Biphasic Polyarylisocyanide Liquid Crystals with Enhanced Enantiodiscrimination for Residual Chemical Shift Anisotropy Measurements

Abstract

Anisotropic NMR spectroscopy has emerged as a powerful tool for the structural elucidation of complex small molecules. Compared with residual dipolar couplings (RDCs), however, the application of residual chemical shift anisotropies (RCSAs) has remained relatively limited, largely owing to the lack of simple and efficient methods for their acquisition. Here, we report a biphasic polyarylisocyanide lyotropic liquid-crystalline (LLC) system based on single-handed helical polyisocyanides prepared by alkyne-Pd(II)-catalyzed controlled polymerization. The biphasic nature of this medium enables straightforward extraction of ΔRCSAs from a single one-dimensional 13C NMR experiment on a single sample, without requiring specialized instrumentation, devices, or postcorrection. We demonstrate the broad applicability of this approach by measuring ΔRCSAs for eight structurally diverse natural products and organic molecules. The resulting 13C ΔRCSAs are sufficiently large to enable reliable structural verification and stereochemical elucidation. Notably, the method allowed us to unambiguously resolve previously questionable 13C NMR assignments in cryptotanshinone. In addition, the chiral LLC medium exhibits pronounced enantiodiscrimination, as demonstrated for indanol enantiomers as well as significant enantiodifferentiating capabilities for several natural alkaloids. Furthermore, 19F RCSA measurements enable direct differentiation of two enantiomers even within a racemic mixture. Together, these results establish biphasic polyarylisocyanide LLCs as a simple, robust, and broadly applicable alignment platform for ΔRCSA measurements, thereby expanding the utility of anisotropic NMR for structural elucidation and chiral molecular characterization.