B.R.S.M. (and it's pure by mass spec!)

19Apr/1212

Woodward Wednesday 4: And All That Could Have Been

Woodward was a member of the highly elite few; organic chemists who won Nobel prizes not for a specific reaction, discovery, or work with a particular element but for simple mastery of organic chemistry - theory, synthesis, methodology, structural determination, biochemistry - the list goes on. The elegant citation for his prize summed this up nicely:

"Professor Woodward's research work covers vast and various fields in Organic Chemistry. A leading feature is that the problems have been extremely difficult and that they have been solved with brilliant mastery. He has attacked them with a maximum of theoretical knowledge, a never-failing practical judgement and, not least, a genial intuition. He has, in a conspicuous way, widened the limits for what is practically possible."

I'd be very surprised if we see a Nobel Prize award to a synthetic organic chemist any time soon. The total synthesis/general organic crowd never seem very high up Paul's lists. As we saw in the very first post in this series, Woodward interestingly didn't use the opportunity given him to lecture on the work that actually won him the prize, instead choosing to speak on his entirely new and unpublished work on cephalosporin C. I think Woodward entirely deserved his Nobel prize, which he gained through an unbelievable pertinacity where chemical problems and puzzles were concerned, as well as the willingness to take on daunting challenges. Woodward's chemical legacy was enviable and it's telling that no conversation or book on classic synthesis can fail to cover such masterpieces as his work on reserpine, strychnine, chlorophyll and B12. That aside, I've heard numerous chemists talk about his contributions to other Nobel Prize winning work, so I thought it might be interesting to write a post on this.

As far as I'm aware, Woodward also made significant contributions to three other Nobel Prizes. We might as well do this in chronological order, so:

 

1. 1964 (Medicine and physiology) - Konrad Bloch and Feodor Lynen 'for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism'

Coming just a year before his own Nobel Prize, in my opinion Woodward was a major contributor to Konrad Bloch's elucidation of the biosynthetic pathways surrounding the production of cholesterol, even appearing on the seminal paper reporting the now well -known cascade cyclisation of squalene.[1]  Even people who don't know much steroid chemistry (and I definitely put myself in this catergory) are probably aware of the beautiful (and much imitated) cationic cascade sequence used by nature to assemble that instantly recognisable tetracyclic ring system.

It was actually Nobel prize winning chemist, mountaineer and former president of the British Chess Federation Sir Robert Robinson who proposed that squalene was the biosynthetic progenitor of the steroids way back in 1934, and he even suggested how the chain might fold up for the cyclisation. However, upon Ruzicka’s confirmation of the lanosterol structure in 1952 Woodward began to consider this problem himself, and when Bloch lectured at Harvard later that year, proposed to him an alternative mode of cyclisation. Woodward’s hypothesis had the merit of explaining the structure of lanosterol quite nicely, and also implicated it as the biosynthetic precursor to cholesterol (a fact that was verified by Bloch four years later). Fortunately, it was easy to test which hypothesis was correct as they had important consequences for the incorporation of labelled acetate as I have attempted to depict below. The idea was that that singly 14C labelled acetic acid is incorporated into squalene via the whole ‘mevalonate pathway’ thing, and this then folds and cyclises either as Woodward proposed (left) or Robinson proposed (right). After quite a bit of biosynthesis you get two slightly differently labelled versions of cholesterol. The main difference is that C-13 would be enriched if Woodward was right but not if Robinson was right. So what now? Well, fortunately, it was known at the time that oxidative degradation of cholesterol with chromic acid gives two equivalents of acetic acid,[2] whose methyl groups represent C-18 and C-19 and whose carbonyls represent C-10 and C-13.

To cut a long story short, the acetic acid obtained was analysed and it turned out that Woodward’s proposal was correct. In due course the relationships between lanesterol, cholesterol and other members of the family would be worked out be Bloch.[3]  However, Woodward undoubtably made a key contribution to this field right at the beginning. Decide for yourselves how much that insight was worth.

 

2. 1973 (Chemistry) - Geoffrey Wilkinson and Ernst Otto Fischer - 'for their pioneering work, performed independently, on the chemistry of the organometallic, so called sandwich compounds'

from J. Am. Chem. Soc., 1952, 2125

Woodward's contribution to the proposal of the correct structure for ferrocene is much talked about, and interestingly this was a prize that he himself felt he should have had a share in. Upon publication of the winners, he wrote a letter to the Nobel Prize Committee to inform them of what he felt was an unfair omission:

'The notice in The Times of London (October 24, p. 5) of the award of this year's Nobel Prize in Chemistry leaves me no choice but to let you know, most respectfully, that you have - inadvertently, I am sure - committed a grave injustice' - RBW 26th October 1973.[4]

