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Woodward 2.0

I really enjoyed this Curious Wavefunction post on being born at the right time. He uses the example of R. B. Woodward, who was several years older than most of the other big names from the glory days of synthetic organic chemistry (Corey, Stork, etc.), and had already had a chance to use his immense talents to make a mark on the field before they came along. The point is that Woodward was not only a tremendously gifted and hard-working chemist, but that he came along at a time when his abilities could have the biggest impact.

The other example in that post is a famous one, the generation of physicists who sorted out quantum mechanics. That was a relatively brief period, and it was done by a relatively small cohort of younger workers in the field (only Schrödinger was a bit older). If you were born outside of the right window, you missed out, no matter how talented you were. Later generations of physicists included a good number of people who could have made the same sorts of contributions, had they been alive at the right time to make them.

What would a postdoc-aged R. B. Woodward (or Woodwardesque equivalent) work on today in chemistry? My guess is that Woodward himself was attracted to total synthesis not because (or only because) it was total synthesis, but because of the technical and intellectual challenges it offered. Remember, Woodward’s quinine synthesis was in 1944, at a time when no one was sure that such complex molecules could be made synthetically at all. It took a great deal of nerve to tackle these kinds of problems, and my guess is that a reincarnated Woodward might apply that boldness to things like (say) artificial photosynthesis or protein folding.

It’s hard to pick, though, because you really wonder how total synthesis of natural products looked to others back in the early 1940s (and thus what areas might look similarly inviting today). We just know a lot more than we did back then, which makes you wonder if any of the current frontiers can have the same character as the ones back then had. By now, it’s hard to think of a really outstanding problem that hasn’t had some work done on it, whereas back then so many things were waiting for the first footsteps to be made in them. I wonder if that’s what it seemed like at the time, though? If anyone knows of any articles in the journals from the 1940s on “outstanding problems in the field” or the like, I’d be very interested in seeing them.

At any rate, we’re not going to see something like the quantum mechanics revolution in chemistry. That, famously, was driven by the increasing divergence of experimental data with any of the existing theories. Quantized spectral lines, blackbody radiation, the photoelectric effect, Compton scattering – these and more indicated that something was seriously wrong with the assumptions of classical physics. I don’t think any such situation obtains today in chemistry; if there’s a major divergence of theory and experiment like those, I can’t think of it at the moment (and there certainly isn’t a collection of them like the ones in turn-of-the-20th-century physics). Admittedly, chemistry is a bit theory-deprived when compared to physics, but so is every science.

The biggest black boxes, to me, are over in biology now, and biology is even less susceptible to sweeping mathematically-reinforced theories than chemistry is. But then again, total synthesis as practiced by Woodward wasn’t theory-driven – he was ready to discover new reactions wherever they might be and push the limits of what we knew about chemical reactivity, in a relentlessly pragmatic way. There wasn’t a prediction that, say, “strychnine could not be synthesized” that Woodward overturned. (New theories might well suggest themselves out of the data obtained by these synthetic experiments, of course). So our hypothetical Woodward 2.0 might well have been attracted to biological problems, although given his well-known love of chemistry, perhaps he might have worked his way in through what we’d now call chemical biology. Heresy?

No matter what, though, I think that a young Woodward today would be out of phase with the course his actual career took. That was a perfect era for the total synthesis work he loved to do, but that’s not the situation today. I just can’t quite imagine Woodward looking around and saying “Well, OK, strychnine’s been done, so. . .strychnine dimer!” So I guess the question is whether he would have (or would have been able to) apply himself in a new field, which is my guess, or would have languished as a talented scientist born in the wrong era. You can only work on the problems that exist. . .

48 comments on “Woodward 2.0”

  1. luysii says:

    “That, famously, was driven by the increasing divergence of experimental data with any of the existing theories. Quantized spectral lines, blackbody radiation, the photoelectric effect, Compton scattering – these and more indicated that something was seriously wrong with the assumptions of classical physics. ”

    Why doesn’t this reasoning apply to the global climate models, which failed to predict the ‘pause’ and the inaccuracy of the predictions of the models of 5, 10 and 20 years ago for present conditions?

    For more on this — see

    1. me says:

      Would you please stop plugging your rambling wordpress mind-dump on all of Derek’s posts? I doubt there are very many people here interested in reading your garbled personal journal, here or more broadly.

    2. Vampyricon says:

      Because 1. the “pause” results from cherry-picking of data, 2. the climate is a chaotic system in the short term, and 3. quantum physics is about the very small, where few factors influence the results.

