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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: Twitter: Dereklowe

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November 15, 2010

Things I Won't Work With: Nitrotetrazole Oxides

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Posted by Derek

Tetrazole derivatives have featured several times here in "Things I Won't Work With", which might give you the impression that they're invariably explosive. Not so - most of them are perfectly reasonable things. A tetrazole-for-carboxyl switch is one of the standard med-chem tricks, standard enough to have appeared in several marketed drugs. And that should be recommendation enough, since the FDA takes a dim view of exploding pharmaceuticals (nitroglycerine notwithstanding; that one was grandfathered in). No, tetrazoles are good citizens. Most of the time.

It's when they get put in with the wrong sort of company that they turn delinquent. What with four nitrogens in the ring and only one carbon, they do have a family history of possible trouble - several sections of this blog category could just as accurately be called Things That Suddenly Want To Turn Back Into Elemental Nitrogen. And thermodynamically, there aren't many gently sloping paths down to nitrogen gas, unfortunately. Both enthalpy and entropy tilt things pretty sharply. A molecule may be tamed because it just can't find a way down the big slide, but if it can, well, it's time to put on the armor, insert the earplugs, and get ready to watch the free energy equation do its thing right in front of your eyes. Your heavily shielded eyes, that is, if you have any sense at all.

Nitro groups are just the kind of bad company I mean, since they both bring their own oxygens to the party and pull electrons around in delightfully destabilizing ways. So nitrotetrazole is already not something I'd feel good about handling (its metal salts are primary explosives), but today's paper goes a step further and makes an N-oxide out of a nitrogen on a nitrotetrazole ring. This both adds more oxygen and tends to make the crystal packing tighter, which raises the all-important kapow/gram ratio. (There is, of course, little reason to do this unless you feel that life is empty without sudden loud noises). The paper mentions that "Introducing N-oxides onto the tetrazole ring may . . . push the limits of well-explored tetrazole chemistry into a new, unexplored, dimension.", but (of more immediate importance) it may also push pieces of your lab equipment into unexplored parts of the far wall.

Turns out that you can make the N-oxides through pretty mild chemistry (oxone at room temp), which is surprising. Until now, only a handful of the things had been made, most using an indirect route using hydrazoic acid (next!). The only direct oxidation of a tetrazole had been done with the relentlessly foul hypofluorous acid (next! keep moving!), which itself has to be made fresh from fluorine gas (next! thank you! next!). These recipes pretty much excluded most reasonable people from skipping through this green and sunny field of knowledge. Still, if you're a reasonable person, you're probably not yearning to make nitrotetrazole oxides in the first place. These things have a way of evening out.

So what are these fine new heterocycles like, anyway? Well, the authors prepared a whole series of salts of the parent compound, using the bangiest counterions they could think of. And it makes for quite a party tray: the resulting compounds range from the merely explosive (the guanidinium salts) to the very explosive indeed (the ammonium and hydroxyammonium ones). They checked out the thermal stabilities with a differential scanning calorimeter (DSC), and the that latter two blew up so violently that they ruptured the pans on the apparatus while testing 1.5 milligrams of sample. No, I'm going to have to reluctantly give this class of compounds a miss, as appealing as they do sound.

Several of the new compounds show similar detonation properties to RDX, albeit with less thermal stability. This is one reason we're reading about them in the open literature; the ideal explosive acts incredibly stable under a wide range of conditions, then loses its composure all at once at just the specified moment. We don't seem to be quite there yet. What I expect is that the authors are probably trying to work this same N-oxide magic on the azidotetrazolates instead of the nitro compounds. Now, that'll be a hoppin' bunch of compounds - for all I know, the research groups involved have already tried this and just haven't been able to get anything out past the lip of the flask yet. I'll be monitoring the literature for signs. On the other hand, if you live in Münich or College Park, you can probably monitor the progress of this work by listening for distant booming noises and the tinkle of glass.

