Hydrolysis of Imidazole-Containing Amide Acetals

Article abstract of DOI:10.1021/ja00346a046

N-(Dialkoxymethyl)imidazoles (amide acetals 1a-c) are shown to hydrolyze by a common mechanism between pH 1 and pH 11 that involves preequilibrium protonation of the imidazole distal N, followed by rate-llimiting C - N cleavage.The Broensted plot of the log C - N cleavage rate vs. pK_a of the parent imidazole has a slope of -1.0 and suggest a transition sate in which (+) is nearly completely transferred to the departing dialkoxymethyl group.Throughout the pH range studied, C - N cleavage is the dominant process.The bicyclic amide acetal 2 formed from 4(5)-(hydroxyethyl)imidazole and triethyl orthoformate behaves similarly to the acyclic cases at pHs > 5 except that the observed rate of C - N cleavage for the former is depressed by (1 - 2) x 10²-fold.This apparent reduction of C - N cleavage rate is analyzed in terms of reversibility of the ring opening.Such reversal is demonstrated by the ability of good nucleophiles such as N3^- or H2NOH to trap the open ion, preventing reversal and hence increasing the apparent rate of loss of 2.From pH 0 to pH 5, an additional sigmoidal event in the pH/log k_obsd profile for 2 is observed, which is analyzed as a protonation of the imidazole of the open ion.Such a protonation prevents the reversible reclosure and concomitantly increases the k_obsd.Bicyclic 2 can be taken as a model for the tetrahedral intermediate formed during intramolecular alcoholysis of an N-acylimidazole or intramolecular attack of an imidazole on an ester.