      1. Nick K says:

        Your assertion that the “Pause” is an artifact of cherry-picking will come as a surprise to the UK Met Office.

        1. Confirmation Bias says:

          So when they say “The first paper shows that a wide range of observed climate indicators continue to show changes that are consistent with a globally warming world, and our understanding of how the climate system works.”, they don’t mean that the data showing a pause is cherry picked.

          Make your own mind up after reading the Met Office’s own words here (papers linked if you want to read it all).

          1. Confirmation Bias says:

            The first (overlong) sentence was supposed to end with a question mark.

          2. Nick K says:

            Thanks for confirming what I wrote. The Met Office accepts that the Pause is real and not an artifact of cherry-picking, but attributes it to natural variability superimposed on a warming trend. Time will tell whether this is the case,

          3. luysii says:

            None of the climate models mentioned in Science in 2009 [ Science vol. 326 pp. 28 – 29 ’09 (2 Oct ’09 ) ] predicted a pause in warming as long as we are currently experiencing (17 years and counting), even when they were run for a total of 700 years. The longest pause found was 15.

            The mainstream scientific press is finally sitting up and taking notice. Nature (16 Jan ’14) has an editorial (pp. 261 – 262) and a news item (pp. 276 – 278) concerning the pause. It is claimed that the Pacific is taking up the heat, without heating up much. The heat capacity of water is USED to define the calorie — it is 1 calorie per gram of water — in contrast the heat capacity of methane with the same molecular mass is 1/116th of water. So there’s plenty of heat capacity in the ocean.

            Adding a new parameter to explain unexpected results is good science when the system being explained is complex. Consider the additions to the central dogma of molecular biology — introns, exons, microRNAs, ceRNAs, reverse transcription etc. etc. Certainly global climate is equally complex. However, more than a little humility is in order.

            This begs the point about whether the ocean as a heat sink was included in the model cited in 2009. If it was, the model had better predict the pause. If it wasn’t and if the latest explanation given for the pause is correct, the model should be thrown out along with its recommendations.

          4. Confirmation Bias says:

            I don’t think it’s that simple, you can read it either as cherry picking the one indicator that supports a pause from a number of indicators, in which the others don’t, or cherry picking data within that single indicator. As I read it, cherry picking is supported in the former interpretation, but not in the latter. Having said that, I haven’t had time to read the papers and I’m just going by the summary.

        2. luysii says:

          “The Met Office accepts that the Pause is real and not an artifact of cherry-picking, but attributes it to natural variability superimposed on a warming trend. Time will tell whether this is the case.”

          How in the world would you ever prove them wrong? If such a way doesn’t exist, is this still a scientific theory?

          1. Nick K says:

            Good question. I have no idea how one could distinguish natural variability from anthropogenic influence in a system as complex, far from equilibrium, and interconnected as global climate.

            According to some statistical analyses, the Pause has now lasted well over two decades. The discrepancies between the models and the observations are huge, and getting bigger with time.

  2. InfMP says:

    he talks way too slow.
    in this age, he would have been left behind. no one has time for that now.

  3. dearieme says:

    “Later generations of physicists included a good number of people who could have made the same sorts of contributions, had they been alive at the right time to make them.”

    An unfalsifiable hypothesis.

    You could argue that the odd thing with the quantum theory was how long it took. Maxwell had realised that there was something fundamentally wrong with classical physics, and he’d died in 1879.

    1. Derek Lowe says:

      If only he hadn’t died of cancer at the age of 48! Maxwell was indeed the real deal, and I think that he might have ushered in both some early quantum mechanics and perhaps some relativity as well. . .

      1. David says:

        I agree, although I think he would have found some resistance from other classicists. I wonder how much experimental evidence was available to push him towards quantum physical ideas at that time.

  4. Hap says:

    1) Maybe neuroscience or synthetic biology?

    2) I wonder where we could use better tools. As CW (and others) have noted, lots of major advances are driven by the availability of tools – once the tools are available, lots of fields open up that looked closed before. I don’t know where those are, but their location is likely to determine where zombie RBW could best operate.

    1. RM says:

      If it’s a tools issue, I’m wondering if “computational X”, or “machine learning for X” are set to take off. There’s a bunch of preliminary work for a bunch of X’s on that front, but I’m not sure if we’ve had a Woodward-esque cracking of that nut yet.

  5. Barry says:

    sir Francis Crick, after great and justified acclaim for the work he published with James Watson on the structure of DNA left the field (of what became “molecular biology”) to address what seemed to him the next “great problem”. He spent the rest of his career trying to explain consciousness, or the relationship of brain to mind.

