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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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March 2, 2009

Hot Chemistry, Low Tech to High

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Posted by Derek

Time for some lab talk. There are usually a number of different ways to attack a given problem in organic chemistry. You go with what you know, or what looks most likely to work, or what you actually have the equipment (or funds) to realize. This range of choices goes all the way down to what you’d think would be pretty trivial questions, such as: how do I heat up my reaction?

The standard way to do this is to take the usual flask you’d run the thing in at room temperature and dunk it into something hot. That can be an oil bath with a heating coil in it (good temperature control, but messy), a solid heating mantle of ceramic or metal (clean, but doesn’t change temperature so readily), a woven glass heating mantle, a sand bath on a hot plate, what have you.

Then you can go a bit higher-tech, and heat up your reaction with microwaves. I talked about this here a few years ago (and I note that somehow that stretch of blog time has never been archived on this site; I'll have to work that in some time). The early days of the technology featured (first) kitchen models hauled directly into the lab, then carousel devices built to go inside their cooking spaces. But over the years things have settled down to custom-built chemistry microwave setups, walk-up instruments that let you drop a sample tube in, set the temperature and time that you want, and walk away to pick things up later. Microwave heating has become a preferred way to run a lot of palladium-catalyzed reactions.

Does the microwave do anything special other than heat things up, though? That’s been an arguing point for several years. Various “microwave effects” have been proposed, with mechanisms ranging from the unlikely to the pretty believable. In that last category is the thought that when you’re using powdered metal catalysts, that since these absorb microwaves strongly they give some sort of local micro-heating effect that drives the reactions forward.

Could be – but apparently isn’t. A recent paper from Oliver Kappe's lab in Graz, Austria looks at Heck reactions done that way. Kappe is a recognized pioneer and expert in microwave synthesis (see his latest book, linked below), and if you're interested in the field he's well worth reading. In this case, careful experimentation established that the microwave reactions work well because of their heating profile: they get up to temperature very quickly, which seems to be beneficial. But they found no evidence of a specific microwave effect when they ran the reactions under similar heat gradients but with different energy sources.

They also tried this reaction via yet another heating technique, flow chemistry, which I last spoke about here. That turned out to be pretty interesting, too. They were pumping their two starting materials hot over a cartridge of supported palladium-on-carbon catalyst, but found a couple of odd effects. For one thing, the first flow runs tended to give a lot of side reactions, which was surprising considering how clean the conventional runs were. Looking over the system carefully, the team found that the two reactants were separating from each other as they went down the catalyst tube. They couldn’t couple as efficiently because they were pulling away from each other – the alkene coupling partner came out first, while the aryl halide dragged behind, presumably slowed down by interactions with the powdered carbon support.

The other unexpected effect was that even after partially fixing that problem, after a dozen runs or so the reactions weren't working so well. Then the earlier fractions collected and left to sit turned out to be depositing shiny mirrors of palladium metal on the insides of the glass tubes, and all became clear. The Heck reaction was leaching the palladium metal off the solid support! This had been a mechanistic proposal before, but the flow apparatus provides some real evidence to back it up. When you do this in batch mode, via microwave or whatever, the palladium species get a chance to re-absorb onto the carbon as the reaction cools down, and you're none the wiser, but the flow system just washes 'em on through.

What finally did the trick was to add very small amount of the palladium to the starting system, pump that through a hot tube reactor, and use another scavenger column to clean out the metal. You can get away with that in a Heck reaction, since they can run using ridiculously low catalyst loads. I have to say, I hadn't thought so much about this possibility; that's somewhere in between my Type I and Type II flow reactions in my own scheme.

I mentioned that Kappe has a new book, titled Practical Microwave Synthesis for Organic Chemists: Strategies, Instruments, and Protocols. I haven't seen it personally, but if you're interested in microwave work, it looks worthwhile.

Comments (22) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Tim on March 2, 2009 9:49 AM writes...

I met Oliver back in 2004 when he came to Australia. We had an interesting conversation about microwave heck reactions - at that stage they were unsuccessful. At the time we thought we may need to perform them under oxidative rather than reductive conditions. I guess he finally worked it out!

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2. Anonymous on March 2, 2009 10:35 AM writes...

It's not surprising that they were getting free palladium in the system, a lot of recent work on palladium nanoparticles has shown their catalytic effect to be simply the result of free palladium ions leaching into the reaction media.

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3. RB Woodweird on March 2, 2009 10:43 AM writes...

