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Can’t Stop the Nitro Groups

OK, since I’m a medicinal chemist, I have an excellent excuse to avoid the nitro functional group. It’s metabolic trouble, and although there are indeed drugs with nitros on them, they’re exceptions. Some of them, in fact, are antibacterials that rely on that metabolic activation to work, in the same way that there are nitrate esters that rely on hydrolysis of that group to exert their vasodilating effect. And in a way it’s too bad, because stereoelectronically there’s nothing quite like a nitro group, and if it weren’t for such difficulties I’m sure we drug researchers would have found many more uses for the things.

But you know who loves them, nitros and nitrates and maybe both at the same time, because why not? Energetic materials chemists, naturally. High-nitrogen compounds of all kinds are their delight, since these can easily turn into rapidly expanding clouds of gas with the release of catastrophic amounts of free energy. You’ve got your azides, your poly-azoles, your nitros and nitrates (which bring along their own oxygen for extra boomification), and more. Trinitrotoluene is merely the most famous of the polynitro explosives, and there are things out there that make TNT look like toothpaste by comparison. I’ve written about some of them in the past, and two new papers prompt me to write about them again. First up is this one from the Shreeve group at Idaho, in collaboration with the Naval Research Laboratory. Her chemistry is often partnered with people who have an abiding interest in explosions; the group is well-known on the short list of those that try to see just how much craziness you can pack into a single molecule’s structure before it flings itself apart out of sheer joie de vivre.

No, that’s a perfectly accurate statement of their research program: this new paper’s introduction includes the phrase “In our continuing efforts to introduce as many nitro groups associated with a tetrazole ring as possible. . .” and to most organic chemists that’s roughly equivalent to saying something like “In our continuing efforts to spray as much graffiti on the snouts of salt-water crocodiles as possible. . .” Because if that were your research program, you’d seek out the most humungous reptiles available and position yourself at the best angle to give them a cloud of Krylon straight up the ol’ nostrils, right? Same difference.

You don’t think so? Here, take a look at the this paper’s target compound at right. Think about preparing that puppy on scale and ask yourself if you might not rather reach for some swim trunks and a spray can of metallic purple (gotta keep the crocs looking stylish). You’re not going be able to cram more nitro groups onto a tetrazole system that small, darn it all, that’s all there is and there ain’t no more. It’s fair to ask whether this hexanitro beast can even exist. As you read the paper the answer turns out to be “Just barely”.

The team can detect its formation, but it decomposes within minutes on standing, which honestly is probably for the best. Although I will confess to some curiosity about its properties, because the corresponding tetranitro compound is actually a slightly better explosive than the pentanitro (which can be isolated, as well as the similarly energetic salts of both of these, since that remaining terrified carbon-acid protein between the two nitro groups flees easily to give you the anions). The pentanitro and most of its salts, though, are described as “very sensitive to impact and friction”, which I’m sure isn’t the half of it. Some of the tetranitros are (relatively) more tractable, which makes you figure that the hexanitro shown would be a hoppin’ good time indeed, if you were so foolish as to try to prepare any amount of it. And if it weren’t departing this world while you watch, and fit to take you with it, too.

The other paper I wanted to mention is this one from the Baran group at Scripps, and I have to say that I didn’t know that they were into this stuff, but here they are along with the US Army Research Laboratory. It’s titled “Impact of Stereo- and Regiochemistry on Energetic Materials”, which is a good one, because these things will give you the chance to study all sorts of impacts if you let them. But the paper has a point: not many people have looked at what the stereochemistry of such compounds does to their energetic properties, because current calculation methods have them coming out pretty much the same. But can that be right? Stereoelectronic properties influence so many other things, why not the propensity for lab-shattering explosions, too?

