Fluorination, or the introduction of fluorine to a compound, has the profound ability to alter its biological properties due to the electronegativity and small size of fluorine. In pharmaceutical research, fluorine is often introduced into the target compound to improve bioavailability and enhance the metabolic stability profile. The field has grown to include numerous strategies for introduction for the fluorine, including several key reactions.

Introduction of a fluorine to a compound via nucleophilic fluorination.

Nucleophilic Fluorination

Nucleophilic fluorination methods employ a fluoride source, such as alkali or ammonium fluoride, for direct displacement of alcohols, additions to aldehydes, ketones and carboxylic acids in highly chemoselective fashions for small molecule synthesis, as well as polyfluorination for materials synthesis.

Introduction of a fluorine to a compound via electrophilic fluorination.

Electrophilic Fluorination

Electrophilic fluorination involves the combination of a carbon-centered nucleophile with an electrophilic source of fluorine. Traditionally, the source of electrophilic fluorine used was fluorine gas, which is highly toxic and a strong oxidizer. However, research has led to reagents that are milder, safer and highly stable alternatives for electrophilic fluorination. These reagents have shown excellent utility in various applications, ranging from electrophilic aromatic substitution to formation of α-fluoro-keto species.

Introduction of a fluorine to a compound via difluoromethylation


Difluoromethylation generates the difluoromethyl group of reagents through nucleophilic addition and radical functionalization of (C–H) bonds. The difluoromethyl group (R-CF2H) has garnered much attention in drug, agrochemical, and material research since it is isoteric to a carbinol group (CH2OH).

Nucleophilic Trifluoromethylation


Trifluoromethylation is a rapidly growing field in chemical research that has interfaced elegantly with catalysis in crafting new chemical methodologies for placing trifluoromethyl groups onto molecules.

Radical Trifluoromethylation

Figure 5.Radical Trifluoromethylation

Electrophilic Trifluoromethylation

Figure 6.Electrophilic Trifluoromethylation


Perfluoroalkylation is the reaction of a nucleophilic perfluoroalkyl group with alkyl, alkenyl, and aryl halides or carbonyl compounds. The stability of perfluoroalkyl reagent groups makes them appealing in a variety of applications such as cross-coupling with allyl phosphates.

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