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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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April 4, 2011

Surely You Have Something Else to Do

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Posted by Derek

Here's a question for all the organic chemists out there. A discussion with some colleagues the other day got me to thinking about the reactions that we all tend to underuse. The category I offered up was gaseous reagents. Outside of hydrogenation, I think that many of us sort of go "Ehh. . ." when we come across transformations that need lecture bottles, cylinder, regulators, and so on.

Add to that the unpleasant nature of many of the gases themselves, and it's easier to find something else to do. But there are a lot of good reactions and reagents in this category - metal-catalyzed CO insertions, reactions with ammonia, acetylene, sulfur dioxide, etc. There's just a bit of a higher activation barrier to getting around to running them.

I'd say that photochemistry and electrochemistry are in this "rather do something else" category as well. Other nominations welcome!

Comments (37) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. weirdo on April 4, 2011 12:12 PM writes...

Rather than specific reagents, I am far more likely to avoid trying reactions reported by specific labs.

But I'd put alkylboranes in the category of reagent types that appear to do cool things, but I'll take a pass on, thanks.

Or anything run at -100 oC.

Permalink to Comment

2. CMCguy on April 4, 2011 12:23 PM writes...

The three mentioned have similar theme in that often require specialized equipment that not every lab has. All these are great to try providing have the correct apparatus to run well and safely.

I would offer Phase Transfer reactions as a possibility for a technique that can be easy/most useful for particular transformations but not sure people consider potential and so avoid.

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3. Hap on April 4, 2011 12:35 PM writes...

Enzyme-mediated reactions - the highlighted directed evolution paper was neat, but most labs aren't used to dealing with microorganisms or enzymes, don't have the equipment, and probably would just prefer using what they know how to handle and set up.

Another option - FVP? You can do anything with FVP, it seems, but it doesn't sound like any fun.

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4. opsomath on April 4, 2011 12:45 PM writes...

Reactions with gas, seconded, particularly catalytic hydrogenations. This is sheer laziness on my part and the fact that I don't keep a separate bottle of hydrogen around, just the one we have for the glove box.

OTOH, I rather like phase transfer catalysis. For alkylation of big, greasy flat aromatic things, you gotta love a biphasic toluene/conc. aqueous hydroxide solution with Aliquat.

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5. milkshake on April 4, 2011 12:51 PM writes...

weirdo - I was going to write exactly the same. I would also add on the to be avoided list any large-scale reaction that uses stoechiometric SeO2 or Bu3SnH.

Gaseous reagents: I was once doing methodology work on thioesters (by trapping ketenes generated by in situ by oxidation of Li-acetylides) and I found out that MeSH was quite wonderful - I condensed an excess of MeSH into my reaction mix, then got if off after the quench with argon sparge. The reek of MeSH is also a much less atrocious than with higher thiols.

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6. David P on April 4, 2011 1:03 PM writes...

Anything that requires paperwork to be filled in before running the reaction has an intrinsically higher activation barrier.

I have heard from a lot of people that they will go to great lengths to avoid working with diazomethane, for example.

Most of these are due to unfamiliarity with the techniques or the reagents involved. Once you have run it once, the barrier to running it again is lowered. Myself, I would not think twice about a reaction with diazomethane (I made it many times).

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7. Laura on April 4, 2011 1:29 PM writes...

When I was young and in organometallic chemistry, I loved using equipment or "extreme" reaction conditions- if I could shoot a laser or sonicate or microwave or high pressure or low temp., etc. then I was there.

However, I spent two years using dimethylsulfide as a solvent and I don't care to ever use it again. I've made various phosphines so I'm not sure why the odour of Me2S irritated me so much.

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8. Deep Lurker on April 4, 2011 1:36 PM writes...

The magic catalyst of "send it to the hydrogenation lab" works to lower the activation energy, especially when the "hydrogenation lab" is set up to work with other gasses at medium to high pressure - e.g. those CO insertions.

Also, I've noticed that the availability of a microwave reactor lowers the activation energy of running pressure-bottle reactions (that just happen to be heated by microwave), and not just microwave-specific reactions.

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9. chris on April 4, 2011 1:39 PM writes...

I guess I've always enjoyed using some of the more unusual reagents. Singlet oxygen using rose bengal (one colleague asked if it was a lady of ill repute), ozonolysis was always rather fun, but using trimethyl aluminium was my favourite.
I always enjoyed the planning required to set up these types of reaction.

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10. SteveM on April 4, 2011 1:56 PM writes...

I've been out of the lab for a long time. But alkali metal chemistry was a pain.

