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  • Professor Christopher Douglas research graphic on acylation
    07/20/18

    Iridium catalysts rewrite the rules for aromatic acylation

Each year, thousands of undergraduates learn the rules for electrophilic aromatic substitution. The Friedel-Crafts acylation and its Lewis acid catalyst have been the go-to reaction for installing acyl groups using acid chlorides or anhydrides as acylating agents. Typically, the byproducts are strongly acidic, like hydrochloric acid. Undergraduates learn that electronic effects existing groups on the aromatic ring dictate where the new acyl group will go. For example, electron donor groups leading to ortho/para products. 

A Minnesota team rewrote all those rules by developing a new catalyst for aromatic acylation. An iridium/phosphine mixture activates esters like phenyl salicylate and transfers the acyl group to the most sterically accessible position of an aromatic ring. The only byproduct of the reaction is phenol, which is not strongly acidic. The reaction was demonstrated in a new synthesis of the biologically active aryl ketone hydroxyphenstatin.

The team, led by Professor Christopher Douglas, used a combination of techniques to study the mechanism including kinetics, isotope effects, substituent effects, and computational modeling using resources from the Minnesota Supercomputing Institute. The researchers propose that an iridium catalyst performs both the rate-controlling C-H activation of the arene and C-O activation of the ester. The catalyst is directed to the ester by the ortho hydroxyl group of the salicylate.

“I’m proud of the hard work the students put in to this developing this chemistry,” said Douglas. “It opens up a new line of research in our lab. Clearly, this is just a start. The limitation to salicylate esters needs to be overcome for this to be widely used.”   

Graduate student Nicholas Serratore was the lead author on the project. He has since graduated from Minnesota with his doctorate and is working locally at Pride One, an intellectual property firm, which contracts with local giant, 3M. Graduate student co-authors Constance Anderson, Steven Underwood, and Grant Frost are working with Douglas to build off this work. 

“I can’t wait to see where this goes,” said Douglas. “Opportunities like these are why we come into work every day.” 

Iridium catalysts rewrite the rules for aromatic acylation

Serratore, N.A.; Anderson, C.B.; Frost, G.B.; Hoang, G.T.; Underwood, S.J.; Gemmel, P.M.; Hardy, M.A.; Douglas, C.J. “Integrating Metal-Catalyzed C–H and C–O Functionalization to Achieve Sterically Controlled Regioselectivity in Arene AcylationJ. Am. Chem. Soc. just accepted, DOI: 10.1021/jacs.8b06476