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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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July 14, 2008

Things I Won't Work With: Cyanogen Azide

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Posted by Derek

Cyanogen bromide is not a nice reagent. It’s not quite on my list of things that I refuse to use, but it’s definitely well up on the list of the ones I’d rather find an alternative to. The stuff is very toxic and very volatile, and reactive as can be.

But it’s not the worst thing in its family. A good candidate for that would be cyanogen azide, which you get by reacting the bromide with good old sodium azide. Good old sodium azide, which is no mean poison itself, will do that with just about any bromide that’s capable of being displaced at all. Azide is one of the Nucleophiles of the Gods, like thiolate anions – if your leaving group doesn’t leave when those things barge in, you need to adjust your thoughts about it. Cyanogen bromide (or chloride) doesn't stand a chance.

Cyanogen azide is trouble right from its empirical formula: CN4, not one hydrogen atom to its name. A molecular weight of 68 means that you’re dealing with a small, lively compound, but when the stuff is 82 per cent nitrogen, you can be sure that it’s yearning to be smaller and livelier still. That’s a common theme in explosives, this longing to return to the gaseous state, and nitrogen-nitrogen bonds are especially known for that spiritual tendency.

There were scattered reports of the compound in the older German and French literature, but since these referred to the isolation of crystalline compounds which did not necessarily blow the lab windows out, they were clearly mistaken. F. D. Marsh at DuPont made the real thing in the 1960s (first report here, follow-up after eight no-doubt-exciting years here). It's a clear oil, not that many people have seen it that state, or at least not for long. Marsh's papers are, most appropriately, well marbled with warnings about how to handle the stuff. It's described as "a colorless oil which detonates with great violence when subjected to mild mechanical, thermal, or electrical shock", and apologies are made for the fact that most of its properties have been determined in dilute solution. For example, its boiling point, the 1972 paper notes dryly, has not been determined. (The person who determined it would have to communicate the data from the afterworld, for one thing).

The experimental section notes several things that the careless researcher might not have thought about. For one thing, you don't want to make more than a 5% solution in nonpolar solvents. Anything higher and you run the risk of having the pure stuff suddenly come out of solution and oil out on the bottom of the flask, and you certainly don't want that. You also don't want to make a solution in anything that's significantly more volatile than the azide, because then the solvent can evaporate on you, making a more concentrated stock below, and you don't want that, either. Finally, you don't want to put any of these solutions in the freezer - a particularly timely warning, since that's one of the first things many people might be tempted to do - because that'll also concentrate the azide as the solvent freezes. And you don't want that. Do you?

Actually, the careless researcher shouldn't even work with cyanogen azide, or anything like it, but you never can tell what fools will get up to. The compound has around a hundred references in the literature, a good percentage of which are theoretical and computational. Most of the others are physical chemistry, studying its decomposition and reactive properties. You do run into a few papers that actually use it as a reagent in synthesis, but I believe that those can be counted on the fingers, which is a good opportunity to remind oneself why they're all still attached.
tetrazine.gif
In fact, the reason I got to thinking about this wonderful little reagent was a recent paper in Angewandte Chemie, which details the preparation of horrible compounds like the one shown. But what does the experimental section spend the most time warning you about? The cyanogen azide used to make them. Enough said.


Comments (31) + TrackBacks (0) | Category: Things I Won't Work With


COMMENTS

1. Sili on July 14, 2008 10:19 AM writes...

I remember the dire warnings against using azide in DCM.

Only think I've ever used it in water or methanol. At least still have all my appendages ...

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2. Allchemistry on July 14, 2008 10:22 AM writes...

Sodium azide no mean poison? Azide is a very potent inhibitor of the mitochondrial cytochrome oxidase, which happens to be the target of cyanide.

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3. imarx on July 14, 2008 10:41 AM writes...

@ Allchemistry

I think he meant "mean" in the sense of average, ordinary, or unexceptional, i.e. "no mean feat." Thus sodium azide is in fact "no mean poison."

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4. Jose on July 14, 2008 12:01 PM writes...

A book begging to be written: "Lowe's Chemical Bestiary."

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5. milkshake on July 14, 2008 2:29 PM writes...

BrCN is a stuff that I worked with extensively. The routine is to use double gloves, pre-weight a closed vial, load it in the hood with sash down and close it in the hood, then weight the difference. Few walks from hood to balances and back are far more preferrable to BrCN vapors wafting around in the lab. The vapors (apart from being very poisonous) have the most irritating odor - one whiff and you can't smell a thing for the whole day - and your nose will feel like being bathed in bleach

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6. Hap on July 14, 2008 2:39 PM writes...

When I was in grad school, some of the businesses in Kendall Square were evacuated for a spill of cyanogen iodide, which is probably just as yummy as BrCN.

I wonder if you could get a bp of NCN3 using a waldo and isolation, similar to nuclear weapons and actinide research, and avoiding any expensive equipment other than the bp apparatus (and maybe a cheap camera with a lens at the long end of a fiberoptic cable).

