TIMING OF THE PROTON-TRANSFER PROCESS IN ACID-CATALYZED CARBONYL ADDITION - EVIDENCE FOR A PREASSOCIATION MECHANISM FOR CATALYSIS OF CARBINOLAMINE FORMATION FROM ACETHYDRAZIDE AND PARA-CHLOROBENZALDEHYDE

General acid catalysis of carbinolamine formation from acethydrazide (CH3C(0)NHNH2) and p-chlorobenzaldehyde in aqueous solution probably occurs by a “preassociation” mechanism that involves rate-determining attack of the nucleophile on the aldehyde in the presence of the acid catalyst in a termolecular encounter complex, and rate-determining diffusion apart of the protonated carbinolamine and the conjugate base of the catalyst, in limiting cases of strongly and weakly acidic catalysts, respectively. Unlike amines of even slightly greater basicity, acethydrazide does not add to p-chlorobenzaldehyde by a mechanism involving a kinetically significant free zwitterionic carbinolamine (T±). The data are most consistent with a mechanism in which there is a small amount of stabilization of the transition state for amine attack, and of the initial product of this attack, by hydrogen bonding of oxygen to strongly acidic catalysts. Evidence in support of the proposed mechanism includes (1) the absence in the pH-rate profile of a break at low pH corresponding to a change from rate-determining hydronium ion catalyzed protonation to uncatalyzed formation of T± (2) the absence of any detectable effect of increased solvent viscosity (50% aqueous glycerol) on the rate constants for catalysis by heterocyclic ammonium ions, and (3) a nonlinear BrjJnsted plot for general acid catalysis, with limiting slopes of ca. 0.11 for strongly acidic and ≥0.8 for weakly acidic catalysts. In contrast, the triazolium ion catalyzed reaction of methoxyamine (CH3ONH2) with p-chlorobenzaldehyde, which is known to involve rate-determining diffusion-controlled protonation of free T±, is inhibited by a factor of approximately 12 in 50% aqueous glycerol. © 1979, American Chemical Society. All rights reserved.