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Abstract

Nucleophilic aromatic substitution (S_NAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain ¹⁸F for use in positron-emission tomography (PET) imaging¹. A wide range of nucleophiles exhibit S_NAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales². During S_NAr, attack of a nucleophile at a carbon atom bearing a ‘leaving group’ leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of S_NAr reactions: the most common S_NAr substrates contain strong π-acceptors in the ortho and/or para position(s)³. Here we present an unusual concerted nucleophilic aromatic substitution reaction (CS_NAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CS_NAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant ¹⁸F−deoxyfluorination reaction of phenols, which can be used to synthesize ¹⁸F-PET probes. Selective ¹⁸F introduction, without the need for the common, but cumbersome, azeotropic drying of ¹⁸F, can now be accomplished from phenols as starting materials, and provides access to ¹⁸F-labelled compounds not accessible through conventional chemistry.