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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: derekb.lowe@gmail.com Twitter: Dereklowe

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November 20, 2009

But These Reagents, Where Are They?

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Posted by Derek

I'm home today (sick children, etc.), so I'm blogging from next to my daughter's guinea pig cage rather across the hall from my lab. But I have a lab-based question to throw out: what would you say is the chemistry technique or reagent with the worst publication-to-real use ratio?

I have a couple of nominees to get things rolling. For reagent, I would like to advance the montmorillonite clay stuff. I cannot count how many papers I have seen on its use as a Lewis acid, catalyst, and all-around good thing to have, but I have never used it myself, never spoken with anyone who has, and never (to my recollection) heard it suggested as a possible thing to try when someone encountered a synthetic problem. For all I know it's a fine reagent, but its footprint does not seem to be very large. I actually have used benzotriazole, but I've never seen an actual container of montmorillonite K-10.

For general technique, I'm tempted to nominate ionic liquids. Man, are there ever a lot of publications on those things, but again, I've never actually encountered them in actual practice. I have heard second-hand of people trying them, so I guess that counts for something, but it still seems to be disproportionate compared to the avalanche of literature citations for the things. The craze seems to have peaked, but still not a week goes by that I don't see a paper.

Nominations? As with the book recommendation post, I'll assemble things into master lists.

Comments (49) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Ed on November 20, 2009 11:30 AM writes...

For synthetic chemists, cyclodextrins have to be pretty high up your list.

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2. Pi* on November 20, 2009 11:43 AM writes...

Et2Zn
apparently its great to add to benzaldehyde

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3. Anonymous on November 20, 2009 12:00 PM writes...

Remember when buckyballs were supposed to solve all of society's problems in the future?

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4. Tok on November 20, 2009 12:07 PM writes...

Buckyballs are sooo 1990's. Now it's carbon nanotubes! But watch out nanotubes, graphene is going to catch up!

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5. joel on November 20, 2009 12:10 PM writes...

watch out graphene! it's straight up benzene! hollah!

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6. Stephen on November 20, 2009 12:19 PM writes...

Isn't montmorillonite cat litter?

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7. Karen on November 20, 2009 12:32 PM writes...

There are a lot of "old school" reagents that you don't see used very often unless someone in your lab used them in the past. The first project I worked on in industry, I was working with a natural product that was very difficult to work with. The last step of the synthesis, I was using HCl and DMSO to put on an acetal, and the workup was awful. One of the old hands in the lab pulled out montmorillonite clay and suggested I try that instead. It worked perfectly, and the only workup was filtering out the clay. I still use that reaction as part of my job interview presentation, and everyone asks about the montmorillonite clay. Great stuff. I never found another good use for it, though.

On the other hand, when I moved into my lab, there were 5 or 6 jars of different types of resins in the back of the hood. I never did figure out what to use them for.

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8. anon on November 20, 2009 1:54 PM writes...

I have a similar story as Karen for montmorillonite K-10. In grad school when we made crotyl silanes in 20-50g batches. The step was an acetal deprotection (prior to this we'd use enzyme for catalytic resolution). I had never heard of the stuff up until that point and havent had the need to use it since. But, super effective, mix up with solvent, wait some time, TLC filter, no purification nesc.

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9. anon#1 on November 20, 2009 2:09 PM writes...

Montmorillonite is used to make a few industrial scale (multi-tonne) terpine-based products for the fragrance industry.

For ionic liquids, the best example is the BASF Basil process.

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10. Rhenium on November 20, 2009 2:14 PM writes...

Microwaves!

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11. TAK on November 20, 2009 2:19 PM writes...

I use microwaves all the time (not so much on the Montmorillonite, but I have talked to people who swear by it).

My nomination is liquid CO2. It seemed for a while there were lots of reports on using perfluorinated compounds in CO2 solvent, but no one I know actually used it.

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12. John Spevacek on November 20, 2009 2:20 PM writes...

Just to stick up for clay a little bit, montmorillonite does get blended into polymers quite a bit.

I know it's not a reagent, but has anybody ever used a microwave to run a reaction?


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13. You're Pfizered on November 20, 2009 2:58 PM writes...

Microwaves are feast or famine. Black tar or spot-to-spot reaction, but faster either way than doing it thermally, for the most part. The explosions are way cool as well.

Great for Pd catalyzed reactions, but also tough displacement reactions. I wasn't a believer until a couple of years ago, and now that most machines have reaction chambers that allow you to do things are fairly nice scale (for a medicinal chemist), it's even more useful.

