B.R.S.M. Pain is temporary, publications are eternal


Unnatural Products 1: Cubane (again)

The two rather tasty Ripostatin B syntheses simultaneously in Angewandte on Thursday notwithstanding, here’s some much older chemistry I’ve been wanting to do a post about for a while.

There are exactly five regular polyhedrons that can be made, and as they were first discussed in detail by Plato, they’re sometimes known as the platonic solids.[1] Now, you might not have heard of them under that name, but I’m pretty sure most of them are familiar  to chemists. In order of increasing size, the series starts with the tetrahedron, the shape of stereogenic centres at carbon, and the source of asymmetry in life. In fact, Jacobus Henricus van 't Hoff won the very first Nobel prize in chemistry ever back in 1901 for being one of the first to notice this. Although the parent hydrocarbon has yet to be synthesised, a number of tetrahedrane derivatives have been reported. Next comes the cube, the corresponding hydrocarbon of which, cubane, was famously first synthesised by Eaton back in 1964. Third up is the octahedron, more of an inorganic chemist's shape and rather unlikely to ever exist with a carbon skeleton due to the crazy C-C bond angles required. Fourth, the dodecahedron, has actually been better studied by organic chemists than most people realise and, after much competition, Leo Paquette was the first to synthesise the corresponding hydrocarbon in 1983. Last and largest in the series is the icosahedron, which I can’t think of a way to link to chemistry, but we’re certainly unlikely to ever see a carbon based version as all the atoms in the skeleton need to have five bonds.

Credit: Wikipedia.org

In this post and the next two I’m going to discuss three syntheses; those of the two platonic solids made to date (cubane and dodecahedrane), and that of the non-regular polyhedron pentaprismane, because it’s also pretty cool. Why do this? Well, when if you consider, say, dodecahedrane in a retrosynthetic sense then unless you lived through the era when these compounds were fashionable targets, have studied them, or are a bit of a genius then it's not obvious where to start so hopefully we can learn a bit of chemistry. I also enjoy a bit of chemical history and some of the methods used were pretty neat as we'll see.

First up is the smallest of the three, cubane. I covered Eaton’s landmark synthesis in the early days of this blog (that is to say, last year) so I thought I’d use this opportunity to write about the extremely short and rather clever synthesis by Pettit and coworkers in 1966.[2] The route began with 2,5-dibromobenzoquinone, and the group planned to functionalise it by doing a Diels-Alder reaction with cyclobutadiene. On the dienophile side of things, this seems perfectly reasonable, as quinones have a long and illustrious history in such a role. The problem is the dienophile; cyclobutadiene is ludicrously unstable, dimerising at 35k and generally being impossible to work with. However, the group had managed to synthesise the somewhat more stable (i.e. isolable and distillable) cyclobutadieneiron tricarbonyl the previous year and had discovered that when this compound was treated with the strong oxidant cerium(iv) ammonium nitrate (CAN) it served as a stable replacement for the crazier parent compound.[3] As best as I can tell, the group actually never reported a yield or any details for this first step, but looking at their other publications aqueous ethanol or aqueous acetone were probably what they used. As for the yield, we can only guess. Presumably it wasn't great, but I’ve heard it said that there are only two yields, 'enough' and 'not enough', and clearly the reaction gave the former. The group then followed up with a swift photochemical [2 + 2] in benzene, closing the cage structure in excellent yield. Next, this was shrunk to the correct size by a double Favorskii rearrangement using aqueous hydroxide. The resulting diacid could then be decarboxylated using Eaton’s three step procedure (acid chloride formation, perester formation and pyrolysis) to give the unnatural product in just 6 steps. Breezy.

Addenda and References

  1. If you want to get all technical about it, a polyhedron is regular if ‘all its faces are congruent convex regular polygons, none of its faces intersect except at their edges, and the same number of faces meet at each of its vertices’. Thanks Wikipedia! I found this old Stoltz group meeting presentation to be helpful when writing this.
  2. Original paper is J. Am. Chem. Soc., 1966, 88, 1328 - 132
  3. Not that you can just buy this. Oh No. The synthesis starts from cyclooctatetraene, uses chlorine gas, temperatures ranging from -30 to +200 ºC, and photolysis.

Credit: Wikipedia.org


Comments (11) Trackbacks (0)
  1. That’s cubane & DODECAHEDRane for the 2 platonic solids made to date.
    The bond angles for an octahedron actually look less crazy than for propellane, which, somehow, really does exist.
    Icosahedrons & fragments thereof dominate borane chemistry; an icosahedron made of 10 boron & 2 carbon atoms exists.

    • Thanks. Fair point on the propellane comparison. Maybe we’ll see it one day! I don’t know if anything’s ever been published on it. I’ll write something if it has! Now you mention the borane chemistry it does sound like something I had heard before…

  2. AWESOME POST…Part of my research as a undergrad was targeted towards methods development specifically for synthesizing tetrahedrane or a derivative of it. My former adviser is still working towards that goal!

    • Yeah, it’s a cool area to work it, although I think the consensus is that tetrahedrane itself isn’t likely to be stable at room temperature. I don’t really know much about it. Maybe I’ll do some reading and write a bonus article. Or you could do a guest post?

  3. Check out a paper by Tsanaktsidis and Bliese in Aust.J.Chem. about ten years back for an updated method for cubane. We use this to make cubane diacid by the kilo. Also, the Barton radical decarboxylation is a far superior method for burning off the acid groups to give the parent hydrocarbon. Cubane is a cool compound and actually pretty easy to make in about six steps. It has boring proton and carbon NMR spectra though 🙂

    • I’ve heard people complain about boring spectra, myself, I don’t mind! I see the good people at synarchive have already covered that Tsanaktsidis paper here. I’m sure you used to be able to buy the cubane diester intermediate from Aldrich, but now I see it’s discontinued.

  4. I remember reading about cubane in the 60’s, and the writer asked the oddly funny question that I’ve yet never stumbled across the answer for:

    “What does cubane SMELL like?”

    Somebody must have cracked open a bottle sometime and had a whiff.

  5. Like Quadracyclane, was available from Aldrich in Kg/Litre quantities though not cheap now unobtainium.

  6. We’re working with a range of cubane derivatives in our research lab and all of these molecules have distinctive and interesting, usually nice odors. They range from soap like to something that resembles dog food.

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