Impaired gephyrin G-domain trimerization and phase separation in a patient with developmental epileptic encephalopathy.

Over the past few decades, fluoroorganic chemistry has emerged as an essential component of modern drug discovery and agrochemical innovation, with fluorine incorporation enhancing chemical and metabolic stability, efficacy, and selectivity in small bioactive molecules. In pharmaceuticals, approximately 20–25% of marketed drugs now contain fluorine, a figure that has risen steadily since the early 2000s, culminating in 58 fluorinated small-molecule approvals by the FDA from 2018 to 2022 alone, representing about 23% of all new drugs in that period. Similarly, in agrochemicals, fluorine's prevalence has surged to over 50% of current products, with 127 fluorinated compounds registered out of 238 total agrochemicals between 1998–2020 (53%). This success positioned fluoroorganics as essential for addressing global health and agricultural challenges, though it raised novel environmental concerns about the accumulation and persistence of artificial fluorinated substances in the environment (). The environmental impact of perfluorinated compounds (PFCs) has been widely recognized, leading to legislative restrictions on their use in the European Union by the European Chemicals Agency (ECHA) and globally under the Stockholm Convention on Persistent Organic Pollutants. In 2023, several European countries submitted a novel proposal advocating for a complete ban on the use of per- and polyfluorinated alkyl substances (PFAS, “forever chemicals”) containing perfluorinated fragments as small as CF– and –CF– (with no halogen or hydrogen atoms attached). This proposal is expected to result in major EU-wide legislative action in early 2027, following the completion of consultation rounds. While the forthcoming EU-wide PFAS regulation does not explicitly include drugs and agrochemicals, legislative restrictions have already been applied to certain agrochemicals. For example, the CF-containing herbicides flurtamone and flufenacet were discontinued in the EU due to their proven release of trifluoroacetic acid into soil and water (). In 2025, Denmark banned the use of 23 pesticides, six of which contained a CF-aromatic fragments, for similar reasons (). The current legislative landscape highlights that the exceptional stability of fluoroorganic substances, once a groundbreaking advantage, has led to unintended consequences. While the resistance of polyfluorinated groups to chemical and metabolic degradation initially drove innovation, it now poses a serious threat to a sustainable and safe human environment. By 2020, over 50% of fluorinated agrochemicals contained a CF group in one form or another, placing the entire agrochemical industry under the looming threat of imminent legislative collapse. The challenge does not readily affect medicinal chemistry, but it may be a matter of a more distant time when similar restrictions will reach drugs and veterinary chemicals, especially in the case of bulk environmental release. This compels chemists to seek viable alternatives to the CF group, solutions that retain the benefits of fluoroorganic chemistry while preventing the release of trifluoroacetate and other persistent perfluoroalkyl substances into the environment. The shift of focus from CF chemistry to other types of groups appears completely inevitable in the years to come, which is why we decided to summarize the successful applications of alternative moieties primarily in drug discovery and agrochemical fields. We believe that such a summary will guide the readership in applying partially fluorinated alkyl moieties and will lead fluoroorganic chemistry into a more sustainable and stable long-term future. We would like to stress that it is not our intention to advocate for a complete abandonment of CF-containing groups, which still drive innovation and seem unavoidable in the area of fine chemicals such as clinical drugs. Instead, our work provides information for critical analysis and aims to promote the diversity of fluoroorganic groups in practical applications.