Comments (22) + TrackBacks (0) | Category: Things I Won't Work With


1. partial agonist on November 16, 2010 8:02 AM writes...

How is this of sufficient general importance to get published in JACS? Is it publishable? Sure! But JACS? Try the Journal of Stuff that Blows Up.

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2. RB Woodweird on November 16, 2010 8:08 AM writes...

You are at your most poetic when writing about deadly explosives.

Images arise and are discarded for the sake of propriety.

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3. ER on November 16, 2010 8:20 AM writes...

Testing compound stability in a DSC just sounds like it's asking for trouble.

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4. FMC on November 16, 2010 8:29 AM writes...

Okay Derek,

probably the best piece you have written, yet.

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5. Joel on November 16, 2010 10:33 AM writes...

so cool! the grad student on this paper worked in our lab (at the University of Alberta) as an undergrad. I can confirm he is exactly the sort of person who would love working with explosives. Working with them safely, that is.

He's mentioned that they have since extended this work to even more explosive compounds...

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6. milkshake on November 16, 2010 10:35 AM writes...

the OXONE oxidation is done at 40C actually, for 3 days. Then they extract nitrotetrazole-N-oxide into ethyl acetate and get it as an oil.

The density of an explosive is an important parameter because more dense explosives tent to have higher detonation speed and impulse, hence more shattering power.

Bangs coming from Klapotke lab: I think they must have decent standard operating procedures, I never heard of a mishap there and they have been publishing papers on some really unpleasant compounds

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7. Hasufin on November 16, 2010 11:05 AM writes...

If CP blows up, I'll let you know. If possible I'll even get you pictures.

As a non-chemist, I'm curious: how do you describe the thermodynamic slope to which you refer? Is that something which can typically be found in the literature?

Also, what sort of insane hell-beast spawned HFO? That's not a molecule, that's got to be distilled ichor or something.

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8. Maks on November 16, 2010 3:12 PM writes...

milkshake: "Bangs coming from Klapotke lab: I think they must have decent standard operating procedures, I never heard of a mishap there and they have been publishing papers on some really unpleasant compounds"
The latter statement is true, the first one unfortunately not. In the annual safety lecture I heard a "mishap" from his lab, safety equipment included a blast shield, two pairs of protective goggles, leather gloves and jacket, still the 15 ml flask penetrated the gloves and the guy was in the hospital for quite some time.

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9. CJ on November 16, 2010 4:38 PM writes...

Having extensive experience in the synthesis and analysis of energetic materials (including a handful of tetrazoles), only a fool would run more than 150 micrograms in a DSC- and that includes both the PE and the TA Instruments. You'll decouple the pan if you're smacking it with that much stuff.

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10. Thor on November 17, 2010 6:57 AM writes...

partial agonist: JACS is a collection of top articles from all fields, not simply a collection of your favourite articles. The very existence of this blog post shows the explosive article to be of interest to those certainly outside the explosives field, such the author of this blog. If that is not the broad interest articles JACS wants, then what is?

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11. Nick K on November 17, 2010 7:36 AM writes...

The guys doing this chemistry must have balls of steel, blast shields and the like notwithstanding. Have they ever looked at the residue after the explosion? What happens to the (few) carbons in the molecule?

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12. partial agonist on November 17, 2010 8:54 AM writes...

Thor: I'm not saying that the paper isn't interesting, in a why-in-the-world-would-anyone-do-that sort of way, I merely questioned if it has sufficient general importance for JACS.

Look at the chemistry. They made an N-oxide of a heterocycle. Wow. Glancing at the tables, it seems like they did a lot of energy calculations. Fine. But I ask, it this work people will repeat, build on, apply to their work, etc? It just seems a reward for doing chemistry that admittedly takes guts to pull off.

No big deal, but if I were a reviewer for JACS on this paper, I would have flagged it as a fine contribution that was submitted to the wrong journal.

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13. Anonymous on November 17, 2010 11:35 AM writes...

