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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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October 10, 2006

Five Things I Haven't Used in Years

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Posted by Derek

1. A Soxhlet extractor. It's not that I don't like them, it's just that I haven't had the need for one. We used to use one to wash polar products out of all the gunked-up salts from big lithium aluminum hydride reactions, and I once used one to slowly wash a more soluble impurity out of a powdery mixture of isomers. I think some of my younger colleagues have hardly ever seen one, which I find vaguely depressing.

2. For that matter, a liquid-liquid extractor. I had one of these built for me back in grad school that came up to my waist if I set it up on the floor. A week's worth of ethyl acetate washing did wonders for my crude material, which was about as crude as it's possible to get, since it was obtained by destructive vacuum distillation of corn starch. I'll have to go into that story in detail some time.

3. An infrared spectrometer. Last time I put something into an IR, I swear, it must have been nearly seventeen years ago. It's a perfectly good, perfectly reasonable analytical technique that's just been totally swamped by NMR and LC/mass spec technology. It still does some things very well (like tell you if you have a nitrile or not), bu as far as I can tell, no one cares.

4. A polarimeter. I've narrowly dodged this one over the years, but I think I haven't had to get an optical rotation since about 1996. You want to avoid chiral centers if you're making pharmaceuticals, and if you have chirality, you want to buy it in your starting material. And if you have doubts about your enantiomeric purity, you want to use something like chiral HPLC and not trust the specific rotation. Tiny bits of impurity with huge rotations can totally throw the number off. Stick with techniques where the error terms are linear and don't have exponents in them.

5. Cyclic voltammetry. One of my first projects in grad school bid fair to wander off into physical organic chemistry, at least until we found that the effect we were trying to explain didn't exist in the first place. I tried all kinds of odd techniques to get a handle on the (nonexistent) anomaly, and that included wandering down to the electrochemists in the other hallway. It didn't hurt that the grad student who ran the apparatus was really cute. But cute electrochemists are thin on the ground, in my data set, anyway.

Comments (33) + TrackBacks (0) | Category: Life in the Drug Labs


1. YellowIbis on October 10, 2006 8:54 PM writes...

We vote for the print edition of Chem Abs.

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2. JB on October 10, 2006 9:29 PM writes...

How about the Abderhalden drying pistol?

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3. Novice Chemist on October 10, 2006 9:47 PM writes...

1, 3 and 4. Wow -- can you tell I'm in academia?

Derek, now you've got me freaked out about LAH reductions. There's always that belief that "boy, there must be a lot of compound in that cake." But a Soxhlet extractor: oh, man. Time to ratchet up the paranoia!

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4. kiwi on October 10, 2006 10:00 PM writes...

you haven't used a sohxlet lately? you'll find no better method for azeotropically removing water (eg old-school esterification, acetalisation) than a sohxlet full of mol sieves. consquently i have the dean-stark trap on my list

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5. mikshake on October 10, 2006 10:32 PM writes...

kiwi: thanx for the Soxlet tip, I am gonna try it for scaleups!

I did a Soxlet extraction of a serie of base-sensitive intermediates that could be isolated only as hydrochloride by salting them out from diluted sulfuric acid with brine. Which then brought the problem of removing NaCl from the dried precipitate. Soxleting the stuff with anhydrous ethanol was the solution.

Levoglucosane: Cleaning the caramel-coated shared group starch pyrolysis equipment was the least popular duty in Cerny/Trnka lab in Prague. A lesser form of punishment was fractional crystallization of the actual crude pyrolysis product.

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6. skatesailor on October 10, 2006 10:53 PM writes...

In the early 70s, I made monomethyl terephthalate from dimethyl terephthalate, using one equivalent of sodium hydroxide. Not surprisingly, the reaction produced the expected thermodynamic mixture of the diacid, the desired monoacid, and the starting diester. With benzene as the solvent, a Soxhlet extractor cleanly and conveniently separated all three compounds. The diacid remained in the paper cup, the diester completely dissolved in the solvent, while the desired monoester crystallized from the boiling benzene as gleaming, colorless plates that were analytically pure (+/- 0.2 % for each element including oxygen). The plates crystallized around boiling chips, forming golf-ball-sized aggregates. We carried out the reaction on scales of 50-100g of dimethyl terephthalate, and on those scales the separation, which required several days, needed scant attention.

