Paper
Conformational Preference of 2′-Fluoro-Substituted Acetophenone Derivatives Revealed by Through-Space 1H–19F and 13C–19F Spin–Spin Couplings
Published Mar 1, 2021 · Chinatsu Otake, T. Namba, H. Tabata
The Journal of Organic Chemistry
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Abstract
The conformational properties of 2′-fluoro-substituted acetophenone derivatives were elucidated based on Hα–F and Cα–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 5J (Hα, F) and 4J (Cα, 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.
2′-fluoro-substituted acetophenone derivatives exclusively form s-trans conformers, which may be useful in drug design due to their stability and potential repulsion between fluorine and oxygen atoms.
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