    1. skeptic says:

      I think you’re shortchanging Crick a bit here. After work with Watson on the structure of DNA, Crick continued to work in X-ray crystallography for a while, then focused on the transfer of genetic data from DNA and protein synthesis. Only later did he focus on neurobiology.

  6. anon the II says:

    On this 100th anniversary of Woodward’s birth, it’s worth going back and reading David Dolphin’s article on RBW in Aldrichimica Acta on the occasion of RBW’s 60th birthday.

    The story of RBW is more than just timing.

  7. K says:

    Two things that are unfair about this analysis:

    1. What if Woodward were born *too early* for his respective field? If Woodward, Einstein, Pauling, and Heisenberg had been born thirty years earlier would they still be viewed as mythic scientific titans? I don’t say this to detract from their brilliance, but let’s not forget that they owe tremendous benefits to those who laid foundations before them.

    2. Why is the subtlety and specificity of modern scientific problems in synthesis seen as less interesting than the “foundational” problems? As intellectually groundbreaking as Woodward’s synthesis of quinine was, if you exclude inspiring scientists to undertake careers in synthetic chemistry it provided little societal benefit outside of academia. Some “unsexy” or “non-foundational” synthetic problems have been invented today which enable the treatment of diseases worldwide. Not to detract from his genius, again, but to say that “no discoveries will ever be that big” is a huge slap in the face to people whose “niche” labors have provided tremendous benefits to mankind.

  8. Mol Biologist says:

    My favorite American scientist Murray Gell-Mann introduced the concept of “strangeness,” a quantum property that accounted for previously puzzling decay patterns of certain mesons. Later he become a linguist with exceptional pan-language theory. In 1984 he cofounded the Santa Fe Institute that supports research concerning complex adaptive systems and emergent phenomena associated with complexity.

  9. Curious Wavefunction says:

    Thanks for the plug Derek. It seems that during his last few years Woodward was contemplating the foundations of what we know today as conducting polymers and organic electronics, so he could have well made a mark in that field if he had been born later (or died later for that matter).

    As for Maxwell, it’s hard to say what he may have accomplished had he lived longer, although his early death was undoubtedly a great tragedy. He certainly had the potential to do much more, but when he died it seemed that his best work was firmly behind him. He had retired to his ancestral home in Scotland before he was invited to head the Cavendish Laboratories. He spent fifteen years there during which he did not produce anything particularly scientifically noteworthy. Most of his time was spent doing administrative work, writing lucid textbooks and editing Cavendish’s papers.

  10. Bryan says:

    I see a lot of Woodward in efforts to build synthetic genomes to answer questions like, what are the minimal set of genes required for a free-living organism? There’s so much we don’t understand about the structure and organization of genomes (esp, what all of the non-coding DNA is doing), and synthetic biology is probably one tool that will be very useful.

  11. Anon says:

    I find it really ironic that you posted this today. Earlier I was reading my LinkedIn feed and there was an article about the ‘next Albert Einstein.’

    Apparently she is a 23 year old studying string theory at Harvard, but all I can think is that no one could have ever guessed a 23 year old Einstein would transform physics.

    He was a mathmatical dreamer at a time and place in need of such people. I really do believe he may have been so exceptional that perhaps no one else could have concieved of his idea, but he was also born at the right time and place. Most importantly revolutionary scientific ideas are NEVER predictable. Else they would have already been published.

    1. dearieme says:

      “perhaps no one else could have concieved of his idea”: that may well be. I do remember reading that some of his ideas had been prefigured in the work of Poincare and Lorentz (amongst others), and that it was improper of him not to have referred to their work in his publications. Is this still an active area of contention?

      1. Erstwhile says:

        Yeah, I’ve seen lots of literature regarding poncaire and Lorentz preceding Einstein, who wrote his papers without reference to their mathematics and works. Some blame it on Einstein’s patent background.

  12. pz says:

    definitely alzheimer’s (I hope). no doubt. very intriguing, very high barrier and very high impact.

  13. Chris Phoenix says:

    How about mechanosynthesis? Put one of your reactants on a surface (not necessarily flat). Put another reactant on something you can control the motion of. Move them together and make them react.

    Simple proximity (by greatly reducing the motion effects of thermal noise) can, in theory, increase reaction rates by something like 10^9. Then, by applying pressure, you can reduce activation energy pretty substantially, which provides another large boost in reaction rates.

    For extra credit, if you do this in a completely inert solvent like supercritical xenon, you can have lots of dangling bonds that would normally react randomly, and take your time and pick your sequence in filling them.

