium (36A) ~ (368) was obtained [76] in solutions of
1-(2-propylidene)-2-methylacetamidrazone hydroiodide which in the solid
state possesses the cyclic structure (368). The contents of (36A) decreases
in the sequence DMFA-d 7 > DMSO-d 6 > CDCI 3 • The conjugate base
possessing the cyclic structure does not show a ring-chain equilibrium in
solution.
192 Chapter 3
Me Me H Me
\ / \+-L
C-N Me N \ Me
{:'';- \ /
jf NH
H-N
'H'"
N=C
"- Me/' "N/
Me I
r Me 1-
(36A) (368)
Walter and Rohloff [77] using 'H-NMR spectroscopy studied in detail

the ring-chain tautomerism of aldehyde and ketone 2-methylthiosemicar-
bazone S,S,S-trioxides (37 A) ~ (37B). A methyl or benzyl group at the
nitrogen atom (R 3 = Me, PhCH 2 ) displaces the equilibrium toward the
cyclic form compared with N-unsubstituted derivatives (37, R3 = H). Steri-
cally-demanding 2,6-dimethyl or 2,6-diisopropylphenyl substituents,
however, destabilize the cyclic form. Increasing solvent polarity (CDCI 3 ,
CD 3 CN, DMSO) favors the ring form. Basic or acidic solvents as well as
raising the temperature shift the equilibrium toward the open form. Ther-
modynamic and activation parameters of the interconversions were deter-
mined [77].
N-(a-Alkylaminoacyl)hydrazones of acetaldehyde (38A, R' = H,

alkyl, R3 = alkyl, R2 = R4 = H) possess an open structure neat as well as
in solution [78] (see also N-(a-hydroxyacyl)-hydrazones [30]). However,
introducing alkyl substituents onto the hydrazone nitrogen (R 2 = Me, Pr)
causes displacement of the equilibrium (38A, R' = H, Me; R2 = Me, Pr;
R3 = H, Me, Et; R4 = Me) ~ (38B) in favor of the cyclic perhydro-I,2,4-
triazine-6-one [79]. Equilibrium constants, determined by the 'H-NMR

method, show that the increasing steric bulk of substituents R2 displaces
the equilibrium toward the ring form; an analogous substitution at R3
(Me < Et < i-Pr) acts in the opposite direction. It seems noteworthy that
an introduction of a methyl group at the a- position of aminoacid (R' = Me)
also destabilizes the cyclic form somewhat. Increasing temperature and
solvent polarity displaces the equilibrium toward the open form.
Ring-chain equilibria (39A) ~ (39B) of N-(2-hydroxyiminoalkyl)hy-
drazones have been described [80]. Here, the cyclic isomer is formed as a
result of an intramolecular addition of a hydroxylamine nitrogen atom to
the hydrazone C= N bond, the hydroxyl amino group changing into a nitrone
function.
R3
I
HO" /C"
N N/ R2
II I .'
/C N
Me ~C; "R'
Me Me
(39A)
3.2.3. 2-Benzimidoyl-benzamides and -benzenesulfonamides

Ring-chain tautomerism caused by the intramolecular addition of
CONHR and S02NHR groups to the C=N group of imines and anils was
observed in a series of 2-benzimidoyl-benzamides and -benzenesul-
fonamides (40) and (41).
(XI
~
X"
NHR
CX:<N-R
~ C=NH
/ Ph NH2
Ph
(A) (8)
(40,X= CO)
(41, X = 50 2 )
Both imine and ani 1 isomers of 2-benzoylbenzamides were obtained.

3-Amino-2-methyl-3-phenylisoindolinone (40B, R = Me) is formed in a
condensation reaction of the dilithium salt of N -methylbenzamide with
benzonitrile [81]. In an analogous reaction the open N-phenyl-2-
benzimidoylbenzamide (40A, R = Ph) was obtained. The isomerization
194 Chapter 3
(40A) -+ (40B) proceeds easily in CDCl 3 at room temperature or on heating

in ethanol.
Two reactions of 2-R 1-3-aryl-3-chloroisoindolinones (42) with primary
amines (R 2 NH 2 ) have been observed [82,83]. Depending on the structure
of the substituents R I and R2 either the chlorine atom of (42) is substitued
forming 2-R I -3-amino-3-arylisoindolinones (43) or an addition occurs at
the carbonyl group of (42), leading to the N -alkyl-2-aroylbenzamide anils
(44A, RI = Ph) and the cyclization products, i.e., 2-R 2-3-phenylamino-3-
phenylisoindolinones (44B, R I = Ph), subsequently [82, 83].
(42) (43)
0
Ar = Ph. 4-CIC 6 H4
o
~
1
/
CONHR2
C=NR 1
4
B:
heating
..
ex)"-R'
Ar NHRI
Ar
(44A) (44B)
Increasingly sterically demanding alkyl substituents R2 hinder the

cyclization (44A, R I = Ph) -+ (44B) of N-alkyl-2-benzoylbenzamide anils:
in ethanol at room temperature the N -benzyl amide isomerizes slower than
the N -propyl amide, but N -isopropyl- and N-t-butylamides are stable under
these conditions. A cyclization was carried out in these cases in boiling
ethanol in the presence of triethylamine.
In dioxan solution at room temperature both isomers, i.e., (44A, Ar =
Ph, RI = Ph, R2 = Pr, PhCH 2, i-Pr, t-Bu) and (44B) are stable. No equili-
brium was formed even after several days at room temperature.
The isomerization (44A) -+ (44B) is favored by increasing polarity of
the C=N bond, i.e., by an introduction of electron-withdrawing substituents
R I at the nitrogen atom. Therefore reactions of 2-( 4-nitrophenyl) and
2-(2-pyridyl)-3-chloro-3-phenylisoindolinones (42) with isopropyl amine
gave 2-isopropyl-3-( 4-nitrophenylamino- or 2-pyridylamino )-3-phenylisoin-
dolinones (44B, Ar = Ph, RI = 4-N02C6 H4' 2-pyridyl, R2 = i-Pr) instead
of the expected open isomers (44A).
2-( tert- Butyl)-3-( 4-chlorophenyl)-3-phenylaminoisoindolinone (44B,
Ar = 4-CIC 4H 4, RI = Ph, R2 = t-Bu) have been obtained from 2-(tert-
butyl)-3-chloro-3-( 4-chlorophenyl)isoindolinone (42) and aniline [83,84].

A thermal isomerization (44B) - (44A) was carried out for the first time by
a short heating at 220°C. The reverse isomerization (44A) - (44B) proceeds
in boiling ethanol in the presence of triethylamine. Both isomers are stable
in dioxan at room temperature.
A thermal isomerization (44B) - (44A) for 2-(n- or sec-alkyl)-3-pheny-
lamino-3-phenylisoindolinones could not be achieved [82]. Obviously, the
above-mentioned example of isomerization is favored by the sterically
demanding tert-butyl substituent in position 2 of isoindolinone thus de-
stabilizing the cyclic structure (44B) [83].
Condensation of dilithium salts of N -substituted benzenesulfonamides
with benzonitrile yielded the cyclic N-methyl-2-benzoylbenzensulfonamide
imine (41B, R = Me), while the N-phenylderivative was obtained as a
mixture of both isomers (41A, R = Ph) and (41B) with a predominance of
the open isomer .[81].
Similarly N-benzyl (41B, R = PhCH z) and N-phenylderivatives (41B,
R = Ph) have been obtained and the last mentioned compound was isomer-
ized in both directions: the conversion (41B) - (41A) could be effected at
140°C or by recrystallization from CCI 4 • The reverse reaction was observed
by heating in ethanol in the presence of triethylamine. Attempts to carry
out a thermal ring opening of the N-benzyl-derivative (41B, R = PhCH z)
were not successful. Evidently, the presence of a phenyl substituent at the
sulfonamide nitrogen atom destabilizes the cyclic structure to a greater
extent.
The introduction of sterically demanding sec- and tert-alkyl substituents
at the sulfonamide nitrogen atom stabilizes the open structure. Therefore
cyclic isomers of sulfonamides (41A, R = i-Pr, t-Bu) have not been observed
[85]. In solutions of (41, R = PhCH z, Ph) the ring-chain equilibrium is
shifted toward the cyclic form.
Surprisingly, acylation of the open isomers (41A, R = i-Pr, t-Bu, Ph)
as well as the cyclic isomer (41B, R = Ph) yielded only cyclic N -acylderiva-
tives (45B).
(YS~2
~N-R'
Ph NHCOR 2
(45A) (458)
Evidently, the introduction of an electron-withdrawing acyl group at

the imine nitrogen atom of the sulfonamide molecule (41A) increases the
196 Chapter 3
electrophilicity of the C=N carbon atom favoring an intramolecular addi-

tion of the S02NHR group to this bond even with bulky substituents at the
nitrogen atom.
In solution the equilibrium (45A) ~ (45B) is observed. Increasing sol-
vent polarity shifts the equilibrium toward the cyclic form (45B).
Me Me Me /OH
........ -'"
-"'C........ -",OH Me-1- N
CH N
II I HONH.--( AO
N CONHAr N
HO-'" I
Ar
(46A) (468)
An interesting example of an intramolecular addition of the NH of a

carbamide group to the aldoxime C=N bond leading to 2-imidazolidine
(46B) has been reported [86,87] for N-arylcarbamoyl-N-{l-oximino-2-
methyl-2-propyl)hydroxylamine (46A). The cyclization requires alkaline
catalysis.
3.2.4. N-(2- and 3-Hydroxyiminoalkyl)nitrones

Koptyug, Volodarskii, and Putsykin, studying the condensation of
anti-a-hydroxylaminooximes (47) with aldehydes and ketones, have
observed an interesting type of ring-chain tautomerism [88,89]. N-(2-
Hydroxyiminoalkyl)nitrones (48A) are the primary products of these reac-
tions. Their cyclization into l-hydroxy-a 3 -imidazoline-3-oxides (48B) may
be considered as an intramolecular addition of the NOH nitrogen to the
nitrone C=N bond transforming the hydroxylamino group into a nitrone
function and the initial nitrone into a hydroxyl amino group on the other side.
Rl OH
"
R2 " C=N /
C/
/"
H NHOH
(47)
Although ring formation occurred as a result of an addition of an

oxime group to a nitrone C=N bond, the molecule still contains both
functional groups.
The condensation of anti-a-hydroxylaminooximes with benzaldehyde

gave only N-(2-hydroxyiminoalkyl)-a-phenylnitrones (48A, R I = Me, Ph;
R2 = H, Me; RI = R2 = (CH 2)4; R3 = H; R4 = Ph) which are stabilized
by a conjugation of the nitrone group with the benzene ring [45,90-92].
Heating aromatic anti-a-hydroxylaminooximes (47, RI = Ph, R2 = H,
Me) with acetaldehyde [92,93], acetone [94], or orthoformic ester [95] led
to 2-substituted derivatives of l-hydroxy-4-phenyl-a 3 -imidazoline-3-oxides
(48B, RI = Ph, R2 = Me, R3 = H, R4 = Me, OEt; R3 = R4 = Me).
Products of condensation of aliphatic (47, R I = R2 = Me) and alicyclic
(47, Rt, R2 = (CH 2 )no n = 4, 5) anti-a-hydroxylaminooximes with acetal-
dehyde in solution (chloroform, methanol, DMSO) form equilibrium mix-
tures (48A) ~ (48B). Two stereoisomeric ring forms (48B) differing in con-
figuration (cis and trans) of the substituents R2 and R4 (R 3 = H) and one
open form (48A, R3 = H) have been established by IH-NMR spectroscopy
[88].
Passing from CDCl 3 to more polar solvents shifts the equilibrium
toward the open form. A linear correlation between the logarithm of the
equilibrium constant and the dipole moment of the solvent has been
observed [88] for the equilibrium (48A, RI = R2 = R4 = Me, R3 =
H) ~ (48B).
Increasing the temperature shifts the equilibrium in DMSO toward the
open form. A linear dependence of 19 KT on 1/ T was detected [88].
Thermodynamic parameters (-aH = 1.69 kcaljmol and -as = 4.1 e.u.) are
near to those obtained for the tautomeric equilibria of oxazolidines
(3A) ~ (3B) (see Table 30) [4].
In the series of N -(2-hydroxyiminocycloalkyl)a-methyl-nitrones (48,
RI, R2 = (CH 2 )no n = 3,4,5; R3 = H, R4 = Me) a decreasing size of the
cycloalkane ring stabilizes the open form (48A): in solution the equilibrium
of the cycloheptyl-derivative (n = 5) is totally displaced toward the cyclic
form (48B), the corresponding cyclohexane derivative (n = 4) shows KT = 9
and when n = 3 no cyclic isomer has been found in deuteriomethanolic
solution.
Surprisingly, the condensation of N-O-hydroxyimino-2-cyclo-
pentyl)hydroxylamine with formaldehyde forms an equilibrium mixture
(K T = 3) in solution, thus differing fundamentally from the condensation
product with acetaldehyde (K T = 0). The replacing of the methyl group in
the nitrone function (48A, R4 = Me) with a hydrogen atom (48A, +
R4 = H)
-
increases the electrophilicity of the carbon atom of the C= N -0 bond
facilitating the cyclization even in case of a less favorable structure of the
connecting link.
Six-membered rings are formed from N-(3-hydroxyiminoalkyl)-
nitrones. Recently it has been shown [96, 97] that condensation products
198 Chapter 3
of l3-hydroxylaminooximes with formaldehyde are cyclic l-hydroxy-I,2,5,6-

tetrahydropyrimidine-3-oxides (49B, R 5 = R6 = H); with acetone the open
structure N-(3-hydroxyiminoalkyl)-a, a-dimethylnitrone (49A, R 5 = R6 =
Me) was obtained, but the condensation product with acetaldehyde was
shown to give an equilibrium mixture (49A, R 5 = H, R6 = Me) ~ (49B) in
solution.
Introduction of methyl groups (R 3 = R4 = Me) into the chain between

interacting groups shifts the equilibrium toward the cyclic form. A cyclo-
hexane ring (49, RI, R2 = (CH 2)4, R3 = R4 = R 5 = H, R6 = Me) [97] resul-
ted in an additional displacement of the equilibrium toward the ring form
(compared with (49, RI = R2 = Me), containing two methyl groups instead
of the tetramethylene bridge [96]).
Summarizing, one can state that introduction of methyl substituents at
the a-carbon of a nitrone group decreases its ability for intramolecular
additions as follows:
>
3.2.5. Fused Systems

Fritz and Losacker [98] studied the ring-chain tautomerism of ehiboline
derivatives (50, RI = R2 = R3 = H, n = 2) in solutions. In acidic medium
a dication of the open structure (51) (see also [99]) is formed, but deproton-
ation is accompanied by cyclization. In solvents of low polarity some
ehiboline derivatives (50, R I = H, R2 = H, Me; R3 = MeO) exist in the
ring form (SOB), but in methanol solution an equilibrium was observed. 0
ring opening is facilitated by I) unsubstituted nitrogen atoms (R I = R2 =
H); 2) a methoxy group in the benzene ring (R 3 = MeO) which lowers the
electrophilicity of the C=N carbon atom in (50A), and 3) increasing the
size of ring D. In solution, ehiboline itself (SOB, R I = R2 = R3 = H, n = 2)
is cyclic; for n = 3 an equilibrium (50A) ~ (50B) was observed, but for

n = 4 no cyclic isomer could be detected.
RD:DHR'.", ~ R' H:
(50A)
Similar influences of substituents, solvents, and medium acidity on the

stability of pyrrolidine or piperidine derivatives was observed [100-102]
also for substituted 2,3,3a,8a-tetrahydropyrrolo[2,3-b]- and 1,2,3,4,4a,9a-
hexahydropyrido-[2,3-b ]-indoles, which are analogues of the alkaloid
physostigmine (eserine).
Comparing the conditions for ring opening of these compounds with
those for 2,3,3a,8a-tetrahydrofuro[2,3-b ]indole derivatives (25B) already
discussed led the authors to the conclusion that opening of a pyrrolidine
ring is more difficult (proceeds at lower pH values) than opening of the
furanidine ring [60, 102]. Compared to a C-O bond the less polarized
C- N bond gives rise to this difference. A general conclusion can be made:
Cyclic isomers being formed by intramolecular addition of NH groups to
a C=N bond possess a greater stability than those from an addition of the
less nucleophilic OH- group.
3.3. S-H-DERIVATIVES OF IMINES AND HYDRAZONES
Condensation products of 2-mercaptoethylamine [103-105], 3-

mercapto-2-butylamine [103] and 2-mercaptoaniline [106-108] with car-
bonyl compounds possess exclusively the cyclic structure (52). The forma-
tion of open derivatives in the course of alkylation (52) -+ (54) or oxidation
(52) -+ (55) in strong alkaline media is an indirect evidence for anions of
open structure (53) [104,106].
200 Chapter 3
(55)
3-Mercaptopropylamine in reactions with formaldehyde and cyc1o-

hexanone forms the corresponding tetrahydro-I ,3-thiazines, but with ben-
zaldehyde a mixture of ring and chain isomers with a predominance of the
Schiff's base was obtained [109). Reaction of 4-mercaptobutylamine with
cyc1ohexanone yielded the corresponding hexahydro-I ,3-thiazepine [110).
The ring-chain equilibrium of mercaptoalkylimines was used [III] for
an explanation of the mechanism of the ring contraction of 5,6-dihydro-1 ,4-
thiazine under the action of elemental sulfur.
Potekhin and Shevchenko [112-117] investigated in detail the ring-chain
tautomerism of aldehyde and ketone N-(2-mercaptoalkyI)hydrazones
(56A) ~ (56B) yielding perhydro-I,3,4-thiadiazines as a result of an
intramolecular addition of a mercapto group to the hydrazone C=N bond.
I H -NMR spectroscopy allowed a determination of the equilibrium constants
at different temperatures in the range of 30-90°C and thermodynamic

parameters !l.H and !l.S were calculated (see Table 38).
Table 38. Ring-Chain Equilibrium (56A" R' = Me) ~ (56B) Constants and
Thermodynamic Parameters Determined by 'H-NMR using Tetrachloroethylene
KT = [8]j[A] -6.H -t"s

R2 R3 R4 R5 R6 at 50°C (kcal/mol) (e.u.) Refs.
Me H H H H 0.11 a 3.20 14.3 114

Me H H Me H 0.29" 3.78 13.6 114
Me H Me H H 0.46 5.07 17.2 117
Et H Me H H 0.16 4.13 16.3 117
t-Bu Me H H H 1.09 7.53 22.9 116
t-Bu Me H Me H 2.63 6.81 19.4 116
t-Bu Me H Me Me 1.09 5.69 17.7 116
t-Bu Pr H H H 2.22 6.17 17.4 116
a At 52°e.
First, it should be noted that, compared to the similarly substituted

