Difluorocarbene has privileged applications in pharmaceuticals, agrochemicals, and materials. However, difluorocarbene transfer is limited in a few types of reaction due to its intrinsically electrophilic nature. To circumvent these limitations, attempts to tune the reactivity of difluorocarbene through coordination to transition-metals date back 40 years. Although various metal difluorocarbene ([M]=CF2) complexes based on groups 6 to 10 have been synthesized and isolated, the metal-difluorocarbene involved catalytic cross-coupling poses a great challenge due to the inert reactivity of isolated metal difluorocarbene complexes.
Direct utilization of difluorocarbene (:CF2) is a straightforward strategy to synthesize difluoromethyl compounds. The intrinsic electrophilic nature of :CF2, however, limits its reaction types. There have been attempts to tune the reactivity of this carbene species through the coordination to transition-metals since 40 years ago, but the metal-difluorocarbene ([M]=CF2) involved catalytic cross-coupling still remains a great challenge due to the inert reactivity of isolated metal difluorocarbene complexes.
In 2013, Mr. Feng Zhang, a Ph.D. candidate of our group at that time, started the journey of exploring the catalytic metal difluorocarbene involved coupling (MeDIC) reactions. He found that the palladium difluorocarbene could be used for the catalytic cross-coupling to prepare difluoromethylated arenes; He also found that it is difficult to isolate the palladium difluorocarbene complexes. After the graduation of Feng, Mr. Xia-Ping Fu took over this hard project, but only got numerous negative results after four years efforts. During this difficult progress, Xia-Ping found that [PdII]=CF2 is extremely instable, and it can be trapped by aniline to produce [PdII]=CNAr, demonstrating the electrophilic nature of [PdII]=CF2. On the other hand, the structure and reactivity of [Pd0]=CF2 remains elusive. After he designed various strategies and conducted numerous experiments, Xia-Ping finally found that KC8 could reduce trifluoromethyl palladium(II) salt [PdII]-CF3 to produce [Pd0]=CF2 and a bulky ligand t-BuXantphos is essential to stabilize this vulnerable complex. In July of 2018, Xia-Ping isolated the first [Pd0]=CF2 complex. The 1H, 13C 19F, and 31P NMR of this complex confirmed that it is a palladium difluorocarbene species. These results inspires us to continue the identification of the exact structure of this [Pd0]=CF2 (monomer or not). For many times, we thought that we had got the single crystalline of the [Pd0]=CF2, but X-ray diffraction results revealed that we got the "wrong crystal" that is usually derived from the decomposition of [Pd0]=CF2. We fell into the ‘dark days’ again. It is in April 2019, a few days before Xia-Ping’s doctoral defense, that we achieved the single crystal structure of [Pd0]=CF2 by modification of t-BuXantphos. While, interestingly, this great idea came from a casual talk in the elevator. This [Pd0]=CF2 shows highly nucleophilic nature, it can react with water to generate difluoromethyl palladium complex [PdII]-CF2H, which is the only one metal difluorocarbene complex that can be protonated by water thus far.
Combining the results of computational and experimental studies, we have figured out the reaction mechanism of this palladium difluorocarbene involved catalytic cross-coupling and developed a novel strategy for controllable catalytic difluorocarbene transfer by altering the valence state of the palladium center, in which [Pd0]=CF2 and [PdII]=CF2 possess opposite reactivity (nucleophilicity vs electrophilicity). We believe that these findings will open a new chapter in metal difluorocarbene chemistry.