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14. Madrid on November 20, 2009 3:32 PM writes...

I would agree that microwaves are used more than what is represented in the literature. I often start with trying something out in a microwave and then if it doesn't work going back to a conventional reaction setup. This may just be my personal bias though, since many of my colleagues almost never go to a microwave unless they are really stuck on something.

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15. Lucifer on November 20, 2009 3:49 PM writes...

More Scientific Fraud..
_____________________
Climategate: the final nail in the coffin of 'Anthropogenic Global Warming'?

http://blogs.telegraph.co.uk/news/jamesdelingpole/100017393/climategate-the-final-nail-in-the-coffin-of-anthropogenic-global-warming/

Permalink to Comment

16. anon on November 20, 2009 3:58 PM writes...

re #1: Febreze is almost 100% beta-cyclodextrin.

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17. BACE on November 20, 2009 4:27 PM writes...

How about James LaClair's "silver oxide in wax"?

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18. Cynical1 on November 20, 2009 4:32 PM writes...

Without a doubt - Combichem......

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19. CMCguy on November 20, 2009 4:46 PM writes...

Maybe more categorized as techniques, rather than reagents, but I would nominate both "Prep GC" and "Spinning band" column distillations although I know actually can be useful in certain situations but the effort verses output would regulate to extreme choices of last resort IMO.

A sometimes "solvent" I likewise know can be of particular value but I found more trouble than its worth is CS2.

#16 anon are you suggesting syn chemist smell bad?

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20. torontochem on November 20, 2009 5:50 PM writes...

+1 for Montmorillonite
we've used it quite a bit as an adsorbent to get rid of reaction byproducts and catalyst residues. Great stuff if you have to do stuff on large (50g) scale as the only workup afterwards is to filter the stuff off.

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21. ex-Pfizerite on November 20, 2009 9:04 PM writes...

Phase transfer catalysts

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22. Pats on November 20, 2009 9:20 PM writes...

SiGNa reagents?

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23. milkshake on November 20, 2009 10:39 PM writes...

Atom economy and green chemistry as pompously vacuous catch phrases

Alpine-borane reagents, Verkade and P4 phosphazene superbase, LS-Selectride, the planary-chiral DMAP from Greg Fu are the famous reagents that no-one uses

Kempf's triacid and calixarenes as oversold building blocks in supramolecular chemistry

Safety-catch linkers and photocleavable linkers in solid phase synthesis as something that was tried by many but never caught on

Permalink to Comment

24. Anonymous on November 20, 2009 11:04 PM writes...

Iron for cross-coupling reactions.

I will second the Fu Chiral DMAPs as totally useless (I'd rather use an enzyme to de-acylate). Do they still separate the catalyst enantiomers with chiral HPLC? Why not just separate your substrate enantiomers with chiral HPLC?

Some of the organocatalysts are getting a little ridiculous (more steps to make them than most synthetic sequences attempted in industry).

Gold catalysts for the regioselective rearrangement of grease.

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25. processchemist on November 21, 2009 2:30 AM writes...

@ex-pfizerite

TBAB is one of the most used reagents both in the lab and on the pilot plant, where I work.

Permalink to Comment

26. Jose on November 21, 2009 3:11 AM writes...

Anything than requires Schlenk ware or a dry box.

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27. Brendan on November 21, 2009 3:53 AM writes...

Click chemistry. It was supposed to the the ultimate bio-orthogonal reaction and then...oh right..copper kills cells. Nothing like riding on the coat tails of a Nobel Prize!

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28. LiqC on November 21, 2009 3:51 PM writes...

So what? There are several reported copper-free methods. See http://www.sciencemag.org/cgi/content/abstract/320/5876/664%20

Permalink to Comment

29. non-pharma chemist on November 21, 2009 6:54 PM writes...

@ ex-pfizerite

I'm with processchemist on this one. PTCs are used all over the place on a giant scale. Just because it may rarely come up in med chem labs...

@ Brendan

Thank you! I've always wondered what precisely we need all those triazoles for...

And just to mix it up a little, Ruthenium metathesis catalysts are totally overrated.

Permalink to Comment

30. milkshake on November 21, 2009 7:51 PM writes...

The click concept is helpful (even if rather oversold) - one ought to look for a bottle-stable high-energy functional groups and see if they can be connected together in a way that is orthogonal to everything else. I also thought that Sharpless was nuts when he started making triazoles but I like the idea now.

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31. Chemjobber on November 21, 2009 9:21 PM writes...

#27: did the Cu-free click reactions get discovered before or because of the copper toxicity issues?