The group prepared all four possible meso stereoisomers of the tetranitrate ester shown at right (and some related compounds with quaternary carbon branches off the ring as well). Making the corresponding primary alcohols in stereoselective fashion was not always so easy, and the group had to pull in both photochemical and electrochemical reaction steps to get some of the intermediates. Nitration of all of them, though, seems to move right along, as you’d expect from the example of nitrocellulose, nitroglycerine, and other polynitrates. This exact compound had never been investigated, although some other small-ring polynitrates have been looked at over the years, only to be abandoned as explosives when it was found that their melting points were too low or the vapor pressures of their liquified forms was too high – that last one is particularly alarming when you consider the likelihood of depositing a sublimed layer of high-purity high explosive crystals on every nearby surface. Noooo, thank you.

The calculated properties (detonation velocities, detonation pressures, heats of formation, and specific impulses) of these stereoisomers were almost identical, as expected, and experimentally they aren’t far off either. But their other physical properties are all over the place. For example, the “three up one down” isomer turns out unexpectedly to be a liquid, and doesn’t even solidify at -40C, while the “two up two down” one (same sides, not alternating) melts at over 100C. Their sensitivities to friction, impact, electrostatic discharge and the like vary quite a bit, too (and to be sure, these are generally experimentally determined properties and not so subject to calculation). Their explosive properties compare well with widely used stuff like PTEN and RDX, so such compounds have possibilities in mixtures for melt-casting and so on. As the paper says, “Such tunability has the potential to cater to both the explosives community and the propellants community”, although in my own work I try very hard to avoid catering to either one, and the community of those of us who aren’t trying to figure out how quickly things can blast through the ceiling will just have to sit these guys out.

Oh, and in case you’re wondering about how these tetranitrates compare to the Shreeve group’s polynitrotetrazoles (just typing that out gives me the willies), the latter have higher detonation velocities and pressures, and are more friction-sensitive. So if you are faced with the choice of handling one or the other, go with the cyclobutane polynitrates. But do consider the alternative, if it’s available, of slathering up with sunscreen and diving in to tag those crocodile snouts instead.

66 comments on “Can’t Stop the Nitro Groups”

  1. Doug says:

    I believe the IUPAC pronunciation of the groups hanging off the tetranitrate ester you diagram is ‘Oh, OH NO’. It’s too bad you can’t create O-O-He-NO (spoken as ‘Oh, Oh HELL NO’.

    I started my life as a clinical chemist. If I’d had organic professors with your flair for linking the dry bits of chemistry with the physical reality, I might have gone pure organic. Thank you for posting these articles.

    1. Scott says:

      That was pretty much my reaction looking at the Baran chemical diagram!

      And huzzah!!! another “Things I Won’t Work With” (Still waiting for that book, Derek)

      1. Daniel Jones says:

        At this point, I doubt he’ll ever publish that book as that would technically be working with these Hellish concoctions.

    2. Jeff Evarts says:

      Another TIWWW! Huzzah!

      Possible typo: “carbon-acid protein”

      probably should be “proton”

      1. Jeff Evarts says:

        C3N10O12? Have I got that right?

    3. Joeylawn says:

      Doug – There’s this reaction of Nitrosyl-O-hydroxide mentioned in Wikipedia:

      Early theoretical work had suggested the HOON structure should be extremely unstable, decomposing with no significant activation barrier as predicted below:

      HOON → OH + NO


  2. Mike G says:

    Looks like this needs a “Things I won’t work with” tag – it fits right in with that, my favourite series of your posts 🙂

    1. Mike G. says:

      Whoops, it IS in that group of posts – the tag just isn’t visible. Sorry!

  3. Quarthinos says:

    I think you linked the wrong image. I haven’t pretended to be a chemist since undergrad, but your text implies the first image should have six nitrogens in the ring, but it only has five?

    1. DW says:

      The ‘hexanitro’ portion of the entertainment refers to the six nitro groups (NO2) attached to the ring. There are only four nitrogens in the tetrazole ring, as well.

      1. Quarthinos says:

        Thanks for giving me a useful answer!

        Like I said, I haven’t been a chemist since undergrad.

