Improving the Sensitivity of Enantioanalysis with Densely Fluorinated NMR Probes

Abstract

Nuclear magnetic resonance (NMR) spectroscopy has long been utilized as a classic method for chiral discrimination of enantiomers. However, its sensitivity limitations have hindered the detection of analytes at low concentrations. In this study, we present our efforts to overcome this challenge by employing chiral NMR probes that are labeled with a significant number of chemically equivalent ¹⁹F atoms. Specifically, we have designed and synthesized three chiral palladium pincer complexes, all of which are labeled with nonafluoro-<i>tert</i>-butoxy groups to enhance detectability. The recognition of enantiomers with the probe induces distinct changes in microenvironments, resulting in differential perturbations on the chemical shift of the ¹⁹F atoms in proximity. This method is applicable to the enantiodifferentiation of various amines, amino alcohols, and amino acid esters. The abundance of ¹⁹F atoms enables the detection of chiral analytes at low concentrations, which is otherwise challenging to achieve through traditional ¹H NMR-based analysis. Two of the probes are constructed with asymmetric pincer ligands with structurally varied sidearms, allowing for facile manipulation of the chiral binding pocket. The C₂ symmetrical probe possesses 36 equivalent ¹⁹F atoms, enabling the determination of enantiocomposition of samples with concentrations in the low micromolar range.