A number of readers have mentioned this new paper by George Whitesides on organic synthesis. I can state as a fact that the first time I heard a joking reference to his attitude towards traditional synthetic organic chemistry was in the summer of 1983, so it’s not like he’s been keeping his thoughts bottled up. But this is certainly a good summary of them, and here’s the key question that’s being asked:
. . .The ability to put together molecules – bit‐by‐bit, simple or complex – is one of chemistry’s great accomplishments, and a source of amazement to those in many other fields of science. More than one physicist has told me that s/he cannot believe that it is possible to manipulate bonds between individual atoms with the skill that organic chemists do. When I look at a complex structure assembled in a beautifully organized campaign, I also am amazed. That said, all fields of science morph with time. The phrase “organic synthesis” has come to mean “synthesis of structurally complex natural products”, or, perhaps, “synthesis of complicated molecules with pharmaceutical activity.” Nature, and relevance to healthcare, define the targets, and provide the utilitarian justification for the effort. Is there (or should there be) more to it than that?
Subsidiary questions are whether organic synthesis of that sort is worth the effort that’s being put into it and whether it trains students to do useful things and whether other types of work could do a better job of that. In order to address these, Whitesides notes, we have to make sure that we’re talking about the same things. He defines “organic synthesis” (small letters) as any sort of putting-together-of-organic molecules, and “Organic Synthesis” (with the capitals) as the sort of complex and often natural-product-based synthesis practiced by R. B. Woodward, his contemporaries, and his intellectual heirs. The latter is what many people mean by those two words, to be sure, and Whitesides has some questions about just what it is.
Is the field a science that generates new concepts and new theory? Is it instead more of an art form, driven at least partly by aesthetic choices (that can be appreciated by skilled observers) rather than utility per se? Or is it something of a craft, achieving its results (in the end) through skilled empirical tinkering? These questions, especially in the way that they’re phrased, are likely to cause intense annoyance in some practitioners. But I think that the annoyance is a sign that these categories are uncomfortably plausible and recognizable.
Of course, the field partakes of all of these characteristics, but on what proportions? I think that the science/craft distinction is actually one question, and that these are on the same scale with opposite signs: the more solid the theoretical framework, the less Edisonian tinkering. My opinion is toward the Edisonian end. Organic synthesis is not bereft of theories and organizing concepts, but they do not operate strongly enough (that is, in a detailed enough fashion) to allow us to predict (for example) reaction conditions. That’s why we do this. The same goes for predicting new reactions, which is why we do this. No one sat down a few decades ago and said “Y’know, my knowledge of organometallic chemistry allows me to predict that palladium, in particular, will show oxidative addition/reductive elimination behavior that will be spectacularly useful in carbon-carbon bond formation. And while I’m making bold predictions, you might try aryl boronic acids for that reaction first, even though hardly any such things have even been described”.
As for art, I would very much like to have a dollar for every total-synthesis person who has talked about the field in terms of its artistic qualities. We have Woodward to thank for this – the man was a tremendous scientist, but his influence has not always been for the good. I don’t think nearly as many people went into spasms about elegance and beauty in reference to total synthesis before him, and what’s more annoying is that those are valid concepts to apply even if Woodward sometimes came across like an Aubrey Beardsley aesthete about them. My own view is that we should let the artistic qualities of organic synthesis, which exist, speak for themselves. Because if they can’t, no amount of raffiniert gushing about them will substitute.
Whitesides isn’t through. That three-parter is just his first of three questions! The second one is a two-parter: is organic synthesis best thought of as an enabling technology to do things (such as make drugs, etc.) or as a framework that lets us ask questions about the nature of molecules and their behavior? That is, are the uses to which we put this field, and the justifications we give for it, best described as practical ones or intellectual ones? We tend to haul out the former first and start talking in better-living-through-(organic)-chemistry style, and that’s understandable. Compounds made through organic synthesis, and available through no other practical means, are crucial underpinnings of the modern world. If we’re not proud of that, what are we to be proud of?
But that second justification, while it sounds like more aesthetic hand-waving to the lay public (and to funding agencies), has some staying power. Ask the physicists, or even the mathematicians. Asking fundamental questions, and having the right framework in which to be able to ask them, can pay off hugely even from the practical end, intellectual satisfaction aside. There’s a lot of number theory that was just another ornament of mathematics until it became vital for modern cryptography and secure communications (G. H. Hardy would have been horrified). Relativity was a fantastic intellectual feat by Einstein, but relativistic corrections are needed to make the GPS system work correctly, among many other things.
The third question is, what should we teach chemistry students about the field? That is, what are the most important things for them to know? There’s a massive pile of empirical knowledge, famously dreaded by sophomores, but it’s taught (or should be!) according to general organizing principles – although those are the very ones that are not quite adequate enough to explain everything that’s going on. At what level should we teach this subject? You can say “Here are reactions that depend on alpha-carbonyl anions, and here’s why they happen”, you can say “Time to learn the difference between the Dieckmann and Claisen condensations”, or “Here are the kinds of products these reactions form and what they’re used for”, or “Here are some tips on how to run these things at the bench”, and on and on. What should be in the syllabus?
My own take on this is that there should definitely be a bias towards the general principles, which is what the better organic chemistry professors already do. Teaching the subject as a pile of reactions is a crime. I may be too loose about this stuff, but I would rather a student, if it came down to it, mess up a bit on the detailed mechanism of the Mitsunobu reaction if they understand that its driving force is the thermodynamic sink of triphenylphosphine oxide formation. The difference between the Dieckmann and the Claisen condensations is that the former is intramolecular and the latter is intermolecular, but I think it’s a waste of brain space to give them different names and memorize them as such. I would much rather that a student, in this case, immediately recognize the mechanism of an alpha-carbonyl anion attacking an ester carbonyl (no matter what the name associated with that process is) and recognize the influence of the leaving group of the ester, the stability vs. reactivity characteristics of the nucleophile, the likelihood of the various ring sizes being formed in the intramolecular reaction, etc.
I have nowhere near exhausted the Annoying Questions of George Whitesides, but this post is long enough as it is! Look for Part II tomorrow or the next day. . .