The installation of C-F bonds in organic compounds can have a significant effect on the chemical and biological of the molecules. The unique properties of organofluorines have lead to the development of successful pharmaceutical drugs in treating health-related conditions from depression to atherosclerosis and for clinical applications such as [18]F positron emission tomography (PET), a highly valuable diagnostic tool for multiple cancers. Although there are a variety of synthetic approaches to create aliphatic sp3 and olefinic sp2 C-F bonds, there are few methods to form aryl C-F bonds. This project's long-term objective is to develop more practical methods to synthesize these bonds through palladium-catalyzed transformations. This project has three specific aims: (i) develop a Pd(ll)/Pd(IV) palladium-catalyzed aryl C-F bond forming methodology using aryl stannanes, silane or boronic acids (with no need for a directioning group) using electrophilic fluorinating reagents, (ii) develop a palladium-catalyzed aryl C-CF3 forming methodology using Cu(l)-CF3 transmetallating reagents and strong electrophilic oxidants, and (iii) demonstrate the key C-F and C-CF3 bond forming steps of these proposed catalytic cycles via isolated Pd(IV)-fluoride and CF3 species. The Pd-catalyzed aryl C-F bond forming methodology will exploit the relative reactivity of Pd(ll) fluorides compared to aryl Pd(ll) species in the presence of electophilic fluorinating reagents. The proposed catalytic cycle involve a transmetallation of an aryl stannane to a Pd(ll)- F to form an aryl Pd(ll) species. This species can be subsequently oxidized to Pd(IV) by the electrophilic fluorinating reagents followed by C-F bond forming reductive elimination. The relative rates of these transformations and the attenuation of the undesired C-C coupling products are proposed to be controlled by sterically and electronically tuning tridentate """"""""pincer"""""""" ligands. The aryl C-CF3 bond forming transformation will utilize existing Pd(ll)/Pd(IV) llgand-dlrected C-H activation and functionalization chemistry to convert aryl C-H bonds to C-CF3 bonds. This will be facilitated by using in situ formation of Cu(l)-CF3 as a transmetallating reagent to an aryl Pdll - species to form a new aryl Pd(ll) CF3 species. This species can then be oxidized to Pd(IV) by a strong oxidant followed by C-CF3 bond reductive elimination formation. Finally, to give mechanistic evidence that both catalytic C-F and C-CF3 bond forming transformations proceed through a Pd(IV) intermediate, efforts will be taken to give stoichiometric evidence of their existence. We are hopeful that this work will provide practiical synthetic tools in the development of new biologically relevant organofluorine compounds.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-CB-N (29))
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Toliver, Adolphus
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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Racowski, Joy M; Ball, Nicholas D; Sanford, Melanie S (2011) C-H bond activation at palladium(IV) centers. J Am Chem Soc 133:18022-5
Ball, Nicholas D; Gary, J Brannon; Ye, Yingda et al. (2011) Mechanistic and computational studies of oxidatively-induced aryl-CF3 bond-formation at Pd: rational design of room temperature aryl trifluoromethylation. J Am Chem Soc 133:7577-84
Ye, Yingda; Ball, Nicholas D; Kampf, Jeff W et al. (2010) Oxidation of a cyclometalated Pd(II) dimer with ""CF3+"": formation and reactivity of a catalytically competent monomeric Pd(IV) aquo complex. J Am Chem Soc 132:14682-7
Ball, Nicholas D; Kampf, Jeff W; Sanford, Melanie S (2010) Aryl-CF(3) bond-forming reductive elimination from palladium(IV). J Am Chem Soc 132:2878-9
Ball, Nicholas D; Kampf, Jeff W; Sanford, Melanie S (2010) Synthesis and reactivity of palladium(II) fluoride complexes containing nitrogen-donor ligands. Dalton Trans :632-40