CF2H

CF2H is the difluoromethyl substituent, commonly written as -CF2H when attached to a carbon skeleton. In some contexts, CF2H also denotes the difluoromethyl radical •CF2H used in radical chemistry. The term is widely used in organic and medicinal chemistry.

The difluoromethyl group is small, comparable in size to a methyl group, but electronically distinct because it contains two electronegative fluorine atoms bonded to a single carbon. The C–F bonds are strong, and the group often confers metabolic stability to the molecules it is part of. The difluoromethyl substituent exerts a strong electron-withdrawing effect, influencing acidity, reactivity, and several physicochemical properties such as polarity and lipophilicity.

Installation of the -CF2H group is achieved through difluoromethylation reactions. Reagents include the Langlois reagent NaSO2CF2H for radical difluoromethylation, and difluoromethylsilane reagents such as difluoromethyltrimethylsilane (TMSCF2H) activated with fluoride. Electrophilic difluoromethylating reagents are also used. These methods enable aryl, vinyl, and heteroaryl substrates to bear the -CF2H motif.

Applications of difluoromethylated compounds span medicinal chemistry, agrochemistry, and materials science. The -CF2H group is used to modulate metabolic stability, acidity, and pharmacokinetic properties, and to tune properties such as polarity and hydrogen-bonding characteristics. In some contexts, it serves as a bioisostere for methyl, helping to optimize drug-like profiles.

Safety and limitations: difluoromethylated reagents and products can be toxic or corrosive and may require careful handling. Reactions can be sensitive to bases or reductive conditions and scale-up can present challenges. Appropriate safety protocols and ventilation are advised.