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

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 antitumoral 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 aprotic solvent and the value of JFF coupling was established. The molecule is very flexible in solution showing cis and trans amide conformers which are in slow exchange on the NMR time scale. 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.