Molecular Recognition and Chiral Discrimination from NMR and Multi-Scale Simulations.

Chiral molecules are particularly interesting to the pharmaceutical and agrochemical sectors due to their chemical and physical properties. Separation and identification of enantiomers are critical for a broad range of compounds, and discriminating stereoisomers in solution remains a key analytical challenge. Nuclear Magnetic Resonance (NMR) with Matrix-Assisted Diffusion-Ordered Spectroscopy (MAD), in the presence of chiral resolving agents, has emerged as a tool to explore these chiral mixtures. However, insight into the intermolecular interactions that lead to chiral recognition is still limited. Here, we combine experimental MAD studies with computational approaches to investigate the enantioselective discrimination of Mandelic Acid (MA) enantiomers using (R)-BINOL and (S)-BINOL. Molecular dynamics simulations explain the differences in diffusion coefficients for heterochiral complexes. Furthermore, quantum mechanical calculations confirmed enantioselective binding preferences due to differences in Gibbs free energies, highlighting the fundamental interactions and structural criteria that explain the NMR shielding and the diffusion trends. This integrated approach bridges experimental and theoretical studies, offering a comprehensive understanding of chiral recognition mechanisms and elucidating the observed heterochiral preference of BINOL for MA enantiomers. Our findings advance the field of chiral analysis and lay a foundation for future developments for identifying stereoisomers and recognition modes underlying enantioselective binding.