Cope et al.
JOCArticle
stabilization, and eventual reaction have led to extensive
1
studies probing the nature of this reactive intermediate.
SCHEME 1. General Base-Catalyzed Enolization in D O
2
7-38
A primary theme of the work completed to date has been the
determination of the effect of substituents in positions R1
and R (see Structure 1) on the rate constants of enolate
2
production, and these results have led to a general under-
standing of the substituent effects. One area that has proved
more difficult to investigate has been the effect of ring strain
on the generation and reactivity of enolates in cyclic ketones.
Such a system is of fundamental interest as it incorporates
structural features that are often invoked to help explain
two prior studies have investigated a series of cyclic ketones, and
both studies concluded that cyclobutanone was significantly
45,46
more reactive than the other cyclic ketones.
In contrast to
these earlier results, our studies showed that sensitivity of
cyclobutanone to a general base catalyst was similar to that
3
9,40
some of the catalysis achieved by enzymes.
Two factors
47
that are often discussed as possible contributors in the
observed efficiency of some enzymes are the induction of
strain and restriction of mobility (both conformational and
found for acetone and a phenylacetone derivative. These
4
7
results pointed to a conclusion that ring strain did not have an
apparent effect on the reactivity of cyclobutanone vs that of
45,46
other ketones, contradicting the results of other studies.
3
9,40
rotational).
cycle is alleviated by an increase in the s-character of the
For example, bond angle strain in a carbo-
The question of why cyclobutanone (2) has not been as
thoroughly investigated as other ketones was not due to a
lack of interest in the compound itself but rather to experi-
mental limitations of the halogenation technique that was
the primary method used to follow enolate generation in
carbon component of the C-H bonds leading to an increase
4
1
in the acidity of these hydrogen. Also, in carbocyclic
compounds, the rotational degrees of freedom of the R-
carbon are reduced, decreasing entropic considerations for
4
2-44
27
alignment of orbitals during proton removal.
In fact,
solution. Problems, such as relative rates of enolate gen-
eration vs halogenation and enhanced reactivity of the
halogenated product relative to that of starting material
which led to byproducts that further consumed halogen,
restricted the structural diversity of the carbonyl derivatives
(
17) Urwyler, B. D.; Wirz, J. Angew. Chem., Int. Ed. Engl. 1990, 29,
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7
(
27
that could be studied. However, the development of methods
and procedures for the investigation of reactive intermedi-
ates has broadened the spectrum of compounds that can
now be studied. One procedure, developed by Richard and
(
8
(
(
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1
(
co-workers, utilizing H NMR as a means of following
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(
1
9-22,24,25,36,37,48-51
4
1
2
to be quite versatile.
In general, these
(
24) Nagorski, R. W.; Mizerski, T.; Richard, J. P. J. Am. Chem. Soc. 1995,
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experiments were performed in deuterated solvents with
the progress of the reaction being measured by the fraction
of deuterium incorporation into the R-position of the start-
ing material (or loss of deuterium). The method is predicated
upon the idea that if the carbanion is stable enough to
separate from the conjugate acid of the base that removed
the proton (free intermediate in solution), then the proton
removed from the carbon acid will mix with the bulk
deuterated solvent. As a result, when the carbanion/enolate
reacts with an acid source, a deuteron will be added (see
Scheme 1). A major advantage to this method was that it
did not lead to significant modification of the reactivity of
the substrate, relative to that of its protonated state, making
the method ideal for the investigation of compounds with
more complex reactivity patterns. Also, by comparing the
rate constants for deprotonation between structurally simi-
(
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