    The range of possible synthetic reactions is large; the range of products is vast^(huge^ginormous), including what can best be described as amorphous covalent solids – but with all the atoms where you want them.

    For someone who liked total synthesis, and liked a big challenge, this might have been a great field to go into.

    For what it’s worth, Richard Feynman really liked this idea.

    1. Barry says:

      Feynman liked this idea because he saw it as a simplifying general solution that would obviate learning hundreds of discrete reactions. That’s the orthodox reductionist physicist’s view of chemistry (more so of biology). Not at all the sort of iconoclastic insight for which we generally look to Feynman.

      1. Chris Phoenix says:

        Feynman also liked the idea because, if enough reactions and structures and capabilities were developed and combined, it would allow nanoscale manufacturing systems capable of building atomically precise products in large numbers. (Most scaling laws make nanoscale machines very attractive; the main one that’s adverse is stiffness.)

        This goal goes back to his 1959 talk “There’s Plenty Of Room At the Bottom” where he talks about the benefits of atomic precision for tools-making-tools, though in that talk he was proposing more traditional machining. He talks about using nanoscale tools to build tiny components for computers; he talks about having a billion copies of a machine all working in parallel. Here’s the talk:

        Feynman liked Drexler’s ideas when he heard them.

        1. Materials Chemist says:

          It’s entirely possible that a modern-day Woodward would be working on really systematizing the synthesis of really large inorganic clusters.

          There’s a big conceptual jump between making even monodisperse, ligand-protected nanoparticles (whether crystalline or amorphous) and making the large ligand-protected clusters that lie on either side of the boundary between “traditional” synthetic chemistry and the less celebrated world of materials synthesis. So much current synthetic work, especially on all-inorganic systems like polyoxometalates and Zintl clusters, is little better than crystal fishing, and that field will take several Woodwardian figures to sort them out and make them as practical and widely appreciated as total synthesis is now.

  14. anon says:

    When I worked for Stuart Schreiber (ca. 2011), he shared an interesting story of the types of research questions Woodward was asking right before his death (Schreiber was a grad student in his lab when Woodward passed). Apparently he was thinking a lot about surface/nanochemistry (e.g. what’s the chemical behavior on the surface of diamond? on the inside?). Could he have another Nobel prize if he lived another 20 years? I wouldn’t doubt it.

  15. exGlaxoid says:

    I agree that someone as bright as Woodword might have not been as productive if born sooner or later, as he was at his prime during the peak of total synthesis, so he could get funding, good students, and lots of unsolved problems to consider. Imagine him now with a cut NIH budget, mostly foreign students, graduate students too distracted by their phone too much to work, and few challenges left. Maybe he would have done great things, maybe he would have worked for the wrong professor and done poorly, Hard to tell. but we have all known very bright people that either did great or flamed out due to some hard to predict thing. I was lucky in that my undergrad advisor professor worked for Robinson and then post doc’d with Woodward, so I got exposed to many great ideas. I would have loved to have had that type of opportunity, Schreiber is one of the best examples in my time frame, he was another exceptionally bright guys. I have heard that he almost dropped out of UVA but then looked at chemistry and got his triple major in 3 years and was upset then he got a single A-, not sure it is true, but he is clearly a genius in many ways.

    The whole concept of being born at the right time is discussed at length in
    “Outliers: The Story of Success” by Malcolm Gladwell, who talks in a fashion similar to “Freakonomics”.

  16. Anonymous says:

    In “Chemical Creativity: Ideas from the Work of Woodward, Hückel, Meerwein and Others,” Jerry Berson (RIP) refers to RBW as a “demigod.” That leaves me conflicted. Sometimes I think of RBW as a once-in-a-century genius but other times he just seems like one of many really smart guys in the right place at the right time AND with the right connections and patrons. (Berson was a post-doc with RBW (1949-1950). )

    In his talk at the 1978 Leermakers Symposium (honoring Woodward), Berson mentioned the quinine synthesis. He praised the ring opening of the isoquinolinone to the cis-piperidine with nitrite noting that the oxime was stable enough not to equilibrate to the trans-piperidine and thus get converted to the cis pendant vinyl. Berson said, ‘I always wondered whether or not that was a planned reaction.’ At the end of the day, RBW addressed numerous topics raised during the earlier talks and specifically addressed Berson’s Q. ‘Yes, Jerry, it was a planned reaction. Just like the 25 other reactions we had tried before it that failed.’ Anybody have a DVD or audio recording of that Symposium? Is it on youtube?

