Understanding Water Activity in Deep Eutectic Solvents: Experimental Screening, Thermodynamic Modeling, and QSAR Predictions

ABSTRACT Understanding water activity ( a w ) and developing reliable predictive models are essential for rational, application‐specific DES design. This study systematically investigates a w in eight cholinium‐ and betaine‐based DESs across a hydration range of 10–90 wt%. The results show that water interacts strongly with DES components up to ∼50 wt%, after which the supramolecular structure progressively breaks down, leading to more aqueous‐like behavior. Most systems exhibit hydration‐dependent crossover behavior, i.e. negative deviations from Raoult's law at low water content, reflecting strong hydrogen bonding, and positive deviations at higher hydration, particularly in betaine‐based DESs. To interpret and predict these trends, a w data were analyzed using empirical (Redlich–Kister), theoretical (Wilson), and predictive (COSMO‐RS) models. Each showed important limitations: Redlich–Kister was flexible but lacked physical meaning and performed poorly for DES mixtures; Wilson model included interaction energies but produced unphysical parameters in strongly hydrogen‐bonded systems; and COSMO‐RS failed to capture key experimental features such as the sign change in activity deviations. On the other hand, quantitative structure–activity relationship (QSAR) modeling using COSMO therm ‐derived σ ‐profile descriptors achieved high predictive accuracy metrics values ( R 2 pred = 0.9720), providing a promising framework for predicting a w in complex DES–water systems and guiding rational DES design.