Fu Yao, Lu Xi Nat. Synth.: The "cobalt-hydrogen" catalytic system breaks through the auxiliary binding of heteroatomic functional groups for alkylation of olefin hydrogen
Among organic molecules and functional materials, sp3 hybrid alkyl carbon centers are ubiquitous, which support the "three-dimensional" structure of materials and play a key role in imparting unique properties and functions to these molecules. Therefore, the development of novel and efficient C(sp3) center construction methods is an important research direction in synthetic chemistry.
The alkylation reaction of olefin hydrogen is based on alkenes with stable properties and a wide range of sources, and alkyl metal intermediates are generated in situ to participate in alkyl-alkyl coupling by inserting metallic hydrogen species into olefins, which realizes the efficient construction of C(sp3) centers under mild conditions. In recent years, the teams of Prof. Yao Fu (click to view introduction) and Associate Professor Xi Lu (click to view introduction) from the Key Laboratory of Precision and Intelligent Chemistry and School of Chemistry and Materials Science, University of Science and Technology of China have carried out systematic research work on the chemistry of alkyl metal intermediates: 1) established a coordination-assisted reactivity regulation and selective control mode, and realized the nickel-catalyzed hydrogen alkylation of olefins with site selective divergence and stereoselective control (CCS Chem. 2022, 4, 605; J. Am. Chem. Soc. 2023, 145, 10411; J. Am. Chem. Soc. 2020, 142, 214; Angew. Chem. Int. Ed. 2022, 61, e202205537; Nat. Commun. 2022, 13, 1890; Nat. Commun. 2021, 12, 1313）； 2) A cobalt catalytic system controlled by non-covalent interaction was established, and the reactivity regulation and stereochemical control of the non-coordination-assisted coupling reaction were realized (Nat. Catal. 2021, 4, 901; J. Am. Chem. Soc. 2024, 146, 3405; J. Am. Chem. Soc. 2022, 144, 13961; Angew. Chem. Int. Ed. 2023, 62, e202218544; Angew. Chem. Int. Ed. 2023, 62, e202306381）。
However, stereochemical selection control of alkylation reactions of olefins is still dependent on substrate Lewis basic functional groups (carbonyls, etc.) or polar heteroatomic functional groups (fluorine, oxygen atoms, etc.). Achieving precise chiral control and eliminating the specific confinement of heteroatom functional groups to substrates in alkylation reactions remains a challenge. Recently, the research team has developed a cobalt-hydrogen catalytic system, established a selective control mode of C-H•••π non-covalent interaction, overcome the limitation of substrate heteroatom functional groups, and realize the aromatic substructure-assisted asymmetric hydrogen alkylation of olefins. The findings were recently published in Nature Synthesis.
Figure 1. Aromatic substructure-assisted cobalt-catalyzed asymmetric hydrogen alkylation of olefins. Image courtesy of Nat. Synth.
The reaction exhibits a wide range of substrates and can react smoothly with a variety of 1,1-disubstituted styrene, including α-alkylstyrene, α-acetal styrene, α-borate styrene, and α-cyclopropylstyrene. It is worth noting that α-cyclopropylstyrene, as a common free radical acceptor, is not directly added by alkyl radicals in this system, maintaining the integrity of the cyclopropane backbone. In addition, the reaction has excellent functional group compatibility, which shows potential for application in the derivatization of drug molecules and natural products. Furthermore, the reaction also expands the deuterated alkylated version of olefins, which achieves excellent regioselectivity, enantioselectivity and diastereoselective control, and takes into account the satisfactory deuteration rate, which provides a potential pathway for the synthesis of deuterated drugs.
Figure 2. Representative substrate expansion and application demonstration. Image courtesy of Nat. Synth.
In order to elucidate the mechanistic process of the reaction and the causes of selectivity, the authors carried out a series of mechanistic experiments and density functional theory (DFT) calculations. In terms of the reaction mechanism, free radical experiments revealed the free radical mechanism of alkyl halide activation. Reaction kinetics experiments show that the rate-determining step of the reaction involves a reduction elimination step, rather than the formation of cobalt-hydrogen species, oxidative addition of alkyl iodide or hydrogen metallization of alkenes, which is supported by quantitative calculations. The quantitative calculation results show that the catalyst stabilization method can effectively avoid the side reaction of direct addition of alkyl radicals and olefins. The spin crossover process of the cobalt catalyst in the hydrogen metallization step and the reduction elimination step is conducive to the smooth progress of the whole reaction. In terms of selective genesis, NPA charge analysis (NPA) showed that the regioselectivity was affected by the electrostatic interaction between the cobalt center and the olefins. Independent gradient model based on Hirshfeld partition analysis (IGMH) and energy decomposition analysis (EDA) showed that enantioselectivity was mainly dominated by the C-H•••π non-covalent interaction between the substrate and the catalyst.
