Organofluoride compounds
Organofluoride compounds have become central in organic chemistry, not only for their critical importance in optical fibers, pharmaceuticals, and agrochemicals but also due to their ability to engage in chemoselective transformations promoted by their unique reactivities, thus becoming a handle for the formation of C-C, C-O, and C-N bonds. C-F functionalization in many cases elicits reactivity orthogonal to, and thus complementary to, C-H and C-X functionalization.[1] Additionally, C-F activation provides a platform for transforming poly- or per-fluorinated compounds to more useful partially fluorinated counterparts.
The C-F Bond: properties and challenges in activation
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Many properties of the C-F bond for a long time made it virtually inert to functionalization. First, the C-F bond is the strongest bond carbon forms, as observed in table 1, the C-F bond strength clearly outcompetes C-O, C-N, and other C-halogen bonds.[2] Due to the high electronegativity of the fluorine atom, the C-F bond exhibits very strong polarization, with a substantial partial positive charge at carbon and a partial negative charge at fluorine. As a result, charge attraction predominates forging a highly ionic bond (43% ionic character). The high strength of the C-F bond renders it with low polarizability (atom polarizability of 0.56 vs 2.2 and 4.7 for Cl and I respectively) and reduces its ability to engage in substitution reactions. Additionally, the lone pairs on fluorine are tightly held due to these electrostatic interactions preventing them from easily engaging in interactions such as hydrogen bonding or coordination to metals. Although these properties posed challenges for their activation, they provide organofluorides with their thermal, photochemical, and chemical stability responsible for their useful properties as freons and pesticides.
Table 1: Bond dissociation energies of C-X bonds in kcal/mol.
| Bond | Bond dissociation energy/ kcal/mol |
| C-F | 105.4 |
| C-H | 98.8 |
| C-O | 84.0 |
| C-C | 83.1 |
| C-Cl | 78.5 |
| C-N | 69.7 |
Applications
General modes of activation
Established activation techniques of fluorocarbons are shown in scheme 1, which include oxidative addition, reduction through hydrodefluorination, and nucleophilic displacement. Many excellent reviews discuss these reactivities.[3][4][5][6][7][8]
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Fluorinated arenes and heteroarenes
Fluorinated aromatics typically engage in SNAr type processes using traditional chemistry when the arene is properly instilled with EWGs. A great example of this type of reactivity was demonstrated by Todo and coworkers in their synthesis of pazufloxacin. Apart from the classical substrate inherent SNAr reactivity, ɳ6 transition-metal complexes have emerged as competent systems in inducing nucleophilic aromatic substitution of electron rich or electron neutral aryl fluorides. A recent example by Shi and coworkers showcases the use of a ruthenium complex bound to a hemilabile phosphine as a competent catalytic system to effect amino defluorination (scheme 2).[9]
When it comes to transition metal activation outside the realm of nucleophilic aromatic substitution, fluorinated arenes and heteroarenes were among the first to showcase success, with nickel being a key player in the field.
Early Stoichiometric Examples
Pentaflorinated pyridine undergoes oxidative addition using Ni(COD)2 and PEt3, forming the corresponding Ni-fluoride complex in 49% yield after 3 hrs (Eqn 1).[10] Initial reports of this reaction were reported using the less activated hexafluorobenzene, which proved to provide low yield of product (7%) after several days of reaction[11] or moderate yield (48%) after 4 weeks.[12] Many examples of stoichiometric transition metal activation were later disclosed, and the review published by Amii and Uneyama is a valuable resource to consult for more detailed historical overview.[13]
An interesting report showcasing chelate assisted oxidative addition was disclosed by Richmond in 1987, whereby imine directed OA affords seven-coordinate tungsten in less than 7 mins (Scheme 3a).[14] It is worth highlighting the chemoselectivity of the OA in the presence of the more acidic C-H bond (Scheme 3b).
Catalytic Systems
Having established feasibility of C-F bond activation using stoichiometric metal means, the connection to catalytic systems was developed soon after. In 1994, Milstein reported catalytic hydrodefluorination of aromatic C-F complexes using Rh(I)-silyl complexes (Eqn 2).[15]
Nickel mediated Kumada coupling has provided a useful avenue to transform Ar-F bonds into Ar- C bonds catalytically. The first report of this transformation was disclosed by Herrmann in 2001 utilizing Ni-NHCs to transform non-activated aryl fluorides into a variety of biaryls (Eqn 3).[16] Generally, OA of the C-F takes place with Ni(0) followed by transmetallation with a Grignard reagent, which is typically driven by the strong affinity of fluorine to magnesium, which allows activation of the strong C-F bond.
