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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 30, 2008

How Not To Do It: Diazomethane

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Posted by Derek

This post will have one of those stories that I can’t vouch for personally, and I’m very glad of that. It involves making diazomethane, which will have already gotten the attention of the chemists in the crowd.

Diazomethane’s a very useful reagent, but it has to be treated the right way. You can’t buy it – no one will ship the stuff – so you have to make it fresh. (There are several such reagents). For many years there have been chemicals in the catalogs whose only real use has been to generate diazomethane when needed. Generally this involves treating some nasty N-nitroso compound with base in ether, then distilling over the ether solution of the reagent, which is a distinctive bright yellow.

There’s where some of the trickiness comes in. That diazo group is looking for an excuse to revert back to nitrogen gas, which process comes with an inevitable no-substitutions side order of kaboom. The chemist’s job is to not give it that excuse. That means that you can’t heat the stuff up, you don’t make it very concentrated, and you don’t even expose it to sharp or rough surfaces, because that can be enough right there. They sell distillation glassware specifically for diazomethane preps, with weirdly glossy ground-glass joints.

You can keep your yellow solution stockpile in the freezer for a while, and the temptation is always to make a lot of it so you never have to do it again. That leads to phenomena like the big flask of the stuff left behind when someone leaves the grad school group. One of those surprises (“Is this yellow stuff what it looks like it is? How long has it been in here? And who the hell made it, anyway?”) was the cause of a new lab inspection requirement while I was getting my degree. You couldn’t leave until someone determined that you weren’t passing on any explosive bequests.

Of course, sometimes you honestly need a lot of these things. One of the guys in my group was in that situation early in his total synthesis. One summer afternoon, the power went out in the labs during a thunderstorm, and the head of our safety committee came rolling a big cooler of dry ice down the hall. “Anybody need to store something in the cold?” was the call. “Well,” I said, “we’ve got a couple of liters of diazomethane solution.” “That’s not very funny,” he said. “That’s because it’s not a joke”, I replied, and we moved to the front of the line.

So, what’s the stupidest way to handle the stuff? That’s the story told to me by a colleague. He attests that when he was in grad school, he looked across the hall to see someone involved in making a goodly amount of diazomethane – in a large standard ground-glass-joint apparatus. Oh, dear. How the guy was going to get his collection flask off without running the risk of grenading everything, that was the question. As my friend watched in disbelief, the guy reached up to just twist the darn thing right off. . .and it was stuck. A frozen joint – just the perfect time for it. (This is the point where the audience for this story began to bury their heads in their hands).

My colleague swears that he then watched this maniac pick up a propane torch to sweat the joint loose. I believe that someone may have stopped him in time, but I think the teller of this tale decided to adjourn for lunch at some distant location right around then, so I can’t vouch for the outcome. But if anyone has a more drooling, slack-jawed approach to an ether solution of diazomethane than running a propane torch over it, I’d like to know what it is. Short of maybe using it as an HPLC solvent, I’m out of ideas.

Comments (29) + TrackBacks (0) | Category: How Not to Do It


COMMENTS

1. NHchem on April 30, 2008 8:38 AM writes...

My first project at one job was to make ~500 ml to 750 ml of diazomethane. With the proper glassware, it is not an issue. Of course, it still makes one a tad nervous but good lab technique always trumps those who may have went to the "right post doc" or "right grad school" yet never learned good lab techniques.

I taught many a highly pedigreed chemist techniques that they should have known but did not....to my surprise.

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2. molecular_architect on April 30, 2008 8:41 AM writes...

Nope, I can't think of anything stupider than taking a torch anywhere near an ether solution of ANYTHING much less diazomethane. I hope this guy never got a degree and isn't working in a lab.

I came to appreciate the potential danger of diazomethane because of a simple accident. When I was in grad school, we never distilled the reagent. Instead, we dried the ethereal solution over KOH pellets. Back then, one could buy a special grade of KOH pellets which were spherical, without the sharp edges of the standard pellets, specifically for this purpose. We would store solutions of this reagent over KOH in the freezer for up to a week. As the pellets absorbed water, they would begin to stick to one another and form a fused mass. One day, an undergrad was pipeting some into a reaction using a fire-polished pipet as instructed. He got careless trying to suck up the last few mls from the pellet mass. Jammed the pipet in to break up the pellet mass and KABOOM!!

