Improving the accuracy of 1H–19F internuclear distance measurement using 2D 1H–19F HOESY |
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| Authors: | Lydia Dewis Ron Crouch Dave Russell Craig Butts |
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| Institution: | 1. Genentech Inc, South San Francisco, CA, USA;2. JEOL USA Inc, Peabody, MA, USA;3. School of Chemistry, University of Bristol, Bristol, UK |
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| Abstract: | 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. |
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| Keywords: | 19F 1H HOESY NMR PANIC quantitative 1H–19F distances |
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