organofluorinating

Organofluorinating, or organofluorination, refers to chemical processes that introduce carbon–fluorine bonds into organic molecules. Fluorine substitution can alter a compound's reactivity, metabolic stability, and lipophilicity, making fluorinated molecules prevalent in pharmaceuticals, agrochemicals, and advanced materials. Fluorination can be achieved by several broad strategies, including electrophilic fluorination, nucleophilic fluorination, and radical or radical-like methods, each with different substrate scopes and selectivities.

Electrophilic fluorination uses fluorinating reagents that transfer a positively charged fluorine to an electron-rich site. Common reagents include Selectfluor and N-fluorobenzenesulfonimide (NFSI), as well as xenon difluoride in specialized contexts. These methods often provide rapid introduction of fluorine to alkenes, arenes, or heteroatoms, but regio- and stereoselectivity depend on substrate and catalyst design and may require directing groups.

Nucleophilic fluorination employs fluoride sources such as KF or CsF in combination with activating agents to form C–F bonds at carbon centers that can be less reactive to electrophilic reagents. Deoxyfluorination reagents such as DAST and Deoxo-Fluor convert alcohols to alkyl fluorides. Other nucleophilic approaches include metal-catalyzed cross-couplings and rearrangements that install fluoride under milder conditions.

Radical fluorination and hydrofluorination utilize radical sources (often based on Selectfluor or NFSI) to install fluorine across unsaturated bonds or at C–H sites, frequently enabled by photoredox or thermal initiation.

Applications include fluorinated motifs in PET radiochemistry with fluorine-18 and in drug discovery for metabolic stability and receptor interactions. Challenges encompass reagent safety, selectivity, and the need for mild, scalable processes. Ongoing research seeks broader substrate scope and improved enantio- or site-selective methods.