There was less than 10 ml of a dilute solution of diazomethane. The flask was pulverized into very small fragments and a very small fire resulted when the ether fumes hit a hotplate in the hood. Luckily, the fire burned out almost immediately and the student was working behind a safety shield. His hands were numb and sore but no permanent injury. His ears rang from the explosion for the next 24 hours. I was at the bench about 10 feet away and felt the explosion from there. Believe me, I've handled diazomethane with kid gloves ever since. Even though using Aldrich's diazald glassware kits is more of a hassle, they are a much safer way to deal with this reagent.

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3. HelicalZz on April 30, 2008 8:54 AM writes...

Always managaged to sucessfully avoid diazomethane. So no I've not seen anything that dumb.

I've twice intervened when someone was doing something dumb with a THF still, but that is almost routine -- notice how when someone fires up the still nearly everyone manages to slide over and check on it. It did blow a year or so after I left the lab, no injuries fortunately.

Zz

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4. milkshake on April 30, 2008 9:49 AM writes...

you can prepare diazomethane solutions from MNNG without distillation but the reagent is hard to buy nowadays because it is shock sensitive and prettyy toxic, major companies discontinued it. You can still buy nitrosomethylurea (rather expensive) which is in use as a carcinogen used to cause cancer in rodents. NMU produced diazomethane has methylamine contaminant though/
Diazald preparation needs a distillation unfortunately.

The other nasty thing about diazomethane is that it is a sure carcinogen and inhaling it also produces a nasty lung burn leading to lung edema. A colleague at institute in Prague ended up on intensive care unit. He then proudly showed a paper from hospital with diagnosis "poisoned with dazo-metals"

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5. processchemist on April 30, 2008 10:18 AM writes...

Undistilled diazomethane it's not such a nightmare in SMALL quantities (NMU can be prepared from the protocol in org synth coll without high expense).

But I remember my awe when I read on an article on OPRD that:
1) Aerojet Fine Chemicals (I don't know the name of the company today) has a dedicated plant for reactions with diazomethane, prepared and distilled in situ
2) some folks designined and operated an industrial scale flow reactor (not microreactor) for this kind of chemistry

By the way, some reactions, like cyclopropanations, don't work with undistilled diazomethane.

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6. CMC guy on April 30, 2008 10:44 AM writes...

Undergrad, grad school and post-doc labs all had the same situation as described where would keep a 1L bottle in the freezer of diazomethane generated in ether with the Aldrich Kit. In most cases people would rotate who generated the stock based on who was using although recall a couple people who refused to make even though they used. Heard stories such as the pulverized glass result but only personal incident with CH2N2 is when someone tipped the stock bottle over in their hood spilling 50-100mL where in the whole lab closed down and preceded to local bar for a couple hours (also may have stuck a dry ice bucket in the joining hood for CO2 introduction).

Probably 90% of use I saw was to make methyl esters which is very convenient but way over kill since plenty of other suitable reagents can do this. I did find no good substitute for performing Arndt-Eistert’s even with several literature offerings.

Milkshake is correct that both explosive and toxic hazard but can be done at larger scales as elluded to by processchemist. In addition to Aerojet (an established DOD Bomb ingredient maker) it is Phoenix Chemical in UK had engineered means to perform multikilogram scale reactions with Diazomethane by continuous feed process.
http://pubs.acs.org/cgi-bin/abstract.cgi/oprdfk/2002/6/i06/abs/op020049k.html

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7. Don B. on April 30, 2008 10:46 AM writes...

I once say a chemist throwing wet towels at a 5L Erlenmeyer flask with ethereal diazomethane that was on fire at the neck.

He finally got a wet towel on top of the flask & the fire went out. I believe he then used the remainder in the desired reaction.

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8. Jose on April 30, 2008 10:54 AM writes...

The A-E rx works quite nicely with TMS-diazomethane; yields are a little lower, but beyond that, no problems in my experience.

Is storing it in the freezer really ever a good idea? Isn't that why they make Diazald?

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9. Merkwurdigliebe on April 30, 2008 10:57 AM writes...

"Nope, I can't think of anything stupider than taking a torch anywhere near an ether solution of ANYTHING much less diazomethane."

How about TWO torches! :) But, no, I have not seen that or anything remotely as dangerous. I had the advantage/disadvantage of always being the less experienced chemist in my groups, and I was never allowed the joy of preparing Diazomethane myself.

A great blog post (with comments) would be "Anecdotes of Asininity in the Lab" but that may be too much for one post and may require a separate blog.

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10. SciChick on April 30, 2008 11:40 AM writes...