    Edwin Land funded the Woodward – Doering synthesis of quinine because he wanted it to use in Polaroid polarizers and the supply had been cut off by WWII. BTW, quinine is also used to treat malaria. The synthesis was published in Life Magazine with photos of the crystals and intermediates. (What goes around, comes around. With easy digital photos and powerpoint, chemists can now put pictures of their crystals, flasks and so on into their presentations without the need of a huge photo / magazine production department.) At least one high school student read the story in Life and knew that he wanted to work for RBW in the future (and he did: Cal Tech BS ’50; Harvard PhD with RBW ’55).

    Mixed stories about the birth of organometallic chem: The Pauson paper came out in Nature and Woodward immediately came rushing into the lab waving the journal saying, “This can’t be right! This can’t be right! It must be (ferrocene).” and took Rosenblum off his project and put him on ferrocene right away. Wilkinson was at Harvard at the time and, apparently, had the same insight independently. But even before the paper was published, while Pauson was visiting Columbia and talking with Doering about his research, Doering said to him, “That doesn’t seem right. It must be this (ferrocene) structure.” My personal opinion is that a few dozen others around the world, including many who did not have the resources or freedom to do anything about their insight, saw the same thing. RBW and Wilkinson had the resources and freedom to act quickly and redirect their programs instantaneously. (Just noticed a paper by Seeman: “Wrong but seminal” Nature Chemistry 8, 193–200 (2016) doi:10.1038/nchem.2455. Paywall – can’t read it. It might mention Doering.)

    I have been told that RBW loved crystals (and named his daughter Crystal!) and always encouraged his students to “keep scratching!” I say that this is one reason why RBW was able to clobber the competition before the days of chromatography. If you read his early papers, it is something like (no journal access so the numbers might be off) 18/24 crystalline compounds to make quinine and 28/37 to make strychnine. Other chemists (e.g., Stork) might have had brilliant concepts and synthetic schemes but when it came down to lab practice, they were stuck with intractable mixtures at steps 2 and 3; forget about getting to step 10. (Stork’s PhD with McElvain had a lot of inseparable mixtures.)

    Another advantage that RBW had over the competition was his close association and friendship with industry. E.g., in the race to cortisone, RBW was given kilos of advanced intermediates by Big Pharma. Other academics in the race might not have had that luxury: doomed losers from the very start for lack of competitive resources.

    Berson (in the Creativity book, above) mentions that Osterhoff may have had the rules of orbital symmetry worked out but he was a stickler for checking everything before publishing and he had a few lingering questions to answer … so he missed out.

    Has anybody here read RBW’s two theses? SB thesis 1936 (signed off by Keyes and Hockett) and PhD 1937 (signed off by James Flack Norris). With all due respect to the lens of time (70+ more years of organic understanding), they were kind of weak.

    I also heard stories about RBW’s Idea Notebooks that were recovered from his office, after his death. Pages and pages of diamond lattices and diamond lattice defects and surface defects. There were signs that he was, indeed, already thinking about what was to become known as chemical biology.

    Other “normal” (non-demigod) people keep idea notebooks, too. I, for one, am sure that there is some very interesting stuff in those notebooks. Most of those people probably never had the chance to develop their ideas or reduce them to practice. Those ideas will never see the light of day. Most of the notebooks will be sent to recycling when the ideators pass away because you have to be pretty famous to have your life and unpublished works examined by others.

    Demigod or “just” a smart guy? I think I have to throw off my undergrad indoctrination (by many Profs who were RBW students or colleagues) and go with “really smart guy.”

    1. me says:

      Great post, thanks for all this info!

  17. Curious Wavefunction says:

    I think Woodward’s reputation is a mix of “demigod” and “really smart guy” along with generous proportions of “really hard working”. For instance, although there were some very smart chemists at the time he was in his prime, most people acknowledge that he was really the first one to seriously start incorporating spectroscopic methods and stereochemistry in his syntheses. Is this an indication of being very smart or just being very forward-looking? Probably a combination, but then genius is often associated with a great ability to anticipate what’s around the corner. On the other hand, there were other instances in which he kept you guessing. For instance Barton has said that Woodward literally drew the structure of terramycin on a piece of cardboard by looking at bits and pieces of IR data (sort of how Will Hunting quickly assigned the structure of ibogamine from the NMR spectrum). That’s more in the “wicked smaht” category. Another indication of pure smarts is his tendency to recognize important problems when they were hidden in the data (such as the clues to orbital symmetry which he saw in the B12 synthesis: I don’t know if Eschenmoser saw these too).

