Regioselectivity plays a crucial role in the diverse range of products containing organic compounds. It is a feature in chemical reactions that selectively adds substituents to specific positions of organic compounds, enabling the formation of desired products with specific functionalities. One notable example of regioselective reactions is the Friedel−Crafts reaction, which allows the addition of substituents to specific positions on aromatic compounds like benzene and phenol rings.
A Significant Breakthrough in Regioselective Reactions
An important breakthrough in the field of regioselective reactions has been made by Professor Takayoshi Arai and his team from Chiba University in Japan. In their recent study published in ACS Catalysis, they have successfully developed a general para-selective aza-Friedel−Crafts type reaction of phenols with imines. This breakthrough holds great potential for the synthesis of medicines and advanced materials, opening up new possibilities for various industries.
Traditionally, the aza-Friedel−Crafts reaction of phenols with imines leads to substitution adjacent to the hydroxy (–OH) group of the phenol ring, resulting in the formation of ortho-products. Achieving selective substitution at the para-position, further away from the –OH group, has been a significant challenge. However, Professor Arai and his team were able to overcome this challenge by drawing inspiration from their previous experiments.
In their earlier work, the researchers discovered that the bis(imidazolidine) pyridine (PyBidine)-metal complex platform could potentially carry out the aza-Friedel−Crafts reaction of phenols with imines due to its dual functionality as an acid and a basic catalyst. Expanding on this finding, they developed a “bulky PyBidine”-Ni(OAc)2 catalyst by substituting the benzyl group of PyBidine with a bulky diphenylethyl group. This catalyst proved to be highly effective in facilitating para-selective aza-Friedel−Crafts reactions with remarkable selectivity of up to 99:1 for para/ortho substitution.
Understanding the Regioselectivity Mechanism
Through a series of tests and employing DFT calculations, the researchers discovered that the PyBidine-Ni(OAc)2 complex exhibited a preference for para-substituted products. They found that this regioselectivity was attributed to the cooperative activation of the highest occupied molecular orbital (HOMO) of 3,5-dialkoxyphenols and the lowest unoccupied molecular orbital (LUMO) of sulfonylaldimines.
HOMO-LUMO Activation: The Key to Regioselectivity
The reaction initiated with the formation of a nickel phenoxide, which enhanced the reactivity at the para-position of the phenol group through HOMO activation. Subsequently, the sulfonylaldimine attached to this position via hydrogen bonds on the bulky PyBidine-Ni(OAc)2 catalyst through LUMO activation, resulting in the formation of the final product. This cooperative HOMO-LUMO activation mechanism played a pivotal role in switching the regioselectivity for the design and development of functional molecules.
Promising Applications and Improved Synthetic Efficiency
This breakthrough study marks a significant milestone in the field of regioselective reactions. The rapid and safe synthesis method developed by Professor Arai and his team has not only improved the synthetic efficiency of an orexin antagonist, but it also holds the potential to contribute to environmentally benign and sustainable chemistry. The development of a general para-selective aza-Friedel−Crafts type reaction of phenols with imines opens up new possibilities for the synthesis of medicines and advanced materials. This breakthrough provides a valuable tool for the design and development of functional molecules, benefiting industries such as pharmaceuticals, agrochemicals, and materials science.
Professor Takayoshi Arai and his team’s groundbreaking research in regioselective reactions has paved the way for significant advancements in the synthesis of medicines and advanced materials. Their innovative approach and the development of a regioselective catalyst have overcome the challenges of selective substitution, offering new possibilities for various industries. This breakthrough holds great promise for the future of functional molecule design and development, contributing to the advancement of pharmaceuticals, agrochemicals, and materials science.
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