Enhanced Direct Crystallization Resolution of Racemates Mediated in Chiral Ionic Liquid Cosolvent Mixtures: Experimental, Statistical, and QM Simulation Studies

Abstract

Four chiral ionic liquids (CILs) of 1-hexyl-3-methylimidazolium-l-2-aminobutyrate ([Hmim][l-2-AbA]), 1-hexyl-3-methylimidazolium-d-2-aminobutyrate ([Hmim][d-2-AbA]), di-1-hexyl-3-methylimidazolium-l-malate ([Hmim]2[l-MA]), and di-1-hexyl-3-methylimidazolium-d-malate ([Hmim]2[d-MA]) were first prepared by a neutralization method and adequately characterized. In light of a gravimetric method, the molar fraction solubilities of dl- and d- together with l-threonine (Thr) were then acquired in the binary cosolvent mixtures (CM) of CILs and water, with different mass fractions (ω) of CILs under 101.3 kPa from 283.15 to 333.15 K. In CIL cosolvent mixtures (CCM), a cosolvency phenomenon was observed with the biggest solubilization and discrepant solubilities of Thr enantiomers, with ω of 0.3. Meanwhile, the asymmetry phenomenon was also found from the ternary phase diagram of Thr enantiomers and CCM, in which the enantiomeric excess values at the eutectic point (eeeut) were sensitive to temperature. Subsequently, the nucleation experiments and appearance probability statistics confirmed that CCM with ω of 0.3 (CCM-0.3) can act as excellent nucleation inhibitors which preferred to suppress the nucleation of enantiomeric crystals with the opposite chirality to them, leading to the preferential nucleation of enantiomeric crystals with the same chirality. Furthermore, by coupling seeds and CCM-0.3, the yield and yield ratio of l-Thr products through a direct antisolvent crystallization resolution were improved greatly compared with that in water, where the largest yield ratio was up to 27.47%. At the same time, isosurface diagrams and binding energy calculations by quantum mechanics (QM) revealed that the higher chiral recognition ability of [Hmim]2[l-MA] than [Hmim][l-2-AbA] stemmed from the stronger weak interactions. Particularly, the enhanced direct crystallization resolution can be feasibly recycled owing to the stability and recyclability of the CILs.