Although nickel showed great success in the OA of aryl-F bonds, palladium does not share the same reactivity and was considered to be inert against C-F bonds. Successful OA is witnessed with 2-nitro fluorobenzene, whereby the nitro group acts as an electronic activator as well as a directing group of palladium (scheme 4a). The 4-nitro counterpart fails due to the absence of the directing effect (scheme 4b).[17] Although the nitro group is sensitive to strongly nucleophilic organometallic transmetallation partners such as organolithium or Grignard reagents, these substrates can be utilized in Stille or Suzuki couplings.
It was also found that dppf is a reliable ligand in these transformations allowing widening of the substrate scope (Eqn 4).[18]
Fluorinated alkenes
In the class of fluorinated alkenes, geminal difluoro alkenes emerge as useful surrogate in C-F functionalization. Reactivity of these compounds typically proceed with nucleophilic addition at the alpha carbon, generating an anion that’s stabilized through the fluorine’s electronegativity and negative hyperconjugation (Scheme 5a).[19] This is then followed by beta fluoro elimination to the functionalized olefinic product. An interesting application of this chemistry is reported by Ichikawa in 1999, whereby zirconocene mediated addition to 1,1-difluoroethylenes to generate vinyl zirconium reagents that can transmetallate with palladium to form styreneyl derivatives (Scheme 5b).[20]
Aliphatic trifluoromethyl compounds
Sp3 C-F activation encompasses selective activation of one or more C-F bonds in mono- or poly- fluorinated substrates in a wide variety of systems including aliphatic, allylic, benzylic, and propargylic. Perhaps one of the most encountered reaction pathways is SN2’-like, whereby allylic/propargylic alkyl fluorides are displaced by nucleophiles. Hayashi reported asymmetric rhodium catalyzed arylation/defluorination of 1-trifluoromethyl alkenes providing the arylated products in excellent enantioselectivity (Eqn 5).[21]
Photocatalyzed decarboxylative/defluorination has also been reported by Zhou in 2016 to form difluorinated beta,delta-ketones (Eqn 6).
References
- ↑ Amii, Hideki; Uneyama, Kenji (2009-05-13). "C−F Bond Activation in Organic Synthesis". Chemical Reviews. 109 (5): 2119–2183. doi:10.1021/cr800388c. ISSN 0009-2665. PMID 19331346.
- ↑ O'Hagan, David (2008-01-07). "Understanding organofluorine chemistry. An introduction to the C–F bond". Chemical Society Reviews. 37 (2): 308–319. doi:10.1039/B711844A. ISSN 1460-4744. PMID 18197347.
- ↑ Braun, Thomas; Perutz, Robin N. (2002-01-01). "Routes to fluorinated organic derivatives by nickel mediated C–F activation of heteroaromatics". Chemical Communications (23): 2749–2757. doi:10.1039/B206154F. ISSN 1364-548X. PMID 12478732.
- ↑ Doherty, Nancy M.; Hoffmann, Norris W. (1991-06-01). "Transition-metal fluoro compounds containing carbonyl, phosphine, arsine, and stibine ligands". Chemical Reviews. 91 (4): 553–573. doi:10.1021/cr00004a005. ISSN 0009-2665.
- ↑ Jones, William D. (2003-10-20). "Activation of C–F bonds using Cp*2ZrH2: a diversity of mechanisms". Dalton Transactions (21): 3991–3995. doi:10.1039/B307232K. ISSN 1477-9234.
- ↑ Murphy, Eamonn F.; Murugavel, Ramaswamy; Roesky, Herbert W. (1997-12-01). "Organometallic Fluorides: Compounds Containing Carbon−Metal−Fluorine Fragments of d-Block Metals". Chemical Reviews. 97 (8): 3425–3468. doi:10.1021/cr960365v. ISSN 0009-2665. PMID 11851496.
- ↑ Plenio, Herbert (1997-12-01). "The Coordination Chemistry of the CF Unit in Fluorocarbons". Chemical Reviews. 97 (8): 3363–3384. doi:10.1021/cr970465g. ISSN 0009-2665. PMID 11851493.
- ↑ "Find your institution". id.elsevier.com. Retrieved 2021-06-12.
