✍ Scribed by Thomas H. Fife; Milton H. Werner
No coin nor oath required. For personal study only.
The kinetic and mechanistic effects of substitution in the leaving group of N-acylimidazoles in Ͱ-chymotrypsin-catalyzed hydrolysis reactions have been investigated. The values of k 2 /K m have been determined for acylation of the enzyme by a series of N-(3,3-dimethylbutyryl)-4(5)-substituted imidazoles at 30ЊC. The plot of log k 2 /K m vs pH for acylation by N-(3,3dimethylbutyryl)-4(5)-nitroimidazole has regions of slope 1.0 and 0 with a pK app of 6.5, in contrast with the nearly pH-independent profiles for N-acylimidazoles without electronwithdrawing substituents in the leaving group. The effect of electron withdrawal is to lower the pK a of the conjugate acid of the N-acylimidazole, which thereby restricts the acylation reaction of that species. The pH independence of the acylation reactions of N-acylimidazoles without electron withdrawal in the leaving group must reflect reactions of the neutral and protonated species that proceed with similar rate constants. The pK app of 6.5 is constant through wide structural variations and is therefore not due to the kinetics of the reaction, but is very likely the pK a of the conjugate acid of His-57. There is only a small effect of the pK a of the leaving group in the acylation reactions with ͱ 1g ϭ Ϫ0.3. Therefore, there can only be moderate C-N bond breaking in the critical transition state. A plot of log k 2 /K m vs m , the Hammett substituent constant for meta substituents, is linear with a slope, , of 2.6 (r ϭ 0.98). When para substituent constants are employed the value is 2.1. The effect of substitution in the leaving group is nearly identical in the enzymatic acylation reaction and in the OH Ϫ -catalyzed hydrolysis of these compounds in regard to the values of and ͱ 1g . Thus, the transition states in the two reactions must be similar in regard to the extent of C-N bond breaking and C-O bond formation with the nucleophile. The transition state very likely resembles the reactants.
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