Thermodynamic and Molecular Recognition Mechanism of Diastereomeric Salt/Cocrystal-Induced Chiral Separation
Jingchen Sui, Na Wang, Jingkang Wang, Xin Li, Jinyue Yang, Yue Liu, Yihan Zhao, Xin Huang, Ting Wang, Lina Zhou, Hongxun Hao
Abstract
To better understand the thermodynamics and molecular self-assembly mechanism of diastereomeric salt/cocrystal-induced chiral separation, a series of 1:1 cocrystals and salts consisting of chiral valines (VAL) and tartaric acid derivatives were synthesized via different methods. Powders of these as-screened cocrystals/salts were characterized by PXRD, TGA, DSC, FT-IR, and Raman spectroscopy. The crystal structures of the five cocrystals/salts were determined and analyzed. It was found that both DBTA and DTTA form diastereomeric salt pairs with VAL enantiomers. Interestingly, l-DMTA cocrystallizes with d-VAL and l-VAL via hydrogen bonding and proton transfer, respectively. Considering this particularity, the differential isothermal (10 °C) ternary phase diagrams (TPDs) of d-DMTA and l-VAL (d-VAL) cocrystals (salt) were constructed in the mixed solvent of MeOH/H2O. Moreover, a pure l-VAL:d-DMTA cocrystal and d-VAL:d-DMTA:0.5CH4O:0.25H2O salt were prepared via equimolar slurry conversion at 10 °C. In situ Raman spectroscopy was applied to monitor the molecular assembly process during the incubation of the cocrystal/salt. Molecular dynamics simulation was employed to rationalize the molecular recognition mechanism, demonstrating the excellent chirality preference of l-DMTA toward l-VAL instead of d-VAL. Calculations of density functional theory approved the synergistic instead of antagonistic effects of binding energy and solvation free energy toward chiral separation.