The modulation of acid-base equilibria by salts is a cornerstone of solution chemistry, yet the underlying mechanisms in complex, multi-component electrolyte mixtures remain poorly understood. While prior studies have established that individual salts can induce ion-specific shifts in the pKa of weak acids, the molecular origins of these effects-especially in mixed salt environments-have not been systematically elucidated. Here, we present a comprehensive investigation combining experiment and constant pH molecular dynamics simulations to unravel how ion pairing and specific ion effects govern the pKa of acetic acid in both single and mixed sodium salt solutions. By spanning a range of anion charge densities (sulfate, chloride, iodide), we demonstrate that the extent of cation-anion association, rather than electrostatic screening alone, dictates the observed pKa shifts. Notably, we reveal that in mixtures of sodium chloride and sodium sulfate, the effects on acetic acid pKa deviate from additivity owing to the underlying complexity of ion–ion interactions in solution. Our work introduces an ion-pairing-augmented Debye-Hückel framework that quantitatively predicts these behaviors, offering a predictive tool for pH control in complex ionic environments. This study establishes a mechanistic foundation for interpreting and forecasting pH-dependent processes in real-world, multi-salt systems—an advance with broad implications for biochemistry, buffer design, and soft matter science.
Mandalaparthy et al. (Tue,) studied this question.