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Leo Paquette, 1934-2019

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.

 

39 comments on “Leo Paquette, 1934-2019”

  1. SP123 says:

    “You can, of course, draw unusual and unsynthesized chemical structures all day long if you choose.”
    Nanoputians, anyone?

    1. curious says:

      Such a high melting point, combined with the fact that they measured it using only 1.5 mg of the stuff, makes me wonder about accuracy. Does anyone know how much Prinzbach made and what the MP was? I don’t have access to ACIE 1987, 26, 452 (https://doi.org/10.1002/anie.198704521).

      1. Derek Lowe says:

        No melting point determined. They isolated it on small scale as part of a multicomponent mixture, so they have mass spec and NMR data, but that seems to be it.

        1. An Old Chemist says:

          I am wondering that after dodecahedrane reaches its melting point, what happens to it? I guess that it will still remain dodecahedrane and may only sublime off. Or could it be that because of the high strains embedded in its many bonds, it will fall apart really quickly?

      2. Liebig says:

        Prof Brückner in Freiburg/Germany has compiled the Deodecahedran syntheses by Prof Prinzbach:
        http://www.cup.uni-freiburg.de/chemie/institute/cheminst-prinzbach/at_download/file

    2. Somhairle MacCormick says:

      I love that one, just the other day I gave that paper to a new grad who joined us at work, as I was reminiscing about old papers, this one always springs to mind as some crazy profs lab work….

      1. Bagger Vance says:

        Prof Tour (as i recall the story) developed the project to keep a graduate student who was interested in art engaged in her work. It succeeded enough that she got publications out of it and graduated, while he developed a public outreach program for interesting kids in chemistry using it.

        He’s undergone a lot of scorn from folks who need their work to be taken “very seriously” at all times, but you may ask yourself if your own graduate advisor would have done so much to make you stay in their group.

        (It’s even more ironic he gets it from those with ‘literary’ tastes, who seem actively antagonized by an interest in aesthetics.)

  2. Marcus Theory says:

    The icosahedron (d20) is the “last of the Platonic solids,” not the dodecahedron. As for funding that one, let alone synthesizing it, is left as an exercise to the reader….

    1. Hap says:

      It’s the last that could be made by organic chemists – there aren’t enough stable pentavalent carbons to make it at all, so while it’s not the highest order Platonic solid, dodecahedrane is the highest that’s actually accessible by synthesis. I don’t think boron can do icosahedrane, either (though it makes a nice dodecahedrane of its own, but that’s cheating).

      1. AVS-600 says:

        Actually, boron does icosahedranes quite nicely. The simple dodecaborate dianion is known, as are various “carborane” boron/carbon hybrids (B11C1 and B10C2). Note that an icosahedron has twelve vertices, while a dodecahedron has 20, so even though it’s named dodecaborane it is structurally an icosahedron.

      2. Marcus Theory says:

        Ah, very good point. Serves me right for trying to be clever!

    2. Jake says:

      The icosahedron is only the ‘last’ if you go by faces; the dodecahedron has the most vertices. It’s also “last” in that the four classical elements are paired with the other platonic solids.

  3. mr mcknuckles says:

    Have there been any good studies on Parkinson’s in chemists? I’m curious if the incidence is higher than the genearl population (depends on what you work with, obviously!).

  4. Nick K says:

    What is so sad about Paquette’s plagiarism is that it was relatively minor, concerning only some generic text he had filched from someone else, and not an idea or concept. His attempt to cover it up and blame others made it vastly worse.

    1. Magrinho says:

      From a legal perspective, you could argue that Paquette’s plagiarism was hardly “material”. But I would not characterize it as “relatively minor” in the larger picture.

      Given his position, it was a big deal. He was a powerful professor with a huge, well-funded group lifting material from grants that he was reviewing. Are we to believe that he only did this once and was caught?

      It was a long time but I remember seeing it as a classic case of hubris.

      1. Hap says:

        If it wasn’t material, though, it doesn’t make sense to do it in the first place, and less to cover it up (though that’s likely a consequence of realizing that your action was worse than you thought it was). It also is problematic because people plagiarize when they need to (when their need exceeds their fear of consequences), and doing it when you don’t need to comes later, out of habit, which makes people wonder bad things about the person doing it for something unimportant.

        Flawed people can do and do do great things, but it is disappointing.

        1. Nick K says:

          I suspect Paquette’s motivation was simply laziness. Rather than write the screed from scratch he simply lifted it ready-made from someone else. Still very stupid, and a permanent blot on his career.

          1. A.W. Czarnik says:

            Don’t ever imagine that Leo Paquette was ‘lazy’. He was a driven man whose love for organic chemistry was on display for the whole world to see and be amazed at. A common joke regarding Leo was that he had written more papers than many of us had read. Leo was a superb teacher, as were all the organic profs at Ohio State. His use of chalk on chalkboard was artistic. Most of Leo’s students idolized him; working in Leo’s group was a sure route into a pharmaceutical company.

