Issue 5, 1993

Triazene drug metabolites. Part 13. The decomposition of 3-acyl-3-alkyl-1-aryltriazenes in aqueous sulfuric acid

Abstract

The hydrolysis of 1-aryl-3-acyl-3-methyltriazenes in aqueous sulfuric acid is described. The 3-formyl derivative undergoes an acid-catalysed deacylation reaction, characterised by a monotonic rise in the pseudo-first-order rate constant, k0 with increasing acidity, solvent deuterium isotope effects, kH2SO4/kD2SO4, of 0.9 (at 0.95 mol dm–3 H2SO4) and 0.8 (at 2.85 mol dm–3 H2SO4) and an entropy of activation of –80 J mol–1 K–1. The 3-alkanoyl derivatives also undergo acid-catalysed decomposition involving cleavage of either the N3–C acyl bond or the N2–N3 triazene bond. Below 3 mol dm–3 H2SO4, only acyl bond cleavage is observed. At higher acidities the extent of N2–N3 bond cleavage increases. The reaction is characterised by (i) solvent deuterium isotope effects of ca. 0.6 at 2 and 5 mol dm–3 H2SO4 and ca. 0.4 at 8 mol dm–3 H2SO4, (ii)ΔS values of –6.7 and –51 J mol–1 K–1 at 2 and 6.1 mol dm–3 H2SO4, respectively, (iii) Hammett ρ values for the substituent in the triazene N-aryl ring of –0.7 and –0.9 at 3 and 9 mol dm–3 H2SO4, respectively, and (iv) an increase in reactivity with electron donating ability of the alkyl substituent of the acyl group. The 3-trifluoroacetyl triazenes are subject to solvolysis of the neutral, as well as the protonated, substrate. The hydrolysis of the neutral substrate involves N–acyl bond cleavage and is characterised by a solvent deuterium isotope effect, kH2O/kD2O, of 2.4, and a Hammett ρ value of +0.8 for the substituent in the N-aryl ring. The reactivity of the neutral substrate diminishes with increasing acidity until 6 mol dm–3 H2SO4, beyond which acid-catalysed N–acyl bond cleavage predominates, for which the solvent isotope effect, kH2SO4/kD2SO4, is 0.8 and the Hammett ρ value –0.5. The 3-aroyl substrates suffer acid-catalysed decomposition, the extent of the N2–N3 bond cleavage process being greater than for the N-alkanoyl counterparts. The reactions are rationalised in terms of a process that involves pre-equilibrium protonation of the substrate either at the N1 triazene atom or the amide oxygen atom, followed by subsequent decomposition of the protonated substrate via either N3–C bond cleavage, involving attack of water at the amide carbonyl, or unimolecular N2–N3 bond cleavage. The relative extents of the N3–C and N2–N3 bond cleavage processes depend on the reactivity of the acyl group and the water activity; the higher the water activity and the more reactive the acyl group, the more deacylation is favoured.

Article information

Article type
Paper

J. Chem. Soc., Perkin Trans. 2, 1993, 865-870

Triazene drug metabolites. Part 13. The decomposition of 3-acyl-3-alkyl-1-aryltriazenes in aqueous sulfuric acid

E. Carvalho, J. Iley and E. Rosa, J. Chem. Soc., Perkin Trans. 2, 1993, 865 DOI: 10.1039/P29930000865

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