N-(2-hydroxyalkyl)hydrazones (11), N-(2-mercaptoalkyl)hydrazones (56)
show a significantly greater preference for cyclization to give 1,3,4-
thiadiazines. Thus, oxygen analogues (11), bearing no alkyl substituents at
the nitrogen atom (R 3 = H), are not at all capable offorming cyclic isomers
[27, 28, 32]. It has been pointed out [114, 116] that the energy of the
intramolecular SH···N bond is low compared to that of the OH···N bond.
In addition, the ring strain decreases on passing from the oxygen containing
heterocycle (11B) to its sulfur analogue (56B) (see also [118]). Evidently,
increasing nucleophilicity in the sequence 0 < N < S [119] plays a sig-
nificant role also.
The introduction of alkyl substituents at the nitrogen atom (56, R3 =
Me, Pr) (similar to that already observed [27-29, 32, 33, 35] in the series
of N-alkyl-N-(2-hydroxyethyl)hydrazones (11B, R3 = alkyl)) strongly
stabilizes the cyclic form. Thus, the majority of N -alkylderivatives (56,
R3 = Me, Et, Pr, i-Pr) exist as stable cyclic isomers (56B), and a tautomeric
equilibrium can be observed only if bulky substituents R2 are present
(R 2 = t-Bu, see Table 38). The cyclic form is stabilized as well by subsequent
introduction of methyl groups in positions 5 or 6 of the 1,3,4-thiadiazine
ring (R 4 = Me or R 5 = Me), methyl substituents in position 5 (R4 = Me)
exerting a stronger influence. However, the introduction of the second
methyl group in position 6 of the thiadiazine ring (R 5 = R6 = Me) destabil-
izes the cyclic isomer, which can be explained [116] by destabilizing nonbon-
ded interactions between syn-diaxial groups (2-Me and 6-Me) in the chair
conformation of the 1,3,4-thiadiazine.
An increase in the number and steric bulk of substituents in position
2 displaces the equilibrium toward the open form as already observed for
N -( 2-hydroxyalkyl) hydrazones (11).
Ring-chain equilibria (56A) ~ (56B) were detected [115] in the series
of N -(2-mercaptoalkyl)hydrazones of aromatic aldehydes and acetoph-
enones (56, RI = H, Me; R2 = C 6 H4X), Surprisingly, on passing from the
benzaldehyde hydrazone (56, R2 = Ph, R3 = Pr, R 5 = Me, other R = H)
(KT = 0.64, in tetrachloroethylene at 90°C) to the acetophenone hydrazone
(56, RI = Me, other substituents are the same) (K T = 11.1) the equilibrium
202 Chapter 3
is displaced toward the cyclic form. A similar effect was observed [34] also
for oxygen analogues (11). Compared to alkylderivatives (56, R2 = alkyl),
aryl analogues (R2 = aryl) equilibrate (56A) +:! (56B) considerably more
slowly, requiring more than 5 hours at 90°C in tetrachloroethylene contain-
ing 0.1 % CF3 COOH.
In the series (56, R' = H, R2 = 4-XC 6 H 4 , R3 = Pr, R 5 = Me) the depen-
dence of the equilibrium constants KT on the polar character of substituents
X is insignificant, and not even an approximate correlation has been
observed between Ig KT and (J'- or (J' + -coefficients [115].
Mayer and Lauerer [120] using 'H-NMR spectroscopy were able to
detect the equilibrium (57 A) +:! (57 B) in solutions of condensation products
of dithiocarbazine acids with aldehydes and ketones. The anions, being
formed in alkaline media, possess the open structure (58).
H R3 S
~S /'
R' C~ "" N-N / R'
""C=N-N / ,,-.S- C:
""C=N-N / "" SH R~~S
R2 / ""R3 R2 S R2 / ""R3
(57A) (578) (58)
The authors [120] assumed an equilibrium (59A) +:! (59B) in acidic
solutions of N,-thioacylhydrazones and (61A) +:! (61B) in the case of N r
substituted thiosemicarbazones of aldehydes and ketones.
R' R3
""C=N-N=C / ••
R2 / "" SH
(59A)
Ii R'
~ '" C=N-NH-C-R 3
2/ II
R S
(590)
(60)
H R3
Rl
" C=N-N-C
I /
R3 NHR4 "
Rl N-N /
~~NR4
4 ~
/ ~
R2 S R2 S
(61A) (618)
Later, it was demonstrated [121] that the condensation products of

acetone and 2-butanone with thiobenzhydrazide are cyclic (59B, R 1 = Me,
R2 = Me, Et, R3 = Ph), but for benzaldehyde phenylthioacetylhydrazone
the open structure was supported by spectroscopic methods, the bipolar
structure (59C, R 1 = H, R2 = Ph, R3 = PhCH 2 ) being preferred by the
authors [122]. IH-NMR investigations showed that an equilibrium
(59C) ~ (59B) occurs rapidly in CDCI 3 , benzene, or acetone-d 6 solutions.
Passing from acetone (KT = 0.33) to benzene(KT = 5), the equilibrium is
strongly displaced in favor of the cyclic isomer (59B).
Acetone thiosemicarbazones have been investigated in more detail by
IH-NMR spectroscopy [123]. Thiosemicarbazone (61, Rl = R2 = Me, R3 =
R4 = H) and its 2-methy1 (R 3 = Me) and 4-methyl (R 4 = Me) derivatives
are open structured (61A) in DMSO-d 6 solution, but cyclic (61B) in
CF3 COOD. In these solvents acetone 2,4-dimethylthiosemicarbazone exists
exclusively in the ring form (64B, Rl = R2 = R3 = R4 = Me).
As a general rule cyclic isomers of imine mercaptoderivatives form
exclusively open structured anions (53), (58), (60).
Me Me S H
" II " N-N
Me~(} C=NNHCPh
C~2 4 ~ Me~ }--Ph
HO N "C=O MeCOCH 2 S
I
/
/C0.. Me
Ph "s
(628) (62A) (62e)
An interesting example of a tautomeric equilibrium between two cyclic
forms (62B) ~ (62C) was presented by Zelenin and coworkers [124]. The
cyclic (62B) obtained in a solution of 2,4-pentanedione thiobenzhydrazone
is the result of an intramolecular addition of a NH group to a C=O bond.
The second cyclic isomer (62C) can be considered as being formed as the
result of an intramolecular addition of a SH group to a C=N bond.
Therefore interconversions (62B) ~ (62C) most likely proceed through an
intermediate hydrazone (62A) which nevertheless could not be detected by
IH and 13C-NMR methods. In the sequence CDCI 3 , CCI 4 , CD 3 0D, and
DMFA-d 7 the equilibrium shifts toward (62B).
204 Chapter 3
3.4. MISCELLANEOUS
Recently, using IR, 'H, '3C, and 29Si_NMR spectroscopy a new type
of ring-chain tautomerism of 2-trimethylsiloxyphenyl isocyanate
(63B) ~ (63A) ~ (63C) was detected [125]. Here the Me3SiO group is added
intramolecularly either to the c=o (63C) or the C=N (63B) bond of the
isocyanate. Rather high activation energies have been reported for the
transitions (63A) -+ (63B) and (63A) -+ (63C).
SiMe 3
I
~ }-OSiMe ~ 0
N N=C=O
3 ~ ~N>=O
~o ~OSiMe3 ~O
(63C) (63A) (638)
An analogous reversible rearrangement was also established [126] for

the trimethylsilyl ester of 2-isocyanatobenzoic acid (64A) ~ (64B), but the
second cyclic isomer (64C) could not be detected. The cyclic (64B) was
isolated; it was stable at room temperature and even on boiling in CCl 4 for
3 hours. The equilibrium (64A) ~ (64B) only occurs on melting of (64B).
Increasing temperature shifts the equilibrium toward the open isomer (64A).
Equilibrium constant KT = [(64B)]2 j[(64A)]2 = 0.174 at 128°C has been
reported assuming that the isomerization is bimolecular. Thermodynamic
parameters have been found: tJ.H = -6.66 kcaljmol and tJ.S = -20.4 e.u. A
cco
comparatively high activation energy tJ.H'" = 22.8 kcaljmol was detected
a
for the transition (64B) ~ (64A).
o
COOSiMe3
I ~ I I
~ N=C=O ~ N/.I::::: n
I
SiMe 3
(64A) (648) (64C)
Recently Medyantseva, Minkin, and co-workers [127-131] have

observed and by using UV, IR, and 'H-NMR spectroscopy thoroughly
studied an interesting type of tautomerism (65A) ~ (65A') ~ (65B), which
can be related to the ring-chain tautomerism or simultaneously to valence
isomerism.
Formally the ring tautomers (65B, X = NR, 0) are formed as a result
of an intramolecular addition of a phenolic OH group to the C=N or C=O
bond. However, the authors supposed that the transformation
(65A) +2 (65A') precedes ring formation, and then a valence isomerization

(65A') -+ (658) results in ring closure.
(65A) (65A') (658)
C\. C\.
X= NR,O
I» ID
U· MeV BrV
a b c d
E-3-(2-Hydroxy-I-naphthyl)propenal (65a, X = 0) and its N -alkyl and

N-aryl imines (65a, X = NR) possess cyclic structure (658) in the solid
state and in non-polar solvents, but on passing to the polar solvents the
equilibrium is displaced in favor of the quinonoid tautomer (65A'). Some
N-alkylimines (65a, X = NR, R = i-Pr, Bu, t-Bu) exist as open isomers
(65A') in the solid state. Cyclic isomer (658) and two supposed E-Z-isomers
of quinonoid structure (65A') have been isolated for N -methylimine
(65a, X = NMe) [128].
E-3-(l-Hydroxy-4-methyl-2-naphthyl)propenal (65b, X = 0) [129] and
its 4-bromoanalogue (65c, X = 0) [130] exist preferentially in cyclic form
(658) in the solid state and in non-polar solvents. Using IH-NMR spectros-
copy the equilibria (65A'a, b, c) +2 (658a, b, c) have been observed in OM SO
solution [129, 130]. In the sequence of solvents acetonitrile, acetone, OMSO
the equilibrium is shifted toward the open isomer (65A').
Generally passing from the benzo[e]- (65a) to the benzo[c]-derivatives
(65b, c) of cinnamic aldehyde the equilibrium is shifted toward the open
quinonoid isomer (65A').
3-Bromo-2-hydroxy-5-nitrocinnamic aldehyde (65d) possesses structure
(65A, X = 0) in the solid state and in OMSO solution, but its N-arylimines
(65d, X = NAr) are cyclic (658) in the solid state as well as in solvents of
different polarity [131].
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Derivatives, Khimiya, Leningrad, 1979, p. 187 (In Russian).
36. J. T. Edvard, P. E. Morand, and I. Puskas, Can. J. Chern. 1961, 39, 2069.
37. J. E. Whitting and J. T. Edward, Can. J. Chern. 1971, 49, 3799.
38. W. Kliegel and H. Becker, Chern. Ber. 1977, 110, 2067.
"39. W. K1iegel and H. Becker, Chern. Ber. 1977, 110, 2090; See also W. Kliegel, B. Enders,
and H. Becker, Justus Liebigs Ann. Chern. 1982, 1712; W. K1iegel, B. Enders, and H.
Becker, Chern. Ber. 1983, 116, 27.
40. H. Mohrle, M. Lappenberg, and D. Wendish, Monatsh. Chern. 1977, 108, 273.
41. H. Mohrle and K. Troster, Arch. Pharrn. 1981, 314, 836.
42. L. B. Volodarskii, Yu. G. Putsykin, and V. I. Mamatyuk, Zh. Org. Khirn. 1969, 5, 355.
43. L. B. Volodarskii, A. Va. Tikhonov, and L. A. Fust, Izv. Sibirsk. Otd. Akad. Nauk SSSR,
Ser. Khirn. 1971 (3), 7,91.
44. H. Ulrich and A. A. Sayigh, Angew. Chern. 1962, 74, 468.
45. J. Hamer and A. Macaluso, Chern. Rev. 1964, 64, 473.
46. Yu. V. Svetkin, M. A. Akmanova, and G. P. Plotnikova, Zh. Org. Khirn. 1974, 10,561.
47. S. L. Zhdanov, K. A. Ogloblin, and A. A. Potekhin, Zh. Org. Khirn. 1975, 11, 1825.
48. A. A. Potekhin, S. L. Zhdanov, V. A. Gindin, and K. A. Ogloblin, Zh. Org. Khirn. 1976,
12, 2090.
49. S. L. Zhdanov and A. A. Potekhin, Khirn. Geterotsikl. Soedin. 1977,417.
50. A. A. Potekhin and S. L. Zhdanov, Khirn. Geterotsikl. Soedin. 1979, 1317.
51. A. A. Potekhin and S. L. Zhdanov, Zh. Org. Khirn. 1979, 15, 1384.
52. H. R. Snyder, R. H. Levin, and P. F. Wiley, J. Chern. Soc. 1938, 60, 2025.
53. S. Wawzonek, H. Laitinen, and S. J. Kwiatkowski, J. Am. Chern. Soc. 1944, 66, 830.
55. W. Flitsch, Chern. Ber. 1970, 103, 3205.
56. R. E. Valters and V. P. Ciekure, Khirn. Geterotsikl. Soedin. 1972, 502.
57. R. E. Valters and V. P. Ciekure, Khirn. Geterotsikl. Soedin. 1975, 1476.
59. V. R. Zinkovska and R. E. Valters, La tv. PSR Zinat. Akad. Vestis, Kim. Ser. 1974, 207.
60. I. I. Grandberg and S. N. Dashkevich, Khirn. Geterotsikl. Soedin. 1971, 1194.
61. S. N. Dashkevich and I. I. Grandberg, Dokl. Tirniryazevsk. Sel'skokhozyaistv. Akad. 1970,
160, 243.
62. C. Chapuis, A. Gavreau, A. KJaebe, A. Lattes, and J. J. Perie, Bull. Soc. Chirn. Fr. 1973,
977.
63. S. Witek, A. Bielawska, and J. Bielawski, Heterocycles 1980, 14, 1313.
64. R. F. Evans, Austr. J. Chern. 1967, 20, 1643.
65. W. Popel, G. Faust, H. Furst, G. Dietz, and E. Carstens, 1. prakt. Chern. 1968, 38, 339.
66. R. E. Harmon, J. L. Parson, and S. K. Gupta, J. Org. Chern. 1969, 34, 2760.
67. J. B. Lambert and M. W. Majchrzak, J. Am. Chern. Soc. 1979, 101, 1048.
68. J. E. Baldwin, J. Chern. Soc., Chern. Cornrnun. 1976, 734.
69. J. E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman, and R. C. Thomas, 1.
Chern. Soc., Chern. Cornrnun. 1976, 736.
70. J. E. Baldwin, R. C. Thomas, L. I. Kruse, and L. Silberman, J. Org. Chern. 1977, 42,3846.
71. H. Piotrovska, W. Sas, and T. Urbanski, Tetrahedron 1977,33, 1979.
72. H. Schildknecht and G. Hatzmann, Justus Liebigs Ann. Chern. 1969, 724, 226.
73. K. Pilgram, R. D. Skiles, and G. E. Pollard, J. Heterocycl. Chern. 1976, 13, 1257.
74. M. Uda and S. Kubota, J. Heterocycl. Chern. 1978, 15,807.
75. V. A. Khrustalev, K. N. Zelenin, V. P. Sergutina, and V. V. Pinson, Khirn. Geterotsikl.
Soedin. 1980, 1138.
*76. K. N. Zelenin, V. A. Khrustalev, V. P. Sergutina, and V. V. Pinson, Zh. Org. Khirn. 1981,
17, 1825; see also V. A. Khrustalev, V. P. Sergutina, K. N. Zelenin, and V. V. Pinson,
77. W. Walter and Ch. Rohloff, Justus Liebigs Ann. Chern. 1977,485.
*78. P. S. Lobanov, A. N. Poltorak, and A. A. Potekhin, Zh. Org. Khirn. 1978, 14, 1086.
79. P. S. Lobanov, A. N. Poltorak, and A. A. Potekhin, Zh. Org. Khirn. 1980, 16,2297.
80. V. A. Dokichev and A. A. Potekhin, Zh. Org. Khirn. 1977, 13,2617.
81. H. Watanabe, Ch.-L. Mao, I. T. Barnish, and Ch. R. Hauser, J. Org. Chern. 1969,34,919.
*82. R. E. Valters, Khirn. Geterotsikl. Soedin. 1973,762.
83. R. E. Valters and G. A. Karlivans, Khirn. Geterotsikl. Soedin. 1976, 1207.
84. R. E. Valters and G. A. Karlivans, Zh. Org. Khirn. 1976, 12,238.
85. R. E. Valters, D. E. Balode, R. B. Kampare, and S. P. Valtere, Khirn. Geterotsikl. Soedin.
1981, 1209.
86. T. G. Kharlamova, Yu. A. Baskakov, and Yu. G. Putsykin, Khirn. Geterotsikl. Soedin.
1975,715.
• See also additions in proof on page 209.

208 Chapter 3
87. T. G. Kharlamova, Yu. G. Putsykin, and Yu. A. Baskakov, Khim. Geterotsikl. Soedin.
1976, 1255.
88. Yu. G. Putsykin and L. B. Volodarskii, Izv. Sibirsk. Otd. Akad. Nauk SSSR, Ser. Khim.
1969 (4), 9, 86.
89. L. B. Volodarskii, Khim. Geterotsikl. Soedin. 1973, 1299.
90. V. A. Koptyug, L. B. Volodarskii, and I. K. Baeva, Zh. Obshch. Khim. 1964, 34, 151.
91. L. B. Volodarskii and Yu. G. Putsykin, Zh. Org. Khim. 1967,3, 1686.
92. L. B. Volodarskii and L. Va. Tikhonov,Zh. Org. Khim. 1970, 6, 307.
93. L. B. Volodarskii, A. N. Lysak, and V. A. Koptyug, Khim. Geterotsikl. Soedin. 1966, 766.
94. L. B. Volodarskii, A. N. Lysak, and V. A. Koptyug, Khim. Geterotsikl. Soedin. 1968, 334.
95. L. B. Volodarskii and E. I. Vityaeva, Zh. Org. Khim. 1972, 8, 1887.
96. A. Va. Tikhonov and L. B. Volodarskii, Khim. Geterotsikl. Soedin. 1977,252.
97. A. Va. Tikhonov, L. B. Volodarskii, and O. M. Sokhatskaya, Khim. Geterotsikl. Soedin.
1979, 1265.
98. H. Fritz and P. Losacker, Justus Liebigs Ann. Chem. 1967, 709, 135.
'"99. M. Taniguchi and T. Hino, Tetrahedron 1981, 37, 1487.
100. I. I. Grandberg and T. A. Ivanova, Dokl. Timiryazevsk. Sel'skokhozyaistv. Akad. 1970,
160, 232.
101. A. H. Jackson and A. E. Smith, J. Chem. Soc. 1964,5510.
102. I. I. Grandberg, T. A. Ivanova, and N. G·. Yarishev, Khim. Geterotsikl. Soedin. 1970,
1276; I. I. Grandberg and T. A. Ivanova, Khim. Geterotsikl. Soedin. 1970, 1489.
103. E. D. Bergmann and A. Kaluszyner, Rec. trav. chim. 1959, 78,315.
104. G. W. Stacy and P. L. Strong, 1. Org. Chem. 1967,32, 1487.
105. G. W. Stacy and P. L. Strong, 1. Heterocycl. Chem. 1968, 5, 101.
106. F. J. Goetz, J. Heterocycl. Chem. 1967, 4, 80.
109. E. D. Bergmann and A. Kaluszyner, Rec. trav. chim. 1959, 78,327.
110. E. D. Bergmann and A. Kaluszyner, Rec. trav. chim. 1959, 78, 331.
III. F. Asinger, A. Saus, and D. Neuray, Justus Liebigs Ann. Chem. 1952, 759, 121.
112. S. M. Shevchenko, T. Va. Vakhitov, and A. A. Potekhin, Khim. Geterotsikl. Soedin. 1978,
1427.
113. A. A. Potekhin, S. M. Shevchenko, T. Va. Vakhitov, V. A. Gindin, Khim. Geterotsikl.
Soedin. 1978, 1568.
114. S. M. Shevchenko and A. A. Potekhin, Khim. Geterotsikl. Soedin. 1979, 1637.
115. A. A. Potekhin, V. V. Sokolov, and S. M. Shevchenko, Khim. Geterotsikl. Soedin. 1981,
1040.
116. A. A. Potekhin, S. M. Shevchenko, T. Va. Vakhitov, and V. A. Gindin, Khim. Geterotsikl.
Soedin. 1981, 1217.
117. A. A. Potekhin and S. M. Shevchenko, Khim. Geterotsikl. Soedin. 1981, 1355.
118. M. I. Page, Chem. Soc. Rev. 1973, 2, 295.
119. R. E. Vaiters, Uspekhi Khimii 1982, 51, 1374.
120. K. H. Mayer and D. Lauerer, Justus Liebigs Ann. Chem. 1970, 731, 142.
121. K. N. Zelenin, V. A. Khrustalev, V. V. Pinson, and V. V. Alekseev, Zh. Org. Khim. 1980,
16,2237; See also K. N. Zelenin, V. V. Alekseev, and V. A. Khrustalev, Khim. Geterotsikl.
Soedin. 1983, 769.
*122. V. V. Alekseev, V. A. Khrustalev, and K. N. Zelenin, Khim. Geterotsikl. Soedin. 1981, 1569.
123. M. Uda, S. Kubota, 1. Heterocycl. Chem. 1979, 16, 1273.
• See also additions in proof on page 209.