Figure 3. Mechanism studies and DFT calculations. Image courtesy of Nat. Synth.
brief summary
Lu Xi, Fu Yao and other researchers established a selective control model for C-H•••π non-covalent interactions, which used the C-H•••π interaction between the π system of substituted styrene substrate and ligand hydrogen atoms to accurately control the reaction region and enantioselectivity, realized the cobalt-catalyzed asymmetric hydrogen alkylation reaction of 1,1-disubstituted styrene, accurately constructed the benzyl chiral tertiary carbon center, and solved the problem of stereochemical control of heteroatom-free olefin hydrogen alkylation reaction. In this study, a new stereochemical control mode for alkylation of olefin hydrogenation was established, which provided a new idea for overcoming substrate specificity limitations.
The research was supported by the National Natural Science Foundation of China, the Youth Innovation Promotion Association of the Chinese Academy of Sciences, the Anhui Provincial Department of Science and Technology, the Anhui Provincial Key Laboratory of Biomass Clean Energy, and the Postdoctoral Innovative Talent Support Program.
Enantioselective Alkene Hydroalkylation Overcoming Heteroatom Constraints via Cobalt Catalysis
Yan Li, Deguang Liu, Xiao Hu, Jun-Yang Zhang, Qing-Wei Zhu, Boru Men, Gen-Wei Gao, Pei-Wen Chen, Yi-Zhou Tong, Zhe Chang, Zhen Li, Xi Lu* & Yao Fu*
Nat. Synth., 2024, DOI: 10.1038/s44160-024-00581-x
About the corresponding author
Fu Yao is a professor and doctoral supervisor of the University of Science and Technology of China, a distinguished professor of "Changjiang Scholars", a winner of the National Science Fund for Distinguished Young Scholars, and a leading talent of the "Ten Thousand Talents Program". He has been engaged in research in the fields of organic chemistry and green chemistry for a long time, and has developed new reactions and catalytic systems of green organic chemistry by combining theoretical and experimental research methods, which have been successfully applied to the catalytic conversion of biomass to produce new materials and chemicals. The research results have been published in Science (2 papers) and other journals, and more than 50 Chinese invention patents have been authorized and 6 technology transfers have been authorized. He has won the second prize of the National Natural Science Award (the second completer), the Min Enze Energy and Chemical Industry Award for Outstanding Contribution Award, the Tencent Science Exploration Award, the first "Lihuayi" Chemical Innovation Award of the Chinese Chemical Society, and has been elected as a fellow of the Chinese Chemical Society.
Links to the Group's website:
https://faculty.ustc.edu.cn/fuyao/zh_CN/index/106601/list/index.htm
https://www.x-mol.com/university/faculty/14770
Xi Lu, Ph.D., associate professor at the School of Chemistry and Materials Science, University of Science and Technology of China, has long been engaged in the research of alkyl-based metal intermediates-mediated coupling chemistry, and the development of nickel, cobalt and other abundant metals to catalyze the hydrogen alkylation of olefins. Since 2020, he has been a (co-)corresponding author in Nat. Catal. (1 article), Nat. Synth. (1 paper), CCS Chem. (3 papers), J. Am. Chem. Soc. (4 papers), Angew. Chem. (3 papers), Nat. Commun. (2 papers), Sci. China Chem. (1 paper), Chin. He has published 20 academic papers in journals such as Chem. Lett. (2 papers). He won the first prize of Anhui Natural Science Award in 2019 (the second completer); Funded by the 2022 Anhui Provincial Natural Science Foundation Outstanding Youth Project; He was selected as a member of the "Youth Innovation Promotion Association" of the Chinese Academy of Sciences in 2023.
Links to the Group's website:
https://www.x-mol.com/groups/luxi_ustc
The research group is recruiting postdoctoral researchers for a long time
Basic Requirements:
1. The postdoctoral position requires a recent Ph.D. degree in chemistry, mainly in theoretical and computational chemistry, organic synthetic chemistry, etc., and any one of them is sufficient.
2. The research work to be carried out during the postdoctoral period includes the following directions: AI-assisted reaction mechanism discovery and synthesis path exploration, green organic synthesis reaction innovation, functional molecule design and synthesis. Specialization in one of the research components is required, and individual strengths are integrated into teamwork. In addition, candidates for postdoctoral positions should have good communication skills, learning and thinking skills, and teamwork spirit.
3. Postdoctoral fellows should not be more than 35 years old, and those who are particularly excellent can be negotiated.
Working Treatment:
1. Postdoctoral fellows enjoy the benefits of postdoctoral personnel of the University of Science and Technology of China, with an annual salary of 30-450,000 yuan before tax, turnover housing on campus, and their children are enrolled in the kindergarten and primary school attached to the University of Science and Technology of China.
Welcome to send your resume to [email protected] (Mr. Lu). The subject of the email should indicate the postdoctoral application in chemistry of USTC.