Concerted nucleophilic aromatic substitution with 19F− and 18F−

Abstract

Nucleophilic aromatic substitution (S N Ar) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain a 18 F for use in PET imaging. 1 A wide range of nucleophiles exhibit S N Ar reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales. 2 During S N Ar, 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 N Ar reactions: the most common S N Ar substrates contain strong π-acceptors in the ortho and/or para position(s). 3 In this manuscript, we present an unusual concerted nucleophilic aromatic substitution reaction (CS N Ar) 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 N Ar is favored over a stepwise displacement. Mechanistic insights enabled us to develop a functional grouptolerant 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-labeled compounds not accessible through conventional chemistry.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsReprints and permissions information is available at www.nature.com/reprints.Correspondence and requests for materials should be addressed to T.R. (ritter@mpi-muelheim.mpg.de). Supplementary Information is available in the online version of the paper. Readers are welcome to comment on the online version of the paper. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptNucleophilic aromatic substitution reactions generally take place via either an additionelimination or elimination-addition mechanism. Both two-step mechanisms display a highenergy intermediate, either an aryne species (elimination-addition) or a Meisenheimer complex (addition-elimination). 2,4 A concerted displacement of the leaving group by an incoming nucleophile could avoid the formation of high-energy intermediates and thus broaden the scope of suitable electrophiles. Displacements at primary aliphatic centers, where charge build-up in a hypothetical S N 1 mechanism is unfavorable, commonly take place via a concerted mechanism involving the σ * (C alkyl -LG) orbital (S N 2 mechanism). For aromatic substrates a direct substitution pathway involving the σ * orbital of the areneleaving group bond (σ ...

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