    But there is also no doubt that much of his prowess simply came from working harder and persevering longer than anyone else, and from his encyclopedic knowledge of details, and these qualities do seem to be unanimously acknowledged by others. It’s also partly about personality: sometimes pure conviction – in Woodward’s case, specifically that organic synthesis could be turned into an ultra-rational science – can make up for deficiencies that might cripple other able men and women. Bottom line is, as is the case with most scientific fields that are not pure math, genius in a discipline like organic synthesis is a combination of brains, encyclopedic knowledge and sheer stamina. Woodward seemed to have all three in copious amounts, and it was this combination – along with his deliberately idiosyncratic habits – rather than any one quality that cemented the “demigod” perception.

    1. Anonymous says:

      I meant to comment on this point, also: “genius is often associated with a great ability to anticipate what’s around the corner.”

      Allow me to rephrase that: “genius is often associated with a great ability to DIRECT THE AGENDA TO CONTROL what’s around the corner.”

      Everyone today knows that the NIH and NSF dictate a significant amount of the research agenda, by which I mean, they have buzzword programs, they have buzzword projects, they have political (Congress, POTUS, electorate) input. The NCI gets $5B and the NEI gets $0.7B. In which field do you think there is more research? FOLLOW THE MONEY!

      Is there still a dendrimer program at the NSF? I don’t think so. So what research project will you choose? The one that you love or the one that has a chance of getting funded? Take those old proposals and replace “dendrimer” with “graphene.”

      The NSF began in the WWII 1940s. Into the 1950s it was mostly the big, powerful scientists (Vannevar Bush (MIT), et al.) that were able to influence future research directions. Within the NIH, panels of outside scientists helped to set direction (before things became more politicized and Congress could add their 2 cents, I mean 2 trillion budget cents). And there are similar influences in other areas (DoE, DoD, DoT, … and their predecessors (Atomic Energy Commision).)
      It’s almost like insider trading, but for science research if you know in advance what the likely RFPs will be … and if you, yourself, helped to draft them!

      I have heard a bunch of stories from those days that I will oversimplify with an example: Outside scientist adviser-panelist realizes, “I know X and Y and can easily move on to do Z. I will recommend AND FIGHT for future funding for Y and Z.” Among the big guy network, the visionaries make sure that their visions get funded. THAT was part of their visionary genius.

      A “true” visionary with no funding might as well be blind and invisible.

  18. Anonymous says:

    There is a lot of legend and lore in all of this. Woodward is often given credit for the correct (beta-lactam) structure of penicillin and upstaging Sir Robert Robinson in the process. However, Sheehan, in his autobiography, points out that the Merck group (or was it the Peoria group? I don’t remember which.) had previously proposed and rationalized the beta-lactam. They used data that most of us would find unusual by today’s standards, including calorimetry. RBW was an adviser to the wartime committee doing the penicillin project and RBW was asked to look over all the data and he endorsed (did not conceive or propose) the controversial beta-lactam structure. Can anybody name any of the chemists that ORIGINALLY proposed the beta-lactam and explained their reasoning? Barely a footnote to history, if that.

    His incorporation of spectroscopic methods was absolutely due to his recognition of their value (Woodward-Feiser UV Rules) but also because he had access! Not everyone could afford the cutting edge instruments. RBW (and there are many parallels today) could get expensive instruments from the big companies and his endorsement and demonstration of their utility could surely generate interest and sales. How many of you mere mortals could not pin down an important detail because you could not get instrument time, despite numerous requests?

    (A recent example might be the Baran lab and their use of electrochemistry. They work closely with one of the electrochem equipment companies. When I was a grad student, I met some resistance to try an electrochem solution to get a really hard step to work. I eventually cobbled together the bits and pieces and tried it a couple of times on the back burner. It was a sub-optimal system, the reaction didn’t work with constrained effort, so I had to abandon it.)

    RBW worked with Waters Corp on the development of HPLC. One version of the story that I heard is that Waters went to RBW (not to Joe Schmoe or Never Heardof Hugh) and asked if RBW would find it useful for his projects. Sure! Free R&D help from industry! HPLC was very important in the B12 synthesis. For Waters, Great! Success and endorsement from RBW!

