Scientists have successfully achieved inert hydrocarbon bonding conversion in organic molecules

On 4 August 2022, Prof Wu Jie of the National University of Singapore, in collaboration with a team of Prof Hong Xin of Zhejiang University, published an article titled “Brønsted acid-enhanced direct hydrogen atom transfer photocatalysis for selective functionalization of unactivated C” in Nature Synthesis. sp3)-H bonds” research results.

This result reports the general strategy of using bronstric acid to improve the activity of hydrogen atom transfer photocatalysts, and realizes the site selectivity and diversity conversion of inert hydrocarbon bonds in organic molecules with inexpensive akebode Y as the photocatalyst, which provides a new scheme for the later modification of drug molecules and functional materials. The corresponding authors of the paper are Wu Jie and Hong Xin; The first author is Cao Hui.

Hydrocarbon bonds, especially inert sp3 hydrocarbon bonds, are widely distributed in organic compounds. The catalytic conversion of hydrocarbon bonds can transform rich and inexpensive chemical feedstocks into high value-added products, significantly improving the economy of synthesis. In the fields of drug structure optimization, natural product synthesis, and functional material modification, the catalytic conversion of hydrocarbon bonds can also avoid the design of synthetic routes from scratch, and play a role in turning stones into gold. However, the selective catalytic activation of inert sp3 hydrocarbon bonds has always been a problem for the scientific community, because their bond energy is very high, the polarity is very small, and different hydrocarbon bonds within the same molecule often have similar chemical environments and are difficult to distinguish. Photocatalysis of hydrogen atom transfer is an attractive method for activating inert sp3 hydrocarbon bonds (Figure 1a). The hydrogen atom transfer photocatalyst that enters the excited state after illumination can selectively activate the electron-rich, small hindrance sp3 hydrocarbon bond, and the resulting free radical intermediates can be further converted into diverse functional groups. The biggest bottleneck facing this strategy is that the catalyst has low activity and generally requires a large excess hydrocarbon substrate, thereby reducing atomic economy and restricting its application in complex molecular post-modification.

In this work, Professor Wu Jie’s team was inspired by the enhanced oxidation of metal oxides by bronst acid (Figure 1b), and used the relatively alkaline sp3 oxygen atoms in the bronster acid selective subaturbed photocatalyst to achieve the effect of enhancing the hydrogen atom transfer activity of the photocatalyst without increasing the catalytic centrosteric hindrance (Figure 1c). With the inexpensive Akebono Y as the photocatalyst and an equivalent organic molecule as the substrate, the inert hydrocarbon bond can be efficiently and selectively converted to alkyl, heteroaryl, fluorine and other groups under blue light irradiation. A variety of drug molecules and natural products can be used to achieve efficient modifications, such as precursors of the tretinoid adapalene, pinane, leucine( leucine), actinomycetonone (cycloheximide), etc. (Figure 1d). The conditions of the reaction are mild and the site selectivity is extremely high, making it easy to expand to more substrate molecules and reaction types.

Figure 1: Strategies and applications for increasing the activity of photohydrogen atom transfer catalysts.

The collaborative team also conducted a detailed experimental and theoretical calculation study of this novel bronster acid regulation strategy (Figure 2). Combining ultraviolet-visible absorption spectra, fluorescence emission spectroscopy, and literature evidence, the authors found that protonated akebono Y is a key species that promotes increased reaction efficiency (Figures 2b-d). Transient spectroscopy and free radical capture experiments also support this finding (Figure 2e-g). Theoretical calculations show that when the sp3 oxygen atom on Akebono Y is protonated, the kinetic and thermodynamic barriers for the transfer of hydrogen atoms are greatly reduced (Figure 2i). Further research shows that this bronster acid regulation strategy is not only suitable for Akebono Y, but also effective for commonly used hydrogen atom transfer photocatalysts such as aromatic ketones and decatungstic acid, which is a general method to improve the activity of hydrogen atom transfer photocatalysts.

Figure 2: Study on the mechanism of bronster acid regulating the catalytic process of hydrogen atom transfer.

The study develops a widely applicable strategy to improve the photocatalytic efficiency of hydrogen atom transfer, providing a new platform for inert hydrocarbon bond catalytic conversion, which is expected to be applied in drug research and development, material synthesis and other fields. This work was supported by the Natural Science Foundation of China (21871205, 22071170, 21702182, 21873081, 22122109). (Source: Science Network)

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