Conformational analysis of 2,2-difluoroethylamine hydrochloride: double gauche effect

Abstract

SummaryThe gauche effect in fluorinated alkylammonium salts is well known and attributed either to an intramolecular hydrogen bond or to an electrostatic attraction between the positively charged nitrogen and the vicinal electronegative fluorine atom. This work reports the effect of adding a fluorine atom in 2-fluoroethylamine hydrochloride on the conformational isomerism of the resulting 2,2-difluoroethylamine chloride (2). The analysis was carried out using NMR coupling constants in D2O solution, in order to mimic the equilibrium conditions in a physiological medium, in the gas phase and in implicit water through theoretical calculations. Despite the presence of σCH→σ*CF and σCH→σ*CN interactions, which usually rule the hyperconjugative gauche effect in 1,2-disubstituted ethanes, the most important forces leading to the double gauche effect (+NH3 in the gauche relationship with both fluorine atoms) in 2 are the Lewis-type ones. Particularly, electrostatic interactions are operative even in water solution, where they should be significantly attenuated, whereas hyperconjugation and hydrogen bond have secondary importance.

Conformational impact of structural modifications in 2-fluorocyclohexanone

“…On the other hand, the equatorial conformer is preferred when X = S and NH eq (except for Y = NH E ). While the axial preference for compounds with X = NH ax can be determined by an electrostatic, dipolar relaxation F···H ax N (since an intramolecular hydrogen bond has not been clearly demonstrated in 3-fluoropiperidine [ 7 – 13 ]), such behavior for compounds with X = CH 2 seems to be dependent on the C=Y bond, since X = CH 2 is not a good proton donor. In this case, the axial population increases according to Y = CH 2 < O < S, since the π* C=C is a bad electron-acceptor orbital in σ C–H2ax → π* C=Y electron delocalizations and the classical steric/electrostatic repulsion of O and S with the equatorial fluorine is remarkable.…”

“…This is the origin of the so-called 'gauche effect', because electronegative C–X bonds do not participate in such hyperconjugative interactions and therefore often give way to the C–H bond in occupying the antiperiplanar orientation relative to the C–F bond [ 2 – 6 ]. The electrostatic fluorine gauche effect has also been introduced in cases where the partially negative fluorine interacts with a positive nitrogen, such as in the 3-fluoropiperidinium cation [ 7 – 13 ].…”

Intramolecular interactions contributing for the conformational preference of bioactive diphenhydramine: Manifestation of the gauche effect

“…According to earlier studies for compounds containing the F-C-C-N + fragment [8][9][10][27][28][29][30][31], the preferred gauche arrangement along this fragment has strong contribution from the electrostatic attraction between the electronegative fluorine substituent and the positively charged nitrogen. According to NBO analysis, the gauche conformers are far more stabilized by hyperconjugation than the anti geometries (Table 1), whose important contribution comes from r CH ?…”

“…Organofluorine compounds, e.g. the milestone 1,2-difluoroethane, are known to exhibit the gauche effect, because they have low-lying r ⁄ C-F orbitals and, therefore, antiperiplanar hyperconjugative electron donation from relatively good donor orbitals (r CH for 1,2-difluoroethane) to the electron acceptor r ⁄ C-F orbital stabilize the gauche conformation, overriding steric or electrostatic repulsions between the adjacent electronegative substituents in an ethane fragment [2][3][4] of the gauche effect in fluorinated compounds can also be due to electrostatic interactions [5][6][7], in which the negatively charged fluorine interacts with the positive nitrogen in b-fluoro-N-ethylpyridinium/ammonium salts [8][9][10], or due to hydrogen bonding, in which the proximity of gauche fluorine and hydroxyl groups allows the establishment of hydrogen bonds [11]. However, the gauche effect in non-fluorinated compounds has been less explored, despite the prospective framework of some relevant molecules to exhibit this effect, i.e.…”

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

“…Yet, conformer I gg is not the global energy minimum. This is surprising, because all- gauche conformations in fluoropropanediol are strongly preferred [ 21 ], while the double gauche effect in difluoroethylamine and its hydrochloride salt stabilizes the gg over ag conformations [ 22 ]. Therefore, I ag is the global energy minimum because it experiences a more stabilizing Δ E L term.…”