    Which reminds me of another story that reveals that RBW was not always right. I don’t have ALL of the details but it was towards the completion of the B12 synthesis. I’m not sure if East and West had already been joined. Based on the stories I was told, I think so. (The rest I am partially guessing at from the published literature.) There needed to be a selective protection (esterification) of the peripheral acids (a mixture of C3 and C2 acids). The Harvard group worked out a procedure on a tiny scale and showed the available data to RBW who, based on interpretation of a subtle UV shift (not enough for NMR back then), concluded that it had worked and he authorized moving along all of the remainder of the advanced material. Upon scaleup and better characterization, it turned out that esterification was not selective and everything was lost. It was called Black Friday. It set back the completion of B12 by many months. (Partially pieced together because there was a paper a few years later by RBW + ?? on the selective hydrolysis of the fully esterified material. Without the “story”, it was “Why bother to do this?” With the story, it is more of “Ah! Now I get it. He had to get someone to fix the mistake.”)

    Re: orbital symmetry. It was actually Eschenmoser’s experiments that exposed the stereochem in the photo vs thermal reactions to the corrins, wasn’t it?

    Detailed knowledge: RBW suggested a procedure or hint or something to a student. It turned out it was from a footnote in the paper. To be fair, some footnotes ARE really important and make a point better than a sentence buried someplace in the text.

    Which reminds me a Q that I would like some help with from Derek’s readership. (There is no other forum where I can ask real chem Qs these days.) Everyone knows Wilkinson’s Catalyst: (Ph3P)3RhCl. The crystals are usually red but sometimes orange (see footnote 6 at wikipedia – I can’t access the paper), I read a paper in a major journal that claimed that the red crystals were active but the orange crystals were not active in their hydrogenation reaction. IF Wilkinson’s is homogeneous and dissolves into solution (as it seems it did), why should red be active and orange inactive, once dissolved? The synthesis paper was PRE-1989; it was JACS-ish or JOC-ish in my mind’s eye. And the red-orange reactivity claim was in a footnote at the bottom of the first column. I have no lit access and cannot search for it by customary means. Any ideas? Or did they just screw up the orange reaction with an impurity or something? WHERE IS RBW WHEN I REALLY NEED HIM?

    1. Derek Lowe says:

      I don’t have the full text of this one, but it might bear on your Wilkinson’s catalyst question:

      1. Anonymous says:

        Thank you. (I’ve heard lots of funny stories about Hercules, too, a Big Guy in his fields. Another precocious phenom, he got his PhD at MIT in a very short time while spending summers working full time elsewhere.)

        The paper with the curious red/good orange/bad footnote was organic synthesis lit. I wonder if the Hercules paper mentions anything about the colors of the different Wilkinson’s preps and their catalytic activity. That could settle the matter.

        It used to be that (almost) anyone (who was not disruptive) could use a university library to read the current and archived hard copy literature. If you are unaffiliated, unemployed or with a small organization that can’t afford lit access, you’re screwed. Today, everything is behind a paywall.

        Imagine if RBW did not have access to the scientific literature.

        1. Isidore says:

          Regarding paywalled papers, here’s a way to get many of them for free, legally. These are papers that have been uploaded by the authors (apologies if this has appeared here before).

    2. anon the II says:

      I remember hearing an interesting twist on the Waters HPLC in Woodward’s lab. The story goes that the first instrument was painted tan and that Woodward told them to get that ugly thing out of the lab. So they went back and painted it blue. All Water’s equipment was blue from then on until a number of years later after Woodward’s death when they got out the tan paint again.

      I have no idea if it’s true but I heard it more than once.

  19. TWS says:

    While I agree I doubt we’ll see a revolution in Chemistry on the scale of QM or Relativity in Physics, I’m always a little cautious of underestimating exactly how much we don’t know about things – nature has a habit of surprising us when we think we know what’s going on. I’d also agree with other comments here that, although Woodward and other masters in the field are rightly respected, we shouldn’t downplay the role of others whose efforts have led to breakthroughs with applications in the real world – yes, the fundamental work is essential & needed first, but unless this is taken further by others and applied, it really isn’t of much use to the rest of society.

    In terms of theory, I wouldn’t take the point of view that all, or even most, of the fundamental bases of chemistry are covered, at least in a rigorous way. Take the debate over the exact nature of the chemical bond, particularly towards more unusual examples of bonding, or take hydrogen bonding interactions – while we understand them at some level (and the impact they have on structure and molecular assembly), we certainly don’t have the truly rigorous, predictive theory you might expect of such key aspects of the chemical sciences. I hope someday we will arrive at a (more) complete understanding of such fundamental chemical concepts. Perhaps this might occur gradually, but there certainly remain areas in chemistry where there might possibly be large shifts in our fundamental understanding.

  20. Chris Phoenix says:

    So – Woodward was interested in diamond surfaces and defects in his last years?

