Skip to Content

Sensitized Redox Photochemistry – And Some Opinions

Redox photochemistry marches on – that’s what I take away from this new paper from a group at Regensburg, which uses sensitized photoredox as a new variation. In this case, the light is harvested by a ruthenium complex (as in many other photoredox system), but the energy is then transferred to a polycyclic hydrocarbon, which does the actual redox reaction with the substrate. This allows access to much higher redox potentials than having everything done by one species, and potentially more reactions can be discovered out in this range.

The tricky part is that the transfer of that energy needs to be fast relative to other possible pathways in the system, but using anthracene or pyrene (for example) seems to do the trick, fortunately. The luminescence of the Ru catalyst is quenched more quickly than it can do electron-transfer with a tertiary amine, which is the order that you want, and the authors demonstrate a range of aryl halides reacting with N-methylpyrrole as a trapping agent to form new C-C bonds in good yields. Even aryl chlorides and aryl triflates are shown to react under these conditions. On the other side of the reaction, photo-Arbuzov reactions are also shown, with a trialkylphosphite as the trap (and those of you who have smelled them will welcome the news of another way to get rid of the awful things).

I would guess that this system will be applicable to a whole range of reactions, and I look forward to seeing what gets developed in this area. But with that in mind, I wanted to bring up another topic which has been on my mind. It seems that every time photoredox chemistry gets mentioned here, there are a number of comments on the work that can only be described as “hostile”. These vary, from accusations that the reactions were known before, or are only minor variations on what’s been published, to talk of how such things have no practical applications in the real world and are only fit for high-profile CV padding, etc. I don’t think I’ve written on any of the newer photochemistry work without these things showing up, and I’ve always been surprised at the vehemence out there.

I would have thought (mainly because this is my own view!) that any new fast way to make bonds would be of interest to synthetic and/or medicinal chemists. So what’s the problem? I haven’t encountered anything like these attitudes at the bench, I have to say. My own colleagues have, over the last few years, enthusiastically adopted photoredox chemisty, recognizing its potential for chemical diversity and ease of synthesis. Talking with friends in other organizations, I hear the same sort of thing. This makes me wonder if these comments are not reflecting the opinions of the broader community of organic chemistry, but just represent a vocal minority. I have no way to judge this other than what I’ve seen and heard myself, of course, but that’s what I have to conclude, for now.

So those readers who are not redox photochemistry fans, if you would take the time to say just what it is that sets you off about the field, I’d be glad to see it. And those of you who just quietly try out these reactions and use them to make new molecules, I wouldn’t mind seeing you put in a quick vote on your side as well.

82 comments on “Sensitized Redox Photochemistry – And Some Opinions”

  1. Old Timer says:

    I will attempt to take a stab at this… Let me begin by stating that I think that these reactions can be very useful. It is my understanding that there is a lot of frustration with regard to how these reactions are “sold/advertised” in the literature. For many folks, when you look past the hype, these are (mostly) nice radical initiators that minimize side reactions due to transient lifetimes of e- transfer agents. Yet, many of these transformations continue to appear in high-profile journals with relatively modest advances, while other radical initiators (e.g., transition metals, tBuOK, etc) do not get nearly as much press. Consequently, there exists a contingent of frustrated chemists who see past the hype, appreciate the field of photosensitizers, but are sick of the seemingly endless string of JACS/Science/Nature papