Keto–enol tautomerism of phenacylpyrazine: acid catalysis with protonation at nitrogen

Abstract

Kinetic and equilibrium measurements for ionisation and enolisation of 2-phenacylpyrazine in aqueous solution at 25 °C yield a tautomeric constant pK_E= 2.05 (where K_E=[enol]/[ketone]) and pK_as for loss of a methylene proton and for protonation at nitrogen of 11.90 and 0.40, respectively. In contrast to 2-phenacylpyridine the low basicity of the pyrazine nitrogens renders an enaminone tautomer less stable than the enol and a value of pK_M= 4.4 (K_M=[enaminone]/[ketone]) is estimated for this equilibrium. Evidence is presented that acid catalysis of keto-enol tautomerism occurs with protonation at the N-1 nitrogen atom rather than carbonyl group (or N-4 nitrogen) despite the proton being bound to oxygen in the enolic product. This preference reflects relative magnitudes of binding constants (1/K_a) and activating factors (PAF) for protonation at the different positions. Brønsted and Marcus equations are used to express catalytic efficiency in terms of equilibrium constants for binding the catalyst to the reactant and products of the uncatalysed reaction. The form of catalysis observed, which reflects the influence of proton binding on the activation energy of the reaction, is contrasted with that in intramolecular or enzymatic reactions, which normally derives from approximation of the reactants and is entropic in origin. The significance of optimum binding of the catalyst to the transition state in the two cases is briefly compared.