Direct Crystallization Resolution of Racemates Enhanced by Chiral Nanorods: Experimental, Statistical, and Quantum Mechanics/Molecular Dynamics Simulation Studies

[Image: see text] Three chiral nanorods of C(14)-l-Thea, C(14)-l-Phe, and C(14)-d-Phe were first synthesized and utilized as heterogeneous nucleants to enhance the resolution of racemic Asp via direct crystallization. Through the statistical analysis from 320 batches of nucleation experiments, we found that the apparent appearance diversity of two enantiomeric crystals of Asp existed in 80 homogeneous experiments without chiral nanorods. However, in 240 heterogeneous experiments with 4.0 wt % chiral nanorods of solute mass added, the appearance of those nuclei with the same chirality as the nanorods was apparently promoted, and that with the opposite chirality was totally inhibited. Under a supersaturation level of 1.08, the maximum ee of the initial nuclei was as high as 23.51%. When the cooling rate was 0.025 K/min, the ee of the product was up to 76.85% with a yield of 14.41%. Furthermore, the simulation results from quantum mechanics (QM) and molecular dynamics (MD) revealed that the higher chiral recognition ability of C(14)-l-Thea compared to C(14)-l-Phe that originated from the interaction difference between C(14)-l-Thea and Asp enantiomers was larger than that between C(14)-l-Phe and Asp enantiomers. Moreover, the constructed nanorods exhibited good stability and recyclability.