Back when I did my Master's in a not-so-well-funded state U I made, let's see, 3-4 L of diazomethane with bootleg glassware - forget about the cute Aldrich kits. We put the setup together from scratch, using rubber stoppers with holes drilled in and glassware with no ground glass joints. It was ugly but it worked. It was good times, I have to say I was proud of doing that. I have since done several other diazomethane preps, never a mishap. Although I did get an explosion from distilling benzyl azide - after the whole distillation was done (it was not distilled to dryness, of course) and I was waiting for it to cool down. Never figured out what had gone wrong.

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11. ... on April 30, 2008 1:52 PM writes...

My supervisor told a story from his post-doc of coming into the lab one morning to find the door to a freezer that held a big bottle of diazomethane embedded in a wall 20 feet away.

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12. Undergrad on April 30, 2008 2:14 PM writes...

We used diazomethane to make phenylsulfinyldiazomethane, a precursor to a significantly more stable carbene.

Anyway, the lab rule was that an undergraduate would transfer the diazald from the 2.5kilo jar to the 500g jars. Because the grad students worried about too much exposure.

So, it was in Texas in the 70's, during the last energy crisis. Someone had decided that the AC shouldn't run at max all night and that the lab hoods which had a central control would be turned off at 7pm.

I'm making diazomethane, which, because we like it more concentrated we codistill with THF. (really).

And the hoods turn off. I was young, and foolish, but I still knew I had a problem. A quick call to facilities management got the hoods turned back on, and as I recall that policy was changed after that exciting afternoon.

We never had any explosions that I know of though.

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13. CMC guy on April 30, 2008 2:21 PM writes...

Jose- looking back probably was not good idea to have a freezer stock of CH2N2/Et2O which is why I mentioned majority of use was matter of convenience. I did try TMSCH2N2 in several A-Es but if I remember correctly crude yields where 40-50% range (and required purification before use) rather than >90% (usable as is) although we suspected quality of the alternate reagent was not as high as grade suggested.

#11. The frig/freezer in question probably was not explosion proof type that are more common/mandated today. This story reminds me of pictures seen of gas cyclinders torpedoing through cinderblock/concrete walls- impressive damage.

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14. S Silverstein MD on April 30, 2008 8:08 PM writes...

As a kid I used to launch Estes model rockets on ballistic trajectories. That's my sole experience with chemical-powered things that could go "kaboom."

I must say, you chemistry pros seem a little nuts to play around with risky substances like this and actually enjoy it...makes for great reading, though.

Then again, we medical types do risky things like hanging around people with really nasty bugs, sticking needles in places where there's not supposed to be places & getting potentially contaminated blood all over the place, and doing 'stuff' on other bodily secretions I won't even mention.

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15. diazo user on May 1, 2008 8:01 AM writes...

You can still buy MNNG from TCI America. They sell it in 5 g bottles as mixture with water (5g of MNNG in variable amount of water-total weight is usually 7-10 g per bottle)

As Milkshake mentioned, you don't need to distill the diazomethane with this reagent.

To use it all you have to do is add MNNG slowly to an appropriate amount of Et2O and aq. KOH at -10 oC (in a plastic bottle for convenience). Then simply freeze the whole thing at -78 oC--the aq. layer solidifies and you can simply pour off the diazomethane solution in Et2O. Definitely the best may to generate diazomethane.

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16. Mark M on May 1, 2008 8:57 AM writes...

"Then again, we medical types do risky things like hanging around people with really nasty bugs, sticking needles in places where there's not supposed to be places & getting potentially contaminated blood all over the place, and doing 'stuff' on other bodily secretions I won't even mention."


....which is exactly why I chose the path of test tubes and crystals.

I nearly fainted once watching my girlfriend get an anesthetic injection into a joint of a freshly broken finger--it wasnt the needler per se, it was all the moving around of the needle in the joint with the accompanying noises that did me in.

And, we can get away with screaming obscenities at inanimate objects in a hood that arent behaving the way we'd like. It would be considered poor bedside manner to do the same during a surgery I would think.

So, yeah, bring on the CH2N2! We have extra fingers we're not using anyway, right?

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17. CMC guy on May 1, 2008 10:39 AM writes...

Mark M bulletin board worthy lines on "screaming obscenities"

Dr. Silverstein guess we do become accustomed to particular environments as I have more fear in a biology/biochemistry lab (with radiation & biohazard signs) than in organic lab. Of course there is a similar reaction when walking into a room full of business/marketing types...

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18. molecular_architect on May 1, 2008 11:47 AM writes...

"walking into a room full of business/marketing types..."

Be afraid, be very afraid. The only thing worse are lawyers!

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19. Sili on May 1, 2008 12:02 PM writes...

I've always managed to avoid the big explosions (though I had a *WHOOF* once when I for some reason tried making a solution of perchloric acid in DMSO).

