# Theoretical Investigation of Tautomeric Equilibria for Isonicotinic Acid, 4-Pyridone, and Acetylacetone in Vacuo and in Solution

journal contribution

posted on 2007-07-10, 00:00 authored by Peter I. Nagy, Giuliano Alagona, Caterina GhioTautomeric equilibria have been theoretically calculated for isonicotinic acid (neutral
and zwitterionic forms), the 4-pyridone/4-hydroxypyridine system, and the keto−enol transformation for acetylacetone in vacuo and in tetrahydrofuran, methanol, and water solvents. Solvent,
basis set, and cavity model effects have been studied in the integral equation formalism for the
polarizable continuum model (IEF-PCM)/B3LYP framework, as well as the effect of the procedure,
CHELPG or RESP, applied in fitting atomic charges to the in-solution molecular electrostatic
potential (ELPO). The in-solution optimized geometries obtained at the IEF-PCM/B3LYP/6-31G*
and 6-311++G** levels differ moderately but deviate from their gas-phase counterparts. Atomic
charges fitted to the in-solution ELPO show small variations in the considered solvents, as well
as when the united-atom cavity model, or a model with explicit consideration of polar hydrogens
and scaled Bondi radii, has been applied. In contrast, the fitting procedure considerably affects
the derived charges producing more separated atomic charges when the CHELPG rather than
the RESP procedure is utilized. The fitted charges increase up to 20% in absolute value when
the basis set is enlarged from 6-31G* to 6-311++G** in the IEF-PCM/B3LYP calculations. The
relative free energy, calculated as Δ

*G*_{tot}= Δ*E*_{int}+ Δ*G*(solv) + Δ*G*_{thermal}+ (symmetry correction), in an ab initio/density funtional theory (DFT) + free energy perturbation (FEP)/Monte Carlo (MC) approximation strongly depends on the accepted value for the relative internal energy, Δ*E*_{int}, of the tautomers. Δ*E*_{int}is to be calculated at the IEF-PCM/QCISD(T)/cc-pVTZ//IEF-PCM/B3LYP/6-31G* level for the isonicotinic acid tautomers for producing relative free energies in aqueous solution close to experimental values. In other solvents, for this system and for the other two tautomeric equilibria, calculation of Δ*E*_{int}at the IEF-PCM/B3LYP/6-31G* level produces Δ*G*_{tot}in agreement up to 1 kcal/mol with the experimental values. FEP/MC Δ*G*(solv) calculations provide robust results with RESP charges derived by a fit to the in-solution ELPO generated at the IEF-PCM/B3LYP/6-31G* level. Molecular dynamics simulations pointed out that isonicotinic acid forms a dimeric zwitterion in tetrahydrofuran, in contrast to what happens in aqueous solution, and this structural peculiarity was interpreted as the reason for the failure of the ab initio/DFT + FEP/MC method in this particular solution.