Triazene drug metabolites. Part 14. Kinetics and mechanism of the acid-catalysed hydrolysis of 3-alkoxymethyl-3-alkyl-1-aryltriazenes

Abstract

Alkoxymethyltriazenes undergo an acid-catalysed hydrolysis reaction to form the parent aniline. The reaction is specific-acid-catalysed, with 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 substituents in the aryl ring of the triazene moiety enhance the rate of decomposition, giving rise to a Hammett ρ value of ca.–1.6. The sign and magnitude of this ρ 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–CH₂bond of the alkoxymethyl group to form a triazenyliminium ion intermediate. This intermediate can be trapped by the inclusion of ethanol in the hydrolysis medium. A Taft plot of log k_Hvs. σ* for the alkyl group of the alkoxy moiety is curved, reflecting the fact that electron-donating alkyl groups enhance substrate protonation but reduce the leaving-group ability of the alcohol in the iminiumion-forming process whereas electron-withdrawing groups will have precisely the opposite effects in both these steps. For the range of substrates studied, electron-donating alkyl groups provide the more reactive substrates. Moreover, the second-order rate constants 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.