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.

Cyclophanes Fall Apart for Rhodium

When chemists design syntheses, they usually think in terms of building up, not tearing down. We alkylate, we esterify, we cyclize, adding always more molecular weight, joining synthons together. Occasionally, bonds must be broken. Considering most protecting groups, severing C-N, C-O, and C-X bonds keeps chemists of all stripes pretty busy. What about C-C scission? Not so much.

Sure, there's your decarboxylations, your ozonolyses, your samarium iodide reductions. Long ago, natural enzymes figured out how to push electron density around to slice up substrates: think about gramine fragmentation, Poitier oxidation, or the (now-defunct) Pictet-Spengler spiro mechanism. But you don't often see fully saturated sp3 carbon-carbon bonds falling apart; after all, we'd be dealing biology a mortal blow with such precarious engineering. 

Wouldn't it be cool, though, if we could just add a specific catalyst, a dash of water, and selectively crack a hydrocarbon?

I don't recall seeing this graphic in the SI...but I can hope.

Turns out you can...if the system's just right. Chinese University of Hong Kong chemistry professor Kin Shing Chan, with coworkers Ching Tat To and Kwong Shing Choi, reported just such a reaction in JACS ASAP yesterday. The scientists mix some Rh(III) porphyrin, some base, and a 100-fold excess of water, heating everything in the dark for 2-3 days. Out pops the "bibenzyl" compound (83%), which initially causes a bit of head-scratching: why don't they see C-H activation products? And where's the hydrogen coming from? 

(**SPOILERS BELOW**)

There's quite a bit of C-H activation, actually - it just doesn't go anywhere under the conditions. Swapping in deuterium oxide leads, unsurprisingly, to "D" incorporation on all the methylene groups and at the two newly-formed methyl groups. So the water indeed provides hydrogen, but not the way we'd usually think about it. No water splitting, no hydride formation, no "M-H." Instead, it's simply a radical quench: each metal-carbon bond, formed from C-C bond homolysis, grabs an "H-dot" from a neighboring water, and the remaining OH radicals shuffle away to produce hydrogen peroxide. And the rate looks pretty screwy, with second-order kinetics in metal, which the authors think means that two separate Rh(II) radical species - from Rh(III) reduction in situ - cooperate to cleave each side of the C-C bond simultaneously.

Source: Chan et. al., JACS ASAP 2012

Well, enough hype: only a few substrates (cyclooctane, cyclophane, strained substrates) have been shown to reliably react with these rhodium porphyrins, and the conditions (200 degrees Celsius, 3-4 days, in the dark?!?) aren't winning any immediate med chem converts. Hey, these things take a little time to become practical, so maybe one day you'll reach for your C-C "knife" of choice, and dial-in your molecular dissection. 

Hi Ho, Silver! (Benzoate)

Ever feel déjà vu? You know, that feeling of having been somewhere before, or crossing a black cat twice?

Carbon dioxide - Silver benzoate "puts a ring on it"
Source: Yamada, et.al. ACIEE, 2012

I've been stalked lately by a certain catalytic reagent: silver (I) benzoate. It's everywhere! Here, Charette's using it for C-H activation, with a little dash of Pd, to produce heterocyclic drug leads. Here, Toste's group turns up the selectivity on a gold hydroamination. Just this week, Yamada and coworkers showed lactone formation via carbon dioxide fixation (see above), using a bit of pressure, some base, and...you guessed it, silver benzoate.


Makes me wonder: Did I somehow miss the signs? How long has this reagent been flying under my radar?

In 1957, the Lone Ranger
ruled the Silver Screen
Source: lonerangerfanclub.com

Quite a while, it seems. Name reaction buffs - have you heard of the Prévost? First developed in the 1930s, it produces an anti vicinal diester, forming two new C-O bonds from opposite directions on neighboring carbons. Later investigations into the "wet Prévost" reaction favored cis diols; not too shabby when you consider that the related osmium or iodonium variants were still several decades away.


In its heyday, the Prévost helped synthesize steroids, alkaloids, and polymers, and found its way into the hands of a Who's Who of the O-Chem 'golden age': Woodward, Fieser, Carothers, Winstein, Streitweiser, Gilman, Djerassi, Fries, Benkeser, Sondheimer, van Tamelen, and Witkop. Perhaps you're more of a mechanisms person? Check out this sweet ¹⁸O labeling work, courtesy of a young University of Washington chemist named Ken Wiberg (1957).

What about silver benzoate makes it so darn useful for these oxidations? First, you have a d¹⁰ late metal species, which loves to coordinate to π-bonds (alkenes, alkynes, allenes). Second, the softer nature of the resonance-stabilized benzoate might switch on different catalytic pathways, say, changing from inner- to outer-sphere. Finally, to the benzoate itself: our buddy Ken showed that it adds twice, producing a transient 5-membered, cyclic species that ultimately permits the second benzoate addition.