Stimulating quasi-erotic excitement through organic structure determination

Thanks to the graces of the intertubes I came across this rare and fascinating video of R B Woodward put up by some kind soul a couple of months ago. The novelty of the quintessential Bostonian accent, the cigarette and glass of scotch adorning the lectern and the man in blue are only eclipsed by his achievements and what he has to say. He especially saves the coup de grace for the end.

Woodward essentially sheds light on the remarkable developments in organic chemistry until then by providing contrasting examples from his own research. He emphasizes how times had changed between his own work and the state of the art in 1979. One can make similar comparisons right now. Woodward basically attributes the astonishing progress in organic chemistry in the last forty years to two factors- an intense infusion of theoretical concepts in their most general form (MO theory, quantum chemistry etc.), and the path-breaking developments in physical methods, including IR, UV and NMR spectroscopy and x-ray crystallography. He then provides famous examples from his own work to starkly emphasize the contrast.

The first example is from his synthesis of quinine. In this synthesis, one of the steps involved the elimination of a quaternary ammonium ion to form a double bond. The question was whether the double bond formed was a vinyl double bond or an ethylidene double bond; it was the vinyl that was desired.



Nowadays, and even in 1979, a graduate student could settle this question in literally a matter of minutes, but at that point (circa 1945), Harvard did not even have the experimental facilities necessary to chemically investigate this fact. Woodward had to send the sample to the famous chemist Max Tischler at Merck. Tischler got back saying it was an ethylidene. This threw the chemists into a state of despondency for a few days, until Tischler called back to inform them that Merck had made a mistake and it was in fact the vinyl double bond. The tense drama during this situation seems almost comical in the light of modern structure determination methods.

The second example concerned Woodward’s astonishing decade-long synthesis of Vitamin B12. He expressed wonder how an NMR spectrometer had been able to obtain the natural abundance C13 spectrum of 1 mg of the synthetic finished product using 995,000 transient scans. This incredulity would sound almost laughable today. Capillary NMR and 1 GHZ machines have pushed the science and art of structure determination to limits, and doing a million scans on 1 mg of material is almost old hat.

The third example was a nice little anecdote. Woodward had a wager with Linus Pauling in the 1950s whether he could chemically determine the structure of the antibiotic terramycin faster than Pauling could do it with x-ray crystallography. Woodward won the wager, but also admitted that he would probably lose it today because x-ray crystallography had gotten so powerful. Today x-ray crystallography is already at the top of its game, and who knows what breakthroughs in structure determination would be possible with AFM and STM.

The last example cracked everyone up. Woodward talked about the structure determination of cantharidin, the active principle of the Spanish fly. Chemists had isolated up to 500 grams of cantharidin to find out its structure. “Just think of it, 500 grams of cantharidin”, says Woodward. “There are many people who would think it’s an absolute tragedy. Realize that that would be enough to keep the entire population of Spain in a state of quasi-erotic excitement for a period of a full year!”

What would be Woodward’s reaction if he were to suddenly materialize today in a poof of chemical pixie dust and survey the synthesis landscape? My humble guess is that he would not be too impressed. He would undoubtedly be excited by the development of the Sharpless and Grubbs methods and the great success of the palladium-catalyzed reactions (not to mention the general development of organometallic chemistry, in the founding of which he himself played a role). But beyond that, I doubt if he would notice any fundamental change in the science of organic synthesis compared to what he witnessed and orchestrated during his own lifetime. Sure, things have become more efficient, streamlined and automated, but those details, as impressive as they are, are really operational details.

My personal guess is that Woodward would be much more impressed by the application of organic synthesis to biology and materials science. But as for the science itself, it probably still stands very close to where Woodward left it thirty years ago, and the whiz-kid from Quincy would have little trouble bringing himself up to speed on it in no time at all.