Metal Difluorocarbene: A New Access to Fluorinated Compounds

What we can do by using metal-difluorocarbene chemistry is described in this post.

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Difluorocarbene is a ground state singlet carbene and has important applications in different areas, such as production of fluorinated polymers and pharmaceuticals. However, due to the intrinsic electrophilic nature of difluorocarbene, it has limited reaction types. To overcome these limitations, efforts to tune the reactivity of difluorocarbene through coordination to transition metal have been made since 40 years ago, but significant challenges remain owing to the inert activity of isolated metal difluorocarbene species.1 In 2015, we reported a palladium-catalyzed difluorocarbene transfer reaction, representing the first example of metal-difluorocarbene involved catalytic cross-coupling.2 Inspired by this novel reaction, the first example of catalytic difluoromethylation reaction from an inexpensive industrial chemical ClCF2H has been realized.3 These results encouraged us to gain mechanistic insight into the reaction and develop new difluorocarbene transfer reactions.

In 2019, the first Pd0=CF2 monomer {(t-Bu-Xantphos)Pd=CF2} was isolated from our group, which shows unique nucleophilicity and can be protonated by H2O.4 This intriguing finding is in sharp contrast to the electrophilicity of normal difluorocarbene. While, the PdII=CF2 has electrophilic nature, which not only can be hydrolysed by H2O to generate CO, but also can provide CF2 unit elongated products.  After deeply understanding the reaction mechanism, a controllable catalytic difluorocarbene transfer reaction has been developed.4 These studies open a new door to understand the metal difluorocarbene chemistry, in particular, the studies provide us a map to design and predict new catalytic difluorocarbene transfer reactions. Along this map, recently, we have developed a palladium-catalyzed difluorocarbene transfer with terminal alkynes using ClCF2H as the fluorine source,5 which can circumvent the radical pathway usually encountered during the coupling of alkynes with fluoroalkyl electrophiles, thus providing a new access to organofluorinated compounds. Most importantly, in the utilization of nucleophilic Pd0=CF2 {(t-Bu-Xantphos)Pd=CF2} with different types of electrophiles (including phenol, alcohol, and other carbon electrophiles), the studies of some novel catalytic difluorocarbene transfer reactions by different metal catalysis are underway in our lab, which will render the difluorocarbene as a good linker to connect two organic molecules. Furthermore, the use of metal difluorocarbene chemistry for polymerization is also underway in our lab, which will pave a new way for the production of fluorinated polymers under safe and mild reaction conditions. We believe that our research will prompt the research in the field of metal difluorocarbene chemistry and open a new chapter on the efficient synthesis of organofluorinated compounds.

References

  1. Brothers, P. J. & Roper, W. R. Transition-metal dihalocarbene complexes. Chem. Rev. 88, 1293−1326 (1988).
  2. Feng, Z., Min, Q.-Q. & Zhang, X. Access to difluoromethylated arenes by Pd-catalyzed reaction of arylboronic acids with bromodifluoroacetate. Org. Lett. 18, 44-47 (2016).
  3. Feng, Z., Min, Q.-Q., Fu, X.-P., An, L. & Zhang, X. Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium. Nat. Chem. 9, 918-923 (2017).
  4. Fu, X.-P. et al. .Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes Nat. Chem. 11, 948–956 (2019)
  5. Zhang, X.-Y.; Fu, X.-P.; Zhang, S. & Zhang, X. Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes CCS Chem. 2, 293–304 (2020).

Xingang Zhang

Professor, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences

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