Fluorination
Fluorination, the process of introducing fluorine into a compound, has a significant impact on the compound's biological properties due to the electronegativity and small size of fluorine. In pharmaceutical research, the incorporation of fluorine is often used to improve bioavailability and enhance the metabolic stability of target compounds. Over time, the field of fluorination has expanded to include a variety of strategies for introducing fluorine, with several key reactions now available for this purpose. These techniques play a crucial role in the development of pharmaceuticals, contributing to the optimization of drug efficacy and stability in the body.
Overview
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.
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.
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
Radical Trifluoromethylation
Electrophilic Trifluoromethylation
Electrophilic Trifluoromethylation
Perfluoroalkylation
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.