Formimidoyl group transfer from activated amidines. Part 1. Hydrolysis of 1-(N-t-butylformimidoyl)imidazole and related imidazole-containing formamides

Abstract

The hydrolysis of 1-(N-t-butylformimidoyl)imidazole (7a) to t-butylformamide and imidazole has been examined in the absence of buffer species at 25° in water. The rate of hydrolysis was pH-independent at pH 7–14 and reaction in this region is shown to occur via HO^– attack on the protonated substrate (whose pK_a is 5.0; protonation site, imidazole nitrogen). Alternative mechanisms such as H₂O attack on the neutral substrate and reaction via the zwitterion (15) were eliminated using solvent isotope effect, deuterium labelling, and substituent effects. Below pH 6 acid catalysis of hydrolysis is observed due to H₂O reaction with the protonated substrate (pH 4–6) and with the diprotonated substrate (pH 0–4); at pH 0, t_½ for hydrolysis is < 10^–2s. The N-arylformamidines (7b) and (7c) react via similar acid catalysed pathways but a new reaction (identified as HO^– attack on the amidine) occurs in base, in preference to the pH independent pathways. p-Nitrophenylformamide [formed from (7c)] is itself hydrolysed in basic solution so that complex kinetics result. The C-substituted amidines (7e) and (7f) react 10⁴–10²-fold more slowly than the corresponding formamidines. Buffer catalysis of the hydrolysis of (7a) by phosphate and amines is complex, the slope of K_obs.versus[buffer] plots being greater at low than at high buffer concentrations. This is consistent with the formation of a tetrahedral intermediate in the reaction pathway whose formation and beakdown is subject to general acid–base catalysis.