I shall be forever grateful to Soxhlet for making memorable if not beautiful a separation that might have been tedious, but was a pleasure instead.

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7. skatesailor on October 10, 2006 11:00 PM writes...

In re Novice Chemist on October 10, 2006 09:47 PM.

Read "Alleged Alklations of alpha-Hydroxyimines to Betaines: Revisions of the Structures of Educts and Products" (Chem. Commun. 1383 (1984)) if you would like to learn the indispensability to an organic chemist of infrared spectroscopy.

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8. kiwi on October 11, 2006 12:03 AM writes...

no worries milkshake, fyi both 3A and 4A mol sieves can absorb up to ~20% w/w in water. i generally use a good excess. 3A's are good for methanol, but 4A's are best for everything else.

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9. Petros on October 11, 2006 2:07 AM writes...

While its some years since I've been in the lab I too used to use a Soxhlet extracter full of MS4A on a regualr basis, don't recall ever using it for anything else

A polarimeter is invaluable if making well charcetrized chiral compounds but the old manual ones were a nightmare to use.

IR spectrometers are occassionallu useful, e.g. for monitoring the conversion of an acid to an acid chloride, but in a synthetic lab of limited other utility.

However, wathcing CSI Miamia last night one of their scientists ran an IR of an unknown powder and then proceeded to deduce a complex pharmaceutical structure from the IR!

I#ve only ever seen your other techniques used once each in over 20 years working in the lab so they are pretty esoteric I'd suggest.

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10. soapchemist on October 11, 2006 8:10 AM writes...

I used IR when working in a QC lab long before grad school... but haven't had the occasion since. As for the Soxhlet, I'll have to give that a try. I have used the DEan-Stark recently for that expressed purpose (azeotropic removal of water) but the soxhlet sounds more eficient.

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11. Cryptic Ned on October 11, 2006 8:29 AM writes...

So is "Soxhlet" an Albanian name or some sort of South African Xhosa or Zulu name?

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12. Derek Lowe on October 11, 2006 10:49 AM writes...

That would be Franz von Soxhlet, from Brno, in what's now the Czech Republic. In those days, Bohemia and Moravia were rather more German than they are now - that's when "Prager Deutsch" was considered an excellent example of the spoken language.

Whenever there's some old apparatus or reaction named after someone in organic chemistry, German is always the high-percentage guess. There are some French, Russian, Dutch, and British/American names sprinkled in there, but you'll hit most of the time with the Germans.

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13. tom bartlett on October 11, 2006 11:41 AM writes...

Prep plates. Nearly obsolete, with the advent of flash silica, IMHO. Oh-- and I'd include the chromatotron in the obsolete list. Maybe good for Spin Art.

In general, though, the modern chem lab would look very much like the lab of 30 years ago, except, of course, in the NMR room....

Things I use increasingly: the microwave.

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14. Novice Chemist on October 11, 2006 12:52 PM writes...

I forgot to add that watching a Soxhlet extractor at work is the most mezmerizing thing in the world.

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15. Jose on October 11, 2006 2:44 PM writes...

Prep plates aren't dead! I just used one a few weeks ago. It's a great way to get enough for an NMR, and then decide if the whole mess is worth flashing / throwing on the Biotage. The best part is it works unattended!

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16. milo on October 11, 2006 3:02 PM writes...

The Chromatotron is obsolete? Say it ain't so! I used on the other day to separate 100mg each of 2 diastereomers. Sure, it is a glorified record player, but it does the job (and generates some great expressions from folks who have never used one).

Now, an oil bath based Thomas-Hoover melting point apparatus is clearly out dated... Especially with these new fancy computer controlled solid-state ones that give pritouts and record movies of the melt.

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17. Milo on October 11, 2006 3:17 PM writes...

"You want to avoid chiral centers if you're making pharmaceuticals"


This is really an interesting phrase. About a month ago, I was talking to a recruiter from a large pharma mega-company and he was rattling off all these reasons why his company encourages the incorporation of chiral centers into their candidates. I always thought that chirality opened the door to lots of costs and additional studies etc... this a "company culture" thing? Company A may love chirality whereas company B might hate it?

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18. Paul on October 11, 2006 3:17 PM writes...

I have a really hard time convincing the chemists in my group that TLC is useful and should be done regularly to check their reactions...they look at me like I would look at someone suggesting I should get IR's of everything.

