A theoretical study of tautomerism of 6-thiopurine in the gas and aqueous phases using AM1 and PM3

Heats of formation, entropies, Gibbs free energies, relative tautomerisation energies, tautomeric equilibrium constants, relative proton affinities, dipole moments and ionisation potentials for the eight possible tautomers of 6-thiopurine have been studied using semiempirical AM1 and PM3 quantum-chemical calculations at the SCF level, both in the gas and aqueous phases, with full geometry optimisation. The COSMO solvation model was employed for aqueous solution calculations. The calculations show that 6-thiopurine exists as the thiol-amino forms in the gas phase whereas the thione-amino forms are the predominant tautomers in the aqueous solution. The thione-N(7)H tautomer is more stable than the thione-N(9)H tautomers in aqueous solution. The results are in good agreement with available experimental and theoretical results. The entropy effect on the Gibbs free energy of the 6-thiopurine base is very small and there is little significance for the tautomeric equilibria of the base. The enthalpic term is dominant also in the determination of the equilibrium constant. (C) 2001 Elsevier Science B.V. All rights reserved.