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Fluorine NMR spectroscopy and computational calculations for assessing intramolecular hydrogen bond involving fluorine and for characterizing the dynamic of a fluorinated molecule

Dalvit, Claudio and Piotto, Martial and Vulpetti, Anna (2017) Fluorine NMR spectroscopy and computational calculations for assessing intramolecular hydrogen bond involving fluorine and for characterizing the dynamic of a fluorinated molecule. Journal of fluorine chemistry, 202. pp. 34-40. ISSN 00221139

Abstract

Intramolecular hydrogen bonds directly involving fluorine atoms are important for pre-organizing the molecule in a defined conformation and for improving the cell permeability of a molecule. Several NMR observable parameters can be used for detecting these intramolecular hydrogen bonds. The two fluorine atoms of the molecule 2-chloro-6-fluoro-N-(4-fluoro-1-methyl-1H-indazol-3yl)benzamide, which is a binder of the target telomeric repeat-containing RNA (TERRA), display through-space JFF coupling values in water and different aprotic solvents. A correlation between the dielectric constant of the solvent and the value of JFF coupling was established. The conformation of the molecule with large JFF is consistent with the presence of a transient intramolecular hydrogen bond involving the two fluorine atoms and the NH of the amide. However, the molecule is very flexible in solution and can adopt at least another conformer of lower population with a larger distance between the two fluorine atoms. The kinetics and thermodynamic parameters of this conformational equilibrium have been characterized using different 19F NMR experiments. Ab initio calculations performed in different solvents reveal the presence of several conformers which are separated by low energy barriers. The computed weighted distance between the two fluorine atoms is in agreement with the JFF values measured experimentally. The conformational flexibility of the molecule could be relevant for its binding to the telomeric repeat-containing RNA.

Item Type: Article
Date Deposited: 07 Oct 2017 00:45
Last Modified: 07 Oct 2017 00:45
URI: https://oak.novartis.com/id/eprint/33176

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