Difluoromethylation

Difluoromethylation is the chemical process of introducing the difluoromethyl group (-CF2H) into organic molecules. The CF2H motif is valued in medicinal chemistry as a potential bioisostere that can influence lipophilicity, acidity, and metabolic stability, and it can serve as a hydrogen-bond donor in certain contexts.

Methods for difluoromethylation are typically categorized as nucleophilic, electrophilic, or radical. Nucleophilic difluoromethylation uses CF2H-bearing nucleophiles or equivalents to form C–CF2H bonds with carbon electrophiles, often under copper- or nickel-catalyzed cross-coupling conditions to install CF2H onto aryl, vinyl, or alkyl substrates.

Electrophilic difluoromethylation transfers a CF2H unit from reagents that behave as difluoromethyl electrophiles to nucleophiles such as amines, alcohols, or heteroatoms, frequently proceeding under mild conditions and enabling difluoromethylation of complex molecules.

Radical difluoromethylation relies on CF2H radicals generated from sources such as difluoromethyl iodide or sulfone-based reagents. Under photoredox or radical-initiated conditions, these radicals add to alkenes, arenes, or heterocycles, enabling difluoromethylated products from diverse substrates.

Notable reagent families include difluoromethylboron reagents (difluoromethyl-Bpin) used in copper-catalyzed cross-couplings to install CF2H onto arenes and vinyl substrates; difluoromethyl iodide; and electrophilic difluoromethylating reagents such as difluoromethyl sulfonium or iodonium salts.

Applications of difluoromethylation span pharmaceuticals and agrochemicals, where the CF2H group can improve metabolic stability, modulate pKa, and enhance membrane permeability. Challenges include toxicity and handling of some reagents, limited substrate scope for certain catalysts, and the need for milder, more sustainable methods.

See also: Trifluoromethylation, difluoromethylating reagents, and late-stage fluorination.