- ↑ Kang, Qi-Kai; Lin, Yunzhi; Li, Yuntong; Shi, Hang (2020-02-26). "Ru(II)-Catalyzed Amination of Aryl Fluorides via η6-Coordination". Journal of the American Chemical Society. 142 (8): 3706–3711. doi:10.1021/jacs.9b13684. ISSN 0002-7863. PMID 32039590 Check
|pmid=value (help). - ↑ Fahey, Darryl R.; Mahan, John E. (1977-04-01). "Oxidative additions of aryl, vinyl, and acyl halides to triethylphosphinenickel(0) complexes". Journal of the American Chemical Society. 99 (8): 2501–2508. doi:10.1021/ja00450a017. ISSN 0002-7863.
- ↑ Reinhold, Meike; McGrady, John E.; Perutz, Robin N. (2004-04-28). "A Comparison of C−F and C−H Bond Activation by Zerovalent Ni and Pt: A Density Functional Study". Journal of the American Chemical Society. 126 (16): 5268–5276. doi:10.1021/ja0396908. ISSN 0002-7863. PMID 15099111.
- ↑ Richmond, Thomas G.; Osterberg, Carolyn E.; Arif, Atta M. (1987-12-01). "Activation of carbon-fluorine bonds by oxidative addition". Journal of the American Chemical Society. 109 (26): 8091–8092. doi:10.1021/ja00260a027. ISSN 0002-7863.
- ↑ Amii, Hideki; Uneyama, Kenji (2009-05-13). "C−F Bond Activation in Organic Synthesis". Chemical Reviews. 109 (5): 2119–2183. doi:10.1021/cr800388c. ISSN 0009-2665. PMID 19331346.
- ↑ Aizenberg, Michael; Milstein, David (1994-07-15). "Catalytic Activation of Carbon-Fluorine Bonds by a Soluble Transition Metal Complex". Science. 265 (5170): 359–361. Bibcode:1994Sci...265..359A. doi:10.1126/science.265.5170.359. ISSN 0036-8075. PMID 17838035. Unknown parameter
|s2cid=ignored (help) - ↑ Böhm, Volker P. W.; Gstöttmayr, Christian W. K.; Weskamp, Thomas; Herrmann, Wolfgang A. (2001). "Catalytic C−C Bond Formation through Selective Activation of C−F Bonds". Angewandte Chemie International Edition. 40 (18): 3387–3389. doi:10.1002/1521-3773(20010917)40:18<3387::AID-ANIE3387>3.0.CO;2-6. ISSN 1521-3773.
- ↑ Widdowson, David A.; Wilhelm, René (2003-02-20). "Palladium catalysed Suzuki reactions of fluoroarenes". Chemical Communications (5): 578–579. doi:10.1039/B212138G. ISSN 1364-548X. PMID 12669833.
- ↑ Saeki, Tomoyuki; Takashima, Yohei; Tamao, Kohei (July 2005). "Nickel- and Palladium-Catalyzed Cross-Coupling Reaction of Polyfluorinated Arenes and Alkenes with Grignard Reagents". Synlett. 2005 (11): 1771–1774. doi:10.1055/s-2005-871571. ISSN 0936-5214.
- ↑ Fujita, Takeshi; Fuchibe, Kohei; Ichikawa, Junji (2019). "Transition-Metal-Mediated and -Catalyzed C−F Bond Activation by Fluorine Elimination". Angewandte Chemie International Edition. 58 (2): 390–402. doi:10.1002/anie.201805292. ISSN 1521-3773. PMID 29953707.
- ↑ "Find your institution". id.elsevier.com. Retrieved 2021-06-12.
- ↑ Xiao, Tiebo; Li, Linyong; Zhou, Lei (2016-08-09). "Synthesis of Functionalized gem-Difluoroalkenes via a Photocatalytic Decarboxylative/Defluorinative Reaction". The Journal of Organic Chemistry. 81 (17): 7908–7916. doi:10.1021/acs.joc.6b01620. ISSN 0022-3263. PMID 27467781.
- ↑ Huang, Yinhua; Hayashi, Tamio (2016-09-20). "Rhodium-Catalyzed Asymmetric Arylation/Defluorination of 1-(Trifluoromethyl)alkenes Forming Enantioenriched 1,1-Difluoroalkenes". Journal of the American Chemical Society. 138 (38): 12340–12343. doi:10.1021/acs.joc.6b07844. ISSN 0002-7863. PMID 27627581.
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