TRIAZENE DRUG METABOLITES .14. KINETICS AND MECHANISM OF THE ACID-CATALYZED HYDROLYSIS OF 3-ALKOXYMETHYL-3-ALKYL-1-ARYLTRIAZENES

Alkoxymethyltriazenes undergo an acid-catalysed hydrolysis reaction to form the parent aniline. The reaction is specific-acid-catalysed, wit h a solvent deuterium isotope effect of k(H)/k(D) = 0.4-0.5; there are no pH-independent or base-catalysed pathways. Electron-donating subst ituents in the aryl ring of the triazene moiety enhance the rate of de composition, giving rise to a Hammett rho value of ca. -1.6. The sign and magnitude of this rho value is interpreted in terms of a mechanism which involves protonation of the substrate at the ether oxygen atom followed by cleavage-of the O-CH2 bond of the alkoxymethyl group to fo rm a triazenyliminium ion intermediate. This intermediate can be trapp ed by the inclusion of ethanol in the hydrolysis medium. A Taft plot o f log k(H) vs. sigma for the alkyl group of the alkoxy moiety is curv ed, reflecting the fact that electron-donating alkyl groups enhance su bstrate protonation but reduce the leaving-group ability of the alcoho l in the iminium-ion-forming process whereas electron-withdrawing grou ps will have precisely the opposite effects in both these steps. For t he range of substrates studied, electron-donating alkyl groups provide the more reactive substrates. Moreover, the second-order rate constan ts for acid catalysis, k(H), of the ethyl, allyl and benzyl ethers are of similar magnitude, precluding processes involving the formation of carbocations derived from the ether alkyl groups.