How Fluorination Collapses Inversion Barriers and Increases Electrophilicity in Bicyclo[1.1.0]butanes

Abstract

Bicyclo[1.1.0]butane (BCB) is a highly strained framework whose reactivity arises from the predominant p-character of its central C-C bond. Using density functional theory (DFT) and Natural Bond Orbital (NBO) analysis, we show that progressive fluorination reduces BCB inversion barriers dramatically from ~64 kcal mol -1 in BCB to ~3.6 kcal mol -1 in the perfluorinated analogue. NBO decomposition reveals that bridgehead substitution (C1/C3) maximizes hyperconjugative stabilization via nF → σ*CC interactions but introduces significant steric penalties, whereas C2/C4 substitution offers a more favorable balance between these competing effects. Fluorination also systematically lowers LUMO energies, particularly at C1/C3, directly enhancing electrophilicity, as evidenced by computed activation barriers for nucleophilic attack by dibenzylamine that drop from 44.2 kcal mol⁻¹ (BCB) to 6.5 kcal mol⁻¹ (hexafluorinated), rendering highly fluorinated BCBs reactive under mild conditions. These structure-reactivity relationships provide a predictive framework for designing fluorinated strained building blocks in synthetic and medicinal chemistry.