Acids, Bases, and Salts in Mixed-Aqueous Solvents

The dependence of the dissociation constants of acids and bases and their tendency to form salts upon solvent composition in mixed-aqueous solvents are reviewed, along with the activities of the solvent components. The acid–base equilibria are dominated by preferential solvation of the ions by water molecules in the mixtures, compounded by the very high water activities across most of the solvent composition range; the neutral components are normally preferentially solvated by the organic component of the solvent mixture. Neutral acids, such as carboxylic acids and phenols, show only modest increases in p K a (1–2 p K units) in solvent mixtures containing up to 60–70 wt % organic component; thereafter is a much steeper, solvent-dependent increase to the value in the pure organic solvent. Cationic acids, such as protonated amines, anilines, and pyridines, display a universal decrease in p K a (∼1 p K unit) up until around 80 wt % organic solvent, almost independent of the nature of the base or the solvent; beyond this, there is a relatively strong increase in p K a to the value in the pure solvent. The protonation of amines by carboxylic acids becomes progressively more difficult as the organic content of the solvent mixtures increases, with equilibrium constants for protonation in 60 wt % solvent being typically reduced by 3 orders of magnitude relative to those in water. The solubilities of salts formed between simple carboxylic acids and amines with a strong difference in aqueous p K a values will show a monotonic decrease with added organic component of the solvent; where one of the acid or base species has a high “organic” (hydrophobic) component, the solubility will typically pass through a maximum as the organic content of the solvent mixture increases. In cases where salt formation is strongly limited in aqueous solution (acids and bases with similar p K a values), the solubilities of the salts will increase continuously with added organic component of the solvent.