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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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« Protein-Protein Compounds - The Flip Side | Main | Hybrid Biomolecules, Edible And Not »

June 27, 2013

Sealed Up And Ready to Go

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Posted by Derek

I was running some good old brute force reactions in the lab the other day, the kind with rock-solid reactants and products. The way to get such reactions to go, if they're a bit slow on you, is of course to heat them up. One of my Laws of the Lab, formulated back in grad school, was "A slow reaction at room temperature is Nature's way of telling you to reflux that sucker".

That's not always true - there are reactants that won't put it with that sort of treatment and find something else to do, just as there are products that are unstable to the heat that might have been used to make them. (That last situation is a natural for flow chemistry, by the way, where you might be able to get the products out of the hot zone before they have a chance to do something else). But for the things I was doing, and for many other kinds of reactions, a good blast of heat can be just the thing.

The microwave reactor is a good way to put this into practice. Seal up your reaction in a vial and tell the thing to heat up the contents to, say, 120C for half an hour. Reaction done, or not? If not, then maybe another half hour - or maybe you should set one up where you hit it at 140C for a shorter time? Or 160? Why not? You might have a bunch of five- or ten-minute reactions ready to go, and you won't know until you crank on them a bit. You might also have a shortcut to a tube of blackened gorp, but how else do you find out that you've gone too far? The nice thing about the sealed microwave vials is that they can take a good amount of pressure. You can use "normal" solvents at higher temperature than you would ordinarily. My limit is acetonitrile at about 190C in a small vial, which is about triple its standard boiling point, and gives (in my case) a pressure of about 17 or 18 atmospheres in the tube.

Now, this can take some getting used to, for less experienced chemists. One of the things that is drummed into students in the lab is the Never Heat a Closed System, and there are clearly a lot of good reasons for caution. But sometimes heating a closed system is just the thing. There are several lab-scale gizmos to allow sealed-tube reactions to be run more safely, for just these Need For Heat reasons. Another nice thing about a sealed tube is that your reactants (and products) can't get away. Running stuff in decalin or sulfolane (classic high-boiling solvents) can put you in a situation where the reaction is merrily boiling away in the flask, but some of your own materials are fleeing up the condenser in terror, likely to whoof off and vanish out the fume hood exhaust if you keep it up.

I would be a lot more circumspect about such conditions if it weren't for the robustness of the commercial microwave platform. People run stuff like this all the time, so you can blast away with more confidence. Not that you can't blow one out, especially if there's an exothermic reaction waiting to take off on you. You'll want to sneak up on a new reaction to make sure that it's not waiting for you with one of those thermodynamic jack-in-the-boxes. And keep in mind that I'm a discovery chemist. A fifty-milligram reaction is fine by me. Proposing to the scale-up group, though, that they run a bunch of sealed acetonitrile reactions at 190C will get you a different reception. You can do that stuff on larger scale, though, if you're truly motivated. That's what those big solid metal reactors with the screwed-down tops are for, but that's also what pressure monitors, blast shields, and differential scanning calorimeters are for, too. Scale matters - it matters a lot, and a liter of hot acetonitrile (much less fifty liters) under high pressure is a very different thing than a couple of mLs in a thick-walled vial. The latter could easily be one of a dozen routine reactions queued up in a microwave rack, but the former could easily be your last sight on this earth, and you'd better plan accordingly.

Comments (42) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Vanzetti on June 27, 2013 8:55 AM writes...

Are Biotage paying you for the advertisement? :-)

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2. Calvin on June 27, 2013 9:02 AM writes...

Hmmmmm. I remember when CEM microwaves (foot spa version!) were pretty new and they weren't quite as sophisticated as they are now. The reaction I was working on was part of a parallel series that up to that point have behaved very well and so I wasn't expecting it to go bang. Very loudly. I have to say that standing next to one of those things when they explode wasn't something I wanted to repeat. Since that incident, I'd hit start and walk rapidly away confident that I'd comfortably hear the bang 2 labs away.

