Thermodynamic and Molecular Recognition Mechanism of Diastereomeric Salt/Cocrystal-Induced Chiral Separation

Abstract

To better understand the thermodynamics and molecular self-assembly mechanism of diastereomeric salt/cocrystalinduced 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/ H 2 O. Moreover, a pure L-VAL:D-DMTA cocrystal and D-VAL:D-DMTA:0.5CH 4 O:0.25H 2 O 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.

Case of Chiral Resolution through Converting Two Racemic Compounds into a Conglomerate

“…Furthermore, the BE of S-NEA_S-NAP (−22.81 kcal/mol) was notably superior to that of R-NEA_S-NAP (−15.87 kcal/mol), which indicated that the former was much more stable than the latter, resulting in the formation of the conglomerate composed of S-NEA_S-NAP and R-NEA_R-NAP …”

“…37 To sum up, the difference of electrostatic potential results in the different interaction strengths between the acceptor (S-NAP) and the donors (S-NEA and R-NEA). Furthermore, the BE of S-NEA_S-NAP (−22.81 kcal/mol) was notably superior to that of R-NEA_S-NAP (−15.87 kcal/ mol), which indicated that the former was much more stable 38 than the latter, resulting in the formation of the conglomerate composed of S-NEA_S-NAP and R-NEA_R-NAP. S4, and Table 2.…”

Strategies for chiral separation: from racemate to enantiomer

“…Hence, it will be a trendsetting topic to explore the mechanism of enan-tiospecic cocrystal formation using crystal structures and DFT calculations including the binding energy, crystal packing mode, and solvation free energy. 233 Besides, coupling crystallization with ultrasound waves or magnetic elds may also raise unexpected discoveries in conglomerate preparation, 89,158 enantioselectivity enhancing 216 and process development. 190 Meanwhile, the successful deracemization of complex racemates besides Cons through crystallization-based methods can also be attributed to the coupling strategy, as exemplied by chemical derivatization-VR-PC, 262 chemical derivatization-TCID-PC, 91 CBR-CIDT process with liquid-phase coupling, 239 TCID-PC process with suspension exchange 86 and reverse PC-VR-TCID.…”

“…Hence, it will be a trendsetting topic to explore the mechanism of enantiospecific cocrystal formation using crystal structures and DFT calculations including the binding energy, crystal packing mode, and solvation free energy. 233 Besides, coupling crystallization with ultrasound waves or magnetic fields may also raise unexpected discoveries in conglomerate preparation, 89,158 enantioselectivity enhancing 216 and process development. 190…”

“…Therefore, D-Val with a higher prot margin could be obtained (96.6% ee and 40.68% yield). 233 Alternatively, enantiospecic cocrystals (iv) are more innovative because they ideally involve only one new solid cocrystal phase. Consequently, this contributes to a less complex phase diagram and a larger solubility difference between the cocrystal and single enantiomer for direct crystallization.…”