Which brings me to one of our masters students. She was doing a reaction that had been done lossa times before, but scaled up, because she'd moved on to doing actual work with it (I think it was meant to be an oxidation catalyst or summat - not my project). Trouble was that this complex was isolated as a perchlorate.

Took out the entire hood and the front of the one across from it. Luckily noöne was standing in front at the time, though one of the post grads had just walked by.

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20. Norepi on May 2, 2008 12:31 PM writes...

Never used diazomethane myself. I did know a guy whom, as an undergrad, was put in charge of making vast loads of the stuff. Either his advisor was dead insane or trying to kill him.

Only good boom I've had in recent memory was when I tried to answer the question of "why does one do a Swern Oxidation at -78C?" And I proceeded to mix (COCl)2 with DMSO at room temperature (on teeny tiny scale, mind you.) The resulting instantaneous bang sent the flask bouncing merrily around the hood, depositing DMSO everywhere and answering my question pretty darn quick. XD

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21. MetMatt on May 4, 2008 2:59 PM writes...

Does anyone have any experience making substituted diazomethanes? I've seen a few recent examples of making these compounds from tosylhydrazones, though I don't recall any explicit warnings or cautions described in these papers. I'm assuming these compounds will be similarly explosive/reactive.

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22. syregnask on May 5, 2008 9:52 AM writes...

re: comment #5 by processchemist,

your point #2 reminds me of Phoenix Chemicals..

http://www.phoenixchem.com/capabilities.htm#continuousProcessing

..I once talked to one of the inventors of their continuous diazomethane reactor, and he explained that the true power of their system was in the modular design: The diazoreactor would blow up every so often, but damage was always confined to this part of the system and they could be up and running again in relatively short time.

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23. SFMedChem on May 5, 2008 10:37 AM writes...

re: #22. Notice that the pictures of the hydrogenation and cyanation reactors feature people working industriously in their lab coats.

Contrast that to the continuous diazomethane system...it looks like everyone avoids that reactor with a 10 foot pole. I probably would as well.

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24. Jonadab the Unsightly One on May 26, 2008 9:13 PM writes...

> But if anyone has a more drooling, slack-jawed
> approach to an ether solution of diazomethane
> than running a propane torch over it, I’d like
> to know what it is.

Well, you could always load some of the stuff into a Super Soaker, then sneak up behind somebody who's doing important and/or touchy work under a fume hood ...

But that would be overkill. The torch approach is quite risky enough.

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25. Lee Poctor on June 10, 2008 10:36 AM writes...

As the primary inventor of the Phoenix process I can categorically say the Phoenix reactor system is intrinsically safe and we have never experienced a diazomethane explosion after nearly ten years of operation. Our plant has produced in excess of 100mt of diazomethane but because the system is continuous there is never more than 80g present at any time. The data supporting our safety studies has been extensively presented at international symposia over the years. Can I refer any interested parties to a publication describing these safety studies and the underlying principals behind the Phoenix process (Development of a Continuous Process for the Industrial Generation of Diazomethane, Lee D. Proctor and Antony J. Warr, Organic Process Research & Development 2002, 6, 884-892)

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26. Allen on August 27, 2010 11:22 AM writes...

50 years ago,when I was a graduate student at Syracuse, Dr. Wiley had me make some diazomethane for DNA methylations. The stuff was fairly new then, and a friend of Dr. Wiley's had been hurt by it. I was allowed to make only 200 mg batches behind a blast shield. I had to wear triple gloves (chloroprene over leather over latex) and a gas mask to use the stuff. I made six batches without incident.
I am amazed how casual some folk have become about diazomethane.

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27. Mark Foreman on September 18, 2011 12:35 PM writes...

I have used diazomethane in the past, when I was in Scotland I used to use solutions of it in ethanol. I never tried using ether solutions of it nor did I ever store any of it. My system of work was to distill it into the reaction flask and use it within seconds of making it. My reasoning was that I could reduce the chance of a big explosion by keeping the amount existing at any one time very low.

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28. Luke Weston on April 16, 2012 7:00 AM writes...

This has got to be one of those great moments in organic history:

I think I'll heat up some diazomethane... just to see what will happen.

"Polyethylene was first synthesized by the German chemist Hans von Pechmann who prepared it by accident in 1898 while heating diazomethane."

(From the Wikipedia page on polyethylene.)

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29. tom on December 16, 2013 5:05 PM writes...

how would one get rid of a 500 gram bottle of Diazald that seem to be a solid mass that has possibly melted in to a solid lump

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