  4. DW says:

    “that remaining terrified carbon-acid protein between the two nitro groups”

    Just when you think you’ve gotten away from med chem, it drags you back in!

    1. anon the II says:

      I think DW is trying to say there’s a typo and it should be “terrified carbon-acid proton between”.

  5. Gareth says:

    One of those exceptions got approved today:

  6. Akdovnoff says:

    “NaH (60% oil dispersion, 4.8 g, 120 mmol, 4 equiv.) was added to a flame dried 3 neck round
    bottom flask, placed under argon, dispersed in DMF (30 mL) and heated to 80 ºC. ” (Baran’s paper)

    Ironic, given the recent OPRD paper.

    1. Derek Lowe says:

      Jeez, you’re right – I hadn’t noticed that!

  7. SirWired says:

    Oh Frabjous Day! A Things I Won’t Work With!

    I have my Credit Card at the ready to order a signed copy when you collect these things into a book!

    1. Chris says:


      1. James Harmer says:

        Me too

  8. Dave says:

    Well, we all know that propellant chemists are insane. As evidence of this, I’ll offer this snippet from the book “Ignition! An Informal History of Liquid Rocket Propellants” by Dr. John D. Clark, who was one of the leading liquid fueled rocket chemists (pages 177-178):

    “All sorts of efforts were being made, during the late 50’s, to increase
    propellant densities, and I was responsible (not purposely, but from
    being taken seriously when I didn’t expect to be) for one of the
    strangest. Phil Pomerantz, of BuWeps, wanted me to try dimethyl
    mercury, Hg(CH3)2, as a fuel. I suggested that it might be somewhat
    toxic and a bit dangerous to synthesize and handle, but he assured
    me that it was (a) very easy to put together, and (b) as harmless as
    mother’s milk. I was dubious, but told him that I’d see what I could do.
    I looked the stuff up, and discovered that, indeed, the synthesis was
    easy, but that it was extremely toxic, and a long way from harmless.
    As I had suffered from mercury poisoning on two previous occasions
    and didn’t care to take a chance on doing it again, I thought that it
    would be an excellent idea to have somebody else make the compound
    for me. So I phoned Rochester, and asked my contact man at Eastman
    Kodak if they would make a hundred pounds of dimethyl mercury
    and ship it to NARTS.
    I heard a horrified gasp, and then a tightly controlled voice (I could
    hear the grinding of teeth beneath the words) informed me that if
    they were silly enough to synthesize that much dimethyl mercury,
    they would, in the process fog every square inch of photographic
    film in Rochester, and that, thank you just the same, Eastman was
    not interested. The receiver came down with a crash, and I sat back
    to consider the matter. An agonizing reappraisal seemed to be

    1. Jim Mowreader says:

      I’ve always been slightly confused by the Kodak guy’s response. Eastman Kodak, at the time, was operating a huge chemical plant in Kingsport, TN. (It’s still there, but it no longer belongs to Kodak.) If Kodak were to make 100 lbs of dimethylmercury, they would have made it there.

      Given that, if anyone seriously suggests running a rocket on a chemical as lethal as dimethylmercury is, they are too stupid to live.

      1. Joe Thompson says:

        Ah, but what if they did? There’s a very entertaining yarn by Charlie Stross along exactly those lines…

        1. Jim Mowreader says:

          Fun link. Thanks for sending it.

          It kinda reminds me of a real counterespionage program revolving around Concorde. While the British and French were developing that project, the Soviets were developing their Tu-144 SST. The Soviets couldn’t get the tire compound right, so they decided to use industrial espionage: they found a runway maintenance man at one of the airports being used to test Concorde and recruited him to get them some rubber shards from a runway Concorde had used. They tried to recruit a patriotic Frenchman. He called his supervisor, who called the police, who called French Military Intelligence, who called Michelin with a simple request: we would like you to create the worst tire compound in the history of rubber and send us a kilogram of it.