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19. tom bartlett on October 11, 2006 3:18 PM writes...

"Especially with these new fancy computer controlled solid-state ones that give pritouts and record movies of the melt."

Sounds better than SOME of the stuff I've seen on YouTube.

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20. Prelim complete on October 11, 2006 4:02 PM writes...

Re: Acid to acyl chloride conversion monitoring-
You can just take a small amount (10 uL), and quench it into MeOH, then TLC against the acid. Great way to see if all of the acid is gone

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21. Chrispy on October 11, 2006 6:30 PM writes...

I always liked IR for azides -- very distinctive peak. It's especially fun wondering if the stuff is going to blow up as you compress it into the salt pellet.

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22. milkshake on October 11, 2006 6:58 PM writes...

With the chiral center in a drug candidate molecule, it's just like with ma other-in-law: It can be sometimes useful, too - but the best is when there is none.

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23. person on October 11, 2006 8:41 PM writes...

In my second year organic chemistry class, we did a lab involving a polarimeter. Our lecture professor (a different person than the lab instructure) later asked the class about lab and noted that she should go check it about because she had never used a polarimeter. I took that as a good indicator that polarimeters aren't used that often.

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24. Handles on October 11, 2006 9:22 PM writes...

One thing I havent used in years, and Im quite glad actually: an ether still. Although playing with sodium is undoubtedly fun, Im much happier throwing sieves into a bottle of HPLC grade THF.

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25. agogmagog on October 12, 2006 3:17 AM writes...

Ah, the chromatotron. One of my favourite memories from PhD land was fixing the UV lamp from the uv cabinet above the chromatotron late one night, to allow me to visualise the bands of anthracene derivatives as they eluted from the plate. Brilliant blue ever widening cirlcles. Beautiful.

This technique worked with most UV active compounds, allowing the bands to be visualised as they travel across the plate. Works best at night with the lights of the lab off.

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26. ZAL on October 12, 2006 4:23 AM writes...

I have a positive memory of the chromatotron, which helped me to separate two diastereomers coming from a resolution that were litterally unseparable on column. Needless to say, when I used them as ligands in an asymmetric reaction, the best one gave 17% ee.
About IR, one very nice application is the REACT-IR, to check in real time the progress of a reaction: very useful for kinetic studies, especially when the reaction involves conversion or fomation of a carbonyl group (I have seen papers of Carreira, Shibasaki and others using this technique).

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27. Glenn on October 12, 2006 9:53 PM writes...

What about Kugelrohr distillation. I haven't used one of those in over 20 years. Does Aldrich even sell those anymore? I think most people used to mistake it for a coffeepot.

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28. milkshake on October 13, 2006 2:08 AM writes...

Don't talk badly of coffee-can Kugelrohr. I used to laugh at people distilling their aza-crown ether crap on Kugelror. Couple of years later, I had to make series of polyamines (that were meant as solubilising side-chain for a kinase compounds) and me and the Great Coffee Can became unseparable pals.

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29. Derek Lowe on October 13, 2006 6:15 AM writes...

I haven't used the "Koog" myself in years, but one of the guys in my lab used one extensively just a month or two ago. When you need it, you need it!

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30. Brad on October 13, 2006 1:20 PM writes...


Was you comment about the vacuum distiliation of corn starch a path to make 1,6-anhydroglucose? That reaction, as I recall, was the ugliest mess ever.

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31. Derek Lowe on October 13, 2006 1:51 PM writes...

That's exactly the reaction, as you and Milkshake guessed. Levoglucosan was my starting material for a while on a natural product synthesis, so I used to crank out 50 gram batches of the stuff, cursing all the while.

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32. Anne on October 15, 2006 11:05 AM writes...

Prep TLC, heck! How about prep GC? I used this to separate two epimers of an ester I needed. I made the column myself: it was about 12 feet long, made from 1/4" copper tubing which I packed (with packing material I also made) and then wound around a Drierite jar.

Then I had to take the ester I isolated from the GC, hydrolyze it, and use the acid to make another compound that I then purified on the Chromatotron.

I feel so old (and this was the late '80's!) and, especiallly after typing that, I am so happy I'm done with graduate school.

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33. Brian on August 22, 2007 6:42 AM writes...

I vote for Bomb Calorimeter.
If you've run one, you get it.

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