The hydrogen bond between N—H or O—H and organic fluorine: favourable yes, competitive no

A study was made of X—H...F—C interactions (X = N or O) in small-molecule crystal structures. It was primarily based on 6728 structures containing X—H and C—F and no atom heavier than chlorine. Of the 28 451 C—F moieties in these structures, 1051 interact with X—H groups. However, over three-quarters of these interactions are either the weaker components of bifurcated hydrogen bonds (so likely to be incidental contacts) or occur in structures where there is a clear insufficiency of good hydrogen-bond acceptors such as oxygen, nitrogen or halide. In structures where good acceptors are entirely absent, there is about a 2 in 3 chance that a given X—H group will donate to fluorine. Viable alternatives are X—H...π hydrogen bonds (especially to electron-rich aromatics) and dihydrogen bonds. The average H...F distances of X—H...F—C interactions are significantly shorter for CR₃F (R = C or H) and Csp²—F acceptors than for CRF₃. The X—H...F angle distribution is consistent with a weak energetic preference for linearity, but that of H...F—C suggests a flat energy profile in the range 100–180°. X—H...F—C interactions are more likely when the acceptor is Csp²—F or CR₃F, and when the donor is C—NH₂. They also occur significantly more often in structures containing tertiary alcohols or solvent molecules, or with Z′ > 1, i.e. when there may be unusual packing problems. It is extremely rare to find X—H...F—C interactions in structures where there are several unused good acceptors. When it does happen, there is often a clear reason, e.g. awkwardly shaped molecules whose packing isolates a donor group from the good acceptors.