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Journal Article

Facile C−F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent


Ritter,  Tobias
Department of Chemistry and Chemical Biology, Harvard University;
Research Department Ritter, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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Neumann, C. N., & Ritter, T. (2017). Facile C−F Bond Formation through a Concerted Nucleophilic Aromatic Substitution Mediated by the PhenoFluor Reagent. Accounts of Chemical Research, 50(11), 2822-2833. doi:10.1021/acs.accounts.7b00413.

Cite as: http://hdl.handle.net/21.11116/0000-0000-7081-F
Late-stage fluorination reactions aim to reduce the synthetic limitations of conventional organofluorine chemistry with respect to substrate scope and functional group tolerance. C–F bond formation is commonly thermodynamically favorable but almost universally associated with high kinetic barriers. Apart from PhenoFluor chemistry, most modern aromatic fluorination methods reported to date rely on the use of transition metal catalysts, with C–F bonds often formed through reductive elimination. Reductive elimination chemistry to make C–X bonds becomes increasingly challenging when moving to higher atomic numbers in the periodic table from C–C to C–F, in part because of higher metal–X bond dissociation energies. The formation of C–C, C–N, and C–O bonds via reductive elimination has become routine in the 20th century, but it took until the 21st century to develop complexes that could afford general C–F bond formation. The availability of such complexes enabled the substrate scope of modern fluorination chemistry to exceed that of conventional fluorination. PhenoFluor chemistry departs from conventional reaction mechanisms for aromatic fluorination chemistry. Instead, we have revealed a concerted nucleophilic aromatic substitution reaction (CSNAr) for PhenoFluor that proceeds through a single neutral four-membered transition state. Conceptually, PhenoFluor chemistry is therefore distinct from conventional SNAr chemistry, which typically proceeds through a two-barrier process with Meisenheimer complexes as reaction intermediates. As a consequence, PhenoFluor chemistry has a larger substrate scope than conventional SNAr chemistry and can be performed on arenes as electron-rich as anilines. Moreover, PhenoFluor chemistry is tolerant of protic functional groups, which sets it apart from modern metal-mediated processes. Primary and secondary amines, alcohols, thiols, and phenols are often not tolerated under metal-catalyzed late-stage fluorination reactions because C–N and C–O reductive elimination can have lower activation barriers than C–F reductive elimination. The mechanism by which PhenoFluor chemistry forms C–F bonds not only rationalizes the substrate scope and functional group tolerance but also informs the side-product profile. Fluorinated isomers are not observed because the four-membered transition state necessitates ipso substitution. In addition, no reduced product, e.g., H instead of F incorporation, as is often observed with metal-mediated methods, has ever been observed with PhenoFluor. PhenoFluor chemistry can be used to deoxyfluorinate both phenols and alcohols. PhenoFluor is an expensive reagent that must be used stoichiometrically and therefore cannot replace cost-efficient methods to make simple fluorinated molecules on a large scale. However, PhenoFluor is often successful when other fluorination methods fail. The synthesis of 18F-labeled molecules for positron emission tomography (PET) is one application of modern fluorination chemistry for which material throughput is not an issue because of the small quantities of PET tracers used in imaging (typically nanomoles). The high emphasis on functional group tolerance, side-product profiles, and reliability combined with less stringent cost requirements render PhenoFluor-based deoxyfluorination with 18F promising for human PET imaging.