As the facts surrounding the discovery of ferrocene seem little known, and a few sources like this Periodic Table of Videos clip get things a bit wrong, I’ll briefly recap a few dates here. The first reported synthesis of dicyclopentadienyliron (as it was called at the time) in the literature is a communication in Nature by Peter L. Pauson (of Pauson-Khand fame) and MS student Tom Kealy, who were actually trying to prepare fulvalene to test theories about its aromaticity. However, when they deprotonated cyclopentadiene with ethylmagnesium bromide and attempted an oxidative dimerisation of the resulting cyclopentadienylmagnesium bromide with iron(iii) chloride they got a surprising yellow powder. CH microanalysis showed this wasn’t actually the desired compound and a little maths found that the results were consistent with a formula of C10H10Fe, which they believed to be a linear organoiron compound.

It later turned out that Miller, Tebboth and Tremaine, three chemists at the British Oxygen Company had actually prepared the compound some years earlier and had submitted a paper on the subject to the Journal of The Chemical Society before Pauson and Kealy even carried out their reaction, but the slower publication times meant that Pauson’s appeared first.[5] Interestingly, even this was almost certainly not the first preparation of the compound, as Pauson relates in a Journal of Organometallic Chemistry paper on the history of ferrocene (free here):

The following tale was told about a year later by E.O. Brimm of Linde Air Products. Brimm, who had done some work on metal carbonyls and other organometallics, was one of several industrial chemists who, on reading our report, wanted to make some of the compound. Therefore he enquired of a colleague at Union Carbide (Lindes parent company) whether they had any cyclopentadiene. The reply that they no longer did so was accompanied by the statement that, some years previously, they had terminated work on the cracking of cyclopentadiene because a yellow sludge clogged the iron pipes they used. They had not attempted to isolate or analyse this but had kept a bottle of it; it was ferrocene. The British Oxygen groups synthesis was, in fact, not dissimilar as it involved passing cyclopentadiene over a heated, iron-containing ammonia synthesis catalyst.

Two independent groups proposed the correct structure, essentially at the same time. Ernst Fischer reported what he called a ‘doppelkegel’ or ‘double cone’ structure, based on preliminary x-ray data showing the compound to be centrosymmetric. Meanwhile, at Harvard, Woodward had suggested to his student Rosenblum that he should repeat the Pauson synthesis, and also attempt to vary the metal used. This had resulted in Rosenblum attempting to borrow ruthenium(iii) chloride from Wilkinson who had demanded to know what it was needed for, leading to a discussion between Wilkinson and Woodward over lunch. Although Rosenblum ran reactions with Co, Cr, Ni and Ru, Woodward never published this work, apparently leaving the extension of the series to Wilkinson by some private agreement. As Woodward apparently left no account of his reasoning we can never know his side of the story. By the admission of both Wilkinson and Rosenblum, Woodward was the first to realise that ferrocene, as he and his group called it in a second paper, should display normal aromatic reactivity, and under his direction Rosenblum carried out a Friedel-Crafts reaction on it to prove this point. The reasoning of Woodward’s and Wilkinson’s paper was mostly based around the compound's paramagnetism, lack of a dipole moment and single IR CH stretch as they had been unable to persuade the Harvard crystallographers to look at the problem in time. In any case, only a few weeks passed before unambiguous crystallographic proof of the structure was obtained by legendary crystallographer Dunitz (of Burgi-Dunitz fame) and Orgel (of the ‘Orgel Diagram’). I think Woodward may have been hard done by here and I, for one, can't wait until 2023 when the records of the Nobel Committee for Chemistry for that year become public.

 

3. 1981 (Chemistry) - Kenichi Fukui and Roald Hoffmann - 'for their theories, developed independently, concerning the course of chemical reactions'

As Hoffman's featuring in this citation was for his part in the Woodward-Hoffmann rules, I think it's fair to say that if Woodward were alive, the chance of his sharing in this prize would have been good. He featured on the classic 1963 paper with Hoffmann that first defined the rules as they're known today, and much of the inspiration for them came from observations made during work towards the total synthesis of Vitamin B12 carried out by Woodward and Eschenmoser. Few would debate this one,[6]  and I think it's fair to say that Woodward only missed out here by dying too young, as Nobel prizes are only award posthumously if the recipient dies after the announcement is made.

 

References Etc.