I had the chance to play with a demo microwave unit a while back. I would like to have one of my own someday. The ability to program in time/temperature profiles, use pulses, monitor by pressure/temperature made for a lot of ways to try and optimize reactions. I did not like the plastic reaction vessel. It had an integrated flexible diaphram on the sealed top. The pressure sensor touched this diaphram. If enough pressure built up, it would vent, so the thing has to be in a hood. I did like the option to put a whole round bottom down into the reaction well. You lose the pressure regulation that way, however, if that is a concern. I was surprised that pure water was very hard to heat.

On the heating note, am I the only chemist who thinks that in the 21st century I should be able to buy off the shelf an oil bath/stirrer that regulates the temperature and/or stirring rate? I mean, the units sold by Aldrich and Chemglass are OK, but I consider them to be relatively primitive.

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4. Ben on March 2, 2009 11:37 AM writes...

This is very cool -- I only did synthetic chem in college and we weren't given access to these "alternative" heating methods (I pretty much did oil baths and water baths and heating mantles only).

Who knew? You can cook microwave dinners AND chemical reactions with microwaves :-).

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5. CMC Guy on March 2, 2009 11:53 AM writes...

So which technique do you consider the Low Tech and which is the High? I have always thought Continuous Reactions, when they work, are very elegant whereas the only microwave chemistry I have seen first hand was with the "kitchen model" mode. It worked but there was some entertaining flashes and sparking involved as Al foil was used to wrap the "reactor" (for some unknown reason).

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6. CMC Guy on March 2, 2009 12:13 PM writes...

Another point is that the Heck reaction may not be a best test comparison case for good multi-phase flow chemistry because there needs to be appropriate combination of Reactants, Catalysts, Base/activator and Ligands. The fact they got is to work is good but does demonstrate that some chemistry less applicable because of physical mass flow/contact constraints that must be considered. Although know was conquered in solid-phase combinatorial syntheses doing Heck type chemistry believe required certain procedural adjustments such as pre-solubilizing Pd complex rather than simply throwing things together as would normally do.

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7. NH_chem on March 2, 2009 1:01 PM writes...

Continuous flow microwave reactors could be a nice way to do some chemistries particularly the ones that come from a med. chem. prep using microwave giving mgs for assays. Hits could be scaled quickly with little process work. This technology is getting very close to reality.

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8. MTK on March 2, 2009 1:33 PM writes...

NH,

I think CEM does have a stop-flow microwave reactor, if not a continuous flow one at this point.

As for heating in general, I just about always use a temperature controller like the type that J-Kem sells to monitor the internal temperature and to control the heating. They're not cheap, but they are handy in turning the heating off and on as necessary.

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9. Maks on March 2, 2009 2:31 PM writes...

As a undergraduate student I had to optimize a microwave reaction for a company. The senior chemist said that the tried the reaction at the same temperature with regular heating and got no reaction at all. In the microwave within 15-45 min we got >60% yield, indicating some specific effect but since it was MedChem no one cared if they get the desired product.
Btw, the strange thing was that the microwave in kitchen had more options than the chemistry microwave for the prize of a mid sized car.....

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10. Anonymous on March 2, 2009 4:11 PM writes...

Check an article by Cathleen Crudden

(http://www3.interscience.wiley.com/journal/117950157/abstract?CRETRY=1&SRETRY=0)

for some evidience of Palldium leaching and deposition.

Ortholithiation

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11. milkshake on March 2, 2009 5:31 PM writes...

We use Biotage microwave reactors very often and they are marvelous because the vials hold up to 21 atmospheres before the pressure error automatic shutdown. great stuff for difficult cyclizations. But I found that on small scale reactions (0.5mL) done in a poorly-absorbing solvent like acetonitrile or dioxane, the temperature readings are way off, the actual temperature in the vial must be much higher under these circumstances than actually shown by the instrument. I have run recently a reaction that was complete at "150C/30min" by the microwave but actually took 1 day at 175C on oil bath. Part of the problem could be that the reaction product precipitated out - any solid in case of microwave can produce strong focal heating

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12. JC on March 2, 2009 5:49 PM writes...

If you run into shutdowns from overpressurization, try heating the microwave vial after crimping to boiling, then with a needle vacuum the vial to negative pressure before you insert it into the microwave. I did this then blasted my sample in EtOH at 175 for 4000 seconds, worked like a charm. Alternatively one can open the reactor cell by overriding the safeties, & carfully puncture the bulging septa altho I don't recommend this because of the spraying that occurs.

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13. Jose on March 2, 2009 8:54 PM writes...

