Page 34 - Advanced Organic Chemistry Part B - Reactions & Synthesis

6 by kinetic control when the product composition is determined by the relative rates of
the competing proton abstraction reactions.
CHAPTER 1
Alkylation of Enolates –
and Other Carbon O
Nucleophiles
R C CCH R'
2
2
k
O a A
[A] k a
R CHCCH R' + B – [B] = k b
2
2
k b O –
R CHC CHR'
2
B
Kinetic control of isomeric enolate composition
By adjusting the conditions of enolate formation, it is possible to establish
either kinetic or thermodynamic control. Conditions for kinetic control of enolate
formation are those in which deprotonation is rapid, quantitative, and irreversible. 8
This requirement is met experimentally by using a very strong base such as LDA
or LiHMDS in an aprotic solvent in the absence of excess ketone. Lithium is a
better counterion than sodium or potassium for regioselective generation of the kinetic
enolate, as it maintains a tighter coordination at oxygen and reduces the rate of
proton exchange. Use of an aprotic solvent is essential because protic solvents permit
enolate equilibration by reversible protonation-deprotonation, which gives rise to the
thermodynamically controlled enolate composition. Excess ketone also catalyzes the
equilibration by proton exchange.
Scheme 1.1 shows data for the regioselectivity of enolate formation for several
ketones under various reaction conditions. A consistent relationship is found in these
and related data. Conditions of kinetic control usually favor formation of the less-
substituted enolate, especially for methyl ketones. The main reason for this result is
that removal of a less hindered hydrogen is faster, for steric reasons, than removal
of a more hindered hydrogen. Steric factors in ketone deprotonation are accent-
uated by using bulky bases. The most widely used bases are LDA, LiHMDS, and
9
NaHMDS. Still more hindered disilylamides such as hexaethyldisilylamide and bis-
(dimethylphenylsilyl)amide 10 may be useful for specific cases.
The equilibrium ratios of enolates for several ketone-enolate systems are also
shown in Scheme 1.1. Equilibrium among the various enolates of a ketone can be
established by the presence of an excess of ketone, which permits reversible proton
transfer. Equilibration is also favored by the presence of dissociating additives such as
HMPA. The composition of the equilibrium enolate mixture is usually more closely
balanced than for kinetically controlled conditions. In general, the more highly substi-
tuted enolate is the preferred isomer, but if the alkyl groups are sufficiently branched as
to interfere with solvation, there can be exceptions. This factor, along with CH /CH 3
3
steric repulsion, presumably accounts for the stability of the less-substituted enolate
from 3-methyl-2-butanone (Entry 3).

8
For reviews, see J. d’Angelo, Tetrahedron, 32, 2979 (1976); C. H. Heathcock, Modern Synthetic
Methods, 6, 1 (1992).
9 S. Masamune, J. W. Ellingboe, and W. Choy, J. Am. Chem. Soc., 104, 5526 (1982).
10
S. R. Angle, J. M. Fevig, S. D. Knight, R. W. Marquis, Jr., and L. E. Overman, J. Am. Chem. Soc.,
115, 3966 (1993).