Hydrogen Bonding and Intermolecular Interactions in Organic Fluorine Compounds

Organic fluorine compounds occupy a unique position in chemistry owing to fluorine’s high electronegativity and small size, which confer distinctive noncovalent interaction patterns. Unlike classical hydrogen bond acceptors such as oxygen or nitrogen, the C–F moiety engages only weakly as a hydrogen bond acceptor, yet its presence can subtly influence molecular conformation, crystal packing and binding in biological systems. Intramolecular C–H⋯F contacts may stabilise particular conformers, while intermolecular interactions such as C–H⋯F, F⋯F contacts and halogen-bonding-like motifs govern solid-state architectures and material properties. Advances in high-resolution nuclear magnetic resonance, crystallography and quantum-chemical methods have revealed that although individual F-involving hydrogen bonds are relatively weak, their cumulative and cooperative effects contribute critically to molecular recognition, drug design and supramolecular assembly. Furthermore, the modulation of neighbouring interactions—electrostatic, dispersion and σ-hole features—permits fine tuning of binding selectivity in protein–ligand complexes and the design of novel functional materials. Current research seeks to quantify the energetic balance between electrostatic and dispersion contributions, to map the directional preferences of fluorine contacts and to exploit these insights in areas ranging from pharmaceuticals to crystal engineering.

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Hydrogen Bonding and Intermolecular Interactions in Organic Fluorine Compounds publication trend

The graph below shows the total number of articles in hydrogen bonding and intermolecular interactions in organic fluorine compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Hydrogen bond: A directional noncovalent attraction between an electropositive hydrogen atom bonded to a donor atom (e.g. C, N, O) and an electronegative acceptor atom, here often fluorine.

Noncovalent interaction: A general term encompassing hydrogen bonds, van der Waals forces, electrostatic attractions and other weak forces that do not involve shared electron pairs.

σ-Hole: A region of positive electrostatic potential on a covalently bonded atom (e.g. halogen) opposite a bonding partner, capable of engaging in attractive interactions with electron donors.

Dispersion forces: Attractive interactions arising from instantaneous fluctuations in electron density, significant in stabilising close-packed molecular assemblies.

References

1. Intramolecular Hydrogen Bonding Involving Organic Fluorine: NMR Investigations Corroborated by DFT-Based Theoretical Calculations. Molecules (2017).
2. Hydrogen Bonds with Fluorine in Ligand–Protein Complexes-the PDB Analysis and Energy Calculations. Molecules (2022).
3. Experimental and computational insights into the nature of weak intermolecular interactions in trifluoromethyl-substituted isomeric crystalline N -methyl- N -phenylbenzamides. New Journal of Chemistry (2015).