*124. V. A. Khrustalev, K. N. Zelenin, and V. V. Alekseev, Zh. Org. Khirn. 1981,17,2451; see
also S. I. Yakimovich, K. N. Zelenin, V. N. Nikolaev, N. V. Koshmina, V. V. Alekseev,
and V. A. Khrustalev, Zh. Org. Khirn. 1983, 19, 1875.
*125. M. G. Kuznetsova, N. V. Mironova, A. V. Kisin, V. P. Kozyukov, V. S. Nikitin, and N.
V. Alekseev, Zh. Obshch. Khirn. 1981, 51, 1096.
126. N. L. Chikina, Yu. V. Kolodyazhnii, V. P. Kozyukov, N. V. Mironova, and O. A. Osipov,
Zh. Obshch. Khirn. 1981, 51, 1803.
127. I. M. Andreeva, O. M. Babeshko, E. A. Medyantseva, and V. I. Minkin, Zh. Org. Khirn.
1979, 15, 1899.
128. I. M. Andreeva, E. A. Bondarenko, N. V. Volbushko, M. I. Knyazhanskii, E. A. Medyant-
seva, A. V. Metelitsa, V. I. Minkin, and B. Va. Simkin, Khirn. Geterotsikl. Soedin. 1980,
1035.
129. I. M. Andreeva, E. M. Bondarenko, E. A. Medyantseva, R. G. Pudeyan, and V. I. Minkin,
130. I. M. Andreeva, E. M. Bondarenko, E. A. Medyantseva, and V. I. Minkin, Khirn.
13!. O. M. Babeshko, E. A. Medyantseva, O. T. Lyashik, and V.1. Minkin, Khirn. Geterotsikl.
Soedin. 1982, 1477; See also V. A. Bren', L. M. Sitkina, A. D. Dubonosov, V. I. Minkin,
M. I. Knyazhanskii, Dokl. Akad. Nauk SSSR, 1983,272, 1382; A. D. Dubonosov, C M.
Sitkina, V. A. Bren', A. Va. Bushkov, V. I. Minkin, Khirn. Geterotsikl. Soedin. 1984, 117!.
Additions in proof: References to some more important papers published in 1983 and 1984
are added below. They supplement with new data the main list references marked with an
asterisk.
*4. For the investigation of the ring-chain equilibria of type «3A) +:t (38), page 170) by
15N_NMR spectroscopy see B. Ch. Chen, W. V. Philipsborn, and K. Nagarajan, Helv.
Chirn. Acta 1983, 66, 1537.
*39. W. Kliegel and L. Preu, Justus Liebigs Ann. Chern. 1983, 1937; W. Kliegel and J.
Graumann, Justus Liebigs Ann. Chern. 1984, 1545.
*76. V. V. Pinson, V. A. Khrustalev, K. N. Zelenin, and Z. M. Matveeva, Khirn. Geterotsikl.
Soedin. 1984, 1415.
*78. For ring-chain tautomerism of N-[2-(N-alkylamino)ethyl]-N-methylhydrazones of for-
maldehyde, acetaldehyde, and acetone see P. S. Lobanov, O. V. Solod, and A. A. Potekhin,
Zh. Org. Khirn. 1983, 19,2310.
*82. For mass spectrometric investigation of ring-chain tautomerism of type «44A) +:t (448),
page 194), see O. S. Anisimova, Yu. N. Sheinker, and. R. E. Vaiters, Khirn. Geterotsikl.
Soedin. 1984, 1080.
*99. M. Taniguchi, A. Gonsho, N. Nakagawa, and T. Hino, Chern. Pharrn. Bull. Tokyo 1983,
31, 1856.
*122. For the detailed investigation of the equilibrium «59A) +:t (598), page 202) see K. N.
Zelenin, V. V. Alekseev, and V. A. Khrustalev, Zh. Org. Khirn. 1984, 20, 169.
*124. For further investigation of the equilibrium «628) +:t (62C), page 203) see K. N. Zelenin,
V. A. Alekseev, V. A. Khrustalev, S. I. Yakimovich, V. N. Nikolaev, and N. V. Koshmina,
Zh. Org. Khirn. 1984, 20, 180.
*125. N. L. Chikina, Yu. V. Kolodyazhnii, V. P. Kozyukov, N. V. Mironova, and O. A. Osipov,
Zh. Obshch. Khirn. 1984, 54, 139.
4
Reactions to the Other Groups
4.1. ADDITION TO THE C_N GROUP
Numerous synthetic methods for the preparation of heterocyclic imines

and amines have been developed [1,2] in which the last stage involves an
intramolecular nucleophilic addition of a hydroxy, amino, or mercapto
group to a C N bond. Intermediates in these syntheses, i.e., hydroxy,
amino, or mercaptonitriles (lA, X = 0, NR, S) usually were not isolated.
Only a few aspects of intramolecular addition reactions to the cyano
group will be discussed here since there are comprehensive reviews [1,2].
The main attention will be paid to cyclization conditions, to structural
influences on the process, and to the reversibility of the intramolecular
addition reactions.
The hydroxy, amino, or mercaptonitriles (IA) which have been isolated
could be cyclized to (IB) easily and irreversibly by heating in polar solvents
[3-5], in the presence of acids [6-11], bases [12-25], or upon melting
[3,4,8,22,26].
2-Cyanobenzamide [27] and 2-thioureidobenzonitrile [3] show double
melting points because of thermal isomerization. After melting the sub-
stances undergo isomerization to (IB) which crystallize and melt again at
higher temperatures.
(;x
C=C
/ "-
Rl NH z
X-H __ (1e)
(
-C=N
(I C~
"'NH ~H)
(1A) (18)
X=O. NR. S
212 Chapter 4
The heterylimines (lB) often isomerize subsequently to heterylamines

(IC) or (ID), the double bond shifting into the ring.
Matsui [28] and Renson [29] with co-workers detected VC=N and VC=N
bands in the IR spectra of w-cyanoalcohols (2A) and 2-hydroxymethylben-
zonitrile (3A) which led them to assume a ring-chain tautomeric equilibrium
(A) i2 (B). Additional corroboration for this conclusion can be obtained by
spectroscopic investigations of hydroxynitrile (2) or (3) in different solvents.
Numerous data [1,2,6] concerning cyclization reactions of hydroxynitriles
confirm the irreversibility of the cyclization. Perhaps Matsui and Renson
[28, 29] dealt not with an equilibrium but a mixture of isomers (compare
[30]).
(I C0.-
"NH
(A) (8)
c = -(CH 2 )n-' (rCH2'-

n=2-5
(2) (3)
Mononitriles of phthalic [27], homophthalic [31], and other ')'- or

8-dicarboxylic acids [2] easily isomerize into imides (4C). The isomerization
proceeds via iminolactones (isoimides) (4B) of little stability [20,31].
0 0
II II
C;O:H -- (C~ -- (C~N_H C
/0
C/
II II
NH 0
(4A) (48) (4C)
Investigation of IR spectra of 2-cyanobenzoic acid in different solvents

[22] showed that in solutions at room temperature this acid is stable and
the equilibrium (4A) i2 (4B) does not occur.
')'- and 8-Aminonitriles [7,8,14,21,32-35], {3-hydrazinonitriles
[12,18,36], cyanoketone hydrazones [4], and cyanocarboxylic acid
hydrazides [5, 37-40] isomerize into the corresponding heterocyclic imines.
3-Cyanopropionamides (SA) [13, 15, 19,41] and 2-cyanobenzamides (6A)
Intramolecular Reversible Addition to Other Groups 213
[22, 26, 27] isomerize either in the presence of bases (sodium alcoholate,
triethylamine) or on heating into iminolactams (5B) and (6B).
o
II
CONHR _____
( ( C"N_R
C=N C/
II
NH
(A) (8)
(=
(5) (6)
Braun and Tcherniac [27] were the first to observe the thermal isomeriz-
ation of 2-cyanobenzamide (6A, R = H) -+ (6B) obtained in a reaction of
phthalic acid diamide with acetanhydride. They detected that 2-cyanobenz-
amide after melting at 172-173°C crystallizes and melts anew at 200°C which
corresponds to the melting point of phthalimide monoimine (6B, R = H).
At 130-160°C an analogous isomerization takes place [42] for 2-cyanoben-
zanilide (7 A, R = H) -+ (7B).
An equilibrium (7 A, X = H) ~ (7B) was observed [42] in polar aprotic
solvents such as DMSO (KT = 38.0 at 25°C), N-methylpyrrolidone (K T =
17.4), dimethylacetamide (K T = 6.6), and HMPT (K T = 2.8). Cyclization
of 2-cyanobenzanilide occurs under base catalysis: a linear relationship was
observed [42] between the rate constant of cyclization and the concentration
of the tributylamine in dimethylacetamide solution.
The kinetics of the isomerization of 2-cyanobenzamide in aqueous
potassium hydroxide is first order regarding the hydroxide concentration
[43] (and not second order as described earlier [44]).
An investigation [45] of the influence of solvents and substituents X
on the isomerization (7 A) -+ (7B) rate (see Table 39) showed that the rate
constants in aqueous sulpholane in the presence of an acetate buffer (pH =
7.45) correlate sufficiently (r = 0.970) with the pKa values of the correspond-
ing benzanilides, i.e., the cyclization rate increases on passing from electron-
donating to electron-withdrawing substituents. It follows that in a given
medium the constant (k l / k 2 ) for the equilibrium (7 A) ~ (7C) exerts a strong
influence on the total cyclization rate.
However, since this rate is defined as k = kl x k3/ k2' electron-with-
drawing substituents X that increase 2-cyanobenzanilide (7 A) N - H acidity
may simultaneously decrease its nucleophilicity and thus slow down the
214 Chapter 4
0(0:-< }-X.".
(7A) (7e)
(70) (78)
transformation (7C) -+ (7D). If kl/ k2 and k3 in the cyclization (7 A) -+ (7B)

are comparable in magnitude, then a linear correlation between 19 k and
pKa (i.e. the if constants of substituents X) of corresponding benzanilides
may not exist. The cyclization (7 A) -+ (7B) in aqueous DMSO solution in
the presence of biphthalate buffer (pH = 8.68) is most rapid for the N-
unsubstituted 2-cyanobenzanilide (7 A, X = H) while increasing electron-
donating as well as electron-withdrawing properties of the substituents X
significantly lowers the cyclization rate (see Table 39). The dependence of
19 k on the substituent constants if is expressed by two straight crossing
lines. As a consequence the rate-determining step of cyclizations of deriva-
tives bearing electron-donating substituents is (7 A) -+ (7C) while a rate
control is exerted by the step (7C) -+ (7D) in the case of electron-withdrawing
substituents.
Table 39. Cyciization Rate Constants or 2-Cyanobenzanilides

(7 A) -+ (78) [45]
Sulpholane-water (9: I), DMSO-water (9: I),

acetate buffer biphthalate buffer
X pH 7.45, 32.4°C pH 8.68, 19.7°C
COOMe 0.23
Br 8.8 0.66
CI 5.9 1.09
F 5.1 1.18
H 2.1 4.36
Me 1.7 3.97
MeO 1.5 3.30
Me2N 0.21
In the IR spectrum of 2-cyanobenzamide Flett [46] observed amide-I

(1753 cm- I ) and amide-II (1667 cm-t, KBr pellet) bands being unusually
high for benzamides. The same is reported in Bellamy's monograph [47].
Later it was established [26] that the IR spectrum of a 2-cyanobenzamide
[27] showed amide-I and amide-II bands at significantly lower frequencies
(1658 and 1626 cm-t, KBr pellet). Apparently, Flett's compound was
phthalimide monoimine, the spectrum of which in dioxan shows two strong
bands IIC=O 1737 cm- I (A = 4.6 pract. un.) and IIC=N 1671 cm- I (3.0 pract.
un.) (see Fig. 11) [22,26].
Increasing steric encumbrance of substituents R at the nitrogen atom
of N-monosubstituted 2-cyanobenzamides (6A) hampers the isomerization
(6A) -+ (6B) which proceeds under base catalysis or thermally [22]. In case
of a tert-alkyl substituent (t-Bu, l-adamantyl) the isomerization (6A) -+ (6B)
does not occur at all. No tautomeric equilibrium was observed in solutions
of 2-cyanobenzamides (6A) and their cyclic isomers (6B) in dioxan,
acetonitrile, or DMSO (IR spectroscopy).
2-Cyanobenzthioamide was isolated [48] as cyclic (8).
S
~N-H
NH
(8)
100----,----.-----.----.----.-----.----.-----.----.------
50
0
0-
Q)
0
c
0
.D
0
L-
0
If)
.D
0
50
3
0
3400 3000 2400 2200 V,CM- 1
Figure II. IR spectra of open and ring isomers of 2-cyanobenzamide: 1-2-cyanobenzamide
in the solid state, 2-its solution in dioxan, 3-3-iminoisoindolinone in the solid state, 4--its
solution in dioxan [26].
216 Chapter 4
2-Ureido and 2-thioureidobenzonitriles [3,17,49] and a-cyanohydrine

urethanes [16] cyc1ize similarly as 2-cyanobenzamides.
The direction of thermal isomerization of the 2-cyanobenzamides
(6A) -+ (6B) differs from that of ketocarboxylic acid amides (B) -+ (A) (see
section 2.1.3). This direction of thermal isomerization also has been observed
for other hydroxy and amino derivatives of nitriles. However, a case has
been reported [35] where a reverse thermal isomerization (9B) -+ (9A) pro-
ceeds. Evidently the aromatic stabilization of the sym-triazine ring of the
open isomer (9A) plays a decisive role.
Both N -monosubstituted 2-cyanobenzenesulfonamide isomers (lOA)

and (lOB) have been obtained [24, 25]. In the presence of bases 2-cyanoben-
zenesulfonamides (lOA, R = Me, i-Pr, PhCH 2 , 4-MeC 6 H4' 4-MeOC 6 H4)
isomerize into 3-iminobenzisothiazoline-l, I-dioxides (lOB). N- (t- Butyl)-
and N-(1-adamantyl)-sulfonamides do not cyc1ize because of steric
hindrance.
(10A) (108)
Unlike 2-cyanobenzanilide (7 A, X = H) which forms isoindolinone

under basic catalysis [25], 2-cyanobenzenesulfonanilide (lOA, R = Ph) does
not cyc1ize under the same conditions, but introduction of electron-donating
substituents in to the phenyl group (10, R = 4-MeC 6 H4' 4-MeOC 6 H4)
renders cyc1ization possible.
Ring opening of (lOB, R = i-Pr, PhCH 2 , 4-MeC 6 H4) -+ (lOA) was
achieved by short heating up to 220°C thus forming equilibrium mixtures
(lOB) ~ (lOA). Sterically demanding or electron-withdrawing substituents
at the nitrogen atom shift the equilibrium toward the sulfonamide (lOA).
Table 40. Ring-Chain Equilibrium Constants (lOA) +:t (lOB)

Determined by IR Spectroscopy with Dioxan and 10%
Triethylamine at 20°C [25]
Time to reach
equilibrium with
R Ky = [(IOB)]/[(IOA)] (lOA)
Me >100 4 years
PhCH 2 2.1 36 h
Ph 0.15 8 min
4-MeC 6 H4 0.29 25 min
4-MeOC 6 H4 0.65 30 min
In dioxan at room temperature both isomers (lOA) and (lOB) are stable.
An equilibrium (lOA) +2 (lOB) is observed only after addition of triethyl-
amine which transfers a proton. N-Isopropylderivatives (lOA, R = i-Pr)
and (lOB) and N-tert-alkylsulfonamides (lOA, R = t-Bu, l-adamantyl) do
not equilibrate. Equilibrium constants of the remaining derivatives were
determined by IR spectroscopy. As may be seen from Table 40 introduction
of electron-donating substituents (Me, MeO) into the aryl group of N-
arylsulfonamides shifts the equilibrium toward the cyclic form. Passing from
N -alkyl to N -arylsulfonamides the rate of equilibration strongly increases.
y-Mercaptonitriles (12A) are transient species during the formation
from S-benzylderivatives (11) which cyclize immediately yielding imino-
C: :H,Ph -- [C: :J -- (I -- h S NH2

C~
NH (12Ca, d)
(11 ) (12A) (128)
1
C S R
-
-C=N .-- CC=N
s-
(14b,C,d)/ (13b, c, d)
(=N N=:)
(15b, c, d)
81
218 Chapter 4
(r ~
1
CH 2 ,
,~
1
CH
2
,
a [53] b [29] c [50]
0 ,0
~CH'/ ~c/' 2 /' ,
Me Me
d [51] e [52]
dihydrothiophene derivatives (12B) [29, 50-53]. These isomerize to amino-

thiophenes (12C) if an a-hydrogen atom is present relative to the C=N
bond [51,53].
Since iminodihydrothiophenes (12B, b, c, d) form both cyclic as well
as open derivatives, Stacy [50, 52] and Renson [29] and coauthors assumed
a ring-chain tautomerism (12A) ~ (12B). For instance, alkylation of (12B)
in the presence of base gave open S-alkylderivatives (14b, c, d) while oxida-
tion yielded disulphides (I5b, c, d). However, this only proves the existence
of the open anion (13) in a basic medium. IR and 'H-NMR spectroscopy
failed to provide evidence for the presence of the open isomer (12A) either
in the solid state or in solution, i.e., within the limits of these spectroscopic
methods the tautomeric equilibrium (12A) ~ (12B) is not detectable.
Actually, there is no reliable evidence for the existence of a ring-chain
equilibrium in neutral solutions of hydroxy, amino, and mercaptonitriles.
No indication for an equilibrium has been obtained as well from an investi-
gation of intramolecular electrophilic addition reactions to C_N bond that
proceed under acidic catalysis [1, 2].
The dependence of the cyclization of cyanocarboxylic acid chlorides
(16A) -+ (16B) on the structure (a-m) has been thoroughly studied by
Simchen and co-workers [54,55] and the formation of five, six, or seven-
membered aza-, diaza-, and thiaza-heterocycles has been reported. Cycliza-
tion proceeds at low temperatures in the presence of anhydrous hydro-
halogenic acids. The cyclization is suggested to be preceded by addition of
hydrochloric acid to the cyanogroup (16A) -+ (17). Depending on the struc-
ture of the connecting chain two ways of cyclization are possible:
(17) -+ (18) -+ (16C) and (17) -+ (16B). Cyclization is favored energetically
by the formation of either a conjugated en amide (16Cb, d, e, j) or aromatic
systems (16D) as a result of prototropic transformations.
In most cases cyclization proceeds irreversibly. An equilibrium
(16Am) ~ (16Bm) was observed during the formation of 3-chloro-2-
benz[f]azepine-l-one (16Bm).
0
(C'l'Cl
O
(C,Cl ---
--- C'
-:;::::.0 II
He!
-He! ~N
C=N C=NH C:/"
/ I
CI Cl
(16A) (17) (168)
/ 1
OH
---
r-'C-:;::::,O "-C=C ..........
/
l 'CI
C
./ ':::-C...- NH 2
-He! LC~N
I
"- Cl
CI
(18) (160)
CH - CH - , /CH 2 ,
(=
I 2 I 2
C
CH 2 CH 2 II
\ \ /C,
CH- 5-
I
a b c d
I I
'C::::,-C, 'c':::::-C' (XCH 2 ,
I I I . (XNH,
I .
S- Se- ~ ~
9 h
Surprisingly, a spontaneous isomerization in the reverse direction was

found: 2-chloro-5,6-dihydro-l,3-thiazine-4-one (16Bc), being incapable of
a stabilization due to the formation of an aromatic or enamide system,
transforms into the initial 3-thiocyanatopropionyl chloride (16Ac) after
several days at room temperature [56].
4.2. ADDITION TO C=C AND C_C GROUPS
Many examples of intramolecular additions of hydroxyl, amino, or

mercaptogroups to ethylene or acetylene bonds are known [57,58]. A
220 Chapter 4
particular group of reactions (strictly not isomeric transformations) proceeds

by intramolecular addition of a nucleophile to C=C or C C bonds, an
electrophilic intermolecular attack occurring simultaneously [59-61].
Depending on the ring size being formed and on the substituents at
the ethylene (R" R2, R3 in (19») or acetylene group, as well as on the
nucleophile XH, intramolecular addition can proceed in two directions:
C X- H
/
RI
C=C
/ ~
R3 R2
C X~<R'
{19A}
X= 0, NR, S
·CH R2
I
R3
{19C}
Thus, E and Z-2-(2-arylethenyl)benzoic acids having phenyl, 1- or

