Chiral analysis by ¹⁹F NMR in PBLG-based weakly orienting media, from high-field to benchtop FT-spectrometers

We present the first and efficient spectral resolution of enantiomeric mixtures using cryogenic free benchtop Fourier Transform (FT)-NMR instruments operating at 1.0 and 1.9 T. Measured in chiral-oriented solvents, enantiomeric discrimination of trifluoromethylated analytes is primarily achieved through ¹⁹F residual dipolar coupling (RDC) differences, which is independent of the magnetic field strength of spectrometers. This approach is therefore applicable to a wide range of B₀ magnetic fields, in contrast to isotropic NMR approaches involving chiral agents, in which the difference of chemical shift between enantiomers, expressed in frequency units, is considerably reduced at low magnetic fields. In this methodology, the chiral enantiodiscriminating medium is a lyotropic liquid crystal (LLC) based on Poly-γ-benzyl-L-glutamate (PBLG) - a commercially available polymer - dissolved in a non-deuterated organic solvent. ¹⁹F 1D NMR experiments performed on illustrative enantiomeric mixtures - involving various chemical functions - aligned in the PBLG-based LLCs lead to enantioresolution factors E from 1.7 to 3.9 with low-field benchtop NMR systems. The B₀ dependence of the cholesteric-to-nematic phase transition undergone by PBLG mesophases is also explored, in order to determine the necessary time for reaching a nematic steady state. Finally, the analytical performance is evaluated on LLC samples containing a chiral active pharmaceutical ingredient (Fluoxetine) in the tens of millimolar range. No systematic quantitative bias was observed in the relative quantitation of enantiomers, which can be addressed with a standard deviation lower than 2%, for 11 min of NMR signal averaging at 1.9 T.