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

Abstract

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.