I learned the basics of organic synthesis some years ago (at the hands of the recently retired Tom Goodwin, which for those who know him will seem quite fitting). But the way I learned it is still pretty similar to the way that students are learning it now, I think. Looking at textbooks (and every so often seeing local students staring at their notes on my train commute!), all the classic reactions are there, as they should be. You learn about distributions of charge – after all, as a much older-school professor of mine (Bob Shideler) used to say, a functional group is “a peculiar localization of charge”. There are positively charged things and negatively charged ones, and the bulk of the classic organic synthesis strategies consist of bringing those two together in the right way. Additions to carbonyls. Anion-driven condensations. Carbocation formation. Umpolung reactions. Nucleophiles and electrophiles. Until you get to cycloaddition reactions and other such rearrangements, you’re mostly pushing partial and full charges around with curved arrows.
Historically, single-electron radical chemistry has come in third to those two categories, but that’s been gradually changing and is going to have to change even more. You can do things with radicals that just can’t be done, or done well, via polar mechanisms – try, for example, this recent JACS paper on directly epimerizing tertiary carbon centers. And I know that there’s a vocal subset of readers here who groan when the topic of redox photochemistry comes up, but you know, it keeps coming up more and more, and I see more and more blue light coming out of people’s hoods, and there’s a lot of single-electron chemistry in there. Students need to know about anion and cation mechanisms, of course – that stuff isn’t going away, and its mechanistic importance can’t be overstated. But they also need to know that there’s more to the world, and more to organic synthesis. What are we going to do, not tell people about whole categories of useful bond-forming reactions?
Here’s an Accounts of Chemical Research paper from Phil Baran and colleagues making this point. It’s titled “Radical Retrosynthesis”, and it points out the number of transformations that are available now in addition to the standard polar disconnections. These things can really shorten routes (and for medicinal chemists, lead as well to completely new analogs and opportunities for SAR). It’s really useful to have these things laid out systematically like this (although it’s a lot to take in), and I strongly recommend that synthetic organic chemists have a look. At this point, if you’re not routinely considering radical disconnections when you’re sketching out synthesis ideas, you are at a real risk of missing out, and it’s just going to get worse. Or better, that is.
And this is another paper from the Baran group, very much in the same line. In this case, they’re extolling the virtues – which are considerable – of combining the way that cycloadditions can lead to instant formation of complex frameworks with radical-driven functionalizations once they’re formed. More specifically, using cycloaddition reactants with known acid/ester activating groups (acrylates, maleic anhydrides, etc.) gives you not only increased reactivity in the Diels-Alders, etc., but provides a handle for decarboxylative C-C bond formation reactions afterwards. It should be noted that one problem with cycloaddition reactions in synthesis has been that setting up the elegant ring formation step has often involved some rather inelegant slogging in order to prepare the reacting partners. Baran’s recommendation is avoid all that work setting up the perfect cycloaddition step. Instead, use the more readily available and reactive partners and transform them after the cycloaddition is accomplished, now that we have reactions that can do that for you.
A few years ago, some colleagues and I were talking about what “classic” sophomore organic chemistry reactions we’ve actually gone on to use the least in our careers. The Diels-Alder was a strong contender (followed, if I recall, by the aldol reaction). Perhaps it can be revived by showing what can now be done with its products. . .