You had to cut, weigh and clean the metal without igniting it. And you had to schlepp the special fire extinguisher into the lab. I actually had put out a Sodium fire in the hood. Quite the mess...

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11. Spiro on April 4, 2011 1:59 PM writes...

Ozonolysis is a very underused reaction, yet very useful (making carbonyls from alkenes) and easy to carry out. Equipment is not expensive, and the reaction is not dangerous at all if you take a mimimum amont of care.

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12. Nick K on April 4, 2011 2:25 PM writes...

I'd nominate high-pressure hydrogenations as the reaction with the highest "activation energy". Those old autoclaves are virtually extinct nowadays, and without them you can't do the reaction.

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13. Rene M on April 4, 2011 3:02 PM writes...

Skraup quinoline synthesis.
Extreme violent reaction. Had serious problems doing an upscale (molar scale)(inert temperature rose >300°C causing reflux of the desired quinoline). But at the end I had a beautiful 75% yield which was amazing.

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14. Josh on April 4, 2011 3:49 PM writes...

ANY distillation

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15. Patrick on April 4, 2011 5:17 PM writes...

Hap, I was working with McNab on FVP until he died, we still have all the kit around here and it's magic, even if I only use it for sublimation purification on a 100g scale ...

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16. SteveM on April 4, 2011 5:42 PM writes...

P.S. as an aside, I could never understand the original commercial Kugelrohr. It blindly copied the invention which was just a Rube Goldberg industrial coffee pot with a hole punched in the side.

So Fisher or whoever simply took industrial coffee pots and cut holes in the sides. Viola! Kugelrohrs!

A five gallon coffee pot to heat up 20 ml flasks. Hah!

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17. NHR_GUY on April 4, 2011 5:55 PM writes...

Two of my favorite gaseous reactions:

Ozonations......get that deep blue color..really pretty, great reliable reaction

and

Ar-Li + S02 -> Ar-S(O)2-Li+
you then react the lithium sulfinate with your electrophile of choice

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18. Emily on April 4, 2011 6:41 PM writes...

To 14. Josh: Amen to that.

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19. Karen on April 4, 2011 7:07 PM writes...

I did a few cool CO2 reactions at my last job. I was imagining having to use bottles of gas until my boss said "just use dry ice". Duh! It actually worked very well and was fun to set up. (I never got a chance to do a lot with it since that was one of the last reactions I worked on before the layoffs but at least it left me with a pleasant memory from that job.)

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20. RTW on April 4, 2011 7:38 PM writes...

Early on I did quite a few reactions where I condensed HBr into a reaction mixture at -40 degrees and stored the resulting reaction mixture for up to 5 days in a -50 degree freezer. That was fun. Worked VERY well. In fact it was the only really good clean method of removing the central methyl group of 3,4,5 trimethoxy aryl natural product. Every other known method for this resulted in black goo. Largest scale I did this on was I believe 10L reaction.

The trick was getting a correctly measured amount of anhydrous HBr into the reaction. Bubbling it in seldom worked all that well, and gave quite a wide range of results. So - I would condense the HBr get a pretty accurate mass of it and add that to the reaction already at the desired temperature. I was going to try the same reaction with HI but by that time the project was pretty muc winding dowm, and I never got to try it.

I have also used pure oxigen with PtO2 contiously bubbling it into a reaction at reflux for several days to perform an oxidation at atmospheric pressure. Rather wasteful I thought but my supervisor insisted this was the only way to do the reaction. Had to really keep an eye on the solvent volume and make sure it didn't get dry. Never worked well.

Several years ago a member of my group a few labs over from where I was once did a reaction with H2Se. Had to do the reaction on the weekend and wear a suit with its own air source.

Hydrogenation reactions we typically sent to our own High Pressure lab group, that did all sorts of Hydrogenations, oxygenations, CO insertions and reactions with CO2. I beleive they also did some pretty exotic gassous or otherwise pressure reactions as well.

Permalink to Comment

21. T on April 4, 2011 8:14 PM writes...

Skraup reaction, McMurry coupling and Shapiro reaction. Ick ick ick.

Chlorosulfonylation of electron deficient aromatics with neat chlorosulfonic acid works pretty well, but the workup is a violent beastie.

Permalink to Comment

22. Anonymous on April 4, 2011 8:22 PM writes...

I remember doing the Zincke-Suhl reaction many years back. Nasty...solvent is CS2 and reagents are CCl4 and AlCl3 and you had to steam distill the product out of a black tar. Nice white product obtained, but after a shitty day of work. this is one reaction that should be high on the list for OUTSOURCING!!!

