Speciation‐Guided COSMO‐RS Screening of Hydrophobic DES for Fermentative Succinic Acid Extraction

ABSTRACT In this work, we present a mechanism‐informed screening workflow that integrates COSMO‐RS with thermodynamic and transport models to translate solute–HDES interactions into process‐relevant mass transfer descriptors for liquid–liquid extraction. This approach enables systematic ranking of extractants and identification of feasible operating windows. Screening 83 hydrophobic deep eutectic solvents (HDESs) identified three lead systems—TBACl:AceAc, TBACl:OctAc, and TBACl:DecAc (1:1)—with infinite dilution performance indices of 8.69, 8.36, and 8.27, respectively. Speciation‐aware calculations reveal strong pH dependence of the apparent distribution coefficient, which reaches extremely high values at pH 3 due to the favorable transfer of neutral succinic acid. As pH increases across the dissociation range, distribution coefficients decline sharply as deprotonation enhances solute hydrophilicity. TBACl:AceAc shows higher performance near this boundary due to balanced hydrogen‐bonding capacity and moderate polarity predicted by COSMO‐RS. Benchscale extractions yield removal efficiencies of 55.2%, 61.4%, and 71.1% for TBACl:AceAc, TBACl:OctAc, and TBACl:DecAc, respectively, reflecting the interplay of thermodynamic affinity, hydrophobicity, phase stability, and mass transfer behavior. Although TBACl:AceAc exhibits stronger specific interactions, its higher polarity increases aqueous miscibility and hinders phase disengagement. In contrast, TBACl:DecAc's lower polarity enhances interfacial stability and extraction efficiency. This integrated framework accelerates solvent discovery for energy‐efficient recovery of platform bio‐acids.