Conformational impact of structural modifications in 2-fluorocyclohexanone

Abstract

2-Haloketones are building blocks that combine physical, chemical and biological features of materials and bioactive compounds, while organic fluorine plays a fundamental role in the design of performance organic molecules. Since these features are dependent on the three-dimensional chemical structure of a molecule, simple structural modifications can affect its conformational stability and, consequently, the corresponding physicochemical/biological property of interest. In this work, structural changes in 2-fluorocyclohexanone were theoretically studied with the aim at finding intramolecular interactions that induce the conformational equilibrium towards the axial or equatorial conformer. The interactions evaluated were hydrogen bonding, hyperconjugation, electrostatic and steric effects. While the gauche effect, originated from hyperconjugative interactions, does not appear to cause some preferences for the axial conformation of organofluorine heterocycles, more classical effects indeed rule the conformational equilibrium of the compounds. Spectroscopic parameters (NMR chemical shifts and coupling constants), which can be useful to determine the stereochemistry and the interactions operating in the series of 2-fluorocyclohexanone derivatives, were also calculated.

Evaluation of the Alicyclic Gauche Effect in 2‐Fluorocyclohexanone Analogs: a Combined NMR and DFT Study

“…Thus, if the N-Boc group is continuously reduced to form analog 4 (which possesses only a hydrogen attached to the nitrogen atom, resembling part of the active nucleus of a 4-quinolone), then one can see a totally different trend (Table 2, see Table S3 in the Supporting Information for details). The conformational analysis of 4 has already been reported in the literature, [22] where the stability of the global energy minimum (which have both fluorine and Nhydrogen atoms in the axial, 4 F-ax H-ax in Figure S1) is attributed to an N-H δ+ ··· δ-F electrostatic interaction (in line with our NBO results in Table S3). This effect becomes stronger by protonating the amine group (to form analog 5, the 3-fluoro-4-oxopiperidin-1-ium cation, in Table 2; schematic representation in Figure S1).…”

“…Even without the influence of the ketone group in 3' , the energy difference between axial and equatorial conformers ( gauche and anti , respectively) is too small to observe any substantial stabilization due to the gauche effect. Earlier reports in the literature, have evaluated other endocyclic groups at the same position of the 2‐fluorocyclohexanone backbone known to induce the gauche effect in acyclic compounds (e.g. X = O and S).…”

“…Earlier reports in the literature, have evaluated other endocyclic groups at the same position of the 2‐fluorocyclohexanone backbone known to induce the gauche effect in acyclic compounds (e.g. X = O and S). However, in all cases the conformational trends could not be attributed to hyperconjugation.…”

Conformational preferences of fluorine-containing agrochemicals and their implications for lipophilicity prediction

“…The lowest energy minimum conformation of each compound was then reoptimized and the dipole moment determined using a higher level of theory, ωB97X-D/6-311++G(d,p) [16,18], in the Gaussian 09 software [31]. The geometries and dipole moments for compounds 1-11 were calculated at the same level, which has been successfully applied to predict the conformational energies of other fluorine-containing compounds [32][33][34]. Frequency calculations were performed to confirm that the optimized geometries were true energy minima (no imaginary frequency) and to estimate thermodynamic energies, at 298.15 K. Solvent effects were accounted for by geometry optimization using the integral equation formalism variant of the polarizable continuum model (IEFPCM) [35].…”

Conformational Preferences of Fluorine-Containing Agrochemicals and their Implications for Lipophilicity Prediction

“…The lowest energy minimum conformation of each compound was then re-optimized and the dipole moment determined using a higher level of theory, B97X-D/6-311++G(d,p) [14,16], in the Gaussian 09 software [29]. The geometries and dipole moments for compounds 1-11 were calculated at the same level, which has been successfully applied to predict the conformational energies of other fluorine-containing compounds [30][31][32]. Solvent effects were accounted by using the integral equation formalism variant of the Polarizable Continuum Model (IEFPCM) [33].…”