Unrecognized Intramolecular and Intermolecular Attractive Interactions between Fluorine-Containing Motifs and Ether,...

In order to elucidate to what extent Coulombic and other interactions contribute to the origins of contrasteric phenomena, we have identified a significant, previously unrecognized interaction between fluorine-containing motifs and groups or molecules containing main-group heteroatoms. The axial conformers of both 2-methoxy- and 2-trifluoromethoxytetrahydropyrans preferentially adopt a rotameric arrangement in which the OCH₃ and the OCF₃ groups are gauche to the ring oxygen. Given that one would expect a repulsive Columbic interaction to exist between the electronegative fluorines of the CF₃ group and the ring oxygen in this rotomeric orientation, this surprising result suggests that an attractive interaction exists between the CF₃ group and the oxygen of the ring. The generality and origin of this interaction was examined using nonpolar CF₄ to probe intermolecular interactions with systems such as dimethyl ether, trimethylamine, trimethylphosphine, and acetone. In each case there was an attractive interaction leading to formation of a complex. The attraction is not due to van der Waals forces. Rather, the fluorine lone pairs of the CF₄ often act as an electron donor in these complexes leading to a transfer of charge between the reactants and formation of the complex. These previously unrecognized fluorine-heteroatom interactions likely play a significant role in the context of understanding the binding interactions of medicinally relevant molecules or pharmaceuticals possessing fluorine-containing pharmacophores with their targets.