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3. Bender on June 27, 2013 9:06 AM writes...

One of the things I hate about microwave reactions is exactly what you described. You basically have to optimize it yourself every time. How these papers dominated JACS for so long is beyond me. Every single group had a different condition, often for similar reactions. There's no universal starting point for anything. You can find all sorts of literature supporting various solvents and temperatures for all sorts of reactions. In a busy lab where there's high demand for the microwave, it's a lot easier to just setup the reflux. You know the conditions, you know it works. No wasting time figuring out the line between product and black gorp.

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4. ADCchem on June 27, 2013 9:12 AM writes...

Is there any convincing evidence that there is something special about microwaves, such as some special non-thermal or specific microwave effect? I have taken those microwave tubes, capped them and set them in a 120C oil bath and have had similar results.

I think the key point here is heating under pressure above the reflux temperature of the solvent at 1 ATM and more often than not convenience.

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5. Org Lett Reader on June 27, 2013 9:18 AM writes...

With the microwave, for me it's mostly about the convenience.

An important safety precaution to remember is to vent the vial after the reaction period (a long-tipped needle does the trick) in case the contents are still under pressure. I've known some people with less experience to simply uncap the reaction and have the contents rapidly eject all over the place.

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6. BG on June 27, 2013 9:32 AM writes...

The most interesting thing about microwave reactors that I've ever read was in the instruction manual: if you heat up water (in the microwave) to a certain temperature/pressure (I don't remember what it was) it will distort the O-H bond angles to the extent that it nullifies some of the dipole,turning it into a "pseudo-organic" solvent- they claimed that it had the solubility properties of acetonitrile. I've never tried this, and I can't anymore because my current lab doesn't have a reactor. Has anyone else heard of this or tried it?

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7. overthetop on June 27, 2013 9:32 AM writes...

I love the microwave, especially for things like Pd couplings. 15 minutes at 130 will push a Suzuki to completion, rather than the 4-8 hours it takes under reflux conditions. That said, the Biotage has been rebuilt several times and still has blackened surfaces on the inside of the shield from exploding vials....

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8. Christoph on June 27, 2013 9:39 AM writes...

A feature of several microwave systems: The use of "heating while cooling". The reaction tube is cooled by compressed air while beeing irradiated at a wattage suitable to reach ~35-40C. While not beeing very energy efficient, several Sn reactions worked for me this way without byproduct formation and in good yield.

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9. APB on June 27, 2013 9:44 AM writes...

"acetonitrile at about 190C in a small vial, which is about triple its standard boiling point,"
I assume this is a Momentary Lapse of Reason. Taking ratios of temperatures in degrees C doesn't make much sense.
I see it as 463K/355K = 1.3 times, which gives one some idea of the relative kinetic energies of the molecules.

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10. A Nonny Mouse on June 27, 2013 10:12 AM writes...

I recently had to develop a process for a client which could be used for GMP manufacture (and we had to supply 100g by this method for pre-clinical work).

The previous 100g had been supplied by that large Chinese CRO which had followed the lab procedure; this involved performing the final step in a microwave reactor 80 times and combining them for purification.

Needless to say that this wasn't required in the new process and the key to our success was using sodium carbonate (as opposed to potassium- always check the two as there can be massive differences as in this case-95% instead of 0%).

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11. PD on June 27, 2013 10:20 AM writes...

Having worked earlier in europe and now postdoc in US, I was struck by the difference in type of vials used for heating "discovery reactions". Back in europe, we had these thick walled tubes with red caps which could be heated in oil bath to well above the boiling point of the solvent. Here in US, reactions in simple "reactivials" seem to be much more common. I was initially skeptical about using these thin walled vials, but surprisingly these do tend to hold up nicely even at high temperatures.

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12. Gaspode on June 27, 2013 10:28 AM writes...

@ADCchem Microwaves are just less messy and safer. The so called "Microwave Effect" is nonsense.

