Substituent Effects in Amine Enantiodiscrimination Using 19F Molecular Probes and Development of a Predictive Design and Screening Tool

Abstract The structural features of 19F molecular probes are critical for effective enantiodiscrimination, with substituent effects, arising from the electronic and steric properties of functional groups, playing a pivotal role in modulating chiral recognition. To systematically investigate these effects, three newly designed chiral probes (P1, P2, and P3), together with P4 from earlier work [ Huang, B.; et al.Anal. Chem.2022, 94(3), 1867–1873]., were employed for the enantiodifferentiation of amines, enabling comparative evaluation of their discrimination efficiencies. Consequently, P3 outperformed P1 and P2, while P4 exhibited superior performance relative to P3. DFT calculations provided mechanistic insight into probe–analyte intramolecular interactions, revealing that larger Gibbs free energy differences (ΔG) between diastereomers enhance chiral differentiation. These trends align with the Boltzmann-averaged 19F NMR chemical-shift differences that reproduce the experimental chiral discrimination. Notably, P3 was capable of distinguishing analytes containing multiple stereocenters, and the probe demonstrated reliable capabilities for determining ee in nonracemic solutions as well as quantitative analysis. Furthermore, a machine-learning (ML)-guided online platform was established for the first time to assist in probe design and screening without preliminary experiments. This work elucidates the role of substituent effects in enantiodiscrimination and provides valuable guidance for the promising development of systematic platforms to design diverse 19F molecular probes tailored to a wide range of analytes.