            Leo had something of a reputation that arose because he succeeded despite bitter conflicts in the OSU organic division. As his colleague, I really never saw that person. One example… as a very unseasoned assistant professor, I spoke with that day’s seminar speaker in the morning. In our talk I made a truly stupid comment about Leo- based not in any fact, but based on his reputation. By the end of the day, Leo came down a floor to see me and let me know the speaker had told him what I’d said. I was mortified. Leo could have used my stupidity as a tool with which to crush me in the division behind my back. He didn’t do that. Instead, he pointed out that what I’d done was not the way one behaves in the big leagues… and that was it. I came to be a regular at Leo’s monthly poker games at his house.

      2. Don C says:

        Are we to believe that he is the only reviewer to ever filch an idea?

        1. Derek Lowe says:

          Not at all. But that’s no reason to minimize the ones that do get caught.

  5. luysii says:

    Paul Schleyer synthesized another elegant symmetric molecule — adamantane by an incredibly elegant synthesis using only the product of a Diels Alder reaction, hydrogenating it with a palladium catalyst and adding AlCl3. Molecular elegance was the only reason to make it. Who would have thought that years later I’d be using a derivative (Symmetrel — amino adamantane aka amantadine) to help treat Parkinson’s disease.

    As long as we’re in the remembrance business here’s more on Dr. Schleyer — please see https://luysii.wordpress.com/2014/12/15/paul-schleyer-1930-2014-a-remembrance/ and this https://luysii.wordpress.com/2014/12/14/paul-schleyer-1930-2014-r-i-p/

    1. Design Monkey says:

      Regarding adamantane – at first it was made by much more messy route and not by Schleyer. Schleyer discovered the practically useful route to adamantane, but he wasn’t the first, who made it for aesthetical/scientific purposes.

  6. Curious Wavefunction says:

    Paquette was my PhD advisor Dennis Liotta’s postdoc advisor, and Dennis attests to Paquette being a hard taskmaster but a great role model who inspired him to work hard and get one of only nine coveted assistant professorships in organic chemistry in the country the next year (this was during the academic market downturn in the 70s).

    Sad to see that an entire generation of organic chemists from the golden age of synthesis and physical organic chemistry have passed away in just the last four or five years: Stork, Djerassi, Schleyer, Breslow, Olah, Roberts and Paquette. Given the rather dismal market for academic organic chemists, I sincerely hope that the tremendous institutional knowledge that these fine people helped create and pass on will continue to impact new discoveries in chemistry and our high standard of living.

    1. John Wayne says:

      The whole market for pure organic chemists isn’t great, but I would argue that the real basic work in organic chemistry (physical organic chemistry) has been in disfavor for even longer. The number of ‘up and coming’ physical organic professors can be easily counted on one hand, and their funding opportunities are unfortunate.

  7. Adamantane says:

    As far as Platonic solids go…keep in mind that tetrahedrane is still up for grabs – only substituted derivatives have so far been successfully synthesized

  8. BeenThereDoneThat says:

    Leo or “Doc” to those of us who worked in his group, was (to those who really knew him) a very charitable, loyal, kind and decent fellow. Yes, he completely botched the plagiarism thing, and yes he was a taskmaster; entirely of the “old-school”. His detractors (rivals) feasted on schadenfreude during his public humiliation. By then I lost touch w/ Doc and recall feeling both sympathetic & upset with him for digging himself even deeper. Doc was generally admired by his students & post-docs; I came to realize he was far from perfect.
    I’ve one personal story that I share with my close friend’s re Doc’s charity. It’s really a terrific story that exemplifies his best qualities (not-suited for a public forum on account of my own embarrassment.) Requiescat In Pace Doc. Thank-you for all that you taught me.

    1. Anonymous says:

      Well said.

      I was a better chemist for the time I spent in his labs. He had a good group, and it’s one of those where people seem to keep coming back.

      At his 70th birthday celebration, after the symposium speakers finished and many told stories of some of the demands he made, Doc made concluding remarks. He said something to the effect of, “Look, you were all young and had a limited amount of time to show that you could do meaningful work in this field. It was my job to push you to accomplish as much during that time as you could.” That was my experience.