Are the products explosive? They look like they have more nitrogen than is consistent with bench stability.

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7. Still Scared of Dinosaurs on July 14, 2008 3:53 PM writes...

Gee, chemists sure know a lot of ways to start reactions they can't stop. So...

Imagine that Heaven has a special entrance for chemists who blew themselves up. What's the most embarassing answer you could give when the guy in front of you asks, "So how'd you do it?"

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8. CMC guy on July 14, 2008 4:31 PM writes...

#7 Still Scared- while it is a little hard to imagine Chemists going to Heaven a couple possible:

I hooked up the water line on the THF Still to the N2 inlet on the condenser and when I turned it on...

Well there was this "Summer Intern" and I wanted to show her how to handle tBuLi but the humidity in the lab made the bottle extra wet so when I picked it up...

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9. Chunkstyle on July 14, 2008 9:30 PM writes...

I remember getting a pretty good whiff of HF. Some things you never forget. Myself, I saw God. He said, "I wouldn't have smelled that."

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10. Nick K on July 15, 2008 5:32 AM writes...

Some German guys recently published a paper on the synthesis and properties of tetraazidomethane (C(N3)4) in Angewante Chemie. Very brave.

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11. eugene on July 15, 2008 8:44 AM writes...

Chunkstyle, don't say those things. Now all the kids will think HF is a powerful hallucinogen and you know where it goes from there.

In other news, the link to the recent Angewandte paper by Derek is broken. I'll just assume that it was done by Klapoetke's group and check out his website.

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12. burt on July 15, 2008 9:41 AM writes...

"A book begging to be written: "Lowe's Chemical Bestiary."

How about: "Derek's Chemical Lowe-down"

from Wonder Drug Press?

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13. Felius on July 15, 2008 11:22 AM writes...

Eugene, you mean Darwin Awards? Because this is basically the only result of sniffing HF on purpose.

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14. Kent G. Budge on July 15, 2008 12:55 PM writes...

Sodium azide is used in automobile airbags.

This gives me a frightening mental picture of my head as a leaving group ...

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15. Glamdring on July 15, 2008 5:02 PM writes...

Azide in DCM is okay, in fact I make TfN3 in DCM all the time! See C.H. Wong's diazotransfer.

Good rule of thumb - ((No. of Carbons) + (No. Oxygens))/(No. of Nitrogens) better be greater than three - or risk not having any thumbs!

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16. milkshake on July 15, 2008 6:37 PM writes...

glamdring - azide in CH2Cl2 is NOT OK - but the diazidomethane formation is quite slow so the ignorant fools like yourself often get away with it.

The problem then arises when some innocent novice picks your inherently dangerous procedure and asumes everything is nice and safe (since it was published) and modifies it, being oblivious to the hazard.

Evans group described alpha bromo displacement on acyl-substituted auxiliary, with tetramethylguanidinium azide in DCM. Hruby group au U of Arizona used this methodology to make homochiral aminoacids with methyl in alpha, beta and orthophenyl position. Since their hindered substrates were much lazier in the substitution reaction, they were refluxing them in DCM with the stuff for days... Oh, and they were doing it on multigram scale, too. They had several nasty detonations, always on rotovap (the diazidomethane concentrated in the mix...)
All that it took to stop their reactions from blowing up was the switch to acetonitrile.

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17. zts on July 15, 2008 9:05 PM writes...

Thanks for the info about NaN3 and DCM. I never heard this caution before, and, while it makes sense, I don't think I would have thought of it before doing that sort of reaction (in fact, I may have done that sort of reaction before). The only stories I remember hearing about azide explosions involved transition metal azides. I'll have to add this to my list. Do folks usually take any precautions with other organic azides, and are these known to explode?

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18. Jonathan on July 15, 2008 10:09 PM writes...

Thankfully I'm a pharmacologist so I don't really have to play with things that go bang (although various neurotoxins I used in my PhD always engendered a certain healthy respect) but I do remember one lab that used to use sodium azide to stop algae from growing in the large waterbaths used for bioassays.

I always thought adding sodium azide to a water bath that was being heated might be a bad idea, but who was I to argue?

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19. processchemist on July 16, 2008 2:04 AM writes...

@Jonathan

As far as I know, there's no problem with acqueous sodium azide in low concentrations. If concentrations are high it's better to control the pH: hydrazoic acid is a nasty beast. Few years ago I caught a newcomer performing a Schmidt reaction in conc. H2SO4 in an *open* flask at r.t. ... He said: "I observed gas emission..."

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20. Hap on July 16, 2008 10:20 AM writes...

1) "I observed gas emission..." You mean, before or after he heard the bang and everything turned black? (I'm pretty sure HN3 is pretty toxic as well as being toxic - bp 37C.) Yeeagh.

2) Couldn't they add something else to water baths than NaN3?

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21. processchemist on July 16, 2008 11:14 AM writes...

