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

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.