On the stability of zwitterions of pyridine sulfonylureas: the effect of isosterism, acidity, and microsolvation.

Pyridine sulfonylureas (PSUs) are known to exist in zwitterionic form in the solid phase. For example, torsemide, a diuretic drug, exists in three polymorphic forms: two of them in the zwitterionic state and one in the "partial zwitterionic" state. Initial computational analysis showed that the energy difference between the canonical and the zwitterionic states of a model PSU is very large in the gas phase (∼15 kcal/mol), thus disfavoring the zwitterionic state. In order to understand the apparent dichotomy on the preferred state of PSUs, extensive computational analysis using density functional theory was taken up on a few analogues of PSU. The zwitterionic isomer was less stable than the canonical form in the model PSU, 4-amino-pyridyl-3-sulfonylurea. However, under implicit polar solvent conditions, the zwitterionic and the canonical forms of the model PSU were nearly isoenergetic. Furthermore, microsolvation calculations showed that the zwitterionic model of torsemide is thermodynamically more favorable over the canonical form in the presence of seven water molecules. A combined microsolvation-continuum solvent model showed that the zwitterionic form starts to dominate the canonical form under the influence of four water molecules. Analysis on the intramolecular interactions, the partial atomic charges, the conformational and tautomeric preferences was also carried out, which enabled the rationalization of the formation of stable zwitterionic species in PSUs.