Thursday, July 11, 2013

New Tricks for Old Reagents: Oxygen Everywhere!

Passed a time, not too long ago, when if you wanted to oxygenate a selected C-C or C-H bond, you had to jump through several hoops: Over-oxidize (read: DESTROY!) then reduce again. Convert it to another functional group first, then use an expensive catalyst. Use toxic heavy metals (Cr, Hg, Pb, anyone?) in their highest oxidation states...and, oh yeah, heat the heck out of it.

The past decade has seen kinder, gentler oxidations emerge in rapid succession. Cobalt. P-450s. Iron. Now, two recent papers bring new wrinkles to the oxygenation of organic molecules in unexpected ways.

The first, from the Concellon / del Amo group in Org. Lett., relates a neat trick performed by Oxone, usually a reagent reserved to make other oxidants.

The researchers deal with their serendipitous discovery with humility and class:
"This work was not originally intended..[but]...was worth studying. [We] remark that Oxone is a crystalline solid oxidant, easy to handle, non-toxic...and, above all, stable and cheap."
All great reasons to run these reactions, which are formally derivatives of the classic Baeyer-Villiger reaction. They blast through a brief substrate table (26 entries, 33-95% yields), and seem pretty excited about investigating the mechanism.

The second reaction, hot off the Nature presses, involves another legacy reagent: phthaloyl peroxide. I suspect the Siegel group was looking for sp3 C-H activation conditions, but instead discovered a serendipitous site-selective arene activation, reliably producing phenols.

The reaction works across a broad functional group palette - azides, silyl groups, boronate esters, primary halogens - that other oxidants would tear apart. They ultimately do about 50 substrates, including 3 natural product-like scaffolds, with yields ranging from 45-95%.

Deciphering the mechanism requires Ken Houk's computational super-powers. The researchers discover a "reverse-rebound" mechanism operates, meaning an oxygen radical from phthaloyl peroxide adds into the ring, the electron bounces around in the pi cloud, and then ejects the ipso hydrogen in a two-step process. Interestingly, other radical oxygen oxidants (di-benzoyl peroxide) led to primarily sp3 oxidation, showing that the structure of the radical precursor plays a big role here.

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