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. 2022 Jun 3;7(23):19828-19841.
doi: 10.1021/acsomega.2c01596. eCollection 2022 Jun 14.

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

Jiaojiao Cao  1 , Boxuan Lou  1 , Yue Xu  1 , Xiaolan Qin  1 , Haikuan Yuan  1 , Lijuan Zhang  1 , Yan Zhang  2 , Sohrab Rohani  3 , Jie Lu  1
Affiliations

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

Jiaojiao Cao et al. ACS Omega. .

Abstract

Three chiral nanorods of C14-l-Thea, C14-l-Phe, and C14-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 C14-l-Thea compared to C14-l-Phe that originated from the interaction difference between C14-l-Thea and Asp enantiomers was larger than that between C14-l-Phe and Asp enantiomers. Moreover, the constructed nanorods exhibited good stability and recyclability.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Flowchart of direct crystallization resolution of dl-Asp by chiral nucleants.
Figure 2
Figure 2
Infrared spectra of l-Thea, myristoyl chloride, and C14-l-Thea (a), l-Phe, myristoyl chloride, and C14-l-Phe (b), and d-Phe, myristoyl chloride, and C14-d-Phe (c).
Figure 3
Figure 3
PXRD patterns of nanorods.
Figure 4
Figure 4
Size distribution curves of C14-l-Thea, C14-l-Phe, and C14-d-Phe.
Figure 5
Figure 5
MSZWs of three Asp chiral species in water (a), with C14-l-Thea (b), C14-l-Phe (c), and C14-d-Phe (d).
Figure 6
Figure 6
Influence of S on the tind of Asp in water (a), with C14-l-Thea (b), C14-l-Phe (c), and C14-d-Phe (d) at 303.15 K.
Figure 7
Figure 7
Plots of tind versus S in the absence/presence of nanorods: l-Asp (a), d-Asp (b), and dl-Asp (c).
Figure 8
Figure 8
ee of initial particles collected from homogeneous nucleation experiments at different S: 1.67 (a), 1.43 (b), 1.19 (c), and 1.08 (d).
Figure 9
Figure 9
ee of initial particles collected from heterogeneous nucleation experiments at different S: 1.67 (a), 1.43 (b), 1.19 (c), and 1.08 (d).
Figure 10
Figure 10
ee of solid products over time at cooling rates of 0.025 (a), 0.05 (b), 0.10 (c), and 0.20 K/min (d).
Figure 11
Figure 11
Snapshots in the final state of C14-l-Thea, l-Asp, and d-Asp (a), C14-l-Thea and l-Asp (b), and C14-l-Thea and d-Asp (c) in the nucleating system.
Figure 12
Figure 12
AIGM isosurface diagrams of C14-l-Thea with l-Asp (a) and C14-l-Thea with d-Asp (b). The isosurface of aIGM = 0.1.
Figure 13
Figure 13
Effect of cycle number on the ee values of products using recovered nanorods (a) and their recovery ratios (b).
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