Energetic insights into the fluorination of Cyclobutane: Mono- and Difluorocyclobutanes

Abstract

Cyclobutane, a key cycloalkane in various functional compounds, including pharmaceuticals, exhibits significant property modifications upon fluorination, such as altered conformation, polarity, and lipophilicity. This quantum-chemical study, performed at the G3MP2B3 level, investigates the effects of mono- and difluorination of cyclobutane. It examines the energetics of incorporating axial and equatorial fluorines at geminal, vicinal, and 1,3-relative positions. Isodesmic reaction analysis reveals that fluorination of cyclobutane is thermodynamically favorable overall. However, introducing axial fluorine is less energetically favorable, rendering diaxial trans-1,2- and cis-1,3-cyclobutanes unstable. Among the isomers, 1,1-difluorocyclobutane achieves notable stabilization via an anomeric-like interaction (n_F → σ*_CF), whereas other isomers experience greater destabilization due to Lewis-type interactions compared to electron delocalization. Axial and equatorial C − F bonds can be distinguished by their ¹J_CF coupling constants. These insights are valuable for the rational design of fluorinated cyclobutane derivatives with properties influenced by the stereochemical arrangement and relative positioning of fluorine atoms.