The more we learn about fluorine, the more we understand why this fascinating element has been extensively explored for use in polymers, surfactants, refrigerants, agrochemicals, pharmaceuticals, and PET imaging. Switching chlorine to fluorine and adding a double bond drastically decreases fluorocarbons’ atmospheric half-lives and pushes the development of new routes to hydrofluoroolefins (HFOs) as 4th generation refrigerants. In another application, the inclusion of fluorine into drugs improves their pharmacokinetic and pharmacodynamic properties. Since the first fluorinated drugs were introduced in the 1960s, the use of organoflruoine compounds has greatly expanded in both the pharmaceutical and agrochemical markets. However, there is still a need for improved synthetic methodologies for late-stage fluoroalkylation of bioactive compounds. Moreover, moving beyond -CF3 and -CF2H, the use of additional RF groups like -CF2CF2H that increase lipophilicity while also allowing for H-bonding may also lead to the identification of improved bioactivity over a broad spectrum.
Previous work in the Baker group demonstrated that regioselective insertion of hexafluoropropene, CF2=CF(CF3) into a Cu-F bond generated the hexafluoroisopropyl group that could be efficiently transferred to aroyl chlorides. Moreover, the insertion of tetrafluoroethylene (TFE) into Cu-H gave a stable Cu-CF2CF2H complex that could also transfer its RF group to aryl iodides in the presence of catalytic CuCl(NHC) (NHC = N-heterocyclic carbene). In this thesis we expand the regioselective Cu-H insertion strategy to include chlorotrifluoroethylene, CTFE, CF2=CFCl, and perfluoro(methyl vinyl ether), PMVE, CF2=CF(OCF3). With the former, we showed the importance of ancillary ligands in stabilizing the Cu complex and enabling the successful transfer of the -CFClCF2H group to aroyl chlorides (aryl iodides gave only biaryls). In contrast, we found that stable Cu[CF(OCF3)(CF2H)] complexes could be prepared using a variety of ligands spanning 2- to 4-coord Cu, and we showed that DMSO serves as a ‘privileged’ ligand for transfer of this RF group to organic electrophiles. With the help of a computational chemistry collaborator, we identified the importance of pre-equilibria that hampered the aryl iodide addition step, leading us to develop a ‘ligandless’ polar solvent-stabilized Cu-RF strategy, using added CuBr to trap the phosphine ligands for efficient transfer of the novel -CF(OCF3)(CF2H) group. Further calculations showed that rate-limiting product elimination for RF transfer to aroyl chloride involves an asynchronous transition state occurring at a single Cu coordination site. Finally, adding the ‘ligandless’ Cu-RF strategy with our previously reported Cu-CF2CF2H complexes, derived from the stable 1:1 TFE: CO2 mixture, allowed for the successful tetrafluoroethylation of alkenyl iodide nucleobases, nucleosides and glycals with potential biological activity. In another collaboration, we report the results of preliminary molecular docking studies of fluorinated-carboxamides as potential fungicide targets.
In an effort to expand the range of readily available fluoroalkenes using the Baker group’s Ni-catalyzed homologation approach, we first collaborated with another computational chemistry to investigate the mechanism of fluoronickelacyclopentane formation. This work showed that the NiL2 fragment often led to reduced activation barriers (vs. NiL) and that the transition state involves a wide L-Ni-L angle of ca. 150°. Using the wide bite-angle bis(phosphine) DPEPhos, we were able to characterize a model for the initially formed pseudotetrahedral metallacycle. We then expanded the range of isolated fluoronickelacycles to include those derived from PMVE and CTFE. While the former gave regio- and stereoselective formation of stable metallacycles with trans -OCF3 groups on C, the stability and regioselectivity of the latter depended on the ancillary ligands. Preliminary reactivity of these metallacycles with Lewis and Brønsted acids is also reported.
In summary, using two functionalized fluoroalkenes, we have advanced our understanding of the stabilization of Cu-RF complexes and their ability to transfer their RF group to organic electrophiles. In addition, we assessed the synthesis, stability, and reactivity of new fluoronickelacycles to provide additional insight into the Baker group’s Ni-catalyzed fluoroalkene homologation strategy.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/44120 |
| Date | 03 October 2022 |
| Creators | Teixeira Nunes Porto, Luana Leticia |
| Contributors | Baker, R. Tom |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
| Rights | Attribution-NonCommercial-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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