2-naphthyl, indol-3-yl, thiophene-3-yl groups at the double bond lactonize
into 3-aryl-3,4-dihydroisocoumarines (path (19A) -+ (19C») whereas 4-
pyridylderivative led to 3-( 4-pyridyl)methylphthalide (path (19A) -+ (19B»)
[62]. The rate of lactonization of the Z-isomer is faster than that of the
E-isomer. On the other hand, N-monosubstituted E-2-(2-phenylethenyl)-
0=)0
~COOH CHPh
0 C _ C - Ph
{20B}
o
{20A}
~O
~Ph
{20C}
benzamides cyclize into 2-alkyl-3-benzylisoindolinones (path

(19A) -+ (19B») in the presence of a basic catalyst [63].
The acid-catalyzed isomerization oftolane-2-carboxylic acid (20A) gave
a mixture of 3-benzylidenephthalide (20B) and 3-phenylisocoumarine (20C)
[64].
In most cases the cyclization proceeds irreversibly under acidic or basic
(rather rarely neutral) conditions or on heating. The negligible propensity
to form equilibria obviously is due to the low polarity of C=C and C_C
bonds.
/COOH
CH z
I
CH z
, /
Me • 200°C·
H
C=C
/ , Me
(21A) (21B)
Linstead and Rydon [65] showed that 5-methyl-4-hexene-l-carboxylic

acid (21A) and 6,6-dimethyltetrahydro-2-pyranone (21B), both being stable
at room temperature, gave on heating at about 200°C for 12-18 hours an
equilibrium mixture containing 40% of the acid (21A) and 60% of the
lactone (21B).
Under milder conditions the equilibrium is observed only if substituents
increase the polarity of the double bond.
OI
o
COOH
~ CH=CHNO z
--.=+
~o
(22A)
O~
I
COO-
CH/
,
OH
+/
0-
O
~I
~
COO-
CH=CHNO z
'CH=N
(23)
'0-
(24)
222 Chapter 4
The condensation product of 2-formylbenzoic acid with nitromethane

has been shown to be 3-nitromethylphthalide (22B) on the basis of IR and
IH-NMR spectroscopic data [66] and not 2-(2-nitroethenyl)benzoic acid
(22A) as reported earlier [67].
An investigation of the action of bases on 3-nitromethylphthalide
revealed [68,69] that ring opening occurs in aqueous alkaline solution to
give the anion of 2-(2-nitroethenyl)benzoic acid (23) which, as indicated
by its UV spectra, is unstable and rapidly transforms into the dianion (24).
Acidification of the solution leads to the regeneration of the initial 3-
nitromethylphthalide (23) --+ (22B) or (24) --+ (22B). A UV spectroscopic
study established that at pH -6 the equilibrium (22A) +2 (22B) is strongly
displaced in favor of (22B) (K T - 10). The acid (22A) could not be isolated.
3-Nitromethyl-2-phenylisoindolinone is also cyclic [66].
The equilibrium (25A) +2 (25B) is a result of an intramolecular addition
of the carboxylic group to the 1,4-benzoquinone C=C bond r70l The
V
HOOC"
o I:~ o O~
Me
I I
C
'R
MeJ(i--~R
I .-H R
Me R Me R
o o
(25A) (25B)
equilibrium largely depends on the acidity of the solvent: a decreasing pH

value shifts the equilibrium toward the less acidic ring form. Methyl sub-
stituents (R = Me) are required for the formation of the cyclic form ("trialkyl
lock" [70]).
One case of ring-chain equilibrium (26A) +2 (26B) is known [71] where
the ring form is obtained by an intramolecular nucleophilic addition of the
t-Bu
Q
nitronic acid group to an enamine C=C bond.
N02
I • ~
t_BUo) Ph
I
Me
~
...... CH N+
, 0-
C)
CH " Me o ./
N) Ph
I
Cx (26A) (26B)
Italian chemists [72] using JR, UV, iH, and 13C-NMR spectroscopy
have shown that 5-( o-aminophenyIcarbamoyI)pyridazine-4-carboxylic acid,
although possessing a bipolar structure (27 A, X = NH) in the solid state,
in DMSO almost completely changes into the spirocompound (278). The
equilibrium (27 A) ~ (278) position strongly depends on the solvent. Passing
from water to methanol the equilibrium is displaced in favor of the cyclic
form (278).
R
H'-...+:;COO- COOH
~ I
N::::..... R~/H
- N
HxA
CO-NH
RX~ >
R , • HN
(27A)
V R= H, Me
N-
(278)
Replacement of the NH group by a less nucleophilic OH group prevents

the cyclization (27 A, X = 0) -+ (278).
The examples mentioned above testify that normally ring-chain equili-
brium brought about by intramolecular addition to a C=C bond is observed
only if the C=C bond is polarized by strongly electron-donating or electron-
withdrawing substituents.
Finally ring-chain equilibrations reflecting intramolecular addition of
a C- MgX group to C=C bonds will be briefly discussed. They have been
called "Grignard reagent cyclization cleavage rearrangements"
(28A) ~ (288) ~ (28A') and are thoroughly treated in Hill's reviews [73, 74].
We shall therefore not discuss them in detail.
Generally, these rearrangements require high activation energies, i.e.,

equilibria are attained after many hours at 100°C or even at higher tem-
peratures. They are usually strongly shifted toward the cyclic form (288) if
five or six-membered rings are formed, and are displaced in favor of the
224 Chapter 4
open form (28A) or (28A'), however, if the cyclic isomer (28B) contains a
three or four-membered ring. A concerted four-center mechanism has been
assumed [73-75] for the rearrangements.
Rate and equilibrium constants of the reversible rearrangement
(29A) ~ (29B) may be considered as an example (see Table 41) [75-77]. If
R I ,e R 3 , then ring opening can proceed in two different directions yielding
(29A) x= CI, Br (29B)
two open isomers. The influence of the introduction of methyl substituents

(R I, R2, R 3 ) on the ring-chain equilibrium constants, the rate constants,
and the activation parameters is shown in Table 41 (some of the reported
data were obtained [75] after extrapolation of determinations carried out
under different conditions). Introduction of methyl substituents stabilizes
the cyclic form as a result of the Thorpe-Ingold effect (see p. 27 for a
discussion), especially if R2 = Me (see [76]). However, if R I = Me the
cyclization which is accompanied by a rearrangement of the less stable
secondary Grignard reagent into the more stable primary one is strongly
favored. This difference in stability between primary and secondary
Grignard reagents was estimated [75] to be -t:..G O - 2.8-5 kcal/mol.
4.3. ADDITION TO THE P=O GROUP
Intramolecular addition of OH or NH groups to P=O bonds yields

hydroxyphosphoranes:
They are, together with their conjugated bases, i.e., phosphorane oxide
anions, usually considered as intermediates or transition states in substitu-
~
....,
III
3
o
CD
o
c:
ii>
.,
::n
CD
Table 41. Ring-Chain Equilibria, Rate Constants, and Activation Parameters for Cyclobutylmethyl Grignard Reagent and ~
Cil
Its Methyl Derivatives (29A) ~ (298) at 1000 in Tetrahydrofuran a c:
CD
Cyclization Ring opening }o
Co
In formula (29) Co
;:;:
tiH" tiS" tiH" tiS" o·
RI R2 R3 kl (S-I) k2 (S-I) ~
K = [(29B)]/[(29A)] (kcal/mol) (e.u.) (kcal/mol) (e.u.) Refs. ...
o
H H H 9 x 10- 5 2 X 10- 8 28.5 -15 2.2 x 10-" 26.55 -4.6 75, 77 o
...::r
H H Me 7.5 x 10- 3 5.2 X 10- 7 7x 10- 5 75 .,CD
H Me H 4 x 10- 3 8.8 X 10- 7 2.2 X 10-" 76
Cl
Me H H 1.33 1.6 x 10-6 23 -24 1.2 x 10-6 75 ac:
Me H Me 3.44 b 6.78 x 10-6 19.6 -28 1.97 x 10-6 25.0 -16 75 "0
en
• Determined indirectly: after reaching equilibrium mixtures were hydrolyzed and the resultant hydrocarbons were analyzed by OLe.
b Ether solvent.
~
UI
226 Chapter 4
tion reactions at a tetracoordinated phosphorus in compounds bearing a

P=O bond [78-80].
Thus, for instance, the formation of the cyclic product (32) in a reaction
of hydroxyneopentyl hypophosphite with diazomethane has been taken as
evidence for the equilibrium (31A) ~ (31B) [81].
OH OMe
Me
I ~
HOCH 2 CCH 2 0P-H.
° ~ Me C° H
o,~/H
I" Me C° H
O,~/H
I"
I I
Me H Me Me
(31A) (318) (32)
Recently the chemistry of phosphorus has developed considerably [82].

The presence of hydroxyphosphoranes of the type (33B) as intermediates
in reactions has been repeatedly discussed [83-85].
Ramirez and coauthors [86, 87] have first described the stable hydroxy-
phosphorane (33B) obtained by the action of hydrogen chloride on
trimethylsilyloxyspirophosphorane (34, R = Me3SiO).
0= ox) 0=0\ OX)

I 0
\ I I I I
~ d~ ° ~
I
~ dl"o ~
°H OH
Later (33B) was obtained [88] by hydrolysis of the chlorospirophos-

phorane (34, R = Cl).
A characteristic feature of the ring-chain equilibrium between 0-
hydroxyphenyl-o-phenylene phosphate and hydroxy-bis-o-phenyl-
enedioxyphosphorane (33A) ~ (33B), which was observed [86, 88] in aprotic
solvents, is a reversible nucleophilic addition of a phenolic hydroxyl to a
p=o bond. Both isomers were characterized by their 3Ip_NMR spectra
[86]: (33A) B31 p = +6.8 ppm, (33B) B31 p = -26.6 ppm (positive values
downfield of BH 3P0 4 = 0; -48°C; CD 3CN)t.
tIn different papers the chemical shifts 831 P are denoted as positive values in different
directions: downfield or upfield from 85% H 3 P0 4 •
The open isomer (33A) is stabilized by an intermolecular hydrogen

bond OH·· ·O=P (2.68 A 0···0 distance) which was established [87] for
the crystalline compound by an x-ray determination.
On passing from less to more polar and basic solvents the equilibrium
is shifted toward the open form (33A) which indicates that the POH group
of (33B) is less acidic than the phenolic hydroxyl group of (33A). Examples:
KT = 3 for acetone-dt,; KT = 1.5 for CD 3CN (-48°C). Coalescence of both
31P-signals were observed: in CD 3CN at + 10°C, but in acetone-d 6 at +55°C.
Methylation of a solution of (33) with diazomethane yields only the
cyclic methyl derivative (34, R = OMe) while acetylation with acety1chloride
provides a 4: I mixture of open and cyclic acetylderivatives.
Ring-chain tautomerism of a number of hydroxyphosphoranes
(35A) ~ (35B) and some analogues (36A) ~ (36B) has also been investigated
by 31p_NMR spectroscopy [89-91].
(3SA) (358)
R' = H; R2 = H. Me. i-Pro Ph
R' = R2 = Me. Ph
(36A) (368)
(=
Some of these hydroxyphosphoranes form cyclic triethylammonium
salts that led the authors [90] to assume a greater acidity for the POH group
than for the COOH group in the open isomer (35A). This is supported by
an equilibrium displacement toward the cyclic anion observed as a result
of an addition of triethylamine to the solutions. Heating shifts the equili-
brium toward the open form (35A).
The cyclic form is stabilized by the presence of 7T-electron systems
(C=O, C=N, benzene ring) in both ligands as well as by the introduction
228 Chapter 4
of one or, more effectively, two methyl groups (35, R 1 = R2 = Me) (Thorpe-
Ingold effect).
Martin and Granoth [92] have investigated the equilibrium (37 A, R 1 =
Me, R2 = H) +::! (37B) using IH and 3Ip_NMR spectroscopy. The acidity of
hydroxyphosphorane was estimated (pKa - 10-11).
Only one broad signal is observed at room temperature in the 3Ip_NMR

spectrum of (37). Decreasing the temperature gave two 31 P signals at 52 ppm
(37A) and -27 ppm (37B) which were detected in CH 30D. The proportion
of the cyclic isomer (37B) increases with decreasing temperature (+5 to
-50°C). Basic solvents, such as pyridine, shift the equilibrium toward the
hydroxyphorphorane (37B); the cyclic anion (38) is formed on addition of
sodium methoxide to the methanolic solution.
Surprisingly, the much more acidic (pKa = 5.3 ± 0.2) trifluoromethyl
derivative (37, RI = CF3, R2 = Me) exists as a stable cyclic isomer (37B)
and does not show ring-chain equilibria in solution [93]. The enhanced
electronegativity of the apical oxygens in the fluoralkoxy ligands increases
the electronegativity difference between the central phosphorus and the
o
~o
~I
o(r o
OH
(38) (39)
apical oxygens, thus stabilizing the cyclic isomer (37B, R 1 = CF3, R2 = Me).
Evidently, the same effect is responsible for the stability of the cyclic
carbonyl analogue (39) which according to indirect data [94] possesses a
greater acidity than (37B, Rl = CF3, R2 = Me).
Besides spirobicyclic hydroxyphosphoranes, monocyclic analogues
form the ring-chain equilibria.
Recently 31p_NMR spectral evidence was given [95] for the equilibrium
(40A) ~ (40B) strongly displaced toward (40A). An equilibrium between
the corresponding anions (41A) ~ (41B) has also been discussed.
From a reaction of 2-diphenylphosphinylbenzoic acid with
thionylchloride a stable cyclic chlorophosphorane (42B, X = Cl) was
obtained [96], being formed by an intramolecular addition of a COCl group
to a p=o bond. The open isomer (42A) could not be detected by spectro-
scopic methods. 2-Diphenylphosphinyl benzoic acid on the other hand
Me Me Me Me
~OH~~O
Vp=o~I
Ph/ I /P-Ph
Ph Ph I
OH
(40A) (408)
0(1
Me Me
0-
,Na+
~ ,
P=O
/ "-
Ph Ph
(41A) (418)
(X
~I
/
C.OX
P=O
"-
rio
~IP-Ph
Ph Ph Ph/ I
X
(42A) (428)
230 Chapter 4
exists in the open form (42A, X = OH) and no equilibrium with the cyclic
hydroxyphosphorane (42B, X = OH) has been observed [96].
In summary, the known hydroxy and chlorophosphoranes have a
five-membered ring which follows the rule [78,79,97,98] that trigonal
bipyramidal phosphoranes are strongly stabilized by bridging of an apical
and an equatorial position by a five-membered ring.
Another type of spirophosphorane formed by ring-chain tautomerism
(43A) +:t (43B) has been observed. Here the cyclic isomer is the result of an
intramolecular addition of an X - H group to a phosphorus atom, the latter
undergoing a coordination change.
(43A) (438)
x ~ 0, NR
The influence of structural and external factors on the equilibrium

(43A) +:t (43B) position has been treated in a review [99] where this
phenomenon is discussed in terms of Pearson's conceptt of hard and soft
acids and bases. The regularities of this kind of ring-chain tautomerism will
not be discussed here in detail particularly since no addition to a multiply-
bonded phosphorus atom is involved in ring formation.
4.4. ADDITION TO THE P=N GROUP
The reversible intramolecular nucleophilic addition of a OH group to

a P= N bond was observed [100, 101] in the study of the tautomeric system
of 2-hydroxyphenyliminophosphoranes and 1,2,3-benzoxaphospholines
(44A) +:t (44B). Equilibrium constants determined by two independent
methods, i.e., 31p and IH-NMR spectroscopy [101], agree well.
Influences of substituents R3 and R4 (by R I = t-Bu, R2 = H) on equili-
brium constants as well as on thermodynamic parameters ilH and ilS have
been investigated [101] showing that increasing electron density on the
oxygen atom displaces the equilibrium in favor of cyclic (44B). If R3 = Ph 3C
the equilibrium is shifted more toward the open form while it is displaced
more in favor of the cyclic form for R3 = t-Bu.
t R. G. Pearson, Ed., Hard and Soft Acids and Bases. Dowden, Hutchinson and Ross,
Stroudsberg, Pa. 1973; T.-L. Ho, Chern. Rev. 1975, 75, I.
Decreasing electron density at the phosphorus atom also shifts the

equilibrium toward the cyclic form. For instance, cyclic isomers (44B,
R4 = F) which contain electron-withdrawing fluorine atoms at phosphorus
are stable [103]. On the basis of such a substituent influence on the equili-
brium position the cyclization is believed to proceed as an intramolecular
addition of the lone pair of the oxygen atom to the electron deficient
phosphorus atom and a subsequent proton migration [101].
Increasing encumbrance of substituents at the phosphorus atom (44,
R4 = Me, Et, Pr) displaces the equilibrium toward the open form; after
introducing a sec-alkyl substituent at the phosphorus atom (44, R I = t-Bu,
R2 = H, R3 = Ph3C, t-Bu, R4 = i-Pr) the cyclization does not proceed at
all [10 I]. Sterically demanding substituents in a position ortho to the hydroxy
group (44, RI = H, t-Bu, Ph 3C) strongly stabilize the cyclic structure [102].
H Ph Ph
'- 1/
ArX'R'
.::' R,VR' R2
(44B)
R' = t-Bu; R2 = H; R3 = Ph 3 C or t-Bu; R4 = Me, Et, Pr, i-Pr, Ph [101].

