A Catalytic Pocket Hidden in Plain Sight: A Metal-Free Platform for Fluorinated Compounds

Abstract A defining challenge in catalyst design is the development of simple molecular platforms capable of organizing complex reactivity through cooperative interactions. Herein, we apply this concept to the synthesis of O-difluoroalkylhydroxylamine (FON) derivatives, an emerging class of fluorinated compounds that combines a difluoromethylene unit – a well-established oxygen atom bioisostere – with an N–O linkage common to bioactive molecular scaffolds. To enable catalytic access to this emerging class of fluorinated compounds, we report the first catalytic synthesis of FON derivatives through hydroetherification-type coupling of gem-difluoroalkenes and hydroxylamines under mild, metal-free conditions. Central to this transformation is pyridine-2,6-dicarboxylic acid (PDA), which serves as a cooperative organocatalyst, functioning independently or in concert with a Brønsted acid cocatalyst to enable efficient access to these fluorinated products under substantially milder conditions than previous thermal protocols. Experimental and computational studies reveal that PDA promotes reactivity through cooperative noncovalent catalysis, creating a hydrogen-bonding environment that organizes complementary activation modes, with the cooperative PDA/Brønsted acid pathway favored energetically over either catalyst alone. More broadly, this work establishes PDA as a catalytic hub that enables cooperative activation through molecular organization, providing a foundation for the development of new noncovalent catalytic systems.