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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: Twitter: Dereklowe

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August 25, 2011

Crazy Shape-Shifting Bullvalenes

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Posted by Derek

You don't hear much about bullvalene, outside of physical organic chemistry textbooks. bullvalene.png It's a funny-looking symmetric tricyclic compound, which just seems to be another weirdo hydrocarbon until you consider what it can do with all those alkenes. Everything is lined up just right to rearrange - and then the product you get is lined up just right to rearrange, which gives you a product that rearranges, and so on and so on. The molecule has no permanent structure at reasonable temperatures; this process never stops.
We owe William von E. Doering and Wolfgang Roth for this one (the background story is here). I hadn't realized that the "bull" in the name was put in there by Doering's grad students - it was his nickname! (Believe me, there are a lot of research groups out there where that trick wouldn't provide anything printable). The molecule was synthesized by Gerhard Schröder of Karlsruhe, who continued to work in the bullvalene field (and on related cycloalkene oddities) for many years

There are 10!/3 distinct bullvalene structures, or 1,209,600 of the things. And while you can see the fluxional character in the NMR (one peak at high temperature in the carbon NMR, four sharp singlets at -60 C, and a mess at room temp), no one's really worked out what happens with substituted derivatives. They're going to wander around, too, but how much of that space do they explore? Schröder's group prepared a number of derivatives over the years and showed that they have dynamic structures, but figuring out just how dynamic is a complicated problem. Here's a picture of what happens with a tetrasubstituted compound, for example.
Now Jeffrey Bode (and coworker Maggie He) at the ETH in Zürich may have started to answer this question. They prepared a chiral trisubstituted bullvalone, no picnic in itself. That structure doesn't rearrange, but then they prepared an enolate and trapped it as an enol carbamate. That completes the three alkenes, and off things go. Of course, the alkenes are rather different from each other now, so not every pathway is going to be energetically similar, but there are still enough of them to make for quite a scatter.

When they analyzed the product(s) of that enolate trapping reaction, they found that there was still some chirality present. That must have been an exciting moment, but checking the HPLC carefully showed that there was a chiral impurity present that was left over from the starting material. Once that was cleaned out, it was clear that the situation was still pretty complex: they pulled out four fractions from the HPLC, all of which were mixtures of rearranging substituted bullvalenes. Two of the fractions had no optical activity at all, and showed (and kept) the same HPLC trace as each other over time. One of the other original HPLC cuts, though, had some residual optical activity, which disappeared over another 24 hours. During that time, too, its HPLC trace gradually evened out to be the same as the other two racemic cuts. The fourth cut of the original HPLC trace had even more optical activity in it, and normalized out even more slowly.

Their best explanation for all this is that the molecule starts off on its crazy course of interconverting rearrangements, but occasionally gets to a structure that, energetically speaking, is somewhat painted into a corner. Its pathways to get back out into the rapidly-rearranging manifold are higher-energy, so that part of the population retains chirality longer than the ones that took a different path. Eventually, though, everything does even out: the metastable structures back out of their respective dead ends and start flipping back around through the lower-energy rearrangement pathways.

As they get more of a handle on these molecules, they hope to start to control some of the rearrangement population, messing with the various rate constants so that the isomers sort themselves out (possibly) into discrete populations. There could be some very unusual applications for such shape-shifting molecules, although I have to say that training them away from their bucket-of-marbles-on-the-floor tendencies will not be easy. Still, this is the kind of physical organic chemistry I've always been happy to read about (and glad that I'm not having to do myself!)

Comments (12) + TrackBacks (0) | Category: Chemical News


1. MDACC Student on August 25, 2011 11:32 AM writes...

Question from a Cancer Biologist: Would it make sense to use this as a very fine buffer for reactions/heat? Maybe even as a way to control entropy for physical chemists? I'd assume C10 sort of just vibrate back and forth at a fast rate. Could you ever tether a molecule like this? I'm really curious about the applications.

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2. Molmechanic on August 25, 2011 11:33 AM writes...

Wow, think of the applications of this to drug discovery! Imagine that each of those colored balls is a different pharmacophore fragment. Let the rearranging bullvalene skeleton explore all of the conformational space. Then, when the optimal conformation is found, the binding energy will lock it in.

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3. Anonymous on August 25, 2011 12:17 PM writes...

I had a professor in undergrad who was interested in semibullvalene derivatives, in particular 1,5-methylenesemibullvalene (and thus several classmates who worked on it.) As far as I can tell, he's still working on it, with the last presentations in at one of the ACS national meetings in 2009.

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4. Hap on August 25, 2011 12:25 PM writes...

2: I think that Bode's already been looking at that (see JACS 126(2006), pp. 14370-14371). I don't know how it has worked, though.

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5. barry on August 25, 2011 1:09 PM writes...

we lived through a craze for appending buckyballs onto everything, and we may yet live through a craze for appending bullvalenes with about as much to show for it.

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6. Curious Wavefunction on August 25, 2011 2:16 PM writes...

-Then, when the optimal conformation is found, the binding energy will lock it in.

Not necessarily. It all depends on the concentration and relative energy of the protein-bound conformation in solution and the energy penalty that the protein can pay for twisting the molecule into this conformation. Someone needs to run some high-level quantum chemical calculations on this.

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7. Noname on August 25, 2011 8:24 PM writes...

2: I don't believe that the relative geometries would change that much. The carbons basically sit in place while the electrons slosh around. So not a lot of conformational space would be explored.

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8. sepisp on August 26, 2011 2:07 AM writes...

#4 Hap: while interesting, your citation is irrelevant and the year is 2004, not 2006. It's an organocatalysis paper on homoenolate formation, nothing to do with binding of shapeshifting alkenes on proteins.

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9. Anonymous on August 26, 2011 6:48 AM writes...

For the record, it was Mait Jones (the Princeton prof. and textbook author) who claims to have been the grad student who came up with the name Bullvalene.

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10. Hap on August 26, 2011 9:43 AM writes...

Sorry. References are JACS 132 (2010), p. 15790 and Org. Biomol. Chem., (2009), p. 1529 (from Bode's group website)

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11. newnickname on August 28, 2011 5:38 PM writes...

The Northeast Section of the ACS (NESACS) is having a full day (7:30 AM - 7:30 PM + dinner) symposium in memory of Doering on Sept 8 in Woburn, cost = $50. See www dot nesacs dot org for the whole program. Several of the early bullvalene guys will be there.

I can't figure out some of the speaker connections to Doering. Jun Liu? Wasn't he a Schreiber guy?

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12. gtechinc on September 11, 2011 1:36 PM writes...

can these be subjected to ring-opening metathesis polymerization? if so, you'd get a chain of semibullvalenes which might have very interesting electron transport properties.

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