Chemists have discovered a novel method for integrating a trifluoromethyl group onto molecules containing sulfur, nitrogen, or oxygen atoms. This technique does not utilize PFAS reagents, making it an eco-friendly approach for synthesizing pharmaceutical and agrochemical compounds that require the trifluoromethyl group.
A team of chemists from the University of Amsterdam has created a method to attach a trifluoromethyl group to various molecules that include sulfur, nitrogen, or oxygen atoms. Published recently in Science, this method avoids PFAS reagents, offering a greener synthesis path for pharmaceuticals and agrochemicals that depend on this functional group.
This simple yet effective method was developed by the Flow Chemistry group at the Van ‘t Hoff Institute for Molecular Sciences, led by Prof. Timothy Noël, in collaboration with researchers from Italy, Spain, and the UK, both in academic and industrial settings. By employing the principles of flow chemistry—where reactions occur inside small, sealed tubes—this approach ensures safe and controlled chemical processes, while also providing more versatility than traditional glassware techniques.
More Environmentally Friendly
Many pharmaceuticals (like anti-depressants) and agrochemicals (such as pesticides) benefit significantly from having a trifluoromethyl (-CF3) group. This group enhances hydrophobicity and stability in metabolism, thus improving effectiveness and reducing required dosages.
To add fluorine to these compounds, their production often necessitates specialized fluorinated reagents, many of which belong to the PFAS family and may face future regulations. The synthesis method detailed in this Science publication offers a practical alternative, needing only caesium fluoride as the fluorine source. This PFAS-free method for synthesizing fluorinated agents presents a more eco-friendly approach that attracted interest from scientists at AstraZeneca.
Furthermore, this new protocol allows for the attachment of the CF3 group via sulfur (S), nitrogen (N), or oxygen (O) atoms. These fluorinated structures give unique properties to drug molecules and agrochemicals, influencing their lipophilicity, oxidation resistance, and acid-base characteristics.
Integrated Flow System
The Science article presents a flexible microfluidic flow module designed for creating reactive N-, S-, and O-CF3 anions, produced in a packed bed flow reactor that contains caesium fluoride. Suitable precursors containing S, O, or N are processed through this reactor, achieving efficient fluorination due to the high surface area of the salt and improved mixing of organic intermediates. Notably, this method enhances safety since all intermediates are confined within the microfluidic system.
An additional significant aspect of this system is the integration of the anion-generating module with a subsequent reaction module where the N-, S-, or O-CF3 anions react with suitable substrates, yielding active ingredients for pharmaceuticals and agrochemicals as the final products.
Application in Academic and Industrial Settings
The combination of the anion generator and downstream reactor creates an efficient platform for modifying molecules that contain N-, S-, and O-CF3 groups. This innovative strategy is set to influence the creation of new pharmaceutical drugs by enhancing their attributes while improving safety and sustainability in production processes. In their Science article, the researchers report on the pairing of various anions with a selection of substrates, resulting in multiple fluorinated products pertinent to pharmaceutical and agrochemical synthesis. The research team achieved satisfactory yields in many cases, and the operational parameters (such as reaction times) suggest promising prospects for implementation in both academic and industrial contexts.
