So Leo Paquette has died, age 84 – he had been ill for some years (Parkinson’s). Paquette will be well-known to any synthetic organic chemist; his research group at Ohio State had a long record of contributions to the literature. This PDF from the Baran group is an excellent summary of his work, which is to be found in over a thousand journal publications and is honestly too varied for any quick summary. He did natural products synthesis, synthetic methods development, physical organic/mechanistic studies, and more.
He’s known for the anion-accelerated oxy-Cope rearrangement and many variations on that theme, but what he’s most remembered for is a famous synthesis of an unnatural product: dodecahedrane. That makes for an interesting case, because I don’t think that we’re going to see the like of that synthesis again. Not just for its complexity or the amount of work it took to finish the molecule – those barriers we always have available – but for the multi-year application of all the arts of organic synthesis to a molecule that didn’t exist and had no expected use. Try getting that funded.
Dodecahedrane was made because it was there – well, actually because the idea of it was there. The dodecahedron is the last of the Platonic solids, and there are a number of natural products with frameworks made up of fused five-membered rings. It would be a major synthetic challenge to extend such chemistry to the point that these rings would curl back around on each other and allow for closure to the three-dimensional structure, and Paquette took it on. This was after efforts from Phillip Eaton and his group (who had earlier prepared cubane, in the Platonic-solid area). They had also investigated peristylane derivates that were clear precursors to at attempt at dodecahedrane. Unfortunately, that route failed due to severe steric crowding in the reactions to attach the “roof” ring (the one in dark perspective bonds in the illustration), and dealing with these effects was a major part of Paquette’s synthesis.
But they did it, relying on photochemistry in some key steps and a final brute-force dehydrogenation reaction. Here’s the final paper, and I can remember seeing it come out when I was early in my chemistry studies. The NMR spectrum is, well. . .diagnostic. One proton peak, at 3.38. One carbon peak, at 66.9. It’s a crystalline solid, with a melting point of around 430C (not so easy to determine with standard organic chemistry apparatus), which is rather startling for a compound that weighs 260 and has no functional groups whatsoever. 1.5 milligrams was the final yield, all the dodecahedrane that had ever existed in this world up to that point. I wonder where the sample is now? (Update: I should note that I was once involved in a decision about whether to purchase intermediates from this work)
There was widespread acclaim for the synthesis, but there were still arguments at the time about whether this was a good use of time and effort or not. You can, of course, draw unusual and unsynthesized chemical structures all day long if you choose. And if you choose to make them for real, you’re probably going to have to invent some new chemistry and be very ingenious and persistent. Dodecahedrane got made (as opposed to all those other zillions of odd molecules) because of its intrinsic aesthetic interest. What’s more, a few years later it was synthesized again by Horst Prinzbach via a completely different route. The final step in that one is another low-yielding brute forcer, a conceptually elegant and startling hydrogenolysis of a symmetrical cage compound. And that’s been that – no one is going to make it again unless they come up with some sort of three-step route that looks like a magician’s trick.
Paquette himself had a pretty fearsome reputation as a boss, like many another top-rank organic chemist of that era. One heard stories about the amount of work people put in, as one heard stories about all the others. Unfortunately, one also heard about two instances of flat-out plagiarism in the 1990s, (one NIH grant proposal and one NSF one). Attempts were made to blame postdocs, but the latter case was particularly grim, involving evidence that Paquette had made false statements during the investigation and that he (or someone acting at his direction) had produced intentionally falsified evidence (altered draft versions of his article in question). He strongly contested the cases, but looking at the weight of the evidence, it was bad. And it cost him a lot of federal funding, and a lot of reputation. The last years of his career at Ohio State could not have been what he had hoped they would be.
Well, as Voltaire put it, one owes respect to the living, but to the dead one owes only the truth. Leo Paquette was indeed a great synthetic organic chemist. But we all have flaws, and his eventually tarnished his reputation severely. If they raise a monument to him, it will probably have a dodecahedron on it – and eventually, the Platonic solid itself will be all that most people see.