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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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: Twitter: Dereklowe

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February 13, 2008

One Time Only. Or Maybe Just a Few.

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Posted by Derek

I’m going to be working up an Arbuzov reaction this morning, which is an odd thing for me to say. That’s because to the best of my recollection, which is pretty good, I’ve only run any of those during one period in my lab career. That was back in grad school, along about 1985, I’d say. I hope this one proves more useful than that one did – I was trying to make some dimethyl diazomethylphosphonate, and the prep was a relentless barrage of No Fun. (The first part of the sequence was identical to this).

I keep a list in my head of songs that I’ve only heard one time (no, I don’t appear to be normal, thanks for asking), and perhaps it’s time for me to assemble a list of reactions that I’ve only run once. That’s a tougher one, because if a reaction fails, you may well run the thing again. Still, I’ve only done one hydrogenation at 2000 psi with rhodium on alumina (July 3, 1984, and it looked like used lawnmower oil afterwards, I should add), and I’ve only used samarium iodide one time (and it didn’t work). But for a longer list I might have to settle for some things that I ran for a brief period and never have since.

The Claisen rearrangement would fall into that class, for sure. A feature of my early grad school work, I’ve never had the need to run one since. I can't think of the reaction without smelling ethyl vinyl ether in my memory, which is not a feature, in case you're wondering. I did a lot of carbohydrate reactions back then that I haven’t had the need to return to, either – Ferrier rearrangements being just one of them. And, like many other chemists, I had a brief photochemistry period, in my case during my post-doc, and have never run one of those again, either. Others that enjoyed their day in the sun and have never been seen again in my hood are the Prins reaction, nitrone cycloaddition (not since I was an undergrad in 1983), Lindlar hydrogenation, and the Henry reaction.

The thing is, any of these could make a comeback at any time. They’re still all perfectly reasonable reactions, and depending on what comes out of the next high-throughput screen or literature search, I might be setting one up next week. You never know. But there are some reactions that I think I’ve said goodbye to forever. In some cases, that’s because better alternatives are now available - I mentioned here that I haven’t used PCC for oxidations in years, and I think that one’s been pretty much superseded.

Others are history because I either very much doubt I’ll have the need for them, or because I just flat out Don’ Wanna. For example, I made Dess-Martin periodinane three times on a hundred-gram scale, during a period in the early 1990s when it wasn’t commercially available, and I plan, with any luck, never to do that again. The prep has been improved since those days, but that explosive intermediate was never something I enjoyed seeing. I don’t think I’ll be synthesizing fluorosulfonic acid starting from hydrofluoric acid any time soon, either. I did that one as an undergrad, too, if you can believe that – this guy must have had confidence in me, which I’m not at all sure was warranted by the evidence at hand. Nor do I foresee any need to make Fremy’s Salt from scratch again. (You can see someone else do it here, though - the internet amazes me sometimes). And if I never do another reaction that requires half a mole of phosgene, that’ll be fine with me, too.

Comments (9) + TrackBacks (0) | Category: Life in the Drug Labs


1. TNC on February 13, 2008 9:18 AM writes...

I clearly remember asking my adviser "when am I ever going to run an Arbuzov?" when I was learning its mechanism. As I recall, the mechanism is rather fun and simple, which must be why it is taught to entering grad students.

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2. Darjeeling on February 13, 2008 10:03 AM writes...

OK Derek, I'll bite: what's on your list of songs that you've only heard one time? Those of us with similar abnormalities want to know!

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3. NDPeter on February 13, 2008 11:07 AM writes...

Funny thing the Arbusov provokes this post. I just ran one last night. Granted I run these fairly regularly in my project right now. And they are proving to be a real nuisance on the way to finishing my thesis. The reaction is great for giving the phosphonate...but it's also great for giving the alkyphosphonate of whatever alkyl phosphite you use. I think in most cases it must not be an issue but for me my dibromide makes the bisphosphonate which is just about the same polarity as that blasted side product. While I can get what should be enough separation on TLC, the columns are a mess. The desired product is likely soluble in the other phosphonate produced and so the nightmare begins each time I run one of these. And to top it off, it usually is on a 10-20 g scale.

Also, along the lines of the smell of ethyl vinyl ether, the phosphites certainly will be leaving a similar memory with me.

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4. agogmagog on February 13, 2008 12:59 PM writes...

NDPeter, try (RO)2P(O)H as your phosphonate source. React with sodium metal (CARE) to get (RO)2P(O)Na then add your bromide. Usually a lower yield than the Arbusov, but the biproduct is NaBr so easily removed.

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5. Real chemist on February 13, 2008 2:51 PM writes...

you are a bloody wanker for talking about simple chemistry like this, not much wonder this industry never comes up with anything.

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6. kiwi on February 13, 2008 5:06 PM writes...

if you use tri(isopropyl)phosphite, the rate of the side reaction with the isopropyl halide produced is slower. works well for primary halides anyway.

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7. ZAL on February 14, 2008 2:58 AM writes...

1) Real chemist #5, you are a moron
2) I also used SmI2 only once, and it did not work for me either. But since the deep blue solution in THF looks really cool, I still keep it under my hood to impress occsional visitors.
3) Reactions that I tried only once: Appel (did not work), Suzuki (oh yes, went perfectly).

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8. Derek Lowe on February 14, 2008 10:34 AM writes...

Darjeeling, let's see. . .there's "The Dream Never Dies", by the Cooper Brothers. Heard that one the morning I took my SATs. And "I Predict" by Sparks - one time on a Little Rock radio station while I was in college. For some reason, I've also heard "Death or Glory" by the Clash only once, when I was half asleep with the radio on in my college dorm room. I heard "In a Mood" by Fabulon while driving late at night across New Jersey ten or twelve years ago.

I've got these written down somewhere; there are about thirty of them. On the other hand, I've heard "Hey Saint Peter" by Flash and the Pan exactly three times - on the night I graduated high school in 1979, once in my German post-doc lab in 1989, and (skipping 1999), once just this past summer, to my shock.

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9. NickK on February 14, 2008 12:25 PM writes...

So many reactions, so little time...

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