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Get With the Radical Program?

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. . .

 

22 comments on “Get With the Radical Program?”

  1. A Nonny Mouse says:

    I have been using the Minisci type reactions recently on pyridines and isoquinolines which work extremely well.

    A nice review is available from Matthew Duncton which can be found online.

  2. Jason Kahn says:

    The aldol reaction may not be vital to a synthetic organic chemist’s work, but any sophomore organic student who plans to take biochemistry should know it forwards and backwards.

  3. MTK says:

    The classical aldol I’m not sure I’ve ever done.

    Aldol-like, however, such as a Baylis-Hillman or a Mannich I’ve used a lot. Evans and Masamune type aldols to set some stereochemistry I’ve used some also.

  4. PhDementia says:

    But MacMillan invented radical chemistry

  5. Bagger Vance says:

    Here’s a question–how much of a difference does familiarity with these newfangled methods matter _on the job market_? I am sure academic departments will be expected to hire the Best & Brightest from the 2 supergroups mentioned, but has anyone noticed this coming up in job interviews or candidate recruitment?

  6. Hatorade says:

    The inclusion of radical based disconnections in teaching retrosynthesis should be left at the discretion of teachers, not the inventors. This way, we will arrive at a fair estimation of the merits and drawbacks of these methods. I do not think, for example that RCC is an universal disconnection, because of the finnicky behaviour of TM catalysts. Think of BH amination for example. Of course, he who shall not be named has shown somewhat extensive scope in their publications. Honest questions, do people in MedChem use these reactions, and what about photoredox catalysis? Personally, I would rather run a RCC instead of something light driven which might be hard to scale later on.

    Second point: I fail to see what is truly groundbreaking about combining DA with the decarboxylative cross-coupling reactions. Only amazing *tHougHt LeAdeRs* from California could have come up with this idea. Not worthy of Nature imho, and likely published there because of academic superstardom.

  7. Design Monkey says:

    Yep, I’m with Hatorade on this. Trivially combining one known reaction with second really anciently known reaction isn’ t any scientific breakthrough and shouldn’t be in Nature. That’s more on level of traditional indian/iranian/mozambican/what not chemistry of taking any reaction, that runs by itself quite well, and stuffing it into domestic microwave, adding clay to it, or grounding it up in a mortar.

    1. Anon says:

      The other day Derek wrote about a MOF paper which was published in JACS. Basically they showed us how you can get different structures at different temperatures. Such a novel discovery! They didn’t even do the experiment using the same crystal. Amazing how it made it into JACS.

  8. John Wayne says:

    I believe that a normal part of the evolution of chemistry is folks discovering new and improved capabilities of known reactions. I’ll take that idea further, and suggest that most of the advancement within the toolbox of reactions that work are small gains in scope. It is a rare thing for something fundamentally new to be discovered, and most of the time that discovery isn’t some ‘eureka’ moment when held in context. Steady improvement is worth something. It may be everything. I’ve heard the exact same arguments (that isn’t new) being made my whole career, but I will refrain from giving examples because it will be clear how old I am.

    Question 2: does this article belong in Nature? Probably not. I’d say it Nature is the wrong audience for this letter. On the other hand, if I had the reputation to publish there, I probably would. Publishing non-contemporary ways of doing a transformation has value, because people won’t try it unless they see it.

  9. B===D says:

    I’m sure all you crybabies squabbling over Nature always send your papers to the journal they “belong” in.

    1. Design Monkey says:

      What’s there to wonder about, crybaby B===D? It saves time to publication, if the paper dosn’t get bounced between various journals. Besides, that’s a basic courtesy and integrity in science. Pity, that you do not get that.

      1. 8======D says:

        Post your publication list and I’ll tell you where to put them

      2. Old Timer says:

        I agree with Design Monkey on this one. It really is only a subset of people in our field that use salesmanship/stature to push mediocre work into higher journals. The rest of us don’t want to waste our time on packaging/repackaging and place solid work where it belongs. JACS is probably best (not perfect) for weeding this out in organic chemistry (not in nano or materials) and Nature is the worst.

        1. Pfizerite says:

          I like to publish on my mom’s fridge

  10. cynic says:

    To be honest I agree with Hatorade that, beautifully executed as the Baran paper is, combining two established steps that are known to be general and powerful doesn’t strike me as Nature material. The quality of the work is admirable and sets a high bar for others in the field, and the disconnection is surely insightful, but I don’t see why it demands the attention of anyone outside of organic synthesis. With all due respect to the team behind the paper, who are doubtlessly talented and hardworking.

    1. achemist says:

      I feel like thats the story with a lot of organic synthesis nowadays.

      I’m quite often left wondering “how did this paper made it into Nature/JACS/Angewandte”, skip back, read the name of the corresponding author and have my answer.
      All those “superstars” do good work, no doubt about it. But it feels like the name of the last author is the difference between publishing in Nature and JACS (or JACS and JOC) more than anything else.

  11. Photoredox Jesus says:

    Give not that which is holy unto the dogs, neither cast ye your pearls before swine, lest they trample them under their feet, and turn again and rend you.

  12. Grignard says:

    #”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. . .”

    Check out a Angewandte review that answers above question. Could have been a valuable citation in Baran’s paper to show applicability.
    “Industrial Applications of the Diels–Alder Reaction”
    https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201201636

  13. Bioguy says:

    What’s your cutoff for an effective drug concentration? Do you trash hits in the double digit micromolar range?

  14. Project Osprey says:

    By sheer chance a review into the use of radicals in natural product synthesis came out on Mon

    DOI: 10.1039/C8CS00379C

  15. Hellavettica says:

    Photoredox? Really Derek? Did you write this blog on your iPhone 4S?? Didn’t know I time traveled back to 2011. It’s all about biocatalysis and machine learning now.

    1. The Chemist says:

      Derek is always a few steps behind modern times. Some call him “slow” others call him “retarded”. He just now is learning about photoredox. In 2025, he will be blogging about biocatalysis.

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