Year: 2025
Type: article
Abstract: Cyclopropane is a significant alicyclic motif, widely utilized in medicinal chemistry, while fluorination serves as a powerful tool to modulate properties that enhance the performance of pharmaceuticals and materials. This quantum-chemical study explores the energetic implications of fluorinating cyclopropane, providing insights into molecular characteristics arising from the polar C–F bond. Isodesmic reactions revealed that the conversion of cyclopropane and methyl fluoride into mono-, di-, tri-, tetra-, penta-, and hexafluorinated cyclopropanes is exothermic, except for the all- cis -1,2,3-trifluorocyclopropane ( 1.2.3-c.c. ). Compounds featuring geminal fluorines are particularly stabilized due to anomeric-like n F → σ* CF interactions. Generally, cis -C–F bonds are less favored than their trans counterparts, not primarily because of steric repulsion, but due to reduced stabilizing electron-delocalization interactions. Among the series, 1.2.3-c.c. stands out as the most polar compound, enabling unique stacking interactions between its electrostatically complementary negative and positive faces. These interactions are mediated through electrostatic hydrogen bonds. This "Janus-like" polarity also facilitates interactions with ions, particularly sodium and chloride. These findings contribute valuable insights for the rational design of drugs and advanced materials, particularly those whose properties rely on the polarity and spatial arrangement of C–F bonds within a cyclopropane framework.
DOI: 10.3762/bjoc.21.137
Author: Matheus P Freitas
Institution: Universidade Federal de Lavras
Language: English
Subfield: Pharmaceutical Science
Domain: Life Sciences
Open Access status: diamond
Award: G1862978056
OpenAlex ID: W4413806760