That said, im glad we have a microwave, because it already blew up two times and still works perfectly.

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13. newnickname on June 27, 2013 10:29 AM writes...

@4 ADCchem: "Is there any convincing evidence that there is something special about microwaves, such as some special non-thermal or specific microwave effect?" Yes and No. Here are two refs:

ACIEE, 2009, 48, 8321. "Microwave Chemistry in Silicon Carbide Reaction Vials: Separating
Thermal from Nonthermal Effects" Obermayer, Gutmann, and Kappe. They use ceramic vials to absorb uwaves and claim it is a thermal, not uwave, effect in the reactions tested.

ACIEE, 2011, 50, 7636. "Activation and Deactivation of a Chemical Transformation by an Electromagnetic Field: Evidence for Specific Microwave Effects in the Formation of Grignard Reagents" Gutmann, Schwan, Reichart, et al. They DO see a temp independent, uwave dependent effect in Grignarding.

Go figure.

Anybody remember using kitchen uwave ovens for lab chemistry? Some people would drill two 1/4 inch holes in the sidewall (avoiding the electrical bits) and place some loops of tygon in the oven and do Poor Man's uWave Flow reactions using a peristaltic pump. Who needs Biotage when you've got Sears Kenmore!


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14. newnickname on June 27, 2013 10:37 AM writes...

@12: Gaspode (10:28) and I (10:29) must have been typing and posting at the same time ... but now I'm wondering ... Are references in "In the Pipeline" counted by Science Citation Index (Web of Science), Scopus, et al?

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15. ADCChem on June 27, 2013 10:47 AM writes...

@Gaspode

I tend to think they are nonsense too or at the very best fairly limited.

"It's not magic! The effects observed in microwave-irradiated chemical transformations can in most cases be rationalized by purely bulk thermal phenomena associated with rapid heating to elevated temperatures. As discussed in this Essay, the existence of so-called nonthermal or specific microwave effects is highly doubtful."

Kappe, C. O., Pieber, B. and Dallinger, D. (2013), Microwave Effects in Organic Synthesis: Myth or Reality? . Angew. Chem. Int. Ed., 52: 1088–1094. doi: 10.1002/anie.201204103

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16. Anonymous on June 27, 2013 11:28 AM writes...

I like to do recrystallisations in the microwave... being able to heat the solvent way above it's normal boiling point lets you force your compound into solution by brute force, then by the time it's cooled back to ambient and popped out the microwave it's normally crystallised already. And the whole procedure only takes two minutes!

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17. NoDrugsNoJobs on June 27, 2013 11:45 AM writes...

#16 - Never heard that one, thats a great idea! I loved sealed tubes but used them long before the microwave made the seen. Another thing is the idea of a reflux requiring a condensor. We found anywhere from 1-3 Kugorohr bump tubes on top of a flask with a nitrogen inlet on the top was sufficient to aircool almost any reaction nprovided you did not heat the bejesus out of the solvent. No more messy refulx condensors, no more leaving the water on and watching hoses get moldy, all done away with! If air cool can work with cars and engines, no reason it cannot work for your precious reactions!

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18. anon on June 27, 2013 12:17 PM writes...

i think the takeaway point from the "microwave effect" myth-busting was that the internal solvent temperature significantly exceeded that reported by the external IR probes

it's certainly a convenient technology. i haven't experienced any explosions but our microwave does have a blast shield erected around it due to previous accidents

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19. Anonymous on June 27, 2013 12:20 PM writes...

My lab uses microwave reactions quite bit, mostly due to ease and convenience, but also because you can get very rapid internal heating. For anyone seriously interested in the subject, I will add this slightly older, but very good, review to the references already listed above Angew. Chem. Int. Ed. 2004, 43, 6250–6284.

Also, if you want to avoid one cause of microwave explosion that we have seen, don't supper heat DMSO...sometimes you can get away with it, but I wouldn't bet on it (see the paper below for details)
Org. Process Res. Dev., 2012, 16 (12), pp 1994–2000.