Absurd TONs are another big issue for uwave chem. Leadbeater diligently looked down to ppm for catalytic metals, but it turned out the low ppb of Ni or Pd was doing the work for his essentially metal free Suzukis. When "homeopathic" species are active, it's the Wild Wild West in your reaction flask....

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14. drug_hunter on March 2, 2009 9:29 PM writes...

Actually, the other Pd effect which Derek is hiding from us is warm fusion. Stochastic superheating, aided by Brownian motion, drives the Pd atoms into a fractional Rydberg state and, via adiabatic tunnelling, drives the meta-stable Prigogine-Onsager intermediates through a charge-radical inversion layer to completion. This is in fact the secret of microwave chemistry. Someday the world will understand.

Permalink to Comment

15. DrSnowboard on March 3, 2009 5:00 AM writes...

@12 JC
So, are microwave vials rated for negative pressure....?

"Alternatively one can open the reactor cell by overriding the safeties, & carfully puncture the bulging septa altho I don't recommend this because of the spraying that occurs."

Not wishing to suggest that you're being a little foolhardy here, but......think of reading the accident report to your 'no win, no fee' ambulance-chasing insurance lawyer and imagine his estimate of your chance of winning.

Permalink to Comment

16. milkshake on March 3, 2009 7:16 AM writes...

hey Snowboard: I don't know if you ever worked with Biotage microwave reactor. We already had couple of vials exploding on us because people were under-filling them (which caused strong local overheating of the glass with heterogennous reactions) or they did something outright silly like NaH + DMF baked up to 200C. Either way, the vial is encased in the instrument resonance cavity and there is a heavy-duty safety lid that comes down automatically, whenever in use. The biggest vials are 20mL volume. If the glass vial shatters it makes a loud pop but not much is flying out. After some disassembly and thorough cleanup the instrument is ready for use; only once we had to get the engineer because the vial explosion damaged the temperature sensor.

Also the vial septa are self-resealable (if the puncture hole is reasonably small) so it makes a perfect sense to vent out while hot - to fully replace the air with the solvent vapors. It can take maybe 2 atmospheres off the final pressure, so when you are at the shutdown limit around 21atm it can make all the difference.

Overriding default protections is not as dangerous, for the reasons above, except that you have to know what you are doing because when you mess up your instrument the manufacturer may refuse to fix it.

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17. MTK on March 3, 2009 7:26 AM writes...

Drughunter,

I had the same theory just before you did.

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18. DrSnowboard on March 3, 2009 9:14 AM writes...

To me, a subtle difference between 'venting' a hot vial and 'vacuuming to negative pressure'. Same as putting a Buchi flask under positive pressure? Maybe I'm just a wuss.
I agree using microwave reactions as pressure controlled reactors is great, just if you start to push the limits that ( presumably ) the manufacturers have thought a bit about, you're asking for trouble.
And that powdered glass gets everywhere when they do pop...

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19. JC on March 3, 2009 12:31 PM writes...

Pushing the envelope off the table. It's a living.

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20. Anonymouse on March 3, 2009 2:30 PM writes...

At our (non-pharma) research center, ambiguous "safety concerns" from senior management prevented us from buying a CEM lab microwave reactor (though they had not actually seen the microwave). The "why bother running reactions in a microwave, since microwaves can't be scaled up" factor was also at play. We remain microwave-less.

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21. JC on March 3, 2009 4:50 PM writes...

I made 4 g of material @ 500 mg per rxn. 8 hours total of microwaving beats 3 days of heating in one go in a sealed vessel in an oil bath.

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22. RandDChemist on March 6, 2009 12:24 PM writes...

Great post and a great article. Very thought provoking.

When I was in graduate school, microwave chemistry seemed more like a novelty than something that would have significant impact. After a few years at my first job, it was starting to become a viable innovation. The biggest problem (as far as I am aware of) with the commercial units is field homogeneity.

#7 and #8: Continuous flow microwave reactors do exist. Milestone makes one.
http://www.milestonesrl.com/analytical/products-synthesis-flowsynth.html

#20: When I led the effort to purchase a CEM microwave at my first job, the scientist said they actually detonated some TNT in a MARS system to demonstrate the safety of the reactor. They filmed it, but that was several years ago and have never seen it.

The Kappe article has raised some interesting questions. So, what is the real benefit of microwave chemistry? Why not place a sealed vessel into a pre-heated bath and go with it? Or, is what Kappe reported dependent on the reaction?

I have found microwave chemistry to be quite beneficial, the few times I've used one.

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