R' = H, Me, t-Bu; R2 = H, Me, t-Bu; R3 = H, Me, t-Bu, Ph, Ph 2 CH, (2-MeOCsH4hCH, (4-
MeOCsH4hCH, Ph 3 C; R4 = Me, Et, Pr, Bu, Ph [102].
Rate constants for transformations (44A) ~ (44B) and activation para-

meters ilH" and ilS" have been determined [102] using dynamic IH-NMR
spectroscopy (see Table 42; lifetimes are given in [102]). Equilibrium con-
stants KT and thermodynamic parameters ilH and ilS were obtained from
3Ip_NMR spectra. However, since equilibrium constants KT and rate con-
stants kl and k2 have been established by different methods the relationship
KT = kl/ k2 is not entirely satisfactory.
Raising the temperature of solutions shifts the equilibrium
(44A) ~ (44B) toward the open form (ilH and ilS are negative).
Solvents exert a large influence on the position of the equilibrium
(44A) ~ (44B). Proton-accepting solvents (pyridine, tripropylamine) dis-
place the equilibrium in favor of the ring form while chloroform and
methylene chloride act in the opposite direction. On the basis of the
thermodynamic equilibrium parameters (ilH, ilS) for different solvents [101]
i'l
CAl
i'l
Table 42. Ring-Chain Equilibria (44A) ~ (44B), Rate Constants, Thermodynamic and Activation Parameters as Determined by
3Ip_NMR and Dynamic IH-NMR Methods in Pyridine-ds [102]
Dynamic IH-NMR
3Ip_NMR (A) ..... (8) (8) ..... (A)
K -f:J.H -f:J.S f:J.H" f:J.S" f:J.H" f:J.S"

RI R2 R3 R4 at 27"C (kcal/mol) (e.u.) kl (5- 1) (kcal/mo1) (e.u.) k2 (5- 1) (kcal/mol) (e.u.)
H H Me Ph 0.33 4.61 17.6

H H t-Bu Ph 0.31 3.06 12.5
H Me H Ph 0.29 4.34 16.9
H t-Bu H Ph 0.26 3.84 15.5
t-Bu H Ph 2 CH Et 2.09 4.79 14.5
t-Bu H Ph 2 CH Pr 1.63 3.80 11.7 3.6 17.4 2.3 2.0 21.6 15.3
t-Bu H Ph 2 CH Bu 1.60 3.52 10.8 4.8 16.5 0.1 2.7 20.1 11.0
t-Bu H Ph 2 CH Ph 2.88 3.51 9.6 0.524 15.9 -6.6 0.252 19.1 2.7
t-Bu H (2-MeOC 6 H4hCH Ph 2.93 4.60 13.2 0.287 16.4 -5.9 0.113 20.6 6.3
t-Bu H (4-MeOC 6 H4hCH Ph 2.60 4.65 13.6 0.286 16.5 -5.6 0.106 21.1 7.7
t-Bu H Ph 3C Ph 1.47 3.59 11.2 0.488 17.4 -1.7 0.426 20.2 7.6
()
::::r
Q)
"tl
r+
!!l
"""
chloroform is believed to specifically interact with the basic iminophos-

phorane group, thus stabilizing the open structure.
A similar ring-chain equilibrium was detected [104] in solutions of
4-alkyl-2,6-bis(phosphoranylideneamino )phenole (45A) ~ (45B).
OH O--~Ph3
Ph,P=N'QN=PPh,. • Ph,P=NqN'-.H
R R
(45A) R = Me, t-Bu, cyclo-CsH11 (458)
4.5. ADDITION TO THE S=O GROUP
Relatively few data are available regarding intramolecular additions

to the S=O bond yielding cyclic hydroxysulfuranes (46A) ~ (46B).
ex
However, the chemistry in this field has rapidly developed (see review [98]).
e /
X- H
S=O
~I
R/I
S:
R OH
CF3 S0 3 H •
(47A) (478)
t-Bu
(48)
234 Chapter 4
Solutions of the sulfoxide (47) in CDCI 3 have been investigated by

19F_NMR spectroscopy showing [105] that the open structure (47 A) pre-
dominates. Addition. of triftic acid (CF3 S0 3 H) to the solution yielded the
cyclic sulfonium triftate (48).
A cyclic chlorosulfurane (50) was formed in a reaction of acety1chloride
or hydrogen chloride with the sulfoxide (49), the hydrolysis of which led
to ring opening [106].
CH,COCI
orHCI
•hydrolysis
(49) (SO)
o-Carboxyphenyl-methyl and -phenyl sulfoxides exist in the open form
e
(51, R = Me, Ph) [107-110].
c(oI
0
(XCOOH COC ]
~
---+
~ S=O ~ S=O
R/ S Ph/
Ph/I
(51)
CI
(528) (52A)
The chlorosulfurane (52 B) obtained by chlorination of the potassium

salt of 2-phenylthiobenzoic acid in solution at room temperature isomerizes
to the open chloride (52A) in the course of several days.
Similarly, the t-butoxysulfurane (53B) at 70°C in chlorobenzene forms
an open ester (53A). Additionally the free acid (51, R = Ph) and isobutylene
are formed [109].
0(
o
0 eCOOBu-t
I I ~ I +
~ ~ S=O
S Ph/
Ph/I
OBu-t
(538) (53A)
4.6. ADDITION TO THE Se=O GROUP
Unlike o-carboxyphenylmethyl and phenylsulfoxides (51, R = Me, Ph)

the analogous selenoxides are cyclic (54, R = Me, Ph) in the solid state
[108] as well as in solution [1I0-112].
(XCOOH .+-- 0(0I --

0
NaOH
(XCOO- Na+
~ Se=O ~ ~I
Se=O
R/' /,Se Ph/'
R I
OH
(54A) (548) (55)
Following tH, t3C, and 77Se-NMR spectroscopy [112] the acid (54,
R = Me) in methanol-d 4 appears to be a cyclic selenurane (54B). However,
the sodium salt of this acid has open structure (55).
4.7. ADDITION TO THE 1=0 GROUP
Intramolecular nucleophilic additions to the 1=0 bond proceed easily

and irreversibly if five-, but more rarely if six-, membered iodinane rings
are formed.
2-lodosobenzoic acid (56) [1l3-116], its amides (57) [115, 117], esters
(58) [114, 116], and a mixed acetic acid anhydride (59) [116, 118] only appear
o:=:
~
I
x
'Y
I
I
I
OH
~9
V-I I
OR
o
II
(56, x-v = C-O) (58, R = alkyl)
o (59, R = COMe)
II
(57, X-v = C-NR)
(GO, x-v = S02-NH)
o
II
(61, X-V = P-O)
I
Me
236 Chapter 4
as cyclic isomers as do 2-iodosobenzenesulfonamide (60) [119], 2-iodoso-

phenylmethylphosphinic acid (61) [120], 2-iodosophenylacetic acid (62)
[121], 2-iodosophenyl phosphate (63) [122] and 2-iodoxybenzoic acid (64)
[ 116].
Stable cyclic hydroxyiodinanes (65, R = Me, CF3 ) bearing a gem-
dimethyl or gem-trifluoromethyl group have been synthesized [123] as well
as the exclusively cyclic chloroiodinane (66) [123, 124].
rl I~
u--
X-y
OH
r10
V-~=O
I
o OH
II
(62, x-v = CH 2 -C) (64)
o
II
(63, x-v = O-P)
I
OH
r19
R R
~9
V-I V-I
I I
OH CI
(65) (66)
(
X-H ~ (1
1=0 ·1
I
OH
(67A) x= 0, NR (678)
No spectroscopic evidence is available in favor of equilibrium

(67 A) ~ (67B) in solution, however, a more far-reaching study of the com-
pounds seems advisable.
cr
~
I
CON,
1
/Cl
(68A) (688)
A ring-chain equilibrium (68A) ~ (68B) has been shown [125] to exist

for N -chloro-2-iodobenzamides. In this case, however, the cyclic structure
(68B) is formed as a result of an intramolecular addition of the N-Cl
group to an iodine atom, the latter changing its coordination.
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5
Generalizations Concerning the
Influence of Structural and External
Factors on the Relative Stability of
Ring and Chain Isomers
Experimental data discussed in the previous chapters mainly apply to

reversible intramolecular nucleophilic addition reactions of hydroxy, amino,
and mercapto groups to polar multiple bonds, the c=o and C=N bonds
being represented most broadly. Special attention was paid to the influence
of structure and external factors on the stability of open and cyclic isomers
and on the mode of their interconversions.
The aim of the present chapter is to acquaint the reader with general
rules concerning these influences.
Equilibrium constants for a large number of compounds determined
under fixed experimental conditions are required to formulate general rules.
The structure of the connecting link should be varied widely; substituents
with different electronic and steric effects should be bonded at significant
places and, finally, the results of these investigations should be compared
with those of systems possessing related pairs of interacting groups.
Unfortunately, there are only a few systematic investigations of this
kind, e.g., in the field of acylcarboxylic acids (Bowden), their derivatives
(Valters, Flitsch, Chiron, and Graff), and hydroxy and mercaptoderivatives
of imines, oximes, and hydrazones (Potekhin). Most available results stem
from studies of ring-chain tautomerism in a narrow range of compounds
which have found interest for the chemical properties of the compounds
and their synthesis.
Certainly, equilibrium constants are most important for the estimation
of the relative stabilities of isomers. The use of the equilibrium constants
in a broader field is often limited by the fact that quantitative investigations
were carried out using different methods and various conditions (see Table
3). Besides, particularly important areas have not been studied adequately
at all.
For many equilibria of the type (IA) ~ (IB), (lA) ~ (lB), and
(3A) ~ (3B) the stability of the cyclic form has been characterized by the
ring-chain equilibrium constant K or by the free energy difference aG,
242 Chapter 5
which is proportional to the logarithm of K. It would be desirable to discuss

the influence of structural and external factors using these parameters. There
are, however, objections which should be taken into account. First of all,
C X H
-
c=o - eLOH
~
k,
k,
/ I
RI RI
(1A) (18)
C X H k,
eLNHR'
-
• K •
k,
C=N
RI
/
(2A)
" R2 RI
I
e
(28)
C X
N=C/
-
H
--r
k,
RI -,;;-
X ,-
C
-N/ "R2
/R'
. . . .R2 I
H
(3A) X = 0, NR 3 , S (38)
even small structural modifications very often shift the system out of the
balanced equilibrium state [1,2], i.e" one isomer can be detected only and
thus no equilibrium constant is available. Moreover, the free energy differ-
ence enthalpy and entropy components (IlH, IlS), are rarely available.
Furthermore, as pointed out by Jencks [3], the use of these parameters
(IlH, IlS) is connected with uncertainties which mainly originate from the
need to introduce corrections for solvation effects.
Energetic aspects of intramolecular reactions which separate enthalpic
and entropic influences and their comparison with those of intermolecular
reactions are discussed in Page's review [4]. It is difficult to estimate potential
energy differences between open and cyclic structures utilizing the changes
in bond lengths, valence angle deformations, non bonded and electrostatic
interactions, steric strain, solvation, and formation of hydrogen bonds.
Many data are available in the literature on the structure of tautomeric
compounds in the solid state. However, these data may rightfully be used
for the estimation of structural factors that influence isomer stability only
in the case when the absence of tautomeric equilibria in solutions is proven
by spectroscopic methods. Moreover, the influence of isolation conditions
on the structure of isomer obtained in solid state should also be estimated
by taking into account that under some conditions a thermodynamically
The Relative Stability of Ring and Chain Isomers 243
less stable isomer can be isolated. Undoubtedly, crystal-field forces may

also play an important role. The situation improves if the structures of a
large series of crystalline compounds are investigated and the conditions
for isolation are essentially the same.
Little attention has been paid to chemical reactions of pure isomers.
The reactivity of individual isomers or isomeric mixtures cannot be used
generally to estimate their relative stability. The reasons for this can be:
I) different rates of reactions of open or cyclic isomers; 2) the influence
of the reagent on the position of the ring-chain equilibrium; 3) the influence
of reaction conditions (heat, presence of catalysts) on the equilibrium
position; 4) ring-chain equilibria of reaction products formed during the
reaction or isolation. Finally, and most importantly 5) there are at least two
reactive centers in the open and/ or cyclic isomers and an attack of the
reagent on both centers must be taken into account. Moreover, the preferen-
tial direction of this attack is determined not only by the structure of the
substrate but also by external factors as well as the structure of the reagent.
Esterification of acylcarboxylic acids provides a good illustration of these
difficulties (see Sec. 2.1.4).
Certainly, the reactivity of tautomeric bifunctional compounds is of
great theoretical and practical importance. However, the scarcity of experi-
mental data does not allow the proper analysis of this complicated problem.
5.1. STRUCTURAL INFLUENCES
5.1.1. Electronic Effects of Substituents at Interacting Groups

If the connecting link allows the interacting functional groups to
approach sufficiently close for an intramolecular addition (IA) -. (IB),
(2A) -. (2B) or (3A) -. (3B), the ring-chain equilibrium will be found more
to the side of the cyclic form the more electrophilic the carbon atom of the
mUltiple bond and/ or the more nucleophilic the heteroatom X.
Nucleophilicity of X - H Group:
t Here and elsewhere the arrow depicts an equilibrium shift toward ring B.
244 Chapter 5
Leaving the remaining structural features unaltered the stability of the

cyclic isomer obtained as a result of an intramolecular nucleophilic addition
of an X - H group to polar multiple bonds increases in the sequence
X=O < NR < S, which can be explained by an enhancement of the
nucleophilicity of the atom X [5] as well as by a diminished steric strain
[4] of sulfur containing heterocycles as compared with oxygen or nitrogen
analogue.
Substituent R3 in the X = NR 3 Group:
H
/
C:~
R'
/
The influence of the nucleophilicity of the amino group on the stability

of the cyclic isomer can be observed in a series of anilino derivatives bearing
different substituents Z in the aromatic ring. The introduction of electron-
donating substituents Z shifts the equilibrium toward the cyclic form while
electron-withdrawing substituents act in the opposite direction. This is
confirmed by the negative value of the p-constant on correlating the ring-
chain equilibrium constants of 3,3-dimethyllevulinic acid N -arylamides (see
Sec. 2.1.3: (47A)~(47B) and Table 10) with substituent coefficients (1"+.
A similar destabilization of cyclic isomers is brought about by decreas-
ing the nucleophilicity of the nitrogen atom, i.e., on introduction of aryl
(R 3 = Ar in (1-3») and acyl (R 3 = COR) substituents, respectively, or
dialkylammonium groups to the nitrogen atom (see Sec. 2.1.3: (71)-+ (72»).
N-Methylated derivatives (R 3 = Me) almost always show a greater
stability of the cyclic form than their N -unsubstituted analogues. Exceptions
to this rule (see, for instance, Sec. 2.3.2: (I66A) ~ (1668») have been
explained by a steric effect of the methyl group destabilizing the ring
structure. By increasing the steric bulk of N -alkyl substituents the estimation
of the influence of their electronic effects on the stability of cyclic isomers
is impossible since steric effects act considerably stronger.
C=o or C=NR 2 Group:

Equilibria involving azomethines (2A)~(28) in solution are more in
favor of the cyclic form that those of carbonyl derivatives (IA) ~ (IB) of
X-H
Rl
~c=0
y= 0 < NR2
-----+~ B
similar structure (see Table 43). However, the substituents R 2 at the nitrogen
atom of the azomethine group are also of great importance.
Substituents Rl and R2 at c=o or C=N Bonds. Substituents at
carbonyl and azomethine groups affect the electrophilicity of the carbon
atom. Electron-withdrawing substituents increase the electrophilicity and
stabilize the cyclic isomer while electron-donating substituents act in the
reverse direction.
Tautomeric equilibrium constants of acylcarboxylic acids increase in
the following order for substituents at the C=O group: aryl < alkyl < H
(see Table 3). The stability of the open-structured aroylcarboxyJic acids was
Table 43. Ring-Chain Equilibrium Constants for Hydroxyketones, Ketocarboxylic

Acids, and Their N-Substituted Imines
y=O y= NR 3
Open isomer structure Solvent KT = [B]/[A] Refs. R3 KT = [8]/[A] Refs.
R n
/OH
H 3 75% aqueous 7.8 6 Me 6.25 7
(CH 2 j" dioxan (Y = 0)
"- C=Y H 4 CCl. (Y = NMe) 15.4 6 Me >100 7
/
R Me 3 CCI. 0.73 8 Me 4.0 7
Me 4 CCl. 0.95 8 Me 7.2 7
(X.COOH
Dioxan 0.07 9 Ph 4.78 \0
~ C=Y
/
Ph
SCODH Dioxan 1.41

2.43
11
13
Ph >100 12
~ /; f=Y
R
246 Chapter 5
(X-H
(1)
C=O
/
®
R' = aryl < alkyl < H B
•
explained not only by the low electrophilicity due to aryl groups but also
by a conjugation occurring in the open isomer.
(X-H (X-H
C=O C=N
@
/
(1)
R'
/
(2)
®
"-
(3)
R' or R2 = ~ • 19 K/ Ko = pu always Ip > 0 I

~z
Introduction of electron-withdrawing substituents Z into 0- or m-

positions of phenyl groups placed at the C=O or C=N bonds (R' and R2
in formulas (I), (2) and (3») always displaces the ring-chain equilibrium in
favor of a cyclic form. The reaction constant p is positive wherever a linear
correlation of ring-chain equilibrium constants with (J' or (J' + coefficients of
substituent Z (see Table 44) was observed.
Using N-(tert-alkyl)-2-aroylbenzamides (see Sec. 2.1.3, Table 12), it
has been shown that electron-withdrawing substituents in the aryl group
bonded to the keto group favors the cyclization reaction more than sterk
hindrance can hinder it, i.e., stable cyclic isomers with a bulky substituent
at the nitrogen atom may be obtained. At the same time increasing rate
constants of isomeric interconversions are observed (see Sec. 2.1.3, Table 13).
The stabilization of protonated cyclic isomers of N-(tert-alkyl)-2-(4-
dimethylaminobenzoyl)- and 2-(2-imidazolylcarbonyl)benzamides (see Sec.
2.1.3: (66)-+ (67) and (69A)-+ (70») is worth noting; this originates from
an - I-effect of the substituent at the keto group. Protonation of the nitrogen
atom of this substituent changes the ring-chain equilibrium totally in favor
of the cyclic isomer, while a deprotonation gives rise to the reverse transfor-
mation.
Table 44. Examples of Linear Correlations of Ring-Chain Equilibrium Constants (KT = [B]/[A]) with Polar Coefficients of
Substituents Z in an Aryl Group Placed at C=O or C=N Bonds -I
=r
CD
(A)~ (8) Solvent Method Ig KT/(KT)o = nQ Refs. ::0
CD
0
...<.iii"
CD
(XCOOH g?0 MeN0 2 IR 0.8700 9 14 ...IIIen

~ I -G <===! ~ MeCN 0.6000 g
CO ~ OH Dioxan 0.5400 ;:i:
- Z Z I -<
CHCI 3 1.1500 0
~
~
0
-
;:,
(Q
H, /COOH III
e ;:,
II Q.
~
Me (")
Me/C'eO-o-z Dioxan IR 0.374001 + 1.885oo~ 6 0.990 15 =r
~ OH
0 III
:5"
Z
~I iii
0
3
eOOH t'
8 ''-4
CD
.,
1/1
Dioxan IR 1.286001 + 2.918oo~ 8 0.970 II

<==' ~
S,,-/; Co-Gz )-fOH
f
/CH=N,
OH IH-NMR
Pyridine-d s 1.2600 9 0.993 16
CH 2 -0- <===! 1.4100 1 + 1.26oo~
"CO f ~ Z P ~H ...,
~I ~
...,
z d continued
I',J
~
00
Table 44. (cont.)
(A) +2 (8) Solvent Method Ig Ky/(Ky)o = na Refs.
~ I COOH ~ I 0
/C=NO --.!
W ~ -OZ Dioxan UV 0.5Su 7 0.94 10
0.35u+
a Ph I
~
Z Ph NH
-
0.97
/OH Me'f:"..0
Me CH,
I ~ N ~
~
'c - Me I I CCI. IH-NMR 0.S56u S 0.973 17
Me/ ' N = C H - Q H ~ 0.543u+ 0.999
Z Z
OH IH-NMR 0.73Su 5 0.993 17

~ 0 ~ I CDCI 3
~ /N-CH 0.6S0u+ 0.999 IS
CH, - Z I
a -0 ex:yO ~ N,
H
()
~
a Number of studied compounds with different substituents Z. III
"0
'*
...,(1)
C11
e X- H
C=N
e /®X- H
N=C
® / "-
R2 '@)
(2) (3)
Rl = alkyl but
Rl = alkyl <H R2 = alkyl < H
B ---_I B ----I B
The influences of substituents RI and R2 at the· C=N group of

tautomeric systems (2A) ~ (2B) and (3A) ~ (3B) are more complicated.
Ring-chain equilibria of imines of hydroxyaldehydes (2, R I = H) are shifted
considerably more toward the cyclic form than those of imines of
hydroxyketones (2, R I = alkyl) (see Sec. 3.1.2: (19A) ~ (19B), Table 35).
Similarly, the stability of cyclic isomers of N-(2-hydroxyalkyl)hydra-
zones of aliphatic aldehydes is superior to that of analogous ketone deriva-
tives (see Sec. 3.1.2: (HA) ~ (HB), Table 31).
In the series of N -(2-hydroxy and 2-mercaptoalkyl)hydrazones of
aromatic aldehydes and acetophenone a reverse effect is detected (see Sec.
3.1.2: (13A) ~ (13B) and Sec. 3.3: (S6A) ~ (S6B»: passing from a benzal-
dehyde derivative to an acetophenone derivative the equilibrium is displaced
in favor of the cyclic form. This has been explained by a steric hindrance
of conjugation in the N-N=C-Ar fragment of the open isomer caused
by the methyl group.
C- C=N
H
RI
/
(2)
"-
®
R2 = alkyl < Ph
1 B
H<COR
B
Substitution of an alkyl group by an aryl group at the imine nitrogen

atom (R 2 in formula (2» (see Sec. 3.1.4: (19A) ~ (19B» or introduction of
250 Chapter 5
an acyl group at the same position (see Sec. 3.2.3: (45A) ~ (45B» strongly
stabilizes the cyclic form. This curious effect is explained by an energy gain
as a result of conjugation of the nitrogen lone pair with the aryl or acyl
C=O group in the cyc1ic isomer.
5.1.2. Steric Effects of Substituents at Interacting Groups

An estimation of steric influences on ring-chain equilibria is frequently
based on a discussion of the optimal route on which interacting centers can
approach. A calculation or an empirical evaluation of energy differences
due to non bonded interactions in both molecules, i.e., the open and the
cyclic isomer, would be desirable.
R3 = Me > Et> i-Pr » t-Bu,

