A ‘New Answer’ to a 120-Year-Old Chemical Reaction

31, 2022

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The latest scientific research achievement of Hang Shi’s group of Westlake University was published in the Journal of the American Chemical Society (https://pubs.acs.org/doi/10.1021/jacs.1c12622).

Anilines are very common structural motifs in pharmaceuticals, functional materials, and natural products. Given the wide prevalence and ready availability of both phenols and amines, aniline synthesis through direct coupling between these starting materials would be extremely attractive. However, the difficulty of combining phenols with amines lies in some "strong personalities" of phenols: 1) phenols have a strong nucleophilic ability, which is difficult to be attacked by amines which are also nucleophilic; 2) the C-O bond energy (111 kcal/mol) is much larger than the O-H bond energy (88 kcal/mol), which means that compared with the C-O bond, it’s easier to break the O-H bond of phenol. Therefore, other researchers have found solutions: using stoichiometric activating reagents or reductants/oxidants. But these methods are not an ideal way to obtain anilines due to the requirement of too many “additives”.

In developing a strategy for the concise synthesis of anilines, Hang Shi’s group designed a rhodium (III) catalyst to reduce the π-electron density of phenols through π-coordination activation, thereby driving the difficult "enol-keto" tautomerization of phenols. The enol-keto tautomerization not only exists in various life systems, but also is widely used in modern organic synthesis. However, the formation of the keto form of phenol is completely inhibited because of the loss of aromaticity. But the researchers imagine that once the nucleophilic phenol can be converted into an electrophilic keto form, then combined with the classic "carbonyl-amine" condensation, it will provide an opportunity for the condensation of phenols with amines.

Recently, Hang Shi’s group at Westlake University published their latest achievement "Catalytic Amination of Phenols with Amines" in the Journal of the American Chemical Society (JACS). They established a new catalytic mode in combination of phenol tautomerization with the classic "carbonyl-amine" condensation. The 2021 Nobel Prize in Chemistry, for asymmetric organocatalysis, is based on this condensation method. This solves the nearly 120-year chemical challenge of the Bucherer reaction; reported in 1904, the reaction can convert "niche" naphthols to naphthylamine, but cannot be used for widespread phenols.

The new catalytic method does not need an activating reagent or a reductant/oxidant, and allows a widely existing pair of "enemy" phenols and amines (both are nucleophilic and therefore repulsive in reactivity) to be smoothly "combined" into anilines along with water as a sole byproduct.

Hang Shi, Zhongzhou Endowed Assistant Professor at Westlake University’s School of Science, is the corresponding author of the paper, and Ph.D. student Kai Chen and associate researcher Qikai Kang are the co-first authors. This paper was the No. 1 most viewed article in a month in the JACS.

More relevant research is currently ongoing in Hang Shi’s group. It is expected that the π-coordination activation of aromatic rings will be further developed into a catalysis system that will pave a new way for the synthesis and modification of aromatic compounds.