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