PFAS (per- and polyfluoroalkyl substances) are a family of synthetic chemicals that have been widely used since the 1950s for their nonstick and water-repellent properties, as well as in the formulation of certain medications due to their metabolic stability, lipophilicity, and physicochemical properties, which enhance the drugs’ effectiveness within the body. Found in many everyday products (food packaging, textiles, firefighting foams, lubricants, medications, pesticides, etc.), they pose a major problem due to their extreme persistence in the environment and in the body, hence their nickname “ —eternal pollutants.”
The accumulation of certain PFAS is associated with various health risks, including hormonal disorders, cancers, and im
s on the immune system, making their regulation a public health issue. In response to this threat, the National Assembly passed a bill in April
2024 to phase out the use of PFAS starting January 1, 2026; the search for alternatives to these molecules has therefore become
a public health emergency.
Frédéric Leroux, a research director at the CNRS’s Laboratory of Molecular Innovation and Applications (LIMA) in Strasbourg and also director of the French Fluorine Network (GIS CNRS Fluor), has been studying chemical compounds capable of replacing PFAS for many years, particularly in the pharmaceutical and crop protection industries: “PFAS represent a vast family of molecules. Certain short- and medium-chain PFAS, which are particularly persistent and toxic, have been banned in Europe since 2009, such as PFOS. Water-soluble and highly mobile, they contaminate groundwater and surface water and can be transported as far as Antarctica. This phenomenon makes them a global problem.”
Recognizing the importance of this public health issue, Frédéric Leroux emphasizes the need to work with industry: “Developing emerging fluorinated groups is one thing, but manufacturers must then take them on for this research to have an impact. Back in 2014, we established a joint laboratory with one of the world’s leading manufacturers of pharmaceuticals and crop protection products: Bayer. This collaboration allows us to understand their constraints and challenges, and to consider from the outset how to produce these molecules on an industrial scale using sustainable, low-cost manufacturing processes.”
Over the past 10 years, 12 patents have been filed jointly by Bayer and the CNRS. Two fungicides containing an alternative fluorinated group, difluoromethyl (-CHF2), have been developed, and their effectiveness is now combined with remarkable biodegradability. “It’s also a matter of sovereignty; we cannot afford to depend on pharmaceutical companies outside Europe, ” the researcher explains.
Frédéric Leroux points out that this field of research is highly competitive: “The stakes are high, and there are many research teams working on alternatives to PFAS. Unfortunately, national and regional funding is very limited. The Jean-Marie Lehn Foundation is a real breath of fresh air, as it has enabled us to fund promising exploratory projects.”
As a recipient of a grant from the Foundation’s 2021 call for proposals, Frédéric Leroux was able to fund a doctoral thesis to develop a method for synthesizing molecules containing the difluoromethyl group, an alternative fluorinated group with high potential. This group does not fall into the PFAS category but retains essential pharmacological properties, notably its lipophilicity, which facilitates the cellular penetration of therapeutic molecules.
The project also involved producing three-dimensional molecules, which are potentially better suited for interacting with drug target proteins. Unlike flat molecular arrangements, 3D architectures can offer greater structural diversity, increasing the chances of discovering compounds that are active against biological targets, as well as providing greater affinity for those targets, thereby improving the efficacy and specificity of treatments.
Frédéric Leroux explains that these 3D structures have great therapeutic potential but may have drawbacks: “Some 3D structures are promising, but they must be carefully selected. For example, certain molecules will interact correctly with the desired target protein, while their mirror image—like our two hands, which are similar but not superimposable—could cause unwanted side effects. It is therefore crucial to be able to specifically synthesize and isolate the correct molecular form.”
1. Direct Deprotonative Functionalization of α,α-Difluoromethyl Ketones Using a Catalytic Organosuperbase. A. Messara, A. Panossian, K. Mikami, G. Hanquet, F. R. Leroux, Angew. Chem. Int. Ed. 2023, 62, e202215899; Angew. Chem. 2023, 135, e202215899.
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