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

Chinatsu Otake, Takuya Namba, Hidetsugu Tabata, Kosho Makino, Kiriko Hirano, Tetsuta Oshitari, Hideaki Natsugari, Takenori Kusumi, Hideyo Takahashi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4638-4645
Number of pages8
JournalJournal of Organic Chemistry
Volume86
Issue number6
DOIs
Publication statusPublished - 19 Mar 2021

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