The Fluorine gauche Effect and a Comparison with Other Halogens in 2‐Halofluoroethanes and 2‐Haloethanols

Abstract

While the gauche effect in 1,2‐difluoroethane is widely known as being due to hyperconjugative interactions between σCH electron‐donating orbitals and σ*CF electron‐accepting orbitals, the corresponding 1,2‐dichloro, 1,2‐dibromo, and 1,2‐diiodo derivatives are preferentially in the anti conformation. 2‐Halofluoroethanes (F‐CH2‐CH2‐X) combine a small halogen (fluorine) and a vicinal low‐lying energy antibonding orbital (σ*CX) that activates a stabilizing antiperiplanar σCH → σ*CX electron delocalization, which can induce the gauche effect. On the other hand, σCX orbitals are good electron donors to σ*CF, that would favor an “anti effect”, in addition to traditional interpretations based on steric and electrostatic repulsion. Therefore, a balance of steric, dipolar and hyperconjugative effects drive the conformational equilibrium of these compounds – hyperconjugation was found to explain the gauche effect in some cases, whilst Lewis‐type interactions determine the anti preference in others. The gauche effect takes place in a polar solvent, but not for 1‐fluoro‐2‐iodoethane. According to NMR three‐bond spin‐spin coupling constants, the gauche population increases when fluorine is replaced by a hydroxyl group (except for 2‐fluoroethanol relative to 1,2‐difluoroethane), but this is not primarily due to intramolecular hydrogen bond.

Stereoelectronic Effects Impact Glycan Recognition

“…The computationally-derived values in Table S4 are on par with previously published values. 38 The low energy L,D-heptose conformation is incompatible with hItln-1 complexation. This analysis is consistent with the binding data indicating D,D-heptose is a better hItln-1 ligand.…”

Fluorine‐Labelled Spiro[3.3]heptane‐Derived Building Blocks: Is Single Fluorine the Best?

“…[11] Meanwhile, introducing the fluorine atom proximal to functional group into flexible building blocks can alter the conformational preferences of the target system because of the structural features contributing to a gauche effect between these key moieties. [14][15][16][17] This issue can be addressed with conformationally rigid sp 3 -enriched building blocks bearing fluorine atom (label) at the outward position. At the same time, monofluorinated cycloalkane derivatives do not meet the above requirements because of interconversion between isoenergetic (or close in energy) conformers.…”

Fluorine conformational effects characterized by energy decomposition analysis

“…In previous computational works, [17][18][19] the natural bond orbital (NBO) method 20 arising when adjacent C-H and C-F bonds align antiparallel. However, the ability of NBO to provide a right balance between Lewis (i.e.…”