Conformational Preference of 2′-Fluoro-Substituted Acetophenone Derivatives Revealed by Through-Space (1)H–(19)F and (13)C–(19)F Spin–Spin Couplings

[Image: see text] The conformational properties of 2′-fluoro-substituted acetophenone derivatives were elucidated based on H(α)–F and C(α)–F through-space spin–spin couplings (TS-couplings), which occur between two atoms constrained at a distance smaller than the sum of their van der Waals radii. This study revealed that 2′-fluoro-substituted acetophenone derivatives in solutions form exclusively s-trans conformers by analyzing their NMR spectra focused on the TS-couplings. The magnitudes of the coupling constants (5)J (H(α), F) and (4)J (C(α), F) correlate linearly with the value of the dielectric constant of the solvents. Furthermore, s-trans conformations of the two derivatives were confirmed by X-ray crystallographic analysis. These conformational preferences were consistent with the DFT calculations. The s-cis conformer, in which fluorine and oxygen atoms lie in a syn-periplanar mode, may be subject to strong repulsion between the two polar atoms and become unstable. The s-trans preference of the 2′-fluoro-substituted acetophenone derivatives may be utilized in drug design.