Solubility of 4-amino-2,6-dimethoxypyrimidine in aqueous co-solvent mixtures revisited: Solvent effect, transfer property and preferential solvation analysis

Abstract

The preferential solvation parameters of 4-amino-2,6-dimethoxypyrimidine in four aqueous co-solvent mixtures of methanol (1) + water (2), ethanol (1) + water (2), isopropanol (1) + water (2) and DMF (1) + water (2) were derived from their available solubility data by using the inverse Kirkwood–Buff integrals method. In water-rich compositions for the four aqueous co-solvent mixtures, the value of δx1,3 was negative, which showed that the 4-amino-2,6-dimethoxypyrimidine was preferentially solvated by water. In intermediate composition and co-solvent-rich composition, 4-amino-2,6-dimethoxypyrimidine was preferentially solvated by the co-solvent (methanol, ethanol, isopropanol or DMF). The preferential solvation magnitude of 4-amino-2,6-dimethoxypyrimidine was highest in isopropanol mixtures than in the other three solvent mixtures. The higher solvation by co-solvents could be explained in terms of the higher basic behavior of the solvents interacting with the Lewis acidic groups of the 4-amino-2,6-dimethoxypyrimidine. The contributions from solute-solvent and solvent-solvent interactions to the solvent effect were studied by using the linear solvation energy relationships. Furthermore, transfer Gibbs free energy (ΔtrGo), enthalpy (ΔtrHo), and entropy (ΔtrSo) were derived, demonstrating that the solubilization capacity was more favorable in the intermediate concentration of co-solvents.