Nonenzymatic Hydrolysis of Cocaine via Intramolecular Acid Catalysis

The spontaneous hydrolysis of the methyl-ester group of cocaine ( 1 ) in vivo contributes to the metabolic clearance of the drug in man. Neighboring-group participation by the tropane N-atom of cocaine in this hydrolysis was suggested by the normal stability of the methyl-ester groups of pseudococaine and N-acylnorcocaine. For cocaine, the relative rate of methyl-ester to benzoyl-ester hydrolysis was ca. 10:1 at pH≤7.4, and, although absolute rates increased with increasing pH, their ratio collapsed at pH>pK_a (8.6). These data are consistent with intramolecular acid catalysis of alkaline hydrolysis of the cocaine methyl-ester group under physiologic conditions.