The Mechanisms of Amide Hydrolysis

Abstract

<p> This thesis presents the theoretical study of the mechanisms of gas-phase formamide hydrolysis using ab initio SCF-MO calculations. Four reaction paths were considered; (i) the reaction of formamide with OH- (ii) the acid catalyzed hydrolysis with protonation on the nitrogen atom (iii) the acid catalyzed hydrolysis with protonation on the oxygen (iv) the uncatalyzed hydrolysis. An unconstrained optimization of all parameters was performed on the transition state and equilibrium structures. The intrinsic reaction coordinate was then followed down from the transition state to the reactants and products. All of the molecular geometries were obtained using the 4-31G basis set and all wavefunctions and energies were calculated at the 6-31G** level of theory. The theory of atoms in molecules was applied to each reaction to study the mechanisms of structural change along the reaction coordinate. Molecular graphs were calculated at points along the reaction coordinate and these give a detailed pictorial outline of the entire reaction sequence. The Laplacian of the charge density successfully predicts the correct site of protonation and the enhanced reactivity of protonated formamide over that of neutral formamide. Both the acid catalyzed reaction with nitrogen protonation and the base enhanced hydrolysis reactions proceed without a barrier with respect to reactants and products. The acid catalyzed hydrolysis with protonation on the oxygen atom proceeds with a moderate activation barrier whereas the neutral hydrolysis involves the passage over a very high activation barrier. The two acid catalyzed reactions are competitive with the N-protonation mechanism being more favourable from a kinetic point of view while the O-protonation mechanism is thermodynamically more favourable.</p>