Concerted nucleophilic aromatic substitution with (19)F(-) and (18)F(-).
Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain (18)F for use in positron-emission tomography (PET) imaging. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. During SNAr, 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 SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s). Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) 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 CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant (18)F-deoxyfluorination reaction of phenols, which can be used to synthesize (18)F-PET probes. Selective (18)F introduction, without the need for the common, but cumbersome, azeotropic drying of (18)F, can now be accomplished from phenols as starting materials, and provides access to (18)F-labelled compounds not accessible through conventional chemistry.
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Constanze N
CN
Neumann
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Jacob M
JM
Hooker
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.|Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.|Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany.
Tobias
T
Ritter
D002244:Carbon / Q000737:chemistry; D004583:Electrons; D005461:Fluorine / Q000737:chemistry*; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D054879:Halogenation; D048288:Imidazolines / Q000737:chemistry; D010636:Phenols / Q000737:chemistry; D049268:Positron-Emission Tomography
D005462:Fluorine Radioisotopes; D048288:Imidazolines; C583239:PhenoFluor; D010636:Phenols; D005461:Fluorine; D002244:Carbon