B I
but Me> H
B-
Sterically demanding substituents R3 at the nitrogen atom of aminocar-

bonyl compounds shift the equilibrium (lA, X =: NR 3 ) ~ (18) toward the
open form. N-Monosubstituted acylcarboxylic acid ami des (see Sec. 2.1.3:
(3A) ~ (3B», N-(3-oxoalkyl)-N'-alkylthioureas (see Sec. 2.3.3:
(167A) ~ (167B», S-(2-oxoalkyl)dithiocarbamates (see Sec. 2.3.4:
(170A) ~ (170B» may be taken for illustration. Many instances are known
where the introduction of tert-alkyl substituents at the nitrogen atom pre-
vents the formation of ring-chain equilibria. However, it should be noted
that for N-methylamides of keto carboxylic acids (see Sec. 2.1.3:
(3A) ~ (3B» the stability of the cyclic form is almost always increased
compared with that of N -unsubstituted compounds which can be explained
by the action of the + I-effect of a methyl group.
A similar influence of steric encumbrance of the substituent R3 placed
at the nitrogen atom holds for imines (2A, X=: NR 3 ) ~ (2B), and (3A,
X=: NR 3 ) ~ (38). Examples are N-(a-alkylaminoacyl)hydrazones (see
Sec. 3.2.2: (38A) ~ (38B», N-alkyl-2-benzoylbenzamide aniles (see Sec.
3.2.3: (44A) ~ (44B» a.o.
(X-H
C=O
/
fii1\
~ (1) R' = Me < Et < i-Pr < t-Bu
B
C= conformationally mobile chain
R' = Me > i-Pr > t-Bu

B
In discussing the influence of branched alkyl groups at the ketone

group a distinction between two cases should be taken into account regard-
ing the structure of the connecting link.
I. The connecting link contains double bonds or aromatic rings in
conjugation with the keto group:
o
II
I C'OH
((
~ Rl
. . . .". C/
II
o
An increase in the steric bulk of the alkyl substituent R 1 in the sequence
Me < Et < i-Pr < t-Bu twists the keto group out of the plane of the ethylene
bond or the aromatic ring and this conformation of the C=O group is most
favorable for an intramolecular addition to it. Furthermore, a diminished
conjugation increases the electrophilicity of the carbonyl group stabilizing
the cyclic isomer.
Thus, equilibrium constants of Z-3-acylacrylic [19], 2-acylbenzoic [9],
and 8-acyl-I-naphthoic [II] acids increase in the sequence of substituents
at the keto group: Me < Et < i-Pr < t-Bu and the ring-chain equilibrium
constants of 8-acyl-I-naphthoic acids are correlated with Taft's steric
coefficients [II]:
r = 0.977, s = 0.12, n = 4.
252 Chapter 5
This effect is observed also for the ring-chain equilibrium of 2-acylben-

zoic acid methyl esters which takes place under conditions of acidic or
basic catalysis (see Sec. 2.1.4: (100A) ~ (100B) and Table 18). On increasing
the steric bulk of the alkyl substituent both rate constants of the equilibrium
(k l and k 2 ) decrease. However, equilibrium constants (K T = kIf k 2 ) increase
at the same time and correlate with Taft's steric coefficients [20]:
19 KTf(KT)o = -0.35Es·
2. The connecting link is conformationally mobile and an Sp3 -carbon
is placed at the a-position of the keto group. Here, an increasing volume
of the substituent R I at the keto group destabilizes the cyclic structure. This
has been shown in the series of S-(2-oxoalkyl)dithiocarbamates (see Sec.
2.3.4: (170A) ~ (170B»), 2-acylmethylthio-benzimidazoles and -perimidines
(see Sec. 2.3.7: (183A)~(183B) and (187A)~(187B), Table 26) and 1-(2-
oxoalkyl)-3-phenyltriazenes (see Sec. 2.3.8: (195A) ~ (195B), Table 27).
There are, however, some exceptions to this rule. I-Hydroxyimino-3-
alkyl-propan-3-ones (see Sec. 2.2.2: (141A) ~ (141B), Table 24) may be
taken as an example where the influence of alkyl substituents has a rather
complicated character. The absence of a correlation of equilibrium constants
with Taft's steric constants Es has been explained by the conformational
mobility of the molecule, i.e., besides steric and electronic effects the
conformation of the open isomer has to be considered.
The planes of o,o'-disubstituted phenyls, 9-anthryl and related fused
systems are twisted out of the plane of the ketone group:
MenMe H
"cy
oII M
"c
II
"c
II
e o o
As a consequence an attack of the nucleophilic part of the molecule

to the shielded C=O group is made impossible. Therefore ami des of
2-mesityloyl, 2-(9-anthroyl)benzoic acids and related derivatives (see Sec.
2.1.3: Table 12) exist independently of the structure of the substituent at
the nitrogen atom only as the open isomers, and they are not capable of
cyclization even under conditions of basic catalysis. The same has been
reported for 2-mesityloylbenzoic and 8-mesityloyl-I-naphthoic acids (see
Sec. 2.Ll), 2-mesityloyl and 2-(9-anthroyl)phenyldimethylcarbinols (see
Sec. 2.2.1: (1I8A) ~ (1188» and dimesityloylformoine (see Sec. 2.2.1:
(135A) ~ (1358».
R2 = Me > Et> ;-Pr > t-Bu

8 +4----------------
Increasing the steric bulk of substituents at the C=N group (R I and

R2 in formulas (2) and (3» in compounds containing conformationally
mobile connecting links destabilizes the cyclic isomers and shifts the equil-
ibrium in favor of the open form.
Thus, for instance, equilibrium constants of N -methyl- N -( I-hydroxy-I-
phenyl-2-propyl)hydrazones of aliphatic aldehydes (see Sec. 3.1.2:
(12A) ~ (128), Table 32), N-2-hydroxy- and N-2-mercaptoalkylhydrazones
of aldehydes and ketones (see Sec. 3.1.2: (lIA) ~ (118), Table 31 and Sec.
3.3: (56A) ~ (568», N -alkylimines of hydroxyketones and hydroxyalde-
hydes (see Sec. 3.1.4: (19A) ~ (198), Table 35) decrease in the sequence of
alkyl substituents at the C=N group: Me> Et> i-Pr> t-Bu.
5.1.3. Structure of the Connecting Link
A study of the influence of the connecting links should be based on a

comparison of equilibria and rates of tautomeric compounds by varying
the structure of the connecting links and leaving the interacting functions
unaltered. Unfortunately, investigations of this kind have only rarely been
reported. Moreover, equilibrium constants have frequently been determined
under different conditions and by different methods which diminished the
value of the information.
254 Chapter 5
Thus, the estimation of the influence of the structure of the connecting

link on the facility of ring formation and on ring stability is a rather
complicated problem. Two theoretical approaches are possible here: I)
estimation of the fulfillment of the structural requirements for a forced
approach of the interacting groups in the orientation optimal for an
intramolecular reaction; 2) estimation of the energy of ring formation from
the thermodynamic point of view, i.e., deriving the enthalpic participation
in the free energy difference from the changes in bond distances, angle
deformations, nonbonded and electrostatic interactions, steric strain etc. [4].
Many investigations in this direction have been carried out with the
purpose of finding a model system explaining the enormous rates of enzy-
matic reactions as compared to normal bimolecular reactions. As a result,
new concepts such as "stereopopulation control" [21-25] and "orbital
steering" [26-28] appeared.
According to the concept of stereopopulation control the enormous
acceleration of the lactonization reactions of o-hydroxydihydrocinnamic
acids observed after introduction of methyl groups into the chain between
interacting functions may be explained by an increase in the content of the
reactive conformer, both interacting centers of which are optimally orien-
tated. Later it was shown [29,30] that this effect cannot make so large an
acceleration and the increase in the strain energy of the open structured
compound by the introduction of methyl groups plays the most important
role. In addition, a reexamination showed [31] that this rate acceleration
is smaller than first observed [26-28].
Koshland's "orbital steering concept" aims to explain the acceleration
of the lactonization reactions of hydroxycarboxylic acids, which was ob-
served in the course of a systematic modification of the connecting link.
Following this concept the highest possible acceleration may be achieved,
if the structural preconditions for an optimal angular orientation of
intramolecularly interacting groups are realized [26-28]. The concept has
been criticized [32] for being too simplified for complicated enzymatic
reactions and for overestimating the influence of an optimal angular orienta-
tion. An experimental disproof has been presented [33], showing no rate
dependence on angular orientation within the confines of 10° changes for
a lactonization reaction (for a discussion see [34]).
Another experimental approach to this problem has been suggested by
Burgi and Dunitz [35-38]. Based on X-ray structure data of suitable bifunc-
tional compounds they have found the optimal geometry of the reaction
path for interacting functions.
On the basis of simple considerations of stereochemical requirements
for an intramolecular reaction Baldwin has proposed [39] simple empirical
rules concerning the favored routes of cyclization reactions.
If the intramolecular addition of a nulceophilic atom occurs at a double

or triple bond with the formation of the smallest of two possible rings, the
cyclization is named exo-cyclic, while the formation of the bigger ring is
called endo-cyclic:
f\
X--Z (Z=CR)
\
y-
~o
Tetrahedral, trigonal, or digonal geometry of the carbon atom at which

intramolecular substitution (tet) or addition occurs is designated by prefixes
"tet," "trig," and "dig." The number of members in the ring is indicated.
Some examples may be given:
xQ x('l
~~y
r-\
xJ 01 y
y
5-exo-tet 5-exo-trig 5-endo-trig 6-exo-dig
If X is a first-row element cyclizations of type (3-7)-exo-tet, (3-7)-exo-

trig, (6, 7)-endo-trig, (5-7)-exo-dig, and (3-7)-endo-dig should be favorable
processes. Cyclizations of type (3-5)-endo-trig and (3,4)-exo-dig should be
disfavorable [39].
Baldwin has suggested a very convenient classification system for
ring-forming reactions. The proposed rules are of general character and
very easy to apply. However, their practical use is bound up with some
limitations, since many structural aspects, e.g., the structure of the connect-
ing link, the presence of substituents having different electronic and steric
effects, and the nature of interacting groups have been neglected. Some
exceptions have been observed in the field treated in this book. Thus, a
"disfavored" 5-endo-trig reaction has been observed for N-2-hydroxyalkyl-
imines of aromatic aldehydes as is shown in Sec. 3.1.1: (3A) ~ (3B). A more
rapid "disfavored" 5-endo-trig cyclization as compared with a "favored"
6-endo-trig cyclization was also reported [40] (see Sec. 3.2.1: (31A) ~ (31B»).
The majority of the cyclic isomers discussed in this monograph contain
five- or six-membered heterocycles. The preference in stability of the five-
or six-membered ring system depends on many factors. Sometimes the
256 Chapter 5
formation of five-membered rings is sterically more favored while in other

cases a six-membered ring forms more easily and/ or is more stable.
3-Acylpropionamides, for instance, being substituted in a definite pat-
tern at the amide nitrogen atom and the keto group, form stable five-
membered cyclic isomers (see Sec. 2.1.3: (45B), Table 9) while six-membered
hydroxylactams totally failed to be obtained from 4-acylbutyramides having
the same substitution pattern (see Sec. 2.1.3: (89A»).
The greater stability of five-membered hydroxylactams compared with
six-membered analogues is supported by the isomerization with ring contrac-
tion for benzile-o-carboxamides (see Sec. 2.1.3: (78C) -+ (78B»).
3-Acylpropanols and 4-acylbutanols (see Sec. 2.2.1: (109A) ~ (109B),
Tables 20 and 21) are examples of an opposite effect: ring-chain equilibrium
constants for the butanols forming six-membered rings are greater than
those of the propanol derivatives. This effect is even more pronounced for
3-acylpropanol and 4-acylbutanol N -alkylimines (see Sec. 3.1.4:
(19A) ~ (19B), Table 35).
'A general rule can be stated: the stability of the cyclic isomer increases
with increasing rigidity of the connecting link, i.e., decreasing conforma-
tional mobility. A possibility to assume a conformation which favors the
interaction of the functional groups is also important.
Bowden [IIJ proposes the following order of the stability of cyclic
isomers (see also Table 3):
COOH ilCOOH 8~COOH COOH

(XI <j < - <
~ COR COR ~ II COR
COR
This order corresponds to a steric approach of the C=O and COOH groups.
An analogous sequence was observed [41 J in the case of 3- and 4-
benzoylcarboxylic acid ami des (see Table 15):
CH 2 CONHR
PhCO(CH2)3CONHR < PhCO(CH2)2CONHR < ( X I <
~ COPh
CONHR (XCONHR 8~ CONHR

< (XI < I <-
~ CH 2 COPh ~ COPh ~ II CO Ph
Here keto groups can assume a conformation allowing the nucleophilic

part of the molecule to approach nearly perpendicularly to its plane.
Noncompliance with this requirement hinders cyclization. Anthraquinone-
l-carboxamides, for instance, are not capable of forming hydroxylactams
because the keto group is rigidly fixed in the plane of the aromatic ring
(see Sec. 2.1.3: (SIA»).
Different pairs of functional groups have different steric (geometrical)
requirements for an optimal path of approach in the course of an intramolec-
ular reaction. Therefore it is impossible from different systems to find direct
correlations between ring-chain equilibrium constants or cyclization rate
constants and the structure of the connecting link. A critical outlook at
trajectory considerations of cyclization reactions is presented in a recent
report [34].
5.1.4. Steric Effects of Substituents at the Connecting Link
Thorpe-Ingold effect. The introduction of alkyl groups at the carbon

atoms placed in the chain between the interacting groups and, especially,
the introduction of two geminal groups increases the cyclization rate and
displaces the equilibrium toward the ring isomer. This effect is commortly
called "gem-dimethyl," "gem-dialkyl" or the "Thorpe-Ingold effect" and
its influence has been repeatedly discussed in previous chapters.
The most satisfactory theoretical explanation of this effect has been
given by Allinger and Zalkov [42] (see Sec. 2.1.1).
The influence of alkyl substituents at the connecting link on the ring-
chain equilibrium constants, as well as on the cyclization rate constants,
depends on the steric encumbrance of these substituents, their position at
the connecting link, and the conformational mobility of the connecting link
itself. If the chain between the interacting groups consists of three Sp3 -carbon
atoms, the greatest influence is exerted by two alkyl groups at the central
carbon atom.
The introduction of methyl groups to the a-carbon of a functional
group, in particular a C=O group, can lead to the opposite effect due to
the steric shielding of the reactive center. Thus, destabilization of the cyclic
isomer was observed on introducing a methyl group at the a-carbon of the
258 Chapter 5
C=o group of N -(3-oxoalkyl)-N'-substituted thioureas (see Sec. 2.3.3:

(167 A) ~ (167B» and 1-(2-oxoalkyl)-3-aryltriazenes (see Sec. 2.3.8:
(195A) ~ (195B), Table 27).
The influence of alkyl substituents is greatly enhanced if the conforma-
tional mobility of the connecting link is decreased. Thus, a strong stabiliz-
ation of the cyclic isomer was observed on introducing two methyl groups
in a connecting link of type -o-C 6 H 4 CR T in 2-acylmethylbenzoic and
o-acylphenylacetic acids (see Sec. 2.1.1: (20A) ~ (20B), (21A) ~ (21B),
Table 5).
Alkyl substituents at Sp2 -carbon atoms of the connecting link stabilize

the cyclic isomer as well, evidently as a result of increasing steric strain of
the open isomer [43]. This has been observed particularly in the case of
Z-3-acetylacrylic acids (see Sec. 2.1.1: (18A) ~ (18B), Table 4) where the
introduction of methyl substituents at both ethylene carbons increases the
ring-chain equilibrium constant by four orders of magnitude!
A large stabilization of the cyclic isomer also has been observed by an

introduction of alkyl substituents at a nitrogen atom that is pan of [he
connecting link. Examples have been reported of compounds being unsub-
stituted at the nitrogen atom (R = H) and existing in the stable open form
exclusively. Ring-chain equilibria were observed only for derivatives con-
taining N -alkyl substituents. Increasing the steric bulk of this substituent
shifts the equilibrium further toward the ring form.
This «flect is well documented by investigations of the tautomerism
of N -alkyl-N -(2-hydroxyalkyl)-N -(2-oxoalkyl)amines (see Sec. 2.2.1:
(114A) ~ (114B», 2-[ N -alkyl- N -(2-hydroxyethyl)amino]-1 ,4-benzoqui-
nones (see Sec. 2.2.1: (116A) ~ (1168), Table 22), N -alkyl-N -(2-hydroxy-
or Q-mercaptoalkyl)-hydrazones of aldehydes and ketones (see Sec. 3.1.2:
(l1A) ~ (l1B), Table 31 and Sec. 3.3.1: (56A) ~ (568), Table 38), as weli
as other systems.
®
¢c
®
"Support" Effect or Steric Assistance Effect. If the connecting link
contains an aromatic ring, the introduction of methyl or other groups in
the ortho-positions to the interacting groups creates steric strain which
favors intramolecular cyclization [44].
Quantitative evidence using ring-chain tautomerism of 2-acetyl [45]
and 2-benzoylbenzoic acids [46] is presented in Table 45.
This effect also governs the acylo- or arylo-tropic tautomerism of
tropolone derivatives (see Sec. 2.4: (211A) +:! (211B»). Introduction of
methyl or benzyl substituents in positions 3 and 7 of the tropolone ring
sterically favors the formation of a cyclic bipolar transition state or inter-
mediate and accelerates the migration of acyl or aryl groups [47].
From the examples discussed above (see also [48]) it appears that the
influences of substitution at the connecting link depend on many factors
Table 45. Steric- Assistance Effect of

ortho-Substituents on Ring-Chain
Equilibrium of 2-Acetyl [45] and
2-Benzoylbenzoic Acids [46]
¢rRI
~
I
COOH
COR
~
o;RI0
~
I 0
R2 R2 R OH
(A) (S)
KT = [B]/[A]
R' R2 R = Me R = Ph
H H 3.2 <0.1
Me H 16 2.85
H Me 0.52 0.22
Me Me 13.3
260 Chapter 5
Table 46. Influence of Methyl Substituents on Cyclization Rate Constants

of 3-Ureidopropionic Acids (4) ....... (5) [49]
RI R2 R3 R4 RS 19 keel
H H H H H 0.00
Me H H H H 0.07
H H Me H H 0.45
Erithro- Me H Me H H -0.08
Threo- Me H H Me H 0.47
Me Me H H H -0.46
H H Me Me H 1.25
H H H H Me 1.66
and a quantitative prediction is difficult. Progress is expected from force-field

calculations.
The introduction of alkyl substituents not only shifts the equilibrium
toward the cyclic form, it also accelerates cyclization reactions if a transition
from open-structured ground state into cyclic transition state takes place
in the rate-limiting step.
The rate constants of cyclization of the methyl substituted 3-
ureidopropionic acids (4) --+ (5) (see Table 46) [49] are taken as an example
where the introduction of two methyl groups at the f3-carbon atom (regard-
ing the carboxylic group) (4, R3 = R4 = Me) as well as the introduction of
a methyl group at nitrogen (R 5 = Me) strongly accelerates the cyclization
reaction while two methyl groups in the a-position retard it, obviously, due
to the steric shielding of the reactive center.
COOH
R+R
1 2
R+R
3 4 WI-H 2 0
N
RS/ "CONH 2
(4)
Blagoeva, Kurtev, and Pojarlieff [49] found a good linear correlation

(r = 0.932-0.993) of free activation energies for the cyclization of methyl
substituted 3-ureidopropionic acids (4) --+ (5) as well as for previously
investigated anhydrizations of succinanilic [50] and succinic [51] acids,
hydrolysis of p-bromophenylglutarates [52], and lactonization of 4-hydroxy-
butyric and 5-hydroxyvaleric acids [53] with steric strain energies estimated
on the basis of the formation enthalpies of homomorphic hydrocarbons [54].
Empirical force-field calculations [44, 55-60] were successfully used

for a quantitative prediction of an acceleration of hydroxycarboxylic acid
lactonizations by modification of the structure of the connecting link and/ or
introduction of methyl groups [30,61].
The potential of these calculations has been well demonstrated by De
Los De Tar [62,63] using cyclization reactions of bromoalkylamines and
their in-chain alkyl substituted derivatives. A good coincidence of calculated
and experimentally determined cyclization rates has been observed. Activa-
tion enthalpies were calculated by the force-field method and activation
entropies obtained from analogous formal cyclization reactions of
homomorphic alkanes.
The results of calculations show that the driving force of the Thorpe-
Ingold effect is mainly an enthalpic effect (and not an entropic effect as
was supposed earlier [21,22]) caused by steric strain in the ground state of
the open structured starting material.
5.1.5. Intramolecular Hydrogen Bonds

If the structure of the open isomer has the steric requirements for the
formation of an intramolecular hydrogen bond with a proton-donating
group participating (X-H···) [64], then stabilization of this isomer may
ensue. The formation of such a bond blocks the proton-donating group
X-H. Moreover, the open isomer may be fixed in a conformation unfavor-
able for intramolecular ring formation.
3 -Acetyl-2- (2-hydroxy -3 -acetylphenylamino) -5-methoxy-1 ,4- benzo-
quinone (6) [65], bis-{l,3-cyclohexanedione-2-yl)methanes (7) [66-68], Z-I-
amino-2-(2-oxoalkyl)ethylenes (8) [69], and N-(2-hydroxybenzyl)imines of
°b:y
aromatic aldehydes (9) [70] serve as illustrations.
Me, ~o..
Cx
C~
~ I
N
OOMe
~
0
I
H COMe
(6) (7)
The open isomers of acylformoins exist as symmetric enediols (lOA)

which are stabilized by two intramolecular hydrogen bonds [71]. Isomeriz-
ation (lOA) -+ (lOB) is possible only after a cleavage of these bonds and
formation of an asymmetric enediol.
262 Chapter 5
~ ~
R
li
HO
0
0
OH
R
(108)
Intramolecular hydrogen bonds are cleaved in polar proton-accepting

solvents. This cleavage leads to a destabilization of open-structured hydroxy-
or amino-carbonyl derivatives and a displacement of the equilibrium in
favor of the cyclic form. This is not observed for open azomethine analogues
which, however, are stabilized by proton-accepting solvents.
(11)
A stabilization of cyclic isomers by means of intramolecular hydrogen

bonds occurs only rarely. Examples are N-{I3-dialkylaminoethyl)amides of
{2-phenyl-l,3-indanedione-2-yl)acetic (11) [72] and {2-benzyldimedone-2-
yl)acetic acids (12) [73].
5.2. INFLUENCE OF EXTERNAL FACTORS
The influence of external factors (temperature, state, solvent properties)

on ring-chain tautomerism has only rarely met with interest. Systematic
physical investigations have not been reported and the available experi-
mental data do not allow any resonable generalizations.
Equilibria should be studied in solution and in the gas phase to
differentiate the influences of structure and solvent. Unfortunately, only a
few mass-spectrometric investigations have been carried out which,
moreover, could not yield exact quantitative equilibrium constants in the
gas phase.
We first consider some general statements. The tautomeric equilibrium
constant (KT = [B]/[A]) is a quantitative measure for the investigated
systems. A control of this constant by external factors is commonly dis-
cussed.
Rate constants kl and k2 of tautomerization
have been but rarely determined because of experimental difficulties.

