C–F Bond Activation and Functionalization in Organic Synthesis

The incorporation of fluorine into organic molecules often confers enhanced stability, lipophilicity and metabolic resilience, but the exceptionally strong and nonpolar nature of the carbon–fluorine bond renders its selective activation a formidable challenge. Recent progress has transformed the C–F bond from an inert spectator into a versatile functional handle, enabling defluorinative coupling, hydrodefluorination and late-stage modification of complex scaffolds under mild conditions. Transition-metal catalysts such as nickel and palladium have been harnessed to mediate ipso-substitution and carbon–carbon bond formation, while photoredox and electrochemical approaches employ light and electrons to generate carbon-centred radicals from fluorinated precursors. Complementary strategies, including frustrated Lewis pair activations and organophotocatalytic regimes, allow stereoselective and site-selective transformations of both aromatic and aliphatic C–F bonds. Collectively, these methodologies expand the synthetic toolbox for drug discovery, materials science and agrochemical development, coupling mechanistic insights with sustainability and scalability to address pressing global demands for efficient, selective and green fluorine chemistry.

Research from Nature Portfolio

Recent studies have demonstrated a light-driven strategy for direct C–F bond activation using an N-anionic organic photocatalyst, enabling defluorinative coupling of trifluoromethylaromatic substrates to yield difluoromethyl bicyclo[1.1.1]pentane scaffolds in a single step. This protocol accommodates diverse trifluoromethyl arenes and propellane systems, streamlining the synthesis of bioisosteric motifs relevant to drug discovery. In parallel, visible-light-mediated defluoroalkylation and hydrodefluorination of trifluoromethyl groups have been achieved using an o-phosphinophenolate photoredox catalyst in concert with a thiol hydrogen-atom-transfer relay. This approach furnishes difluoromethylene-containing carbonyl and heteroaromatic intermediates with broad substrate scope and potential for late-stage functionalisation. Foundational work also includes nickel-catalysed defluorosilylation of aryl fluorides under mild, ligand-free conditions, facilitating the introduction of silyl and boron groups for subsequent derivatisation.

C–F Bond Activation and Functionalization in Organic Synthesis publication trend

The graph below shows the total number of articles in c–f bond activation and functionalization in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

C–F bond activation: cleavage of a carbon–fluorine bond to enable subsequent chemical transformations.

Defluorinative functionalisation: replacement of one or more fluorine atoms with new substituents via selective C–F bond cleavage.

Photoredox catalysis: use of light and a photocatalyst to mediate single-electron transfer processes.

Bioisostere: chemical motif that mimics the properties of another functional group to modulate biological activity.

Frustrated Lewis pair (FLP): combination of Lewis acid and base that remain unbound, enabling activation of strong bonds.

References

1. Applications of Transition Metal-Catalyzed ortho-Fluorine-Directed C–H Functionalization of (Poly)fluoroarenes in Organic Synthesis. Chemical Reviews (2024).
2. C−F bond activation enables synthesis of aryl difluoromethyl bicyclopentanes as benzophenone-type bioisosteres. Nature Communications (2024).
3. Synthetic Advantages of Defluorinative C−F Bond Functionalization. Angewandte Chemie International Edition (2023).
4. Stereoselective Synthesis of Fluoroalkanes via FLP Mediated Monoselective C─F Activation of Geminal Difluoroalkanes. Advanced Science (2023).
5. Defluorosilylation of fluoroarenes and fluoroalkanes. Nature Communications (2018).
6. Photocatalytic defluoroalkylation and hydrodefluorination of trifluoromethyls using o-phosphinophenolate. Nature Communications (2022).