Theoretical and X-ray Crystallographic Evidence of a Fluorine-Imine Gauche Effect: An Addendum to Dunathan's Stereoelectronic Hypothesis

The preference of β‐fluoroimines to adopt a gauche conformation has been studied by single‐crystal X‐ray diffraction analysis and DFT methods. Empirical and theoretical evidence for a preferential gauche arrangement around the NCCF torsion angle (?) is presented ((E)‐2‐fluoro‐N‐(4‐nitrobenzylidene)ethanamine: ?_NCCF=70.0°). In the context of this study, the analysis of a pyridoxal‐derived β‐fluoroaldimine was performed, a species that is implicated in the inhibition of pyridoxal phosphate (PLP)‐dependent enzymes by β‐fluoroamine derivatives. The gauche preference of the internal aldimine (=NCH₂CH₂F) that can be rationalized by stereoelectronic arguments does not hold for the corresponding external system (N?CHCH₂F) (E_min when ?_NCCF=120°). Moreover, the C? F bond is lengthened by more than 0.02 Å at ?_NCCF=±90°, when it is exactly antiperiplanar to the conjugated imine. This activation of the C? F σ bond by an adjacent π system constitutes an addendum to Dunathan’s stereoelectronic hypothesis.