Site- and species-specific hydrolysis rates of cocaine

[Display omitted] •Protonation macro- and microconstants of cocaine and its derivatives were determined.•Site- and species-specific hydrolysis rate constants of cocaine and its hydrolysis products were detemined.•The experiments were performed with NMR spectroscopy.•Nitrogen protonation accelerates the hydrolyses approximately 10 times both at site 2 and site 3. The hydroxide-catalyzed non-enzymatic hydrolysis of cocaine is quantified in terms of ten site- and species-specific rate constants in connection with also ten site- and species-specific acid-base equilibrium constants, comprising all the twelve coexisting species in solution. This characterization involves the major and minor decomposition pathways via benzoylecgonine and ecgonine methyl ester, respectively, leading to ecgonine, the final product. Hydrolysis has been found to be 10–330 times faster at site 2 than at site 3, depending on the ionization status of the amino moiety and the rest of the molecule. Nitrogen protonation accelerates the hydrolyses approximately ten times both at site 2 and site 3.