Electrostatic and non-electrostatic free energy contributions to acid dissociation constants in cosolvent—water mixtures

Abstract

Thermodynamic p K a values were determined for barbituric acid and several derivatives in solvents containing 0–50% ethanol in water. The data were analyzed using a model which accounts for electrostatic and non-electrostatic contributions to the p K a changes as a function of solvent composition. The Born equation was used to calculate p K a changes due to electrostatic effects and the difference between observed and calculated p K a changes was attributed to non-electrostatic effects. The non-electrostatic effect was not constant for a given solvent system as suggested by previous investigations. When compounds possessing a different acidic group are analyzed by this approach, it becomes apparent that the type of hydrophilic functional group has a large influence on the non-electrostatic effect. The original model was thus extended such that the non-electrostatic effect was divided into a lipophilic and hydrophilic component, where the hydrophilic component was determined from the p K a data of the parent compound of each series. The lipophilic non-electrostatic effect was found to correlate well with the hydrophobic surface area and log octanol-water partition coefficient of the solute. These results indicate that a linear free energy approach can be used to estimate p K a changes for weak organic electrolytes in cosolvent-water mixtures.