  9. Anonymous says:

    Chiming in anonymously with some negative (but I hope chemically interesting) comments.
    – Someone already mentioned isosahedrane (pentavalent carbons) but octahedrane also remains to be made. en.wikipedia.org/ wiki/ Platonic_hydrocarbon Arguably inaccessible from C and H only due to angle strain.
    – An accessible Archimedean solid is icosadodecahedrane, C30. It’s a bunch of 3 and 5 membered rings. I had a proposal for C30 long ago that was never funded.
    en.wikipedia.org/ wiki/ Icosidodecahedron Think cyclooctadiene + atomic carbon :C:
    – anion oxy-Cope: Paquette? I learned that it was accidentally discovered by Golob while Evans was out of town. (Left out the protection step and saw that product formed very quickly. Good catch!) Golob ran some more examples and there was a paper ready to roll when Evans returned. (Where did Golob end up?)
    – Plagiarism, etc.: I had heard of many other accusations against Leo, absolutely credible but not always made public.
    – See, for example, the curious case of:
    Tetrahedron Letters, 1981, 22(4), 291-294
    Threefold transannular epoxide cyclization. Synthesis of a heterocyclic 17-hexaquinane
    Leo A.Paquette, Michel Vazeux
    published along with
    Tetrahedron Letters, 1981, 22(4), 287-290
    Synthesis of the first topologically non-planar molecule
    Howard E.Simmons III, John E.Maggio
    The back story of that back-to-back story is rather interesting.
    – Nanoputians: Tour was not the first to “draw pictures” with chemical compounds. There was a guy who published a paper in JChICS in the early 1980s with ridiculously twisted but chemically “correct” structures. I’d look it up in 2 minutes if I had lit access.
    – Melting point: I don’t think that 1.5 mg is a problem. A crystal in a sealed capillary (quartz, if you think you need to get really hot) will keep everything intact. You don’t want to use a Mel-Temp or similar due to sublimation to the cold part of the tube, so you use a bath to make sure the entire (stubby) tube is submerged.
    – Stability: Prinzbach made pagodane (because it looks like a pagoda), another C20H20 isomer. en.wikipedia.org/ wiki/ Pagodane It isomerizes to dodecahedrane upon heating. Within reason (non-oxidizing atmosphere, reasonable “organicky” temps and not super hot flames or plasma temps), I think that dodecahedrane is at the bottom of the thermodynamic well. The strain energies have been calculated but I don’t remember the entire energy landscape.
    – Plagiarism comments: I thought that he was accused not just of copying background material and references but of taking the same synthetic approach to the goal. As I recall, it only came to light because another referee (in Texas, who refereed the original, rejected proposal from Florida) also refereed Paquette’s subsequent submission and noticed that the routes Ohio and Florida routes were too similar. As someone else said, how do we know how many other times he did this and got away with it because the career of the ripped off guy fizzled out. (Example: a big guy with a big group and big money can pull together a team of students and post-docs to force through a synthesis to quickly beat out smarter but “weaker” competition with limited resources.)
    (Not the same kind of situation, but I recall a situation where the seminar speaker put up the structure of a brand new not yet published natural product; the prof in the audience sketched out a route during the talk; back upstairs, a couple of students were switched to the project and they finished the job in a few weeks. It was something fairly simple, NOT palytoxin.)
    – Adamantane: One of several such beautiful stories! Prelog did adamantane the hard way in 1941. Then Schleyer! (See also cyclooctatetraene: Wilstatter, the hard way, in 1905. Reppe, the spectacular one-step way in 1948. More examples, but I’m getting tired.)
    – Liotta: I am an admirer of much of his work, but I am also a cynic. I believe that many coveted positions are battles between powerful PIs and not the candidates themselves. There were probably MANY highly qualified candidates that year (and many other years). If the position had gone to someone else, they would likely be known in this forum while Liotta went into industry or ended up in patent law.
    – Another recent departure: James Briggs Hendrickson, co-author of the once-popular organic textbook Hendrickson, Cram, and Hammond, 3rd Edition. Hendrickson’s career was also tainted by ethical lapses. See: Lysergic Acid, Hendrickson, J. B.; Wang, J.
    Org. Lett. 2004, 6(1), 3–5 debunked by Dave Nichols, Org. Lett. 2012, 14(1), 296-298. He was physical (early studies on conformational analysis of 6 and 7 membered rings), synthetic (natural products synth), and computational (CAOS : computer assisted organic synthesis).

    1. Larry McGee says:

      Alan Golob did a postdoc at Caltech in Chemical Biology after his time in the Evans group, developing Calcium sensors. He then took an industrial position working on Organic Light Emitting Diode materials. His listing on the Evans group website shows him as a research scientist at Intel Mask Operations. That website is not being updated anymore. The ‘group news’ is from 2007.

  10. Scott says:

    Actually, I think I can see a reason for attempting to make dodecahedrane (aside from aesthetics and bragging rights): Figuring out how to close that structure.

    Doesn’t matter when you’re making it out of simple carbon, but trying to bolt the top down in more complex final structures should be a lot easier with people having done the heavy lifting on dodecahedrane first.