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32. Brendan on November 21, 2009 9:51 PM writes...

#30 I think you are right that the new Cu-free click reactions have had a larger impact because of all the Cu-catalyzed click hype, but the Cu-free has been around since the 50's or whenever Huisgen was doing his thing.

Permalink to Comment

33. Jose on November 22, 2009 5:27 AM writes...

Although, Montmorillonite can save your bacon:

Synthetic Studies on the Sulfur-Cross-Linked Core of Antitumor Marine Alkaloid, Discorhabdins: Total Synthesis of Discorhabdin A
Angewandte Chemie International Edition
Volume 41, Issue 2, Date: January 18, 2002, Pages: 348-350

Permalink to Comment

34. allylator on November 22, 2009 9:33 AM writes...

The haffner allylation reagent -- I am not aware of any examples beyond the original pubication. Don't know anyone that got it to work of scale greater than 50 mg.

Permalink to Comment

35. DrSnowboard on November 22, 2009 12:22 PM writes...

Fluorous reagents?

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36. Anonymous on November 22, 2009 7:11 PM writes...

I agree with #1. The only use I've gotten out of cyclodextrins is a dissertation. And no, they didn't take the smell out of it.

Permalink to Comment

37. bootsy on November 22, 2009 7:37 PM writes...

Derek, I remember doing a 300+ g scale reaction at the Wonder Drug Factory using Montmorillonite K-10 as a catalyst. I'm pretty sure you were on that project....
It saved our bacon there too, went from dirty reaction to "dirty" reaction.

Permalink to Comment

38. Kuchs on November 22, 2009 9:40 PM writes...

I have used Montmorillonite-KSF as both a solid support for the Cu(NO3)2 and acidic media for a rather difficult nitration. 30% yield which was somewhat of an improvement on my 0% for other classical nitration methods.

Permalink to Comment

39. Big Bob on November 23, 2009 3:39 AM writes...

Don't knock "silver oxide in wax", I gave it a whizz to see if it was any good, and I suspect many others tried it too...needless to say it didn't work, maybe it was the wrong parafin? ;)

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40. lfert on November 23, 2009 9:29 AM writes...

I would love to use ionic liquids, ala the BASIL process developed by BASF. We make ca. 8000 lb/week of an intermediate that produces 2 equiv.HCL per equiv. of starting material, which we suck up with a tertiary amine. What a waste (literally), but not sure of the cost of the ionic liquids. Probably prohibitive for most things except pharma intermediates.

Permalink to Comment

41. Little Miss Process on November 23, 2009 11:58 AM writes...

#21, I'm with #25 and #29 - PTCs are great for replacing the omnipresent NaH/DMF combination that Med Chem groups continue to use... Do't Do It, Kids:
http://www.crhf.org.uk/incident101.html

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42. Cloumbia on November 23, 2009 3:16 PM writes...

What about Leighton's chiral silane reagents?!?

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43. anonymoose on November 24, 2009 9:19 PM writes...

re 40

No. Basil is quite reasonably priced if you can recover the base, which is very doable on large scale.

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44. Anonymous on November 27, 2009 3:50 AM writes...

I don't see the point in lumping "ionic liquids". That risks discrediting successful and rather traditional approaches - like producing a spontaneous phase separation of target and side products as in BASIL.

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45. InfMP on November 27, 2009 7:52 PM writes...

Yeah I have seen that slay stuff enough times to be curious about it. Most recent was Trost synthesis of Laulimalide 10.1021/ja907924j
and so i wanted to know more but there was no seminal reference to help.

Amberlite resin really helped me once to remove 2 acetonides from a carbohydrate, when normal conditions were crap.

Microwaves got our group a science paper...

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46. HJorgensen on December 3, 2009 5:21 AM writes...

As a palladium-monmorillonite they work niceley as catalysts (altough tricky to filter sometimes).

Palladium trifluoroacetate ion exchanged with montmorillonite for example works as a very efficient catalyst with Wacker oxidations.

http://linkinghub.elsevier.com/retrieve/pii/S0040403905027590

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47. Process Chemistry on December 5, 2009 1:07 AM writes...

Anyone remember 10M LiClO4 in diethyl ether?

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48. Jose on December 5, 2009 1:27 AM writes...

Or Eaton's reagent?

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49. milkshake on December 5, 2009 8:57 AM writes...

Eatons reagent is pretty useful - ask anyone who had to work up PPA on large scale. There is a nice paper in Org Process R&D journal that just came few days ago, that does acyliminium cyclization in Eatons reagent.

Permalink to Comment

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