Catalysis of the Methoxyaminolysis of Phenyl Acetate by a Preassociation Mechanism with a Solvent Isotope Effect Maximum’

General-acid catalysis of the reaction of methoxyamine with phenyl acetate by the proton, carboxylic acids, and ammonium ions follows a nonlinear Bransted curve. This curve agrees quantitatively with the behavior expected for the enforced preassociation mechanism of catalysis that was predicted for this reaction. The stronger acids, including the proton, follow a Bransted slope of a = 0.16 that represents rate-limiting amine attack assisted by hydrogen bonding, weaker acids react with partially rate-limiting proton transfer to the addition intermediate T*, and the weakest acids follow a steeper Bransted slope approaching a = 1.0 that represents rate-limiting separation of the conjugate base from the protonated intermediate T+. There is no decrease in the rate constant for catalysis by chloroacetic acid with increasing viscosity in water-glycerol mixtures; a decrease is observed for the reaction of methylamine with p-tolyl acetate catalyzed by acetate buffers, which is believed to proceed by a diffusion-controlled trapping mechanism. A sharp maximum in the solvent isotope effect at pKm = 6.8 confirms the kinetically significant proton-transfer step in the intermediate region near ApK = 0. The decrease with stronger acids represents a decrease in the isotope effect for this proton-transfer step, which is largely rate limiting for acids of pK, = 4-7, but the decrease with weaker acids can be explained by the change to rate-limiting diffusional separation of T+ and A-. Two explanations are offered for the decreased isotope effect with increasing acid strength. (1) There is a sharp change to an asymmetric structure of the transition state for the very rapid proton-transfer step, as suggested by Melander and Westheimer. (2) There is a shift to a rate-limiting change in solvation that occurs immediately either before or after the proton-transfer step with stronger acids. It is possible to fit the observed Bransted curve and isotope effect maximum with calculated rate constants that are based on a rate law and estimated rate constants for the steps of the latter mechanism. We describe here evidence that the reaction of methoxyamine with phenyl acetate proceeds through a tetrahedral addition intermediate, T’, which is sufficiently unstable that the reaction is forced to proceed through a preassociation mechanism in which the amine, the ester, and a molecule of catalyzing acid come together in an encounter complex before the N-C bond is formed. We also discuss possible explanations for the sharp solvent isotope effect maximum with changing pK, of the catalyzing acid for this reaction, including a mechanism that involves kinetically significant solvent reorientation steps. Some of this work has been reported in preliminary communication^.*-^ The attack of methylamine on p-tolyl acetate gives an addition intermediate, T*, that reverts to reactants with a rate constant of k q = 3 X lo9 s-l if it is not trapped by protonation after encounter with a molecule of buffer acid or base (eq 1). These conclusions are based on typical “Eigen curves” for catalysis of ester formation and on a leveling of the product ratio as the acid concentration is increased when the addition intermediate is generated by addition of water to the corresponding imidate.4 (1) Supported by grants from the National Science Foundation (Grant BG-31740) and the National Institutes of Health (Grants GM20888 and GM20168). M.M.C. was supported by a training grant from the National Institutes of Health (Grant 5-T01-GM00212). (2) Cox, M. M.; Jencks, W. P. J . Am. Chem. SOC. 1978,100,5956-5951. ( 3 ) Cox, M. M.; Jencks, W. P. Fed. Proc., Fed. Am. Soc. Exp. Biol. 1979, 38, 473. 0002-7863/81/1503-572$01.00/0 T’ k, r C., , !HA