Theoretical Studies of Competing Reaction Pathways and Energy Barriers for Alkaline Ester Hydrolysis of Cocaine

Abstract

Reaction pathways, solvent effects, and energy barriers have been determined for the base-catalyzed hydrolysis of the benzoyl-ester and methyl-ester groups of neutral cocaine and three smaller alkyl esters in aqueous solution by performing a series of ab initio molecular orbital and density functional theory calculations. The reaction coordinate calculations indicate that both the benzoyl-ester hydrolysis and the methyl-ester hydrolysis occur through a two-step process known for the majority of alkyl esters, i.e., the formation of a tetrahedral intermediate by the attack of hydroxide oxygen at the carbonyl carbon (first step) followed by the decomposition of the tetrahedral intermediate to products (second step). This is the first first-principles study of the whole reaction pathway for cocaine benzoyl- and methyl-ester hydrolyses. The decomposition of the tetrahedral intermediate requires a proton transfer from the hydroxide/hydroxyl oxygen to the ester oxygen, as the C−O bond between carbonyl carbon and...