Axially Chiral Binaphthyl Isothiocyanates as Versatile 19F NMR Probes for Chiral Discrimination

Abstract

The rapid determination of enantiomeric excess (ee) for structurally diverse chiral primary and secondary amines remains a formidable challenge due to conformational flexibility and variable steric demands of these substrates. Herein, we report the design and synthesis of novel 19F-labeled axially chiral isothiocyanate probes based on a “privileged” binaphthyl scaffold. Leveraging the high conformational rigidity and steric environment of the binaphthyl framework, these probes react with the tested amines under mild conditions to form covalent thiourea adducts. Together, probes P1 and P2 provided distinguishable 19F NMR signals for 27 of the 29 tested substrates, including primary amines, amino alcohols, and acyclic secondary amines. The observed signal resolution further enabled the proof-of-concept discrimination of multicomponent chiral amine mixtures. Complementary mechanistic studies, incorporating variable-temperature NMR, spin relaxation measurements, X-ray crystallography, and density functional theory (DFT) calculations, suggest that molecular and conformational dynamics may contribute to the differential peak broadening observed for certain diastereomeric adducts. Furthermore, the model system demonstrated excellent linearity for ee determination, supporting the potential application of this method in rapid 19F NMR-based analysis of chiral amines.