Advancements in Sustainable Trifluoromethylation: A Visible-Light-Induced Approach for Introducing CF3 Groups

The trifluoromethyl (CF₃) group is play an important role in organic chemistry and pharmaceuticals due to its unique properties and effects on molecules to which it is attached. The CF₃ group is highly electronegative due to the presence of three fluorine atoms which influences the electronic distribution in the molecule, often increasing the acidity of adjacent protons and affecting the molecule’s reactivity and stability. Moreover, incorporation of CF₃ groups can increase a molecule’s lipophilicity, which is a important property in drug design and results in enhanced drug’s absorption and potentially improves its ability to cross biological membranes. Furthermore, the strong carbon-fluorine bond in the CF₃ group makes it resistant to metabolic degradation which results in prolonged half-life of pharmaceuticals, allowing them to remain active in the body for longer periods and possibly reducing the frequency of dosing. Furthermore, the CF₃ group is relatively large and bulky, which can influence the three-dimensional structure of molecules. This steric effect can be exploited to enhance the selectivity of molecules towards their biological targets by improving the fit into specific sites on enzymes or receptors. Introducing a CF₃ group into a molecule can be challenging due to the harsh conditions often required. Traditional methods for CF₃ incorporation involve reagents that are toxic, expensive, or difficult to handle, such as elemental fluorine, HF, or strong bases. Developing milder, more selective, and environmentally friendly synthetic routes remains an area of active research.

A new study published in ACS Catalysis by PhD candidate Lilian Geniller, Dr. Marc Taillefer, Dr. Florian Jaroschik, and Dr.  Alexis Prieto from the Institut Charles Gerhardt Montpellier (ICGM), at the University of Montpellier, CNRS in France developed a novel method for the introduction of CF₃ groups into organic compounds, particularly focusing on alkyl-CF₃ moieties. The new approach focused on a visible-light-induced formal trifluoropropanation process. The researchers used 2-Bromo-3,3,3-trifluoro-1-propene (BTP) as a readily available and inexpensive building block for the introduction of CF₃ groups. BTP’s accessibility and ease of handling make it an attractive reagent for such transformations. The core of their methodology is a photocatalytic system that employs visible light to drive the reaction. This system combines a catalytic amount of supersilane with sodium borohydride (NaBH₄) as an additional reductant. The use of light as a catalyst aligns with sustainable chemistry principles, avoiding harsh conditions and toxic reagents. The authors proposed a mechanism which involves halogen atom transfers (XAT) and the generation of carbon radicals from halides, followed by their addition to BTP. The process also includes hydrogen atom transfer (HAT) steps facilitated by the silyl radical generated from the supersilane, leading to the desired alkyl-CF₃ compounds. A notable aspect of their methodology is its compatibility with a wide range of functional groups. This feature is important for the late-stage functionalization of complex molecules, a common challenge in synthetic chemistry. The researchers also demonstrated the ability to incorporate double deuterium atoms at the α-position of a CF₃ group by substituting NaBH₄ with sodium borodeuteride (NaBD₄), which is unprecedented. This capability opens new possibilities for synthesizing deuterated compounds, which have desirable properties in pharmaceutical applications. For example, the presence of both deuterium and fluorine atoms in a molecule can facilitate its analysis using NMR spectroscopy where deuterium can be measured using deuterium NMR (²H NMR), providing insights into the compound’s metabolism and distribution, while the fluorine atoms in the CF₃ group can be observed using ¹⁹F NMR, offering a high degree of sensitivity and specificity due to fluorine’s wide chemical shift range and the fact that it is relatively rare in biological systems. Moreover, incorporating both deuterium and a CF₃ group can be useful for isotopic labeling of compounds, enabling their tracking in biological systems without significantly altering their biological activity. This can be particularly valuable in pharmacokinetic and pharmacodynamic studies, as well as in metabolic and environmental fate investigations.

The researchers successfully applied their method to a broad range of substrates, including both alkyl and aryl halides, demonstrating the method’s broad scope and potential applicability in various contexts. The mechanistic insight provided in their study sheds light on the photocatalytic cycle and the role of silane and NaBH₄ in the reaction. This understanding not only contributes to the theoretical foundation of fluorine chemistry but also guides the design of future experiments and methodologies. The successful application of their method to a variety of substrates, including challenging aryl halides and natural product derivatives, further demonstrates the method’s robustness and potential impact on synthetic chemistry. In conclusion, the researchers developed a novel, photocatalytically driven method for the direct trifluoropropanation of organic halide molecules using BTP, underpinned by a sustainable and versatile approach. the study by Alexis Prieto and colleagues represents a significant milestone in the field of fluorine chemistry and organic synthesis.