Construction of CF₂ moieties in FDA-approved drugs (2016–2025): industrial routes, mechanisms, and scale-up considerations

• Wenyan Yao,
• Huanhuan Zhang,
• Xiaolong Yang and
• Feng Liu

Beilstein J. Org. Chem. 2026, 22, 1122–1150, doi:10.3762/bjoc.22.91

• drugs, from strategic design to scale-up evaluation. Keywords: difluoromethylene group (-CF2-); difluoromethyl group (-CF2H); FDA-approved drugs; fluorination methods; process scale-up; Introduction In recent years, the CF2 group has demonstrated unique advantages in drug discovery and clinical

• during clinical and commercial manufacturing phases. The term "CF2" structural unit discussed in this review broadly refers to fragments in drug molecules containing a gem-difluoromethylene group (–CF2–) or a difluoromethyl group (–CF2H), as well as derivatives such as –CF2Cl. In addition, molecules

Quantifying the ability of the CF₂H group as a hydrogen bond donor

• Matthew E. Paolella,
• Daniel S. Honeycutt,
• Bradley M. Lipka,
• Jacob M. Goldberg and
• Fang Wang

Beilstein J. Org. Chem. 2025, 21, 189–199, doi:10.3762/bjoc.21.11

• ][10][11][12][13][14]. Of particular interest is the difluoromethyl group, CF2H, which exhibits hydrogen bond donating character due to the highly polarized F2C–H bond (Figure 1) [14][15][16][17][18][19][20][21][22][23][24]. This functional group is often used to mimic hydroxy or thiol groups but