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

• Published in: Magnetic resonance in chemistry Vol. 57; no. 12; pp. 1143 - 1149
• Main Authors: Dewis, Lydia, Crouch, Ron, Russell, Dave, Butts, Craig
• Format: Journal Article
• Language: English
• Published: Bognor Regis Wiley Subscription Services, Inc 01.12.2019
• Subjects: 19F; Distance measurement; Fluorination; HOESY; NMR; Nuclear magnetic resonance; Organic chemistry; PANIC; Pharmaceuticals; quantitative 1H–19F distances; Quantum chemistry; Spectrum analysis; Stereochemistry
• ISSN: 0749-1581; 1097-458X
• DOI: 10.1002/mrc.4904

With the rise in fluorinated pharmaceuticals, it is becoming increasingly important to develop new 19F 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 1H–19F Heteronuclear Overhauser Spectroscopy (HOESY) experiment to measure 1H–19F internuclear distances, with accuracies of ~5% when compared with 1H–19F internuclear distances calculated by quantum chemical methods. We demonstrate that correcting for cross‐relaxation of 1H, using the diagonal peaks from the 2D 1H–1H Nuclear Overhauser Enhancement Spectroscopy (NOESY), is critical in obtaining accurate values for 1H–19F internuclear distances. Finally, we show that by using the proposed method to measure 1H–19F internuclear distances, we are able to determine the relative stereochemistry of two fluorinated pharmaceuticals. Accurate 1H–19F distances can be obtained from 2D 1H–19F HOESY Nuclear Magnetic Resonance (NMR) experiments by correcting for differential relaxation of the 1H nuclei using the intensity of diagonal peaks from the corresponding 2D 1H–1H NOESY. The resulting internuclear distances were compared with those calculated by quantum chemical methods and showed <5% average deviations, in line with the accuracy obtained for 1H–1H distances in previous studies.