1. I learned about this unintentionally while reading the mini-biography of Woodward’s life written by Lord Todd and Sir John Cornforth in Biographical Memoirs of Fellows of The Royal Society. There's also a similar biographical memoir of Bloch himself (by Westheimer and fellow Nobel Laureate Lipscombe available here. Both are worth reading for those with an interest in chemical history, and the first is a useful summary of Woodward's life achievements. Perhaps rather unfairly, RBW’s is 68 pages in length, whereas Bloch’s is just 9. Bloch, however, was a great man and after he was awarded his Nobel prize a very telling incident occurred:

The selectmen of Lexington, Massachusetts (the town where Bloch lived), called on him to ask whether there was anything they could do to honour their most famous citizen further. Konrad replied that indeed there was. He worked six days a week, and had no opportunity to take his trash to the town dump, which was open only on weekdays. He hoped that the town dump could be opened for several hours on Sunday. And, to honour Konrad, the selectmen agreed.

Well, that’s probably not what I would have asked for! And all this from a man who failed his PhD viva in Switzerland for neglecting to cite a key paper of one of his examiners!

2. Woodward and Bloch got 1.7 equivalents of acetic acid out, not bad if you think how crazy this step is.

3. So, if you had to perform a labelling study, what animal would you chose? Presumably, something inexpensive, that you can keep on your desk, and that’s fairly tractable. Mouse? Rat? Or Rabbit? Nope, Konrad’s first attempt to obtain labelled squalene and cholesterol was done in sharks:

In order to verify the general hypothesis, I attempted to demonstrate the formation of squalene from labeled acetate in the shark, an animal species which, for reasons yet unknown, accumulates this hydrocarbon in unusually large amounts. The project involved an excursion into comparative biochemistry for which the Biological Station in Bermuda was chosen. Experimentation with intact sharks or with the lipid-rich shark liver posed, however, considerable technical difficulties and I failed in the desired objective.

In the end, the successful experiments were done on rats, which, personally, I’d’ve tried before the man-eating marine carnivores.

4. A very interesting piece featuring several interviews and other material from the time can be found in the article 'Of Sandwiches and Nobel Prizes: Robert Burns Woodward' published by Thomas Zydowsky in the extremely hard to find journal The Chemical Intellegencer, 2000, 29 - 34. It took several weeks for the British Library to track me down a copy but there’s a text only version that some kind soul put on orglist.net many years ago. The missing schemes schemes don’t detract much and it’s worth a read if you want more detail than I have given here.

Another, more readily accessible, account is given by Hoffmann in an Angewandte Essay (Angew. Chem. Int. Ed. 2000, 39, 123-124), which non-subscribers can get for free off Hoffmann's personal website here. There's also an account by Wilkinson in J. Orgmet. Chem., 1975, 100, 273 that I haven't managed to get hold of yet.

5. Being industrial chemists they were probably less in a hurry to publish.

6. Unless you count E. J. Corey. See the wikipedia entry for a fairly impartial analysis.

Comments (12) Trackbacks (0)
  1. I’ve got to say that, while I appreciate (a) how awesome Woodward was and (b) that his contribution to the structure of ferrocene was very important, he only published those 2 papers on ferrocene alone. Wilkinson and Fischer spent the Rest of Their Lives doing organometallic chemistry.

    The citation isn’t for “the discovery and elucidation of the structure of ferrocene”, it’s for “the chemistry of the organometallic, so called sandwich compounds”.

    I think that on the scale of hideous mistakes made by the Nobel prize committee – even just for chemistry – this is on there somewhere, but it’s not at the top. Are 2 papers worth a share in a Nobel prize?

    • I think that’s a fair analysis, although he did have the idea of expanding the series apparently before Wilkinson, but then never look at it further or published on it again. Presumably some agreement was made, or RBW didn’t want to move his group in that direction. It’s interesting that Woodward himself seemed to feel left out by what happened.

      • It would be more interesting to know some other data to put it in context:

        – How many other times did Woodward write to the Nobel committee complaining he’d been left out?

        – How often do other people do it? I bet it’s more common than we think!

  2. And for bonus points…while looking up RBW’s papers on Scopus I checked out his h-index. Anyone want to guess what it is? You might be surprised…

  3. Just found out the answer to Neil’s question – and amazed at how close my h-index is to RBW’s. That means I’m as awesome as him, right? Right?

  4. And Woodward’s h-index…(according to Scopus)…is 33! For comparison, the top of the tree at the moment, George Whitesides, has one of 169, and the Chemistry World list I linked to above ‘only’ goes down to those with one of 55, a total of 547 chemists.

    Among those on 55 is some guy called Heck, RF. He’ll never amount to anything…

    (and for completeness: a h-index of 33 means that, of Woodward’s 160 papers on Scopus, 33 of them are cited 33 times or more. Whitesides has 169 papers cited 169 times or more, and so on)

  5. A historical article on the metallocenes just appeared in Angewandte:
    http://onlinelibrary.wiley.com/doi/10.1002/anie.201201598/abstract

    Key quote: “I cannot help feeling that you have been at the hashish again”.


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