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 kH/kD= 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 kHvs. 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, kH, of the ethyl, allyl and benzyl ethers are of similar magnitude, precluding processes involving the formation of carbocations derived from the ether alkyl groups.