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Easy Access To Phenols

Organic Synthesis: Peroxide provides new route to valuable molecules

by Bethany Halford
July 15, 2013 | A version of this story appeared in Volume 91, Issue 28

This scheme shows how phthaloyl peroxide adds a functional group to an arene.
Arene oxidation proceeds via radical mechanism.

Whether it’s in a drug candidate or an agro­chemical, transforming a milquetoast C–H bond into a reactive C–OH opens a world of possibilities for making more varied and complex molecules.

To do this with aromatic compounds, however, has typically been tough. Such reactions give overoxidized by-products or they require reagents, such as super­acids or metals, which limit the kinds of aromatic hydro­carbons, or arenes, that can be oxidized.

Now, chemists have come up with a mild, metal-free oxidation of arenes that tolerates a broad range of functional groups and gives chemists easy access to structurally complex phenols (Nature 2013, DOI: 10.1038/nature12284).

Arene oxidation has been “a long-standing challenge in synthesis,” says Dionicio Siegel, the University of Texas, Austin, chemistry professor who headed the work. “It’s an important transformation because you’re taking a commodity chemical and you’re putting a handle on it—a phenol that you can do all sorts of things with.”

Siegel’s group discovered that phthaloyl per­oxide can easily oxidize aromatic C–H bonds to produce phenols, without oxidizing activated aliphatic C–H bonds that may be present. The reaction works best in fluorinated alcohol solvents, such as hexafluoroisopropyl alcohol. It also tolerates many functional groups, including aldehydes, epoxides, and boronates, without modifying them.

Because the oxidizing agent is a peroxide, Siegel cautions that it may be susceptible to detonation or explosion. He advises not running any reactions with the reagent above 80 °C. “It’s like any other peroxide,” he says. “You need to be thoughtful when working with it.” Currently, chemists have to make their own phthaloyl peroxide, but Siegel is working with Sigma-Aldrich to make the reagent commercially available.

To determine the mechanism of the reaction, Siegel enlisted the help of UCLA computational chemist Kendall N. Houk. Houk figured out that the oxidation occurs via a mechanism in which the peroxide bond breaks into two radicals. One bonds to the arene, and the other then abstracts a hydrogen radical from the arene, generating an aromatic ester. Subsequent hydrolysis produces the phenol.

“For installing a hydroxyl onto an arene, there really isn’t another way that works like this,” Siegel points out. “We’re really going to think about this mechanism and maybe apply it to other types of transformations for forming other aryl-heteroatom bonds.”

The new approach “represents an incredibly simple and convenient way to access phenols from arenes by an intriguing mechanistic pathway,” comments Phil S. Baran, a synthetic chemist at Scripps Research Institute, La Jolla, Calif., who has worked on C–H oxidation. “There’s no doubt that this will find extensive use.”



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