Conformational Preference of 2'-Fluoro-Substituted Acetophenone Derivatives Revealed by Through-Space H-F and C-F Spin-Spin Couplings.

The conformational properties of 2'-fluoro-substituted acetophenone derivatives were elucidated based on H-F and C-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 - conformers by analyzing their NMR spectra focused on the TS-couplings. The magnitudes of the coupling constants (H, F) and (C, F) correlate linearly with the value of the dielectric constant of the solvents. Furthermore, - conformations of the two derivatives were confirmed by X-ray crystallographic analysis. These conformational preferences were consistent with the DFT calculations. The - conformer, in which fluorine and oxygen atoms lie in a -periplanar mode, may be subject to strong repulsion between the two polar atoms and become unstable. The - preference of the 2'-fluoro-substituted acetophenone derivatives may be utilized in drug design.