Triazene drug metabolites. Part 12. Base catalysed formation of 3-alkyl-1-aryltriazenes from 3-alkyl-3-hydroxymethyl-1-aryltriazenes

Abstract

3-Alkyl-3-hydroxymethyl-1-aryltriazenes are stable in aprotic solvents, but decompose in non-aqueous protic solvents to the corresponding 3-alkyl-1-aryltriazenes. The reactions are catalysed by the presence of bases, and the catalytic activity of the base depends upon its aqueous pK_a. A Brønsted plot of the catalytic rate constant, k_B, versus base pK_a gives rise to a Brønsted β value of 1.1. Tertiary bases have no catalytic effect. The deuterium isotope effect for the piperidine catalysed reaction is ca. 1.4. The catalytic rate constants k_B depend upon the triazene structures, increasing with the size of the 3-alkyl group (Pr > Et > Me) and with electron-withdrawing ability of the substituent in the 1-aryl group (Cl > H > MeO). The observations are rationalised in terms of a six-membered transition state involving the N–CH₂–OH group of the triazene and the N–H of the base and in which proton transfer from the hydroxy group to the nitrogen atom of the catalyst is extensive. In mixed aqueous–ethanol solvents tertiary bases also have a catalytic effect. A Brønsted β value of 0.67 and a solvent deuterium isotope effect of 1.18 identify the proton as ca. 70% transferred to the base in the transition state. In no reaction was aminomethylation of the base observed.