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20. Helical_Investor on June 27, 2013 12:41 PM writes...

The process development group hates you don't they?

: )

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21. Hap on June 27, 2013 12:51 PM writes...

It would be nice to have the full list of "Lowe's Laws of the Lab" included somewhere, either here or in a book when published. I've searched for the list on the Internet, but all of what I get points here which doesn't seem to have the full list (it's missing such aphorisms as "A good undergrad will double your workload. A bad undergrad will take out a wall." and the thermodynamic observation cited above). I've heard of the physical list, but only long after I was in a position to find a copy.

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22. Troggy on June 27, 2013 1:54 PM writes...

@13,

If you read the Grignard paper in detail, they mention arcing at the surface of the Mg and hypothesize a superheating or surface ablation effect.

In general heterogeneous reactions in the microwave are iffy business. I was 'involved' in a few attempts to perform microwave accelerated reactions on carbon nanotubes. Mostly, my involvement was cleaning bits of glass and nanotube off the inside of the microwave chamber.

--
Troggy

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23. MoMo on June 27, 2013 2:48 PM writes...

There's plenty of instances where reactions that take days are done in minutes with a uW reactor. We do transition metal based couplings in minutes compared to hours and days, and sterically hindered reactions proceed with high yeilds, find Canney et al. for a good read on this.
The good part is that there are companies out there working on scalable hardware and you can bet it wont be long before a commercially useful material comes out of this.

Adapt or Die Dinosaurs!

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24. anon on June 27, 2013 3:06 PM writes...

In peptide synthesis one can find different coupling efficiencies for sterically bulky residues when heated with oil bath vs. microwave heating.

There is a Sam Gellman paper on it in the lit. I think its this, but dont have journal access to double check.

http://www.springerprotocols.com/Abstract/doi/10.1007/978-1-61779-012-6_5

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25. Calymene on June 27, 2013 4:00 PM writes...

Microwave reactions going bang seems to have been much more common a few years ago than it is now. At the time we suspected that the vials were of highly variable quality - you'd get two identical reactions behaving and the third would pop. The manufacturers seem to have improved the consistency significantly.

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26. MTK on June 27, 2013 5:02 PM writes...

I can't remember exactly where I heard this, so TIFWIW, but wasn't it shown that Pd nanoparticles were the culprit in most microwave kabooms?

I vaguely remember someone noting that when the explosions occured that they were generally in vials that had been used often for Pd coupling reactions. They then thoroughly acid washed their vials and found they no longer had explosions vs. vials that they didn't acid wash which went off if some bit of regularity.

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27. Anonymous on June 27, 2013 6:30 PM writes...

In medchem, you always want to think ahead and plan to have a need for scale-up. Of course, all the planning in the world is not going to help if your compound was not thoughtfully designed.

My rule of thumb is 1.5x the bp of the solvent. Change the solvent if higher temp is required. By not pushing up to 3x the bp, (1) you stand a better chance of not having an explosion; (2) you have a wider range of rxn concentration to work with (solvent pressure vs. exotherm); and (3) you have a better chance of scaling-up the reaction in a flask (remember: 2x rxn time for every 10C increase). And always mixed well before heating.

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28. Knock on the Sky on June 27, 2013 7:11 PM writes...

Ah yes. I remember as a post-doc optimizing multi-component coupling reactions for an SAR study using the microwave. Basically choose an appropriate solvent, set up a whole bunch of automated runs of the same reaction with a slight increase in time and/or temperature (within reason, typically starting at 2-5 minutes), press start, go to lunch. Come back and determine at what point everything started turning into a good material to resurface a driveway with and use that as the upper limit. Good way to optimize time/temperature for med chem projects and generate lots of black goo.

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29. Chemcat on June 27, 2013 9:14 PM writes...

