Dual-Selector Biphasic Recognition Chiral Extraction for Naproxen Enantiomers: Experimental Evaluation and Molecular-Level Mechanism

Abstract A dual-selector biphasic recognition chiral extraction (BRCE) system was developed for the resolution of racemic naproxen using hydrophobic l-di-p-toluoyl-d-tartaric acid (L-DTTA) in the organic phase and hydrophilic hydroxyethyl-β-cyclodextrin (HE-β-CD) in the aqueous phase. Single-selector screening first identified HE-β-CD as the preferred aqueous selector for S-naproxen and L-DTTA as a complementary organic selector for R-naproxen. After optimization of selector concentrations, feed concentration, pH and temperature, the single-stage enantioselectivity yields 2.10, with an enantiomeric excess of 31.93%. Quantum chemical calculations and molecular dynamics simulations were then used to interpret the experimentally verified selectivity trends. The results indicate that HE-β-CD preferentially stabilizes S-naproxen through cavity-size matching and a directional hydrogen-bonding network near the modified cavity entrance, whereas L-DTTA favors R-naproxen through steric complementarity and extensive van der Waals contacts. The opposite recognition preferences of the two selectors generate a cooperative thermodynamic driving force across the oil/water interface. This experimentally validated mechanism provides criteria for selecting dual-phase chiral selectors and designing intensified liquid–liquid extraction systems for enantiomeric separations.