Permalink to Comment

23. Iridium on April 5, 2011 2:36 AM writes...

One more vote for:
ANY distillation

Permalink to Comment

24. sepisp on April 5, 2011 2:43 AM writes...

Gas skills are sorely missing certainly. The attitude seems to be that it's something too esoteric and outright weird. This leads to running even elementary gas reactions like hydrogenation at ridiculous conditions: glass reactor, low pressure, excess of a very expensive, unsupported catalyst, etc. Too bad that in the organic industrial chemicals business, most operations are done outside the "lab-comfortable" conditions. It's like training to be a sea captain but then accept sails only as the motive power.

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25. Young Padawan on April 5, 2011 6:24 AM writes...

What is FVP ???

Permalink to Comment

26. Obi-Wan on April 5, 2011 7:11 AM writes...

Flash vacuum pyrolysis

Permalink to Comment

27. Anonymous on April 5, 2011 7:36 AM writes...

Process chemists tend to use reactions that give cleaner reaction profiles and controllable energy release, such as hydrogenations & carbonylations. Most gas reactions are very clean. We try to avoid changes in oxidation state, as these tend to be dirtier, and harder to control. Also, we typically have specialty groups set up with nice equipment to facilitate the process...so equipment set up is not an issue. Distillation is integral to the crystallization process, and is used considerably. As a Process chemist, I feel I can manage any reaction, as long as I can understand the mechanisms of both the desired and UNdesired reactions. The specialty groups have freed me to do whatever I want, as long as it is cost effective.

Permalink to Comment

28. Anonymous on April 5, 2011 10:39 AM writes...

BF3(g) = best lewis acid in the world.

Permalink to Comment

29. lbf on April 5, 2011 10:44 AM writes...

#27, agreed. I deal with gases regularly, since we have the equipment (autoclaves, regulators, valves, etc..) it makes it easier. Also, distillation (esp. fractional distillation)...no problem; again, having the equipment (splitters, trayed columns) readily available makes all the difference. Even anhydrous HF reactions... Teflon reactors, no problems. Quartz tube reactions @ 700C? Again, easy to do if your lab has the equipment. In a contract lab that I work in, we quote prices to our customers based on how difficult the equipment is to setup, among other things, this can typically be as much as or even more than the actual charge for running the reaction.

Permalink to Comment

30. nitrosonium on April 5, 2011 11:19 AM writes...

i worked for a number of years preparing C-nitroso compounds by reacting silyl enol ethers (and silyl ketene acetals) with NOCl. Not difficult to generate but it is really nasty, corrosive stuff. glad to not be doing that any more.

Permalink to Comment

31. barry on April 5, 2011 5:39 PM writes...

I've done photochemistry,and reactions under atmospheres of hydrogen, tritium, carbon monoxide, hydrogen chloride, ammonia, methyl-amine (but never H2S). When it has come to making organostannanes, I do that myself rather than delegate it to a chemist working for me.
Yet still, I've never surmounted the barrier to electrochemistry

Permalink to Comment

32. Stephen on April 5, 2011 8:01 PM writes...

Microwave chemistry -looks neat but cant be bothered trying to optimise

heterogenous solid phase catalysts - just throw a bit of TsOH or Pd(PH)4 instead of making or buying expensive solid catalysts which may not work

Permalink to Comment

33. Curt F. on April 5, 2011 9:20 PM writes...

It's funny. I couldn't synthesize my way out of a paper bag and earn a living as an industrial microbiologist/biochemist. If I somehow landed on a project that required synthesis, enzymes would be the first place I turned.

Permalink to Comment

34. sepisp on April 6, 2011 2:46 AM writes...

Electrochemistry is indeed something that's missing from the regular synthetic chemists' arsenal. It's funny that we often start with reducing reagents that have been prepared by electrolysis, and then do chemical reductions with them. In principle, you could deliver the reducing equivalent directly by electrolysis. Maybe it's the radical/one-electron nature of the reaction that's limiting its scope.

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35. Design Monkey on April 7, 2011 10:18 AM writes...

14. Josh on April 4, 2011 3:49 PM writes...
ANY distillation

---

Wha? Vacuum distillation on 20 or more gram scale is WAY more preferable than trying to flash chromatograph the same stuff on monstrous columns with buckets of solvents.

Permalink to Comment

36. GladToMoveToProcess on April 7, 2011 1:41 PM writes...

Re 27,29,35: AMEN! The disdain towards distillation shown by some comments is rather remarkable. There aren't many separation methods that get easier and more efficient on scale-up. Forget about flashing 20 kilos, let alone 20 tonnes.

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