I have had the privilege of using a microwave reactor in a number of my undergraduate synthesis projects, and at times it has given interesting and unexpected results. In one experiment, microwaving my reagents yielded a homogeneous, clear solution right after I removed the vial from the instrument. At first, I was disappointed to see this solution because I was expecting a solid product. I showed the result to an older student, who (very carefully) shook the vial... and immediately a beautiful precipitate filled the entire vessel! I am not sure whether superheating or another metastability phenomenon caused the solid formation to occur in this manner, but I will always remember the dramatic finale of that microwave experiment.

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30. Gaspode on June 28, 2013 2:02 AM writes...

@18: That really was the argument that got me when i was working with microwaves.

@26: Nano Particle in microwaves are a no go. Metals in Microwaves lead to hot spots in the solvent (activated charcoal too), but nano goes beyond that point...

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31. CHM on June 28, 2013 2:31 AM writes...

@9

Temperatures in Celsius and Kelvin are separated by a constant. The ratio of two temperatures is the same in Kelvin as in Celsius. I don't know where he got his 3x from.

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32. Paul on June 28, 2013 7:25 AM writes...

The ratio of two temperatures is the same in Kelvin as in Celsius.

Obviously not. x/y != (x+c)/(y+c), in general.

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33. Troggy on June 28, 2013 8:44 AM writes...

@24,

There are thousands of papers where MW worked better/worse than conventionally heating. Likewise, multinode and single node microwaves have been shown to have a substantial effect.

This is due to various local heating effects within the vessel.

Have at look at #15's reference.
--
Troggy

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34. Anonymous on June 28, 2013 12:25 PM writes...

The ratio of two temperatures is the same in Kelvin as in Celsius.
Obviously not. x/y != (x+c)/(y+c), in general.

Since x/y = (x+c)/(y+c) reduces to c(x-y)=0, c=0, x-y=0 or c=x+y=0. In all cases, temperature never changes.

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35. Anonymous on June 28, 2013 12:47 PM writes...

...c=0, x-y=0 or c=x+y=0

That should read: "...c=0, x-y=0 or c=x-y=0".

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36. Anonymous on June 28, 2013 12:48 PM writes...

...c=0, x-y=0 or c=x+y=0

That should read: "...c=0, x-y=0 or c=x-y=0".

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37. josh on June 28, 2013 3:05 PM writes...

" but the former could easily be your last sight on this earth, and you'd better plan accordingly."
Just plain hilarious

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38. Amide Summer Night's Dream on June 28, 2013 11:15 PM writes...

I love using the MW. Helped me avoid major byproduct formation for a certain reaction, and saved me days in reacting time! Can't argue with that. If the CEM machine had a function to work up and purify, I would be in forever greatful...

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39. ScientistSailor on June 29, 2013 5:11 PM writes...

I love the uWave. I always tell people in the lab "There's no such thing as 'no reaction', you just haven't heated it high enough yet."

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40. matt on June 30, 2013 4:55 PM writes...

@Anonymous #34,35,36: right...you just proved x/y is not equal to (x+c)/(y+c) for any values of c other than zero (as Paul #32 said) or when x and y are the same number. Was that the intent?

All of this is a little pedantic...the original commenter (APB #9) had no problem figuring out which temperatures were involved, he was saying that "triple its boiling point" implied "triple the heat energy" which I don't think was implied or intended. Chalk it up to poetic license for dramatic effect. Try rewriting it, using Kelvin and the 1.3x heat content ratio, and see for yourself how crappy it sounds.

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41. This guy on July 1, 2013 12:14 AM writes...

"Microwave effects" are nonsense, caused by discrepancies between the measured and actual internal temperature. "Heating while cooling" makes the problem worse. Kappe is the only one to have done a thorough, systematic study on the matter, so I'm glad to see his papers cited here.
I won't argue against convenience, but when it comes to theory too many chemists are gullible to marketing campaigns.

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42. ed on July 5, 2013 4:41 PM writes...

Significantly off-track, but has anybody done chemistry with super-critical solvents? My line of work, they get expanded through turbines, but I've heard they have chemically interesting properties.

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