Fluorination Techniques in Organic Synthesis

Fluorination has emerged as a cornerstone of modern organic synthesis, driven by the profound influence of fluorine on molecular properties such as lipophilicity, metabolic stability and binding affinity. Techniques span electrophilic, nucleophilic and radical pathways, and extend to deoxyfluorination of alcohols and late‐stage radiofluorination for positron emission tomography. Electrophilic reagents such as N-fluoro-sulfonimides enable introduction of fluorine under mild conditions, whereas nucleophilic approaches often employ fluoride sources activated by metal catalysts or hydrogen-bond donors. Radical routes, frequently powered by photoredox catalysis, offer site-selective C(sp3)–H functionalisation via hydrogen atom transfer. Deoxyfluorination strategies transform hydroxyl groups into C–F bonds using tuned reagents that balance reactivity and selectivity. Meanwhile, 18F radiochemistry has driven the development of robust, automatable protocols to incorporate this radionuclide into bioactive scaffolds. Collectively, these methods underpin the synthesis of pharmaceuticals, agrochemicals and radiotracers with unrivalled precision and efficiency.

Research from Nature Portfolio

Recent studies have advanced radical C(sp3)–H fluorination by exploiting methyl radical as a hydrogen atom abstractor in a photoredox cycle. Sequential hydrogen atom transfer and oxidative radical–polar crossover generate carbocations that engage nucleophilic fluoride, enabling diverse C–F bond formation at late stages of complex molecules. This strategy has broadened site-selectivity and allowed incorporation of fluorine, water, alcohols and heteroatoms without pre-functionalisation. In parallel, the design of N-fluoro-N-arylsulfonamide reagents with reduced N–F bond dissociation energies has transformed radical fluorination under metal-free conditions. These reagents facilitate clean hydrofluorination of alkenes and remote C–H fluorination via 1,5-hydrogen atom transfer, minimising side reactions and extending the scope of radical processes. Foundational work on cyclopropene-based deoxyfluorination reagents has also provided tunable, all-carbon scaffolds for the conversion of alcohols into alkyl fluorides with high site-selectivity, illustrating the power of reagent design in deoxyfunctionalisation chemistry.

Fluorination Techniques in Organic Synthesis publication trend

The graph below shows the total number of articles in fluorination techniques in organic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Electrophilic fluorination: Introduction of fluorine using electron-deficient reagents that deliver F⁺ equivalents.

Nucleophilic fluorination: Use of fluoride ion or its complexes to attack electrophilic centres, often mediated by catalysts.

Radical fluorination: Generation of carbon-centred radicals that react with fluorine donors, typically under photochemical or thermal conditions.

Deoxyfluorination: Conversion of alcohols into alkyl fluorides via reagents that activate the hydroxyl group and deliver fluoride.

Photoredox catalysis: Use of light-activated catalysts to drive single-electron transfer processes in organic reactions.

Hydrogen atom transfer (HAT): Abstraction of a hydrogen atom by a radical species, forming a new radical intermediate.

Bond dissociation energy (BDE): Energy required to homolytically cleave a chemical bond, influencing reactivity in radical processes.

References

1. A general strategy for C(sp3)–H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor. Nature Communications (2021).
2. A third generation of radical fluorinating agents based on N-fluoro-N-arylsulfonamides. Nature Communications (2018).
3. Deoxyfluorination of alcohols with 3,3-difluoro-1,2-diarylcyclopropenes. Nature Communications (2016).
4. A Catalytic Three‐Component Aminofluorination of Unactivated Alkenes with Electron‐Rich Amino Sources. Advanced Science (2024).
5. 18F‑Fluorination: Challenge and Opportunity for Organic Chemists. The Journal of Organic Chemistry (2021).
6. Catalytic C(sp 3 )–F bond formation: recent achievements and pertaining challenges. Green Chemistry (2020).