Well, it's at least more interesting than the DFT-calculation/nanotube/click chemistry BS that normally populates JACS

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14. anon for this one on November 17, 2010 12:01 PM writes...

Well, after I finished my PhD at College Park, I had dreams of the entire chemistry department disappearing from a giant explosion (that came from my rocket propelled grenade launcher, the rocket fired as I drove away from the place and never looked back). It's too bad that Klapotke takes all the safety precautions and only works on small scales...

Then again, he's just a visiting professor there for some strange reason, as no one on the faculty deals with explosives. I bet it will be his base of operations when he deals with the military types around Washington D.C. Maybe he'll teach a few classes or something. Sadly, I will have to wait longer for College Park to be blown to hell. And the longer I wait, the dimmer the memories of the grad school experience become; hell, sometimes I'm even having fond memories of the time there.

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15. Thor on November 17, 2010 12:34 PM writes...

A survey of JACS ASAP articles:
nanoparticle mass spec
phosphorus NMR shifts
chromium complexes
ion transfer kinetics
cobalt peroxo complexes
All much more highly specialized than discussed paper, and this is not mentioning the psuedo-chemistry present such as ribosome structure (sorry, JACS is a chemistry journal, not a biology journal)

As I am decently well-versed in tetrazole chemistry, this is one of the few N-oxides of tetrazoles known, which others can exploit in other areas of tetrazole chemistry (both energetic and non, ex biological activity of N-oxides as NO releasing agents) so it is work that can easily be built on.

As for it only being in JACS because it took "guts", the sensitivites section seems to show that other than a couple of the salts, most of the stuff they made is less sensitive than RDX, which soldiers carry around all day without incident. So unlike the azidotetrazole work they published a while ago, it seems pretty safe.

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16. milkshake on November 17, 2010 12:53 PM writes...

@15: RDX being carried around all day by the military: the stuff is always used phlegmatised. The main reason for all these compositions with RDX (that typically contain only 70-90% of RDX by weight) is to make it reasonably insensitive to impact.

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17. Jelly bean on November 19, 2010 6:55 PM writes...

Search the terms " nitrotetrazole-2N-oxide" or " nitrotetrazole oxide". The Klapotke group is not the first to make these salts. JACS publication?

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18. Anonymous on November 20, 2010 2:13 PM writes...

I'm not going to judge whether this is JACS worthy, but #17 is spot on...most of the salts were made by SRI International in 2003 using the same OXONE treatment that Klapotke uses. Klapotke claims that the 2N-oxide was never made before 2010...he missed this paper in his citations.

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19. befuddled on November 20, 2010 6:39 PM writes...

@partial agonist:

AFAIK, acceptance to a general interest journal, whether it be JACS, Science, or PLoS Biology, is dependent on a number of things. Significance is one, "coolness" is another. And for chemists, explosives are cool. Similarly, while I suspect there are comparatively few paleontologists in their readership, Science, Nature, PLoS Bio et al seem to have a superabundance of dinosaur articles.

You could rationalize the publication of the tetrazole N-oxide article in JACS by saying that chemistry is about reactivity, and since these compounds are particularly reactive, they are of particular interest. But I think it's really about coolness.

Not that there's anything wrong with that..

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20. befuddled on November 20, 2010 6:43 PM writes...


The ribosome structure is pseudo-chemistry? So understanding a peptide synthesis mechanism of unparalleled processivity and accuracy isn't of interest to chemists? The fact that something is also of interest to biologists doesn't mean it's not also chemistry, I think.

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21. Norepi on November 30, 2010 6:48 PM writes...

Is it wrong that as soon as I saw the title of this entry I thought "Klopotke's at it again?"

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22. Dark-Star on December 4, 2010 10:49 PM writes...

I second the motion that these articles bring out the poet in you, Mr.Lowe. Nevermind the hilarious lines like the one about pushing unexplored limits and pushing lab equipment into unexplored parts of the wall.

It's always a treat to come here and see new entries in How Not To do It or Things I Won't Work With. Turn these into a book already!

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