    Re my earlier comment, about mechanically-synthesized atomically precise amorphous covalent solids possibly being an interesting field for him – it’s worth noting that one proposed target for this kind of synthesis is diamondoid materials. (Though, IIRC, Drexler said that he picked diamondoid as a proof of concept, for its mechanical properties and because it was difficult, not because it was easy and should be attempted first.)

  21. JG4 says:
    There is a tide in the affairs of men.
    Which, taken at the flood, leads on to fortune;
    Omitted, all the voyage of their life
    Is bound in shallows and in miseries.
    On such a full sea are we now afloat,
    And we must take the current when it serves,
    Or lose our ventures.
    …[interesting window of time]
    1955: Back to the future
    Gladwell argues that Bill Gates wouldn’t have founded Microsoft if he wasn’t born at just the right time (and have access to the right opportunities). Gladwell cites 1955 (specifically between 1952 and 1958) as the right time to be born to make it big in high-tech. This sweet-spot ensures an ideal age to be ready for the 1975 personal computer revolution.
    He lists the birthdays of these famous tech millionaires:
    Bill Gates, Microsoft Founder : October 28, 1955
    Bill Joy : SUN Co-Founder November 8, 1954
    Scott McNealy : SUN Co-Founder November 13, 1954
    Steve Jobs : Founder Apple. February 24, 1955
    Eric Schmidt: Google & Novell CEO: April 27 1955
    Paul Allen: Microsoft Founder: January 21, 1953
    Steve Balmer Microsoft Founder: March 24, 1956
    Vinod Khosla SUN Co-Founder January 28, 1955
    Andy Bechtolsheim SUN Co-Founder September 30, 1955

  22. An Old Chemist says:

    Phil Baran is Woodward’s reincarnation. See what he has been working on. Smart people create their own fields, no matter at what time in history they are born. We all should vow our heads to them and accept that these pioneers are/were smarter than the smartest of the humans ever born over centuries.

  23. Anonymous says:

    More thoughts and notes on RBW 2.0. Above, I said that I thought his SB and PhD theses were kind of meh. I have reread them again and, boy, have I flipped on that.

    I have only read a handful of classic (old) theses from that era so I really have no strong basis for comparison among those (1930s) theses. Nevertheless, … In the discussion section of his SB thesis, he is already discussing what came to be known as the “arithmetic demon” or diminishing returns after a series of sub-quantitative reactions. He already states clearly that you need a practical source of starting materials, not just a nice idea. He is clearly aware of the concepts and problems of stereochemistry and diastereoisomerism in planning his routes to steroids.

    The experimentals are, as I already knew, full of crystals and distillable liquids or crystalline derivatives. Some experiments sat for months(!) in order to deposit crystals. He improved old methods that were not usable for practical synthesis. He came up with improved separations, something that might have led him to publish his (1st or 2nd) paper on “A Pressure Regulator for Vacuum Distillation.”

    I should also call attention to his early paper on “The Staling of Coffee” (not accessible, so from memory). He mentions the occurrence of a C30 hydrocarbon (terpene) that could not be fully characterized (at that time). However, it was noted that the amount of the C30 decreased as the amount steroid increased. Was this the beginning of RBW’s interest in steroid biosynthesis? … The story goes that Konrad Bloch was visiting Harvard to give a seminar on steroid biosynthesis and he met with RBW. At that lengthy office meeting, it is alleged that RBW mapped out for Bloch his ideas on the pathways of steroid biogenesis (ideas going back to the staling of coffee, perhaps?) and key experiments that could be done to prove it. Soon after, Bloch joined the Harvard Chem Dept and won the Nobel Prize (Med) in 1964. (It is also alleged that RBW claimed that he should have won 3 Nobel Prizes: his own synthesis prize ’65, a share of the Bloch-Lynen steroid prize ’64 and a share of the Wilkinson-Fischer organometallic prize in ’73.)

    Back to the theses: RBW also describes some “evil smelling compounds” and maybe a few Things that some Won’t Work With.

    And RBW was doing electrochemistry in his thesis research. He was doing large scale preparative reactions using equipment borrowed from the Electrical Engineering Department.

    There is a LOT more work than I remembered from the reading years ago (which I was comparing in my mind to modern theses, not 1930s theses).

    See also this paper about some of his thoughts on organic superconductors: “RB Woodward’s unfinished symphony: designing organic superconductors (1975–79).” MP Cava, MV Lakshmikantham, R Hoffmann, RM Williams. Tetrahedron, 2011, 6771. (PAYWALL)

    I guess if there is just one message, it would be “Keep scratching!” And if you read that correctly, you will realize that the advice doesn’t just refer to crystallizations but to every aspect of your research.

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