Experimental and Theoretical Characterization of Short H-Bonds with Organic Fluorine in Molecular Crystals

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The existence of short H-bonds with organic fluorine is still under debate. We report herein the occurrence and nature of such short contacts to fluorine connected to an aromatic ring in the block form of N-(4-fluorophenyl)-3-(trifluoromethyl) benzamide and 4-fluoro-N-[3-(trifluoromethyl)phenyl]benzamide. The magnitude of the stabilizing interaction energy is −2.15 and −2.89 kcal/mol, respectively. It is important to note that such contacts have been observed in the presence of strong N—H···O═C H-bonds whose energies are in the range of 6.0–8.0 kcal/mol. Thus, the observed strength of an H-bond with fluorine is ∼30–40% of the strength of a strong traditional H-bond in amides. The acidic hydrogens were observed to be involved in the formation of a short C—H···F contact, the interaction energy having a substantial Coulombic contribution in comparison to the other weak interactions which are primarily of a dispersive character as obtained by PIXEL method. A full topological analysis does establish the fact that C—H···F interactions at short distances are indeed a “true H-bond”. These are not a consequence of crystal packing and have implications in the generation of polymorphs in the solid state. This is expected to have implications in the binding of a ligand (organic molecule containing fluorine) with the protein active site.