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

Abstract

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.

Stereochemical Analysis of Trifluoroacetamide Derivatives Based on Through-Space 1H–19F Spin–Spin Couplings

“…It is worth mentioning that the coupling constants ( 5 J HF = 1.4–1.8 Hz) (Table ) associated with through- space coupling in compounds 1 and 2 are smaller than those in 2′-fluoro-substituted acetophenones ( 5 J HF = 3.2–5.0 Hz), as reported in our previous study (Figure ). The TBC constants ( 5 J HF ) of most compounds are generally less than 1 Hz, which is similar in magnitude to those observed for compounds 1 and 2 . However, it should be noted that, although 1 H– 19 F coupling was observed in one of the diastereotopic protons (H 6a ′ and H 4a ′ in compounds 1 and 2 , respectively), no such couplings were observed for other diastereotopic protons (H 6b in compound 1 and H 4b in compound 2 ), which are both five bonds apart from the F in CF 3 group.…”

“…Two nuclei, such as 19 F/ 19 F, 19 F/ 1 H, and 19 F/ 13 C, can exchange spin information when in van der Waals contact through space, regardless of the number of chemical bonds separating them. 4 In the course of our studies on the syntheses of bioactive compounds, 5 we accidentally observed TSCs with significant magnitudes ( 5 J HF = 3.2−5.0 Hz) in the 1 H NMR spectra of 2′fluoro-substituted acetophenone derivatives. These TSCs revealed that 2′-fluoro-substituted acetophenone derivatives in solution exclusively form s-trans conformers (Figure 1).…”

“…These TSCs revealed that 2′-fluoro-substituted acetophenone derivatives in solution exclusively form s-trans conformers (Figure 1). 5 Additionally, the principles of TSC have been used to distinguish between amide conformations in recent years. 6 These studies prompted us to elucidate the conformational properties of trifluoroacetamides based on their TSCs.…”

“…These TSCs revealed that 2′-fluoro-substituted acetophenone derivatives in solution exclusively form s - trans conformers ( Figure 1 ). 5 Additionally, the principles of TSC have been used to distinguish between amide conformations in recent years. 6 …”

Molecular dynamics and NMR reveal the coexistence of H-bond-assisted and through-space JFH coupling in fluorinated amino alcohols

“…Heteronuclear nOe (nuclear Overhauser effect) was observed between H8 and fluorine atom, indicating spatial proximity between these nuclei and bringing to the discussion the possibility of a through-space transmission pathway via intramolecular H-bond ( 1h J FH8 ), instead of a solely through bond transmission pathway ( 4 J FH8 ). Recently, studies conducted by Takahashi and coworkers 48,49 and by Suryaprakash and coworkers 50–53 have also employed 1 H– 19 F HOESY experiment to confirm the presence of intramolecular H-bond. What is intriguing about these compounds is the presence of this kind of interaction in a polar solvent such as DMSO- d 6 , once it is expected that the solvent molecules would prefer to interact with the solute, thus breaking the intramolecular H-bond.…”