Tuesday, July 3, 2012

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? 


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.