Species-Specific Hydrolysis Kinetics ofN-Methylated Heroin Derivatives

Abstract

The hydroxide-catalyzed hydrolysis of 3,6-diacetylmorphine (heroin) was shown to take place predominantly via its positively charged form. N-Methylated quaternary derivatives of heroin bearing a permanent positive charge were synthesized, and thus, hydrolysis kinetics of these cationic species could be studied over a wide pH range. Specific rate equations were introduced to characterize either the simultaneous or the consecutive decompositions. The kinetic constants determined for the diester are distinctive for the site of hydrolysis. The rate of 6-acetyl-N-methylmorphine was quantified in terms of microscopic kinetic constants of hydrolysis, in which the protonation state of the phenolic OH group had also been taken into account. The site-specific data indicate that the 3-acetoxy moiety is hydrolyzed 6 – 12 times faster than the 6-acetoxy function. The latter, previously ignored minor pathway was shown to represent a non-negligible 10% of the overall decomposition process. Protonation of the 3-O− site accelerates the rate of hydrolysis of the 6-acetoxy moiety by a factor of 4, and replacement of the adjacent OH group by MeO or AcO substituents slows the rate of hydrolysis slightly, presumably due to the increased local hydrophobicity caused by the alkyl or acyl moiety.