Trace components of your chemical system might play important roles in your experiments- that’s the broad message of a new correspondence appearing in the journal Angewandte Chemie. It comes from chemists Stephen Buchwald of MIT and Carsten Bolm of RWTH Aachen University. The collaborative work points out that a small set of iron-mediated bond-forming reactions is significantly affected by other metals, in particular, by vanishingly small amounts of copper (down to just a few parts per million). You can read C&EN’s coverage of the work here.
As was cited in the Angewandte report, Derek Lowe noted that this kind of thing has happened before in the field of catalysis. It’s worth briefly recounting the story of one of those historical cases.
Organic chemists rely on metals to make many different chemical bonds, including carbon-carbon, carbon-nitrogen, and carbon-oxygen bonds. But this particular tale dates to a time when many of the most famous metal-catalyzed reactions used today were just hitting their stride.
In 1983, Tamejiro Hiyama, Hitosi Nozaki, and coworkers at Kyoto University in Japan reported a new chromium-mediated reaction for forming carbon-carbon bonds. Because the reaction could selectively form particular types of structures, and it could be run without disturbing potentially sensitive parts of molecules, the reaction caught the eye of several of the research groups working on making highly complex structures, including that of Yoshito Kishi at Harvard University.
At the time, Kishi’s team was trying to make a monster of a molecule from scratch. The target was palytoxin, a dauntingly complex molecule first isolated from a coral reef animal, and one of the most poisonous small molecules known to man. At the time, it was the most poisonous substance known, with the exception of some proteins from bacteria and plants. Why make such a molecule at all? Well, part of it’s the challenge of the journey, the realization that making such a tough molecule will push your chemistry toolkit to the limit and force you to innovate, to invent new reactions or improve old ones. (The latter is what happened here).
The Kishi team had a tough carbon-carbon bond to make en route to palytoxin, and most of the tools in their toolkit weren’t cutting it. So they turned to Nozaki’s chromium-mediated method, which, after some adjustments, turned out to be successful.
As an aside, I should mention that chromium salts are very toxic. But I suppose if you’re trying to make something as dangerous as palytoxin, using chromium salts in the synthesis is the least of your problems. My cursory web searches suggest it takes only micrograms of palytoxin to kill a person- it’s a potent neurotoxin. Anecdotally, folks making palytoxin had to wear hazmat suits once they got past a certain point in the synthesis. That makes sense to me, given the experimentals (the team made about a milligram of palytoxin and several milligrams of closely related compounds). I haven’t been able to verify this in the papers, though.
But there’s more to the story. From the original report:
The Cr(II)-mediated coupling reaction provided an excellent solution to our problem except one technical difficulty we had yet to overcome….the success of this coupling mysteriously depended on the source and batch of CrCl2. We also tested the homemade Cr(II) reagent without success. These facts naturally suggested an intriguing possibility that the success of this reaction might depend on some unknown contaminant in CrCl2.
Imagine the situation- the reaction worked better, worse, or not at all, depending on which company the chromium reagent came from, or the particular lot number on the bottle. So Kishi’s group tested the several metal salts to see whether anything affected the reaction. Sure enough, nickel(II) chloride had a beneficial effect when combined with CrCl2. Nozaki and colleague Kazuhiko Takai independently uncovered the same thing. The teams’ 1986 reports appear in the same journal, within 500 pages of each other. Today, the reaction is known as the Nozaki-Hiyami-Kishi coupling reaction.
It was a nifty find, but what elevates these papers beyond niftiness is that the discovery transformed a somewhat erratic reaction into a reliable one that chemists have since harnessed for building many molecules.
Kishi’s group went on to use this reaction in a key step on their odyssey to palytoxin, which they completed in 1994. The sheer size and complexity of palytoxin renders the work a major achievement for organic chemists.
It’s important to remember that contaminants happen outside of organic chemistry, too. And the contaminants aren’t always doing beneficial things. Take, for example, a recent report in Science, which notes that additives used to make disposable plastic labware, such as pipette tips, can leach and interfere with biological assays. It’s something to keep in mind, no matter what kind of labwork you’re doing.
Angew. Chem. Int. Ed., DOI: 10.1002/anie.200902237
Classics in Total Synthesis, Chapter 36
Tet. Lett. 1983, 24, 5281
J. Am. Chem. Soc. 1986, 108, 5644.
J. Am. Chem. Soc. 1986, 108, 6048.
J. Am. Chem. Soc. 1989, 111, 7525 and 7530.
J. Am. Chem. Soc. 1994, 116, 11205.
Science 2008, 322, 917.
Images: Albert Kok (Wikimedia Commons); J. Am. Chem. Soc. 1994
UPDATE 7/13: Added link to C&EN Online coverage.
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