36
Y. Nomura et al. / Bioorganic Chemistry 32 (2004) 26–37
fit the straight lines for the aryl esters. This result further confirms the critical role of
the basicity of leaving group in determining the magnitude of a-effect.
With the reactions involving a poor leaving group (the methyl esters and mono-
fluoroethyl esters), however, the removal of leaving group from the carbonyl carbon
atom is rate-limiting (the dashed line in Fig. 4A) and a tetrahedral intermediate is
formed in pre-equilibrium. The reaction rate is mostly governed by the basicity of
leaving group, and the plot of log k1 vs. pKa is accordingly steep (the closed circles
in Figs. 1A and B). Under these conditions, the pre-equilibrium concentration of
the tetrahedral intermediate is little affected by the ‘‘a-effects’’ in nucleophiles. Even
though the pre-equilibrium formation of this intermediate is accelerated by the lone-
pair electrons in the a-position, the backward reaction is also accelerated in the same
magnitude. Consistently, the rate constants for the cleavages of methyl esters and
monofluoroethyl esters by HOꢀ (k2) are even larger than those by HOOꢀ (k1), re-
flecting directly the difference in intrinsic nucleophilicity between HOꢀ and HOOꢀ.
The substituent in the acyl portion of substrate (benzoates in this study) alters the
electrophilicity of the carbonyl carbon and thus affects the nucleophilic attack by
HOOꢀ and HOꢀ (and other nucleophiles) in a similar extent to each other. As the
result, the magnitude of a-effect is almost independent of the structure of acyl group.
We have argued above the origin of a-effects simply in terms of a stepwise reaction.
However, there is also a possibility that the reactions are concerted ones without very
stable tetrahedral intermediates. It is not very clear at present, which is really the case.
However, the arguments on the origin of a-effects are unchanged in either of the cases.
Acknowledgments
This study was partially supported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sport, Culture and Technology, Japan.
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