Steric Effects in the Hydrolysis Reactions of N-Acylimidazoles. Effect of Aryl Substitution in the Leaving Group.
The kinetic and mechanistic effects of aryl substitution in the leaving group have been determined in the hydrolysis reactions of N-acylimidazoles. N-Acyl derivatives of 2,4,5-triphenylimidazole hydrolyze rapidly in OH(-) and water reactions. The latter reactions are pH independent from pH 4 to 9. The N-acetyl derivative hydrolyzes with rate constants similar to those of N-acetylimidazole in the OH(-) reaction but 40-fold larger in the pH-independent reaction. N-(trimethylacetyl)-2,4,5-triphenylimidazole hydrolyzes at 15 degrees C with k(OH), the second-order rate constant for the OH(-) reaction, 26-fold larger than the rate constant for alkaline hydrolysis of the corresponding N-acetyl derivative, even though steric hindrance to approach of a nucleophile is extreme in the former reaction. The pH-independent reaction of the N-trimethylacetyl compound is 4-fold faster than that of the N-acetyl derivative and is characterized by a D(2)O solvent isotope effect (k(H)2(O)/k(D)2(O)) of 2.0. A phenyl substituent in the 2-position of the imidazole ring exerts a small rate-retarding effect in the hydrolysis reactions. N-(Trimethylacetyl)-4,5-diphenylimidazole hydrolyzes 10- and 55-fold faster in the OH(-) and water reactions, respectively, at 15 degrees C, than N-(trimethylacetyl)benzimidazole at 30 degrees C, although the pK(a) of the leaving group is identical in the two cases. The additive nature of the steric rate-accelerating effects in the acyl group and the leaving group indicates an effect on the ease of C-N bond breaking; the hydrolysis reactions very likely proceed in a concerted manner without the formation of a stable tetrahedral intermediate.
Lee
J. P.
JP
Department of Biochemistry, University of Southern California, Los Angeles, California 90033.
Bembi
Ramesh
R
Fife
Thomas H.
TH