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About this Author
Derek Lowe
Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com

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May 15, 2008

Copper: A Gentleman's Disagreement

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Posted by Derek

I was running a copper-catalyzed coupling reaction the other day when my summer intern asked me how it worked. I showed her the mechanism that the authors of the paper had proposed, but pointed out that it was mostly hand-waving. The general features are probably more or less right: the copper iodide presumably does form some kind of soluble complex with the amino acid that’s needed in the reaction mix, and that may well form some sort of complex with the aryl halide, which opens up the ring to nucleophilic substitution, etc. If this were an exam, I’d give full points for that one.

But a lot of these couplings are, as I pointed out to her, very hazily worked out. The Ullman reaction, in various forms, has been with us for many decades, and there are more variations on it than you can count. If it always worked reasonably well, or if people had any strong ideas about how it did so, the literature on it wouldn’t be in the shaggy shape it is. Copper chemistry in particular has been (simultaneously) a very useful area for people to discover new reactions, and a horrible trackless swamp for people trying to explain how they work.

All you have to do is look at the vicious exchanges between Bruce Lipschutz and Steve Bertz during the 1990s about whether such as thing as a “higher-order cuprate” exists. I have absolutely no intention of reconstructing this argument; I would have to be paid at a spectacular hourly rate to even attempt it. It's enough to say that the arguments raged, in an increasingly personal manner, about what state the copper metal was in, what ligands coordinated to it, and what the active form of these reagents might be (as opposed to what the bulk of the mixture was at any given time). It culminated in what must be one of the most direct titles for a scientific paper I've ever seen: It's on lithium! An answer to the recent communication which asked the question: 'if the cyano ligand is not on copper, then where is it?'. That's in Chemical Communications 7, 815 (1996), if you're interested (here's the PDF for subscribers). Bertz continued to shell Lipshutz's position past the time when any fire was being returned, as far as I can tell, and continues to work in the area. Lipshutz, for his part, hasn't published on the higher-order cuprates in some time (being no doubt heartily sick of the whole topic), but has kept up a steady stream of work on new reactions involving copper, nickel, and other metals.

So if well-qualified researchers, brimming with grad students, postdocs, and grant money, can argue for years about copper mechanisms, I'm going to stay out of it. As time goes on, I'm increasingly indifferent to reaction mechanisms, anyway. I want to get product out the other end of the reaction. And while there are times when knowing the mechanism can help reach that goal, those times do not occur as frequently as you might hope.

Comments (13) + TrackBacks (0) | Category: Chemical News | Inorganic Chemistry | Life in the Drug Labs

April 28, 2008

A Salute

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Posted by Derek

Dr. Warfield Teague is retiring this year, which makes me feel old. He was one of the professors who helped make me what I am today – in his case, partly by keeping me out of his chosen field of inorganic chemistry. It was a good move on his part; I’d surely have blown something up good and thoroughly when I got to grad school, such are the opportunities in that area.

Unfortunately for both him and for me, his Advanced Inorganic course ended up scheduled for 7:40 AM back in early 1983. I started out my college career with a barrage of classes at that hour, and made every one of them. My sophomore year, I only skipped one class, and I waited for the lightning bolt to descend even for that one. But my junior year I had a professor or two whose lectures could be safely (even profitably) missed, and I began to get in the habit.

Teague wasn’t in that category, though. His lectures were fine; it’s just that they took place so early in the morning. My roommate David and I, both chemistry majors, found it harder and harder to summon the activation energy needed to make it out of the thermodynamic sinks of our beds. Dr. Teague’s threat to come over and teach the class in our dorm room didn’t quite do the trick (while lying there in bed, actually, the idea had a certain appeal). But his threat to start giving top-of-the-morning quizzes did. I showed up, and kept showing up. First year of grad school, now that’s where I started slacking off in my classes in earnest. But not all of the professors I had that year could communicate the facts of their specialty as well as Dr. Teague could for his.

The lab part of the course, that I would have shown up at 6 AM for. I don’t know how he’s done it in recent years, but 25 years ago (not possible, that), we could do pretty much any lab procedure that Dr. Teague would sign off on. There was a requirement that we do at least one low-temperature one, one high-temperature one, one metal complex, and so on. So the dozen or so of us in the class would root around through Inorganic Syntheses or the like, looking for interesting stuff. And there’s plenty of it in there, let me tell you.

In my case, the most memorable included the preparation of fluorosulfonic acid from scratch. Scratch means you start from concentrated hydrofluoric acid, a fine substance for the spirited undergraduate chemist to become familiar with. I can still hear the peculiar whine that solid KOH pellets make when you toss them into a plastic dish of the acid – they’ve a pretty short half-life in there, I can tell you. And I also made the magnesium analog of ferrocenemagnecene, I guess you’d call it – by one of those don’t-be-afraid-of-the-obvious routes: heat some magnesium turnings to about 600 C in a tube furnace, and pass fresh cyclopentadiene monomer vapors over them. Works great. And while you shouldn’t be afraid of the paper synthesis, red-hot magnesium metal is something else again.

While I was thus engaged, my classmates were setting off thermite reactions, making phosgene from carbon tetrachloride (chromium trioxide, five hundred degrees, nothing to it), and preparing titanium tetrachloride from the ground up. (I can’t recommend that particular prep – the liquid “tickle-four” comes out bright green from being around 1 molar in dissolved chlorine gas, so you’re going to want to redistill it, most likely). We learned a fair amount of inorganic chemistry, and more than a fair amount of lab technique. As evidence for that, we all survived.

Whether the latest generation of undergrads will get these kinds of experiences, I don't know. But I'm glad I did, and I'd like to thank Warfield Teague for providing them.

Comments (13) + TrackBacks (0) | Category: Inorganic Chemistry