Radical fluorination

Radical fluorination is a type of fluorination reaction, complementary to nucleophilic and electrophilic approaches. It involves the reaction of an independently generated carbon-centered radical with an atomic fluorine source and yields an organofluorine compound.

Historically, only three atomic fluorine sources were available for radical fluorination: Fluorine (F₂), hypofluorites (O—F based reagents) and XeF₂. Their high reactivity, and the difficult handling of F₂ and the hypofluorites, limited the development of radical fluorination compared to electrophilic and nucleophilic methods. The uncovering of the ability of electrophilic N—F fluorinating agents to act as atomic fluorine source led to a renaissance in radical fluorination.

Various methodologies have since been developed for the radical formation of C—F bonds. The radical intermediates have been generated from carboxylic acids and boronic acid derivatives, by radical addition to alkenes, or C—H bond and C—C bond activations. New sources of atomic fluorine are now emerging, such as metal-fluoride complexes.

Fluorine can act both as an electrophilic and atomic source of fluorine. The weak F—F bond strength (36 kcal/mol (150 kJ/mol)) allows for homolytic cleavage. The reaction of F₂ with organic compounds is, however, really exothermic and can lead to non-selective fluorinations and C—C cleavage, as well as explosions. Only a few selective radical fluorination methods have been reported. The use of fluorine for radical fluorination is mainly limited to perfluorination reactions.

The O—F bond of hypofluorites is relatively weak. For trifluoromethyl hypofluorite (CF₃OF), it was estimated to be 43.5 kcal/mol (182 kJ/mol). The ability of trifluoromethyl hypofluorite to transfer fluorine to alkyl radicals was notably demonstrated by reacting independently generated ethyl radicals from ethene and tritium in presence of CF₃OF. The high reactivity of hypofluorites has limited their application to selective radical fluorination. They can, however, be used as radical initiators for polymerization.

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