    But I am not a chemist, so I don’t know how often some crazy 3d structure really comes into play. Arguably not often, since isowurtzitanes apparently show up almost exclusively in exotic photochemistry, but still something worth chasing down how to do.

    1. Anonymous says:

      “a reason for attempting to make dodecahedrane (aside from aesthetics and bragging rights): Figuring out how to close that structure.” – One of the most famous FAILED attempts to make dodecahedrane was from the Woodward labs at Harvard. If you cut it in half, you get two bowl shaped molecules of triquinacene en.wikipedia.org/ wiki/ Polyquinane . 2+2+2+2+2+2 dimerization was going to produce C20H20 … but it never did. Woodward first made triquinacene in 1964. Very recently, I read that H. E. Simmons, Jr. (proved the intermediacy of benzyne in 1953 as a student at MIT with JD Roberts; Simmons-Smith reagent 1958; Head of DuPont Central Research for many years) had proposed the triquinacene route to C20H20 in an internal memo at DuPont in 1956!! The memo suggests some possibilities and uses. Paul Wender (Stanford) also had a clever approach to C20H20 involving two cyclopentane “caps” connected by 5 ethene bridges (1-1′, 2-2′, 3-3′, 4-4′, 5-5′) that could (potentially) undergo a 2+2+2+2+2 cycloaddition to product. (Sciencemag.org needs to add a structure drawing applet to the Pipeline webpage so we can draw stuff like that for non-chemistry readers.)

  11. drsnowboard says:

    Ironic that the beautiful synthetic dodecahedrane synth is eclipsed in utility by graphene, which only needed some scotch tape and the idea.

  12. Bob says:

    I would like to weigh in with my own comments about a man whom I hold in high regard. I was a Ph.D. student under Professor Paquette and yes, I was the one who carried out that “brute-force” reaction and made the 1.5 mg of dodecahedane.

    It is so easy to criticize people but if I may paraphrase “he who never did wrong cast the first criticism”. Leo Paquette was an amazing chemist, scientist, mentor and human being. “Doc” put everything he had into all he did, from chemistry to teaching even to playing softball with “Armand’s Army” in the department intramural league.

    Was he demanding of his students and postdocs? Yes incredibly demanding. But Doc never asked more of anyone that he did not do ten times over. His work ethic always amazed and inspired me.

    Doc came to me one day and said that I could finish up in 12 months. And when that date arrived 12 months later, HE came to ME and said “OK, you can write-up”. He was a man of his word. I replied saying, “Gee Doc, can I stay a little longer to see if I can make dodecahedron ?” Of course he said yes and the rest is history.

    So although many have and will criticize him I would like to leave this message that Professor Paquette was great a great man and contributed great things to organic chemistry and to many peoples’ lives. May he rest in peace.

    1. Bob Galemmo says:

      Bob, I agree with you wholeheartedly. I was there and saw the relentless effort you put in to making that 1.5 mgs.

      Leo was a scientist and a leader. He was a master of ‘curiosity driven’ research and a role model for his grad students and post-docs. I owe my professional career to the training I received in his lab.

      Thanks Doc, you won’t be forgotten.

      1. Bob says:

        Thanks “Guido”….much appreciated 🙂

  13. ethermunky says:

    During my first week in Doc’s group as a grad student, I went out for an afternoon cup of coffee with some post-docs. We were gone probably half an hour. A few minutes after I returned to lab, Doc appeared and said, “I hear you’re the new queen of the coffee crew.” The look on my face must have been priceless, going from confused to “Oh, sh*t.” He then said, “Let’s not do that anymore.” And I didn’t, ever, even years later in industry.
    Rest in peace, Doc, you were a great and sincere human being; thank you so much for everything you taught me.

  14. John Scovill says:

    I am a Michigan man. One of my best buddies entered Ohio State’s graduate program in 1970 as I was entering Michigan’s. He took his PhD under Professor Paquette and went on to quite a successful career in synthetic organic chemistry. I am grateful that my buddy had this opportunity and his subsequent professional success is testimony to his sound eduction and mentoring in the Professor’s group. I am sure that his experience there was also a factor in his successful family life, a factor that doesn’t usually receive much attention in the history of science.

  15. Willy Begley says:

    Saddened to hear about “Doc”. He was inspirational, and a great chemist, whom I will always remember fondly. He was more than a role-model and a mentor. As a fresh post-doc in the mid-70’s, I consider myself honored to have contributed to the synthetic development of dodecahedrane, in its early stages. I remember having to tell him the world’s supply – about 2 grams – of what was then the intermediate at the forefront of the synthesis, had rearranged on purification, over re-cycled silica gel. He didn’t say much. I could tell he sensed I was more disappointed than he was. A few days later, the inevitable publication was on its way.

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