Improving the accuracy of ¹ H-¹⁹ F internuclear distance measurement using 2D ¹ H-¹⁹ F HOESY

With the rise in fluorinated pharmaceuticals, it is becoming increasingly important to develop new ¹⁹ F NMR-based methods to assist in their analysis. Crucially, obtaining information regarding the conformational dynamics of a molecule in solution can aid the design of strongly binding therapeutics. Herein, we report the development of a 2D ¹ H-¹⁹ F Heteronuclear Overhauser Spectroscopy (HOESY) experiment to measure ¹ H-¹⁹ F internuclear distances, with accuracies of ~5% when compared with ¹ H-¹⁹ F internuclear distances calculated by quantum chemical methods. We demonstrate that correcting for cross-relaxation of ¹ H, using the diagonal peaks from the 2D ¹ H-¹ H Nuclear Overhauser Enhancement Spectroscopy (NOESY), is critical in obtaining accurate values for ¹ H-¹⁹ F internuclear distances. Finally, we show that by using the proposed method to measure ¹ H-¹⁹ F internuclear distances, we are able to determine the relative stereochemistry of two fluorinated pharmaceuticals.