          1. milkshake says:

            reminds me story about Soviet nuke design – western intelligence learned about appalling lack of safety features on early Soviet-made nuclear weapons, and eventually the decision was made to leak details of safety mechanisms used in US weapons (used to prevent accidental detonation, and unauthorized use in case of a theft).

      2. Fred Muggs says:

        Actually, Eastman Kodak did have chemical manufacturing capacity for specialty chemicals in Rochester back in the day. I spent a summer as an undergraduate in the analytical labs supporting them. I can’t speak to whether they had the physical capacity to do 100 lbs of dimethyl mercury, but they certainly made batches of various funky intermediates for commercial sale to the fine chemicals trade there.

      3. eub says:

        I know, yikes. It’s like it’s deliberate rocket-propulsion shitposting.

        Running a ramjet engine by flowing hot high-pressure atmosphere across the fuel elements of a fission reactor, on the other hand… well, at least we mothballed that one.

        1. BlueTemplar says:

          That “we” doesn’t extend to other countries, sadly…

    2. Baylink says:

      For the record, I am told that _Ignition_ is *back in print now*, so if you’ve always wanted an actual copy of it, now you can get one.

      And I still have a title sitting handy for Derek’s book when he decides to publish it. 🙂

      1. John Stracke says:

        _Ignition_ is indeed in print—and in ebook format, too, if that’s what you prefer.

      2. Hap says:

        Rutgers Press has it (I ordered it through Amazon); I had the PDF but if I want people to write stuff, then I needed to buy it when I actually could.

        1. loupgarous says:

          I found my personal copy of Ignition! at the local K-Mart’s remainder pile of books in the late 1970s, for fifty cents. First edition, Rutgers University Press. I’ve been lucky that way, my first edition of On Thermonuclear War by Herman Kahn was the same price, at a rummage sale held by LSU’s Catholic chapel, and a nonprofit bookstore in metro Denver sold me an autographed copy of John Brunner’s Stand On Zanzibar for $1.

  9. JIM says:

    Software engineer with 1 college semester of chemistry. Is O2NO the same thing as ONO2?

    1. Isidore says:

      Yes, it depends on which side of the molecule one puts it if one is attempting to write a structure using a standard keyboard. For example, ethylene glycol dinitrate might be written as O2NO-CH2CH2-ONO2 in an attempt to convey some of the connectivity between the various atoms. Similar to writing OH and HO for hydroxyl, e.g. HO-CH2CH2-OH for ethylene glycol.

  10. Click on my name to hear Red Simpson singing the “Nitro Express”. (From 1966.)

    Notable quote:

    “… and Mister I have to confess,
    That’s the last run I’ll make in a rig called the Nitro Express.”

  11. Eric Nuxoll says:

    I was surprised to hear about Dr. Shreeve’s current work. When I was in the program a quarter century ago her research was almost entirely in fluorine chemistry. I guess that’s not dangerous enough anymore. Considering that the University of Idaho mascot is the Vandal and the University spent several years (inexplicably) in the Sun Belt Conference alongside Louisiana schools, I’d guess that spray-painting crocodiles is the athletic department’s job. If they won’t let you encroach on their turf, then you’re stuck stringing together nitros instead.

    1. Jim Mowreader says:

      Eric, I don’t have hard proof but it seems to me that Dr. Shreeve’s current research is related to Idaho’s hard-rock mining industry…which is not all that interested in fluorine but is extremely interested in better ways to blow silver ore off the bottom of mountains.

  12. Uncle Al says:

    Vyzulta is a recent bifunctional nitrate ester (“bunod”) pro-drug, aqueous eye drops, for lowering intraocular pressure. Do not blink in amazement.

  13. TroyBoy says:

    Just today from CNN: A 7-foot crocodile was swimming in an Ohio creek as elementary school kids played in the water!

    Derek, you’re wonderfully prescient!

  14. Humble Scrivener says:

    I laughed until I cried. The last time I did that was at a Capitol Steps live performance. Derek, *please finish the book*!