However, a change of external conditions can influence rate constants kl
and k2 of the interconversion while leaving equilibrium constants (KT =
k l / k 2 ) almost unaffected. 3,3-Dimethyllevulinic acid amides may serve as
an example (see Sec. 2.1.3, (47 A»). Solvent properties influence the equili-
brium constants only weakly while the equilibration rates vary to a large
extent.
Protolytic ring-chain tautomeric interconversions, being considered
here, differ from other protolytic tautomerizations in one significant respect.
The thoroughly investigated keto-enol tautomerism proceeds through
one common anion (13A):
o R2 OH R2
1:'- / 1 /
"2
RI-C=C RI-C=C
R '"R 2
(13K) (13A) (13E)
In the protolytic ring-chain tautomerism, however, two anions (14C)

and (14D) can participate. Usually one anion is less stable than the other,
the relative stability being determined by the acidity of the X - Hand Y - H
groups: if the X - H group is more acidic then the open structured anion
(14C) is the more stable, which was observed for acylcarboxylic acids (see
Sec. 2.l.l). A more acidic Y - H group stabilizing the cyclic anion (14D)
has been noticed for the amides of acylcarboxylic acids (see Sec. 2.1.3).
Proto lytic transformations of the keto-enol system
(13K) +:t (13A) +:t (13E) proceed rapidly, ring-chain tautomeric interconver-
sions generally take place considerably slower. Obviously, the formation
264 Chapter 5
and/ or the cleavage of a C- X bond is responsible for this difference. Apart

from the anions (14C) and (14D), bipolar (14E) and (14F) or even protonated
(14G) and (14H) intermediates are conceivable. The conversion mechanism
(14A) ~ (14B) is determined by acid-base properties of X - Hand Y - H
groups and by protolytic characteristics of the medium.
C-: CH
+
X-
X
CC=VH
4 ~ -
C=YH l-Y-H
/ I /
R R R
(14G) (14H) (14F)
+Wll-H+
+~+
11
C-H C=Y
4
-H+
+H+
~
C=y
X-
4 ~
CLy- 4
+H+
-H+
~
G-Y-H
/ / I I
R R R R
(14A) (14C) (14D) (148)
11
C1- C-Y-
H
X,Y=O,NR
I
R
(14E)
Many ring-chain tautomeric systems are known which require 10 days

or even more for equilibration in solution. Water, acids, or bases strongly
accelerate this process. Therefore, sometimes equilibrium constants have
to be established in the presence of these catalysts.
Proton-donating or proton-accepting properties of the medium affect
directly the proton migration and therefore also determine the rate of
tautomerizations.
Solvents control the position of equilibria by solvation. Open and cyclic
isomers usually have different polarities. As a consequence, in polar solvents
the equilibrium is shifted toward a more polar form while in solvents of
low polarity the opposite is observed.
In addition, the formation of intermolecular hydrogen bonds with

solvent molecules is of great significance for stabilization of either tautomer.
The solvent may act as a proton donor or proton acceptor, the latter being
observed more often. Tautomeric systems which are exclusively controlled
by intermolecular hydrogen bonds have been observed [74]. In various
systems solvent-proton-accepting properties differently influence the stabil-
ity of the cyclic form.
Hydroxycarbonyl Compounds (14, X = Y = 0). Solvent polarity and
proton-accepting ability show comparatively little influence on the ring-
chain equilibria of hydroxyketones (see Sec. 2.2.1: (109A) +::! (109B), Table
21). The insensitivity of the proton-acceptor properties of the solvent is
easily understood since both types (open and ring) of isomers have similar
proton-donating hydroxyl groups. The equilibrium position is strongly
affected by the addition of water to the solutions (see Sec. 2.2.1:
(109A) +::! (109B»). The considerable decrease in enthalpy and entropy taking
place is explained by hydration of the open isomer.
In the series of 2-aroylbenzoic acids polar solvents shift the equilibrium
toward the more polar lactol form (see Table 47) [14]. The highestequilib-
rium constants was detected in dioxan though its dielectric constant is lower
than those of acetonitrile and nitromethane. This can be explained by a
participation of the dioxan molecules in the formation of intermolecular
hydrogen bonds with the lactolic hydroxyl group.
The sensitivity of the ring-chain equilibrium of 2-(3- or 4-X-
benzoyl)benzoic acids to electronic influences of substituents X depends
on the solvent being used. As a rule increasing stabilization of the cyclic
isomers by solvent diminishes the sensitivity, i.e., decreases the reaction
constant p of the equilibria (see Sec. 2.1.1: (lOA) +::! (lOB), R = C 6 H 4 X,
X = H, 4-Cl, 4-Br, 4-CN, 4-N02' 3-N02-4-Me, 3-NOT4-Cl, and Table 44
for detailed information) [14]. Diluting solutions of acyl carboxylic acids
shifts equilibria toward the open forms. In acidic media the equilibria are
displaced in favor of the less acidic ring forms.
Table 47. Solvent Influence on the

Ring-Chain Equilibrium Constant of
2-Benzoylbenzoic Acid [14]
Solvent KT = [8]j[A]
Chloroform 0.006
Nitromethane 0.025
Acetonitrile 0.030
Dioxan 0.033
266 Chapter 5
Aminocarbonyl Compounds (14, X = NR, Y = 0). An increase of

proton-acceptor ability and polarity of the solvents displaces the equilibria
toward the ring form. Z-I-Amino-2-(2-oxoacyl)ethylenes (see Sec. 2.3.2:
(I64A) ~ (I64B), Table 25), 6-acylmethylmercapto-4-chloro-5-methyl-
aminopyrimidines (see Sect. 2.3.2: (166Ab) ~ (164Bb), 3-aryl-I-(2-
oxoalkyl)triazenes (see Sec. 2.3.8: (19SA) ~ (19SB), Table 27) are examples.
The influence of proton-accepting solvents may be explained by a
greater energy of formation of intermolecular hydrogen bonds of the type
(ISB) as compared to that of type (ISA). Besides, the formation of an
intermolecular hydrogen bond of type (ISA) increases the nucleophilicity
of the nitrogen atom favoring an intramolecular addition of N - H groups
to the C=O groups.
(15A)
There are, however, exceptions, as for example the 5-(2-acetylamino-

phenyl)tetrazole equilibrium which is shifted toward the open form in
pyridine (see Sec. 2.3.1: (IS2A) - (IS2B»).
The stabilization of cyclic isomers of aminocarbonyl compounds
repeatedly observed is caused by self-association. Sometimes dilution of
these solutions with nonpolar solvents leads to displacement of the equi-
librium in favor of the open tautomer (see, for instance, Sec. 2.3.7:
(183A) ~ (183B»).
Hydroxyderivatives of Azomethines. Unlike aminocarbonyl compounds
hydroxy derivatives of Schiff's bases and their analogues bear a hydroxyl
group in the open isomers. This explains the opposite effect of solvent
properties on equilibrium positions as compared to the carbonyl analogues
considered above. Increasing proton-acceptor ability and polarity of sol-
vents shift equilibria toward the open form, obviously, due to a preferable
formation of intermolecular hydrogen bonds O-H· ··solvent. Such solvent
influences were observed for benzaldehyde N -{l-hydroxy-2-methyl-2-
propyl)imines (see Sec. 3.1.1: (3A) ~ (3B), Table 30), 5-hydroxy-2-
pentanone N -methylimines (see Sec. 3.1.4: (19A) ~ (19B»), 2-benzoyl-
benzoic acid anils (see Sec. 3.1.5: (2IA) ~ (2IB), Table 37), and other
azomethines.
Paukstelis and Hammaker [74] have detected a most interesting linear
correlation between hydroxyl group frequency displacements (~VO-H) in
the IR spectra of di-tert-butyl-carbinol solutions and enthalpies of benzal-

dehyde N -( l-hydroxy-2-methyl-2-propyl)imine ring-chain equilibria in the
same solvents. As a consequence the displacement of the hydroxyl band
frequency of di-tert-butylcarbinol (~VO-H) was used as a measure of the
proton-acceptor ability of solvents involved in intermolecular hydrogen
bonds with the hydroxyl group of the open isomer
(Ph-CH=N-CMe2CH20-H···solvent).
For N -alkylimines of hydroxycarbonyl compounds (see Sec. 3.1.4:
(19A) ~ (198), Table 35), on passing from the liquid state to solutions in
solvents of low polarity there is a shift in the equilibrium toward the cyclic
form. Hence, it appears that self-association stabilizes the open form.
Temperature Influences. In the majority of the equilibria discussed in
this monograph an increasing temperature was shown to displace the ring-
chain equilibrium in favor of the open isomer. This often has been used
preparatively for a thermal isomerization of cyclic isomers to open ones.
+ + +
In conclusion it should be noted that our knowledge of the influence
of solvation on ring-chain equilibria is rather limited and investigations in
this field would be welcome.
A deeper understanding of these influences could be achieved in at
least two ways:
I) From temperature dependencies of ring-chain equilibria in different
solvents (see [74, 75]) information concerning thermodynamic parameters
(~H and ~S) of the equilibria is to be expected; this could be correlated
with solvent parameters.
2) Ring-chain equilibria in the gaseous phase should be investigated.
A comparison of these results with those obtained for solution would lead
to a better understanding of solvent effects.
It is not yet clear whether experimental observations which have been
attributed to structure are due to solvent effects and vice versa.
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Index
Acid 5-formyl-3-hydroxy-2-methylpyridine-4-,
acetic 28
o-acylphenyl, 37 3-formylthiophene-2-, 33
anthraquinone-I-yl 34 5-methyl-4-hexene-I-, 221
2-iodosophenyl, 236 tolane-2-, 221
acrylic 3-trichloroactyl, 28
Z-3-acetyl, 35 dithiocarbazinic, condensation
Z-3-acyl, 21, 34 products with aldehydes and
3-( l-adamantylcarbonyl)-2-( or ketones, 202
3)halogeno, 35 glutaric, 2-oxo-3,3-disubstituted, 150
Z-3-aroyl, 22, 34 levulinic, 21, 27
Z-3-(4-X-benzoyl)-3-methyl, 34 methyl substituted, 27
Z-3-formyl, 34, 35 2,3,3-trimethyl, 24, 27
E-3-pivaloyl, 35 naphthoic
anthranilic 3-acetyl-2-, 21
N- benzylidene, 185 8-acetyl-l-, 21, 38
N-pyruvoyl, 40 8-acyl-I-, 38
benzoic 8-aroyl-I-, 22, 39
2-acetyl, 23, 28 8-benzoyl-I-, 39
2-acetyl-3-amino, 33 8-(4-methoxybenzoyl)-I-, 39
2-acetyl-3-hydroxy, 33 nitronic, 3- or 4-oxo, 117
2-acetyl-3-nitro, 33 opianic, 28
2-acetyl-6-X, 33 penicillic, 34
2-acyl, 5, 21, 28 propionic
2-acylmethyl, 37 3-acyl, 27
2-aroyl, 32 3-aroyl, 27
2-diphenylphosphynyl, 229 3-benzoyl, 27
2-formyl, 21, 24, 28, 33 3-formyl, 27
2-formyl-5,6-dimethoxy, 28 3-(2-hydroxyphenyl), 27
2-formylmethyl-5,6-dimethoxy, 38 3-(3-indolylcarbonyl), 27
2-heteroyl, 33 3-trichloroacetyl, 27
2-iodoso, 235 3-ureido, methyl substituted, cyclization
2-iodoxy, 236 rates, 260
2-(2-nitroethenyl), 222 terephthalic, 2,5-dibenzoyl, 30
butyric, 4-acyl, 36 valeric, 4-formyl-4-methyl-3-phenyl, 37
carboxylic Aldehyde
5-acyl, 39 N-(2-pyridyl)aminoacet, 135
2-acyldiphenyl-2' -, 39 2-(2-hydroxyethyl) benz, 103
5-( o-aminophenylcar- 2-hydroxymethylbenz, 103
bamoyl)pyridazine-4-, 223 Alcohol
anthraquinone-I-, 33 2-benzoyloxybenzyl, 137
benzile-o-, derivatives, 10, 29, 45, 78 w-cyano, 212
271
272 Index
Alkane Anile
l-nitro-3{or 4)-oxo, 117 N-alkyl-2-benzoylbenzamide, 194
Amide 2-benzoylbenzoic acid, 186
acet 2-methoxycarbonylbenzophenone, 10, 186
o-acylphenyl, 83 Anilide 2-cyanobenz, cyclization rates, 214
(2-benzyl-2-dimedonyl), 51,66 Aniline
(2-phenyl-I,3-indanedione-2-yl), 51, 63 2-mercapto, 199
acryl, Z-3-acyl, 81 2-{2-oxoacyl), 122
benz 2-{2-oxoalkyl), 122
2-acyl, 67 2-Azaadamantane,l-hydroxy, 121
cyclization rate constants, 73 I-Azabicyclo/ 5.3.0/ decane,7 -hydroxy-2-oxo,
2-acylmethyl, 82 143
2-{9-anthroyl), 76 2-Azabicyclo/ 5.4.0/ undecane,9-acyl, 122
2-aroyl, 50, 68 I-Azacyclodecane-2,7 -dione, 122
2-benzimidoyl, 193 Azacyclols, 140, 142, 143
2-benzoyl, 9, 69
N-chloro-2-iodo, 237 Baldwin's vectorial rules, 190, 254, 255
2-cyano, 5,213,215 Benzile, 2-acetamino, 123
2-{ 4-dimethylaminobenzoyl), 50, 75 Benzimidazole, 2-acylalkylmercapto, 131
2-formyl, 68 1,2-Benzisothiazoline-I,I-dioxide
2-{2-imidazolylcarbonyl), 50, 74, 76 3-alkyl{or 3-phenyl)-3-hydroxy-, 127, 128
2-iodoso, 235 3-imino-, 216
2-mesityloyl, 76 1,2-Benzisothiazoline-I-oxide,2-benzyl-3-
butyr, 4-acyl, 82 hydroxy-3-phenyl-, 129
carbox 1,3-Benzodioxan-4-one
anthraquinone-I-, 79 2-alkoxy-2-methyl, 48
benzile-o-, 78 2-aryl-2-methyl, 48
2-benzoyldiphenyl-2'-, 85 3-Benzo/ e/ morpholinone,2-{ N-arylhydroxy-
3-cycloalkanone, 62 lamino), 182
trans-bicyclo/ 5.3.0/ -6-decanone-I-, 63 Benzophenone,2-cyano, 72
levulin, 57 Benzopyran-3-one, 46
3,3-dimethyl, 60 I A-Benzoquinone
naphth, 8-acyl-l-, 85 2-/ N-{2-hydroxyethyl)-N-alkyl/amino,
propion 102
3-acyl, 57 2-{2-hydroxyphenylamino), 106
3-cyano, 212 intramolecular addition to the C=C
3-{2-hydroxycarbonylbenzoyl)-3- bond, 222
phenyl, 29,64 1,2,3-Benzoxaphospholine, 230
valer, 5-acetamino-2-oxo-, 120 2H-I,3-Benzoxazine
Amidrazone 2,2' -bis, 172
1-{2-propylidene )-2-methylacet, 191 2-{4-X-phenyl)-3,4-dihydro, 170, 172
1-{2-propylidene)benz, 191 1,3-Benzoxazine-2,4-dione,3-{ N- ethy-
Amine laminocarbonylmethyl), 143, 144
2-acylbenzyl, 122 Benzoxazoline,2,2'-bis, 171
o-acylmethylmercaptohetaryl, 124 Benzthioamide,2-cyano, 215
N-{2-hydroxyalkyl)- N-{2-oxoalkyl), 102 Bicyclo/3.3.1 / nonan-3-one
3-mercapto-2-butyl, 199 7-amino, 121
4-mercaptobutyl, 200 7-aminomethyl, 121
2-mercaptoethyl, 199 7-hydroxymethyl, 101
3-mercaptopropyl, 200 Butanal,4-hydroxy, 99
Index 273
Canadine,8,I 3-dioxo-14-hydroxy , 79 Cyclooctanone,5-hydroxy, 113

