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Did anyone else see that paper on Thursday in Chem. Comm. titled "Use of Dimethyl Carbonate as a Solvent Greatly Enhances the Biaryl Coupling of Aryl Iodides and Organoboron Reagents without Adding Any Transition Metal Catalysts", and think "here we go again"? I immediately though it kind of appropriate that Chem. Soc. Rev. very recently published a history of transition metal contaminants in catalysis (DOI: 10.1039/C2CS15249E). However, on reading the Chem. Comm. paper, it seems the authors were very careful both to check all their reagents, and not make any grand claims. Not surprising, really, given the numerous examples of misunderstanding of such results in the literature. Even the title is cautious, saying 'without adding any transition metal catalysts', quite a step down from the bold claims of 'transition metal free' reactions seen in the literature of a decade or so ago.
A classic (and highly teachable) example is that of the Leadbeater group's 'Transition-Metal-Free Suzuki-Type Coupling' which began in 2003 with a triumphant Angewandte paper (DOI:10.1002/anie.200390362), and ended in 2004 with a slightly more subdued J. Org. Chem. paper (DOI:10.1021/jo048531j) when it turned out palladium in the sodium carbonate was present in large enough quantities to be catalysing the reaction. The problem is that palladium is fantastically good at effecting coupling reactions, even in what people irritatingly call 'homeopathic quantities'. Obviously, when doing a transition metal catalysed reaction, or, more importantly, publishing one, it's pretty important to make sure that the metal written on the bottle of reagent you're using is actually the one that's doing the magic. It's good to see that people are being a lot more careful these days.
It's not all bad, though. There are several example of reactions and methodologies being developed from investigation of trace impurities. One of the oldest and best known examples of this lead to what we now know as the Nozaki Hiyama Kishi reaction. This chromium(II) catalysed coupling of vinyl and allyl halides with aldehydes is a useful and very mild coupling widely employed in total synthesis, especially for medium sized rings. I've even done one. It was originally reported by Nozaki and Hiyama as a synthesis of homoallylic alcohols, but was found by Kishi and others to be a touch capricious with vinyl iodides. I'll let Kishi tell it (J. Am. Chem. Soc, 1986, 108, 5644):
"Unlike the Cr(II)-mediated coupling of allyl halides with aldehydes, the success of this coupling mysteriously depended on the source and batch of CrCl2... These facts naturally suggested an intriguing possibility that the success of this reaction might depend on some unknown contaminant in CrCI2. For this reason, we have examined the effect of transition metals for the Cr(II)-mediated coupling reaction and found that NiCl2 and Pd(OAc)2 have a dramatic effect... It is now possible to achieve the coupling using CrCl2 from any source with excellent reproducibility"
The secret? Just a touch of Ni (or Pd) to help with the formation of the organochromium species as these metals undergo oxidative insertion into the carbon halogen bond more readily, and then transmetallate with chromium:
Important not to add too much, though, as more than 0.1 - 1.0 wt% in the CrCl2 causes problems with dimerisation of the vinyl iodides.
More importantly, but less interestingly for organic chemists, trace nickel impurities also played a key role in the history of Ziegla-Natter polymerisation, a Nobel prize winning reaction of incredible industrial importance. But that's another story...
Addenda and Random Musings
1. Actually, a couple of things prompted me to write something about this. For example, a friend of mine involved in a medchem project has been forced to spend much of the last couple of weeks getting the products of his rather palladium and tin-heavy route tested for trace metal impurities which might affect the upcoming biological tests. Also, a comment in Rawal's recent welwitindolinone paper (covered by me, with Garg's, here) concerning the requirement to use brand new virgin glassware in order to obtain a high yield in the hydrazone formation step.
2. Ultimately the key ingredient in gold-meditated Sonogashira reactions, and several different 'iron catalysed' processes, palladium is by far the most common culprit for such things.
3. I do so hate this term, which, while often incorrectly credited by Leadbeater to De Vries (in, for example the JOC paper above), actually first appeared in a Chem. Rev. by Beletskaya on the Heck Reaction (DOI:10.1021/cr9903048). The interesting thing is that as the concentration drops the reaction does get better (to a a point):
Fig 1. From Org. Lett., 2003, 5, 3285.
4. A previous supervisor of mine used to joke that when he was a PhD student the only green chemistry anyone did was chromium oxidations.
5. One of the things I'm hoping we'll see one day is the industrial route being used by Eisai for the production of eribulin. Modified from Kishi's work on the halichondrins but scaled up for hundred gram batches, I've heard that the route features a large (~1kg) NHK. I do hope they get all that lovely chromium out of the final product.