  15. gippgig says:

    A couple unrelated but significant articles:
    De novo design of bioactive protein switches
    Nature Vol. 572 issue 7768 p. 205 doi: 10.1038/s41586-019-1432-8
    Flower isoforms promote competitive growth in cancer
    Nature Vol.572 issue 7768 p. 260 doi: 10.1038/s41586-019-1429-3

  16. metacelsus says:

    Typo: PTEN -> PETN

    1. NJBiologist says:

      Between that and the carbon-acid protein, I’m guessing Derek has been spending lots of time with biochemists, and has proteins on the brain….

  17. Sam says:

    Venetoclax has a nitro group.

  18. An Old Chemist says:

    Octanitrocubane has a detonation velocity of 10,100 m/s, making it the fastest known explosive. Octanitrocubane was first synthesized by Philip Eaton (who was also the first to synthesize cubane in 1964) and Mao-Xi Zhang at the University of Chicago in 1999, with the structure proven by crystallographer Richard Gilardi of the United States Naval Research Laboratory.[3][4]

    The R.E. factor of octanitrocubane is 2.38, making it the most effective chemical explosive known.

  19. Simon Auclair says:

    Ha! I put on a banding machine at that Kingsport plant. The synthetic yarn section. The plant was lik a two square mile chemistry set.

  20. Sketch says:

    I have a new, more fitting name for that hexanitro compound, it reads:


    It has to be read while screaming in panic for proper pronunciation.

  21. Cynthia Virtue says:

    You may be interested in Adam Savage’s new episode “Savage Builds: Nitro Explode-aganza” in which he entertainingly answers the question “how unstable is nitroglycerine, really?” It’s fascinating. Not heavy on the science, but definitely will persuade anyone with two brain cells to Never Do This at home or, in fact, anywhere.

  22. David Edwards says:

    And, at long last, a new TIWWW entry!

    Which also provided me the educational link to the “I Want A New Nitro” post, that on its own was fascinating reading. But … back to the main course!

    If HNIW makes TNT look like toothpaste, what price that scary azidoazide azide from the Klapötke lab? That one I learned quickly, is utterly seething with spare bond energy, just waiting to be snapped up by those fourteen nitrogen atoms rearranging themselves into seven nitrogen gas molecules … that’s going to deliver several megajoules per mole when it happens.

    But I have to admire the thinking that results in questions such as “can we synthesise a hexanitro tetrazole derivative?” Not to mention the fortitude that must have been needed to ask the question “just exactly how do all these stereoisomers of this tetranitro ester of cyclobutane behave?”

    The next question that springs to my mind in the case of the Shreeve paper, is whether or not they’re going to break those N=N double bonds, and hang some more nitro groups off the whole assembly. That gives you the potential for a decanitro compound (please uncurl from the foetal position as you read this, Derek!) at the very least, or, if you hang four more trinitromethane groups off the assembly, a compound with no less than eighteen nitro groups attached. Hey, perhaps Shreeve and friends are already working on this, who knows? If the hexanitro one is lively, the 18-nitro variant must be one utterly fizzing beast.

    I am also tempted, at this juncture, to ask how Derek knows so much about dangerous reptiles. He seems to have a penchant for slipping these into a TIWWW post. We’ve had cobras, Komodo Dragons, and now Salties. (My late brother, who emigrated to Australia in 1967, had a fun encounter with a Saltie when starting out as a roadtrain driver). Though I’d suggest, with my part time background in invertebrate zoology, that certain spiders are far more troublesome than something you can see from a quarter of a mile away, and stay a quarter of a mile away when you see it. 🙂

    And now … off to see if I can blag myself some copies of those papers, and have fun learning what the people at the crazy end of organic chemistry are up to these days, pausing only to say “thank you” to Derek for another epic piece of TIWWW goodness!