Carbinol Cyclopentanone,2-( w- hydroxyalkyl), 101
8-acyl-I-naphthyl, 104
2-acylphenyl, 103
di-tert-butyl, 173 N-Dealkylation, in conc. sulfuric acid, 72
Catalysis, intramolecular with the neighbor- N-Demethylation, under mild conditions of
ing group participation, 4, 90, 91 4-hydroxy-2,3-dimethyl-4-phenyl-
Chloride 3,4-dihydro-phthalazone, 78
O-acetylsalicyloyl, 48 Depsipeptides, 140
acyl carboxylic acid, IR spectra, 42 Dialdehyde, cyclization by hydration
anthraquinone-I-carbonyl, 45 aliphatic 1,4 or 1,5, 113
2-(9-anthroyl)benzoyl, 43 phthalic, 113
(2-aryl-I,3-indanedione-2-yl)acetyl, 45, 63 l,3-Diazaheterocycles, 130
4a-azoniaanthraquinone, 45 Dichloride
2-benzoylbenzenesulfonyl, 48 glutaryl, 47
2-benzoylbenzoyl, 41 phthalyl, 47,48
4-benzoylbutyryl, 46 succinyl, 47
4-benzoyl-4,4-dimethylbutyryl, 46 2-sulfinobenzoyl, 49
2' -benzoyldiphenyl-2-carbonyl, 46 2-sulfobenzoyl, 49
4-benzoylthiophene-3-carbonyl, 45 Dithiocarbamate,S-(2- or 3-oxoalkyl), 127
(2-benzyldimedone-2-yl)acetyl, 45
cyanocarboxylic acid, 218 Ehiboline
2-(2,4-dimethylbenzoyl)benzoyl, 5 derivatives, 198
2-formylbenzene sulfinyl, 49 protonation, 198
2-formylbenzene sulfonyl, 48 Ephedrine,N-amino-I-, 178
2-iodosobenzoyl, 236 Equilibria, ring-chain
levulinyl, 41 constant correlation with u-coefficients,
2-(2',4'6'-trimethylbenzoyl)benzoyl, 43 32, 35, 39, 60, 92, 94, 115, 170, 172,
Chromium tricarbonyl complex of,4,4- 180, 187,244,247,248,252
dimethyl-2-( 4-tolyl)oxazolidine, influence of
171 connecting link structure, 85-87, 253
Cobalt (III) amine complexes, car- intramolecular hydrogen bond, 261
binolamine formation, 136 solvents, 40, 60, 62, 65, 100, 173, 184,
Covalent hydration of 192, 197,265
2-alkyl-3,4-dihydroisoquinolinia, 118 substituent in connecting link steric
2-aryl-3,4-dihydroisoquinolinia, 118 effect, 257
l-arylpyridinia, 118 substituent electronic effects, 87, 243
azaheterocycles, 117 substituent steric effects, 87, 250
2-(2,4-dinitrophenyl)isoquinolinium, 119 temperature, 40,267
pteridines, 120 Ergotamine, 141
tetrazolo/ l,5-c/ quinazolines, 119 Erythromycin, 113
1,3,6-triazanaphthalenes, 120 Erythronolide B, 113
1,3-Cyclohexanedione,4-(2-hydroxyben- Ester
zoyl), 104 Z-3-acylacrilic, 87
Cyclohexanone 2-acylbenzoic, 5, 87
4-aminomethyl, 121 4-acylcarboxylic, 88
4-(2-amino-2-propyl), 121 acylcarboxylic acid, C=O band frequen-
2-( w- hydroxyalkyl), 101 cies, 88
2-(2-hydroxybenzyl), 104 3-acylpropionic, 87
Cyclols, 140 hydrolysis, 91
274 Index
Ester (cont.) 2,4-pentanedione thiobenz, 203

2-isocyanatobenzoic acid trimethylsilyl, phenylthioacetyl, 203
204 N\-thioacyl, 202
(2-phenyl-I,3-indanedione-2-yl)acety- thiobenz, 203
lamino acid, 64 Hydrogen bond
Ethylene intermolecular, 11,29,30,53,56,66,68,
Z-I-amino-2-(2-oxoacyl), 123 73, 112, 125, 132, 173,227, 265
E-I,2-diacyl-I,2-dihydroxy, III intramolecular, 11,51, 107, 110, Ill, 113,
diamine, N-methyl, 188 114,201,261
Hydroxyacyl incorporation into peptides, 4,
Fischer-Speier esterification, 9, 90 141
Formoine, diacyl, III Hydroxylamine
Furan, 2-hydroxy-2,5-dihydro, 104 N-arylcarbamoyl-N-(I-oximino-2-methyl-
3-Furanidone,4-(2-hydroxybenzylidene)- 2-propyl), 196
2,2,5,5-tetramethyl, 105 N-methyl-N-(tetrahydro-2-pyranyl), 182
Furanone O-(3-0xoalkyl), 135
5-chloro-5-methyl-2,5-dihydro-2-, 35 Hypophosphite, hydroxyneopentyl, 226
2,5-dialkyl( or diaryl )-2,4-dihydroxy-3-,
III Imidazole
Furol 2,3-bI indole,2,3,3a,8a-tetrahydro, 2-S-acylalkylmercapto, 130
187, 199 5-S-acylalkylmercapto-4-nitro, 130
Imidazolidine, 1,3-dimethyl, protonation,
Glyoxal,2-hydroxyphenyl, 104 189
Imidazoline
Hantzsch synthesis, 136 2-S-acylalkylmercapto, 130
1,3,4,6-Hexanetetrone, 112 2-aroylphenyl, 130
2-Hexanone, 6-hydroxy, 99 Imidazoline-3-oxide, l-hydroxy-il 3 , 196
Hooker reaction mechanism, 150 Imidazolinium, 2-S-acylalkylmercapto-l-
Hydantoin, l-salicyloyl-3-ethyl, 144 methyl, 130
Hydrazide Imidazolol I ,2-bl isoquinoline-5, I O-dione,
Z-3-acylacrylic acid, 81 76
2-acylbenz, 77 Imide
anthraquinone-I-carboxylic acid, 80 N-ethylphthal, 67
(2-benzyldimedone-2-yl)acet, 67 N-methylglutar, 82
cyanocarboxylic acid, 212 Imine
(2-phenyl-I,3-indanedione-2-yl)acet, 64- 1,5-diketone mono, 135
66 f:l-ketoester N-hydroxyalkyl, 175
Hydrazone N-hydroxyalkyl, 169
N-(a-alkylaminoacyl), 192 4-hydroxybutanal, 183
cyanoketone, 212 6-hydroxy-2-hexanone, 183
1,3-dicarbonyl compound, 135 5-hydroxypentanal, 183
D-glucose, 184 5-hydroxy-2-pentanone, 183
N-(a-hydroxyacyl), 192 1,3-Indanedione
N-(2-hydroxyalkyl), 176 2-12-( N-cyclohexyl)aminoethylj -2-
4-hydroxybutanal, 184 phenyl, 121
N-(2-hydroxyiminoalkyl), 193 2-guanidino-2-substituted, 127
6-hydroxy-2-hexanone, 184 2-(2-nitroethyl)-2-substituted, 121
5-hydroxypentanal, 184 2-thioureido-2-substituted, 127
5-hydroxy-2-pentanone, 184 2-ureido-2-substituted, 127
N-(2-mercaptoalkyl), 200 Indoline, 2-hydroxy, 122
Index 275
Iodinane acidity, 50
chloro, 236 association, 56
hydroxy, 236 IR spectra, 54
Isatin N-hydroxyacyl, 141
dithiocarboxyhydrazones, 148 polyamino, 145
thiobenzoylhydrazones, 148 f:l-, N-sulfochlorides, 144
a-thiosemicarbazones, 148 N-thiosalicyloyl, 143
I-Isochromanone,3-methoxy-3,4,4- valero
trimethyl, 37 N-glycolyl, 142
Isocoumarine, 46 N-(3-hydroxypropionyl), 142
3-aryl, 83 N-salicyloyl, 142
3-chloro-4-oxo-3-phenyl-3,4-dihydro, 45 Lactol, 19
3-methyl 83 Lactone,
3-phenyl, 221 acyloxy, 20, 96
Isocyanate, 2-trimethylsiloxy.phenyl, 204 alkoxy, 20, 22, 90
Isoindoline, I-hydroxy, 122 chloro, 19,41
Isoindolinone reactions with nuc1eophiles, 46
2-( t-alkyl)-3-aryl-3-chloro, 72 hydroxy, 19
3-amino-3-aryl, 194 imino, 212
3-aryl-3-chloro, 194
3-aryl-3-hydroxy, 72 Maleylacetone, 36
3-hydroxy, 68 Melting points, double, 15,64, 211
3-imino, 5, 213 Mercaptane, S-(2-hydroxyalkyl)-S-(2-
3-nitromethyl-3-phenyl, 222 oxoalkyl), 102
Isoindolinthione, 3-imino, 215 Methane
Isoimide, 212 bis-(1,3-cyc1ohexanedione-2-yl), 110
Isomerism Z-E, 35, 81 bis-( cyc1ohexanone-2-yl), 108
I-Isoquinolones, 83 Methods of investigation of ring-chain
3-Isoquinolones, 84 tautomerism
3-Isoxazolidinone, 5-hydroxy-4,4- chemical, 8
diisopropyl, 116 chromatographic, 14
Isoxazoline, 5-hydroxy-~2, 114 mass-spectrometric, 13
molar refractivity measurements, 14
Ketones, 3-hydroxyimino, 114 polarographic, 14
potentiometric titration, 15, 21, 22
Lactam spectroscopic,
amino, isomerization with ring-opening, IR, 11,21,23,30,51
195 NMR, 11,23
N-3-aminopropyl, 145 UV, 10,22
butiro visible, 10
N-glycolyl, 142 X-ray diffraction analysis, 13
N-(3-hydroxypropionyl), 142 Migration, intramolecular
N-(2-methylaminobenzoyl), 142 acyl and other group, 4, 8, 136, 139
N-salicyloyl, 142 nitroaryl group, 139
capro Mononitrile
f:l-carboxymethyl, 146 homophthalic, 212
N-salicyloyl, 142 phthalic, 212
f:l-carboxy, 146 Mutarotation
f:l-carboxymethyl, 1-46 aldose, ketose, 21
hydroxy, 19 glucose, 98
276 Index
Naphthaline, 1,8-( 1,8-naphthalyl), deriva- 4-amino-2-methylamino-2-methyl, 189

tives, 113 2,4-diamino-2-methyl, 189
Naphthol 1,2-d/imidazole, 2-S-acylalkylmer- 2-Pentanone
capto, 130 5,5-dinitro, 116
1,4-NaphthoQuinones, 2-(2-hydroxypheny- 5-hydroxy, 99
lamino), 106 Peptide, 140
I H- Naphthl 1,2-el -I,3-oxazines, 2,4-diaryl- Perimidine, 2-S-acylalkylmercapto, 130, 132
2,3-dihydro, 173 Perinaphthalide
Nitramide, decomposition, 21 3-alkylamino-3-phenyl, 187
Nitrile 3-arylamino-3-phenyl, 187
amino, 212 3-chloro-3-phenyl, 47
l3-hydrazino, 212 Phenole, 4-alkyl-2,6-bis(phosphorany-
hydroxy, 212 lideneamino), 233
2-hydroxymethylbenzo, 212 Phosphate
'Y-mercapto, 217 o-hydroxyphenyl-o-phenylene, 226
2-thioureidobenzo, 211 2-iodosophenyl, 236
Nitrone Phosphorane
aryl-N-(2-hydroxyalkyl), 180 chloro, 229
a-( 4- hydroxybutyl)- N-methyl, 182 hydroxy, 226, 227
N-(anti-2-hydroxyiminoalkyl), 197 2-hydroxyphenylimino, 13,230
N -(syn-2-hydroxyiminoalkyl), 181 hydroxy-bis-o-phenylenedioxy, 226
N-(anti-3-hydroxyiminoalkyl), 197 Phthalane,3-hydroxy, 103
N-(anti-2-hydroxyiminocycloalkyl)-a- Phthalazine, 2-(2-formylbenzoyl)-l-
methyl, 197 hydrazono-I,2-dihydro, 135
N-(2-hydroxy-l-naphthyl)methyl, 181 Phthalide
3-acetoxy-3-phenyl, 97
3-arylamino-3-phenyl, 10, 186
Orbital steering, 254 3-aryl-3-chloro, 6, 68
Oxacyclols, 140 3-benzoyl-3-chloro, 45
1,3,4-0xadiazines, perhydro, 176 3-benzylidene, 221
4H-I,2,5-0xadiazines, 5-hydroxydihydro, 3-bromomethyl-3-hydroxy, 31
181 9-chloro-9,10-dihydroanthrylidene, 43
1,3-0xazaheterocycles, N-methylated, 174 3-chloro-3-phenyl, 9, 97
1,3-0xazepine, hexahydro, 171 3-chloro-3-(2-pyridylcarbonyl), 45
1,3-0xazine, tetrahydro, 171 3,3-dichloro, 47
1,3-0xazolidine, 4,4-dimethyl-2-phenyl, 3-hydroxy, 28
170, 173 3-hydroxy-3-methyl, 28, 31
Oxethane, 151 3-nitromethyl, 222
Oxime 3-phenylamino-3-phenyl, 68
2-aryl-2-benzoyl-I,3-indanedione, 115 Physostigmine, 199
1-aryl-2-phenacyl-I,3-indanedione, 115 Physovenin, 187
6-hydroxy-2-hexanone, 185 Pinacol, triftuoroacetete, 137
5-hydroxy-2-pentanone, 185 Piperazine, N-(a-hydroxyacyl)diketo, 142
anti-a-hydroxylamino, 196 4-Piperidone, I-methyl, 110
syn-a-hydroxylamino, 181 Propane
S-hydroxypentanal, 185 l-benzylideneamino-3-t-butylamino, 189
1,3-diamino, 189
Pearson's HSAB concept, 230 1,3-Propanedione, 1-(2-hydroxyphenyl),
Pentanal, 5-hydroxy, 99 104
Pentane Propene,2-nitro-l-phenyl-I-, 116
Index 277
Pseudoacid, chloride, 19 Steric assistance effect, 72, 259

Pseudoester, 19 Stereopopulation control, 27, 254
Purine, 8-S-acylalkylmercapto, 130 Sulfinamide,2-benzoylbenzene, 128
Pyrane, 2-arylaminotetrahydro, 183 Sulfonamide
2-Pyranone,6,6-dimethyltetrahydro, 221 2-acylbenzene, 127
Pyrido-2,3-b/indole, 1,2,3,4,4a,9a- 2-aroylbenzene, 128
hexahydro, 199 2-benzimidoylbenzene, 193
2( I Hl-Pyridone, 2-cyanobenzene, 216
5-carboxy-6-(2'-oxocyclohexyllmethyl, 2-iodosobenzene, 236
129 Sulfoxide
3-hydroxy-6-(3' -oxoalkyll, 129 o-carboxyphenyl methyl, 234
3-hydroxy-6-( 2' -oxocycloalkyl lmethyl, o-carboxyphenyl phenyl, 234
129 Sulfurane
Pyrimidine, chi oro, 234
2-S-acylalkylmercapto-3,4,5,6-tetrahydro, hydroxy, 233
130
4-amino-5-aminomethyl- 2-methyl, Tautomerism
(or phenyll, 189 acylotropic, arylotropic, 139, 259
1,3-dimethylperhydro, protonation, 189 azide-tetrazole, I
hexahydro, 189 keto-enol, 263
5-nitro-I,2,3,4-tetrahydro, protonation, ketolo-Iactolic, 98
190 oxo-cyclo, 98
Pyrimidine-3-oxide, l-hydroxy-I,2,5,6- Tetrahedral intermediate, cyclic, 136
tetrahydro, 198 Theophilline,8-S-acylalkylmercapto, 130
Pyrimidine-2-thione, 4-hydroxyhexahydro, Thiacyclols, 140, 143
125 1,3,4-Thiadiazine, perhydro, 200
Pyrrolo/2,3-b/indole, 2,3,3a,8a-tetrahydro, 1,3,4-Thiadiazino/ 5,6-b / indole, 9b-hydroxy,
199 148
3-Quinazolinone (and thionel 4-hydroxy- 1,4,5-Thiadiazoline, 3-acyl-2-hydroxy-5-
1,2,3,4-tetrahydro, 126 phenyl, 148
1,3-Thiazepine, hexahydro, 200
Rearrangements 1,3-Thiazine, tetrahydro, 200
acylotropic, 139 1,3-Thiazine-4-one, 2-chloro-5,6-dihydro,
arylotropic, 139 219
Grignard reagent cyclization cleavage, 1,3-Thiazine-2-thione
223 4-hydroxytetrahydro, 127
Recyclization, of pyridine derivatives, 119 6-hydroxy-4,4,6-trimethyl, 148
Ring contraction Thiazolidine-2-thione, 5-hydroxy, 147
chlorolactone, 45 Thiazolinia,4-hydroxy, 136
5,6-dihydro-I,4-thiazine, 200 Thiophene
hydroxylactam, 78, 79 amino, 218
Selenurane, 235 iminodihydro, 218
Semicarbazone Thiosemicarbazone, 202
acetone 2-phenyl, 191 Thiosemicarbazone-S,S,S-trioxide, 2-methyl,
acetophenone 2-phenyl, 191 192
4-alkyl-2-phenyl, 191 Thiourea
2,4-dimethyl, 191 N-(3-oxoalkyll-S-methyl, 126
Shielding effect on C=O group of N-(3 -oxoalkyl)- N' -substituted, 125
anthryl group, 43, 252 Thorpe-Ingold effect, 27, 37, 114, 134, ISO,
mesityl group, 43, 252 224, 228, 257, 261
278 Index
Transacylation, intramolecular, 136, 140 1,2,4-Triazolidin-3-one, 191

Transannular interaction, 146 1,2,3-Triazoline, 5-hydroxy-a 2 , 133
Triazene, \-(2-oxoalkyI), 133
1,2,4-Triazin-5-one, 3-S-acylalkylmercapto- Urea, N-(anthraquinone-l-yI)-N' -phenyl,
6-methyl-2,5-dihydro, 130 126
1,2,4-Triazin-6-one, perhydro, 193
1,2,4-Triazole, 3-S-acylalkylmercapto, 130 Zip-reaction, 146

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RING-CHAIN

PLENUM PRESS • NEW YORK AND LONDON

© 1985 Plenum Press, New York

which should help to appraise unknown ring-chain tautomeric equilibria

2. Intramolecular Reversible Addition Reactions to the

2.3.8. Triazenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

3. Intramolecular Reversible Addition Reactions to the

4. Intramolecular Reversible Addition Reactions to Other

5. Generalizations Concerning the Influence of Structural

5.1. Structural Influences ........................................ 243

1.1. RING-CHAIN ISOMERIC INTERCONVERSIONS. GENERAL

The problem of ring-chain isomeric interconversions of organic com-

Ring systems which are formed in this way contain (0 - 2) 7T-electrons.

Many other examples of such valence isomerism are known [4,9,10].

As in the case of electrocyclic reactions, a 1T-bond is transformed into a

I) Structural influences such as the polarity of Q- X and Y =Z bonds,

These regularities of ring-chain tautomerism are of great significance

chain - [ring] - chain

ring - [chain] - ring

Familiar examples of the first scheme comprise a) intramolecular catalysis

1.2. TAUTOMERISM OR ISOMERISM? SYSTEM MOBILITY

Ring-chain isomeric interconversions are often referred to as ring-chain

Small modifications of the structure of substituents at interacting func-

cyclic 3-aryl-3-chlorophthalide (8), whereas 2-(2,4,6-trimethylbenzoyl)ben-

Recently Zefirov and Trach [10], in considering general problems and

t A. Ihde, J. Chern. Educ. 1959, 36, 330.

adjustment of the equilibrium affords more drastic conditions such as

and its energy profile (Fig. I).

1.3. METHODS OF INVESTIGATION OF RING-CHAIN

Chemical and physical methods of the investigation of the tautomerism

1.3.1. Chemical Methods

[1,3,11,49]. A solely chemical approach for this purpose is unreliable and

When aniline is used as a nucleophile, the attack proceeds at both

1.3.2. Visible and UV Spectroscopy

The second model compound, i.e., 3-(N,N-diphenylamino)-3-

1.3.4. Nuclear Magnetic Resonance

tive determination of equilibrium mixtures. Commonly this method deals

In the estimation of ring-chain equilibrium constants of 2-hydroxy-

1.3.5. Mass Spectrometry

1.3.6. X-Ray Diffraction Analysis

Dunitz [80-82] who suggested that structural information, mainly obtained

1.3.8. Other Physical Methods

42. K. Bowden and G. R. Taylor, J. Chem. Soc., Sect. B 1971, 1395.

2.1. ALDEHYDO- AND KETO-CARBOXYLIC ACIDS

Ring-chain isomeric interconversions proceeding by intramolecular

-:;::-0 °II -:;::-0

Some of the possible connections (a)-(h) of two mutually interacting

2.1.1. Aldehydo- and Keto-carboxylic Acids

Solutions of the methyl substituted levulinic acids in the solvents of

C=o O=C C=O (c=O

(18) (18) .. ·(18)

The authors [19] suggested that the ring-chain equilibrium constantt

constants of carboxylate anions and the dissociation constants of the corre-

Table 1. C=O Band Frequencies in IR Spectra of 3-Acylcarboxylic Acids (la--c)

H CCI 4 1749 I7I I 1795 30

H, "" H (KBr) 1795,1761 35

hydrochloric acid caused fast interconversion of the tautomers and the

Table 2. Protolytic and Tautomeric Rate Constants of 3-Acylcarboxylic Acids

2,2,3-Trimethyllevulinic 9 l.15 X 108 9.3 X 104 6.5 X 105 6.9