Quantum-chemical study on the relative stability of sildenafil tautomers

Abstract The tautomeric equilibrium of sildenafil molecule was theoretically studied using B3LYP and M06-2X density functional theory (DFT) methods in connection with aug-cc-pVDZ correlation consistent basis set. Calculations were performed for gas phase water solution conditions modelled by polarizable continuum model (PCM). Three forms are possible. Two keto forms: A — where the proton more distant from carbonyl group B it is closer, one enol form denoted, C . Both DFT qualitatively give similar tautomer stability order: > dominant environment, whereas too high energy to be present mixture. Regarding tautomer, not but small amounts solution. According B3LYP/aug-cc-pVDZ, relative Gibbs-free energies 10.05 kcal/mol 11.91 5.49 12.49 M06-2X/aug-cc-pVDZ, 9.12 10.60 4.27 10.23 Therefore, vivo conditions, we expect that dominant, there may exist tautomer. at all. This picture very different parent system: 4-hydroxypyrimidine/4-pyrimidinone less stable than only about 1 least In order understand these differences, additional calculations a series molecules starting 4-hydroxypyrimidine/4-pyrimidinone, going through two in-between ending Sildenafil molecule. We found most important reasons destabilization dearomatization 6-membered ring caused fusion pyrazole ring, lack strong intramolecular hydrogen bond presence destabilizing steric interaction oxygen nitrogen atoms 6-memberd rings this