    1. Barry says:

      In energetic materials, one generally doesn’t break N=N bonds. One extrudes dinitrogen and gets out a bunch of heat in the process

    2. Hap says:

      The N=N bonds are partly what keeps it together – the tetrazoles are aromatic and so partly stable (more stable than they would be in their absence, anyway). A five-membered ring with only N-N bonds would probably not be very happy; you wouldn’t be able to hang nitros off of the nitrogens because they would be too busy waving “Goodbye” to your lab and achieving their desired destiny (as Dr. Lowe put it, roughly) of becoming nitrogen gas.

      1. David Edwards says:

        So, the cyclic compound ((NH)4)CH2 would be too unstable to exist if one tried to synthesise it?

        At this point I’m wondering if there are any aliphatic style chains of -NH- groups, a sort of extension of hydrazine. Or would these be too unstable as well?

        1. An Old Chemist says:

          David, although not exactly an extension analog of hydrazine, metformin comes quite close to it. The chemical structure of metfoemin has always amused me. It has got more nitrogen atoms than carbon atoms. BTW, metformin and rapamycin are two known life-extension medicines:

        2. Hap says:

          Triazenes exist and are OK (they’re used as intermediates in arylations) but two of the nitrogens in them are double-bonded (RN::NNR1R2). I don’t know if saturated versions of heterocycles with more than two nitrogens bonded to one another exist (if there’s a saturated 1,2,3-triazine or 1,2,3-triazole, for example), and I don’t know if there any hydrazine homologs. Azide and the N5+ cation have N-N bonds but some are multiples and they’re not really stable (azides are OK under some conditions but not under others).

      2. Dana Carson says:

        E.E. Smith in his novel Spacehounds of IPC had the aliens from one of the moons of a outer gas giant us N26 as a explosive. They did warn you don’t want to take it closer then Jupiter’s orbit to the Sun because it will explode when it gets that hot.

        1. Derek Lowe says:

          You’ve read a *lot* of Doc Smith if you’ve read Spacehounds of IPC, gotta say

          1. Sacha says:

            I have it too! Also The Galaxy Primes 🙂

    3. James McDougall says:

      You may be interested to hear that azidoazide azide has been synthesised by amateurs several times now.
      Once by an Aussie undergrad.
      In his shed.
      Using chemicals bought at the hardware store and online.

      Overall yield was <1%, but still…

  23. TCG says:

    And T minus 3 years for another TIWWW.

  24. Simon Auclair says:

    Sir I think thats terrified proton not protein…

  25. Simon Auclair says:

    My proteins are terrified too…

  26. Simon Auclair says:

    Tht nitro xpress is hilarious. I’ve been to Nitro Ky, every one google it for a good story.

    Akdovnoff why is that ironic?

    1. Jim Mowreader says:

      Nitro, Kentucky? IIRC it’s in West Virginia.

      1. loupgarous says:

        You’re right. Nitro, WV is the site of many chemical plants, one of which made methyl isocyanate as an intermediate for carbamate pesticide. Union Carbide’s other MIC plant was the one that killed all those people in Bhopal, India after human error caused a massive leak of MIC. Nitro had a release the year after the Bhopal incident, but that was mostly aldicarb oxime (another intermediate for carbamate pesticides like Sevin).

        1. eub says:

          Belatedly — yipes, I was not aware of those releases into the atmosphere. I… appreciate? this nice safe unit safer quote

          The Institute plant was shut down after the Dec. 3 Bhopal leak because of fears about the safety of its MIC unit. It resumed production May 4 after installation of $5 million in new safety equipment that company spokesman Thad Epps said made “a safe unit safer.”

  27. jz78817 says:

    drag racers love nitro groups as well, at least the Top Fuel teams running their cars on nitromethane.

  28. Matthew says:

    You forgot to mention what conditions these drugs could treat…

    (I am new here).

    Testing testing – step right up and test these new nitro-genius drugs to see what they can do for/against you ^^

    Also, there was mention some of this is unstable and begins decomposing fast…
    Would keeping it frozen help?

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