Molecular Insights into Water-Driven Structural Evolution of Choline Chloride/4-Methoxyphenol Deep Eutectic Solvent

Deep eutectic solvents (DESs) represent a promising class of sustainable media whose properties can be modulated by adjusting their composition and introducing cosolvents. This work provides an integrated thermal and structural characterization of the choline chloride (ChCl)/4-methoxyphenol (4Met) system and its aqueous mixtures. Differential scanning calorimetry revealed a primary eutectic point at the 1:2 composition, confirming the deep eutectic nature of the mixtures. Small- and wide-angle X-ray scattering (SWAXS) combined with molecular dynamics (MD) simulations showed that neat and low-water-content systems are homogeneous at the nanoscale, whereas the addition of water beyond a certain concentration induces nanoscale heterogeneities. Atomistic analysis demonstrates that water progressively disrupts the original ChCl-4Met hydrogen-bond network, leading to clear segregation into hydrophilic (ChCl-water) and hydrophobic (4Met-rich) domains. At high water contents, 4Met forms weakly interacting clusters stabilized mainly by van der Waals forces. The excellent agreement between SWAXS and MD results provides a coherent multiscale picture of nanostructure formation and offers key insights for optimizing DES–water mixtures for sustainable extraction procedures and related applications.