@Hap
-anedocte mode on-
No detonation occured, and the fumehood removed all the produced HN3... a pretty lucky guy. When I imposed an ice/water bath and an acqueous NaOH trap he said: "Why??? What was supposed to happen?" . I told him something about HN3 properties (one of the few substances that have explosion limits also for mixtures with N2).
His objection was that the experimental details in the reference paper (a JACS from the goden age, when diazomethane methylations were routine) reported no safety problems...
-anedocte mode off-

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22. eugene on July 16, 2008 11:25 AM writes...

Felius, I do believe no one has won a Darwin Award for HF, although milkshake related a heartwarming story about a candidate a few years back on this blog about someone who wanted to impress their boss... It made me have nightmares for the next few days actually.

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23. Norepi on July 16, 2008 7:53 PM writes...

No. 17-

It depends on the azide. I work with a lot of large (mw >300) azides, and they're all comparatively well-behaved; most are stable to well over 200C.

Generally, as the molecular weights get smaller, the vapor pressures get higher, and the % of nitrogen in the molecule gets higher, the more you have to worry about having unexpected pyrotechnics.

Oh, and to everyone else; I've used very small amounts of azide in things like CHCl3 and I still have all of my appendages.

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24. milkshake on July 17, 2008 12:00 AM writes...

Alkyl azides are more stable than aryl azides. Aryl azides can have decomposition onset below 100C. (Acyl azides being the least stable, especially of hindered o,o-disubst benzoic acids - those can do Curtius even at RT).

Tertiary alkyl azides are more stable than secondary, primary ones because no alpha H. Trityl azide lives up to about 250C when it slowly splits N2 (and rearranges to N-phenyl benzophenone-imine).

The reason why low molecular weight azides are more detonation prone, especially in concentrated form, is that the kinetic energy transfer from a fragment recoil (after highly energetic decomposition of single molecule) onto the next azide molecule is more efficient: you have less opportunity for unproductive recoil transfer on inert parts of a molecule to dissipate it.

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25. Carbanion on July 19, 2008 12:18 AM writes...

Great post !! So many things to learn from here. Do we have some published source for these kind of techniques and important aspects of synthetic chemistry ??
For Milkshake-Please,please,please write down all the tricks you know and publish it- I bet it will be a bestseller in chemical world. I am sure not many professors even know all these finer details of the practical chemistry.

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26. Norepi on July 27, 2008 10:21 AM writes...

Huh. I also love how the paper refers to the aforementioned horrible compounds as "energetic." It's like the word "explosive" is politically incorrect or something!

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27. Hap on October 20, 2008 10:09 AM writes...

Another cyanogen azide paper is in OL from Shre'eve's group. The explosiveness of N3CN isn't mentioned as much, although her group has substantial explosive experience so it may be why. Much more emphasis is placed on the potential explosiveness of the aminotetrazole products than of cyanogen azide (which doesn't turn out as badly as it could have).

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28. chem1907 on February 26, 2010 4:04 AM writes...

Diazidomethane Explosion
Raymond E. Conrow* and W. Dennis Dean
Alcon Research, Ltd., 6201 South Freeway, Fort Worth, Texas 76134, U.S.A.

DOI: 10.1021/op8000977

Org. Process Res. Dev., 2008, 12 (6), 1285-1286

Sodium azide and DCM combination does explode in scale up conditions even causing fatality.

I hope anyone to deal with azides would read this very important experience article, in advance; before they experience anything bad.

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29. MHermes on November 29, 2010 12:24 PM writes...

Cyanogen Azide
In fact it turns out to support longevity. I was coauthor of the papers Derek first quoted two years ago and it is now just under 50 years since Frank Marsh and I did that work successfully at DuPont Central Research. Oh, I forgot to tell you of the welder's jacket, the face mask, the leather gloves and the sliding face shield. N3CN proved to be essentially useless - except that you could pump it though a heated tube and get NCN=NCN.

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30. nick012000 on December 25, 2010 2:21 AM writes...

Out of curiosity, I noticed you mentioned CN4 as a part of this substance, and after a bit of googling, I noticed that CN4 by itself doesn't seem to exist. I've never done any chemistry past high school (other than some stuff for my engineering classes on the phases of steel), but why not? I would think it'd work; you'd have a square of nitrogen atoms linked to the pair of atoms on either side, and with each of them linked to the carbon atom sitting on top.

I'd imagine it'd probably be a liquid (since it'd be shaped sort of like water), and explosive (with all those single links between nitrogen atoms), but neither of those seem likely to deter scientists from making it, so why haven't they? Is it just so explosive that noone's managed to create it, or is there some sort of quantum physics reason that this chemical wouldn't work?

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31. AR on September 25, 2012 6:56 AM writes...

We had a Chinese supplier who was prepared to make an intermediate we needed commercially )think 100Kg+) via a BrCN cyclization. I spend a week digging out every obscure paper in whatever language (and having them professionally translated) to avoid this.

Turned out KSCN worked BETTER but they would have done it...!

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