The Importance of Methyl Positioning and Tautomeric Equilibria for Imidazole Nucleophilicity.

Imidazole (IMZ) rings catalyze many biological dephosphorylation processes. The methyl positioning effect on IMZs reactivity has long intrigued scientists and its full understanding comprises a promising tool for designing highly efficient IMZ-based catalysts. We evaluated all monosubstituted methylimidazoles (xMEI) in the reaction with diethyl 2,4-dinitrophenyl phosphate by kinetics studies, NMR analysis and DFT calculations. All xMEI showed remarkable rate enhancements, up to 1.9×10 ⁵ fold, compared with spontaneous hydrolysis. Unexpectedly, the electron-donating methyl group acts to decrease the reactivity of the xMEI compared to IMZ, except for 4(5)methylimidazole, (4(5)MEI). This behavior was attributed to both electronic and steric effects. Moreover, reaction intermediates were monitored by NMR and surprisingly, the reactivity of the two different 4(5)MEI tautomers was distinguished.
(© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)