Wisps of Metal, Whispers of History

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.

A coral reef animal of the genus Parazoanthus, a relative of the animal that makes palytoxin. 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.

PalytoxinIt 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.

More reading:
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.

Author: Carmen Drahl

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7 Comments

  1. This is a really lovely piece, Carmen. Nice work.

  2. I agree–a really nice complement to the print piece. A small collection of these stories would make an awesome book…”Behind the Bench”…or something.

  3. One key take-home message from this is to keep sure to record lot numbers in your lab book. I cannot count the times that I have encountered lot-to-lot variation. Many times, this discovery led to new understanding of the reaction.

  4. I wouldn’t call palytoxin a small molecule though. But yeah, I wouldn’t want to be one of the people synthesizing it. Hazmat suits tend to get pretty uncomfortable when you have to wear them ten hours a day in your total synthesis organic lab. Washing glassware to make sure every last microgram is gone is also a bit of a pain. Just lab coat and goggles chemistry for me.

  5. Are you aware of the literary connection here? In Robert Louis Stevenson’s The Strange Case of Doctor Jekyll and Mr. Hyde, the transformation — first to Hyde, then to Jekyll as Hyde becomes the default, ultimately hinges on unknown impurities in Jekyll’s reagents. By the end of the story, he is begging his suppliers for any quantity of the original lots.

  6. @Dan: Amazing! I hadn’t known that (and I don’t remember it having come up in the Broadway musical version I saw in high school). Thanks for bringing it to my attention.
    For anyone who’s interested, here is some relevant text from the Project Gutenberg free e-book:

    My provision of the salt, which had never been renewed since the date of the first experiment, began to run low. I sent out for a fresh supply, and mixed the draught; the ebullition followed, and the first change of colour, not the second; I drank it and it was without efficiency. You will learn from Poole how I have had London ransacked; it was in vain; and I am now persuaded that my first supply was impure, and that it was that unknown impurity which lent efficacy to the draught.

    About a week has passed, and I am now finishing this statement under the influence of the last of the old powders. This, then, is the last time, short of a miracle, that Henry Jekyll can think his own thoughts or see his own face (now how sadly altered!) in the glass.

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