The Fluorine Gauche Effect: A Brief History

Abstract

AbstractTransforming the fluorine gauche effect from an academic curiosity into a powerful acyclic conformational control strategy has enriched molecular design. This expansive approach to modulating structure has proven to be particularly valuable in the construction of functional small molecules, thereby finding application in diverse disciplines, ranging from therapeutic medicine to enantioselective catalysis. In contrast to the well‐established arsenal of conformational control tactics, in which conformer populations result from minimising nonbonding interactions, (e.g., A1,3‐ or A1,2‐strain), the fluorine gauche effect is attributable to stabilising interactions comprised of two components: stereoelectronic and electrostatic. Conformer populations are partially determined by favourable, hyperconjugative interactions involving proximal electron‐rich σ‐bonds, π‐systems, and nonbonding electron pairs with the antibonding orbital of the C−F σ‐bond: σ→σ*, π→σ*, and n→σ*, respectively. Electrostatic, charge‐dipole interactions (e.g., N+⋅⋅⋅Fδ−) also play a crucial role in stabilising what are often counter‐intuitive conformations. These noncovalent interactions, permissible on account of the low van der Waals radius and high electronegativity of the fluorine atom, render this effect fundamentally important and practically valuable in structural chemistry. In this contribution to the Rosarium Philosophorum in honour of Prof. Jack David Dunitz FRS, we endeavour to delineate, albeit in an abridged form, the evolution of the fluorine gauche effect from a fundamental spectroscopic study to a ubiquitous component of physical organic chemistry.