Structural adaptability of aromatic F⋯O contacts: insights from crystal geometry, charge effects and energy decomposition

Abstract Quantum-mechanical calculations combined with geometric analysis of crystallographic data from the Cambridge Structural Database were used to investigate relatively unexplored aromatic F⋯O interactions. These contacts are slightly weaker than those involving aliphatic fluorine, yet their solid-state geometric distributions are remarkably similar. Neutral aromatic systems exhibit weak interaction energies (−1.1 to −1.5 kcal/mol), whereas introducing a positive charge on either interacting species significantly strengthens the interaction, often exceeding −6 kcal/mol and surpassing the hydrogen-bond strength between two water molecules. Despite this energetic sensitivity to charge, crystallographic geometries remain largely invariant, indicating a dominant influence of environmental and packing effects on supramolecular organization. Energy decomposition analysis shows that aromatic fluorine substituents enhance dispersion and exchange stabilization while increasing Pauli repulsion, explaining their weaker interactions relative to aliphatic analogues. Model systems with oppositely charged species display strong electrostatic stabilization, with interaction energies reaching −61.5 kcal/mol. QTAIM analysis confirms the non-covalent character of aromatic F⋯O contacts and reveals frequent cooperative interactions supporting their structural adaptability. Molecular docking indicates that charge has limited influence on binding modes of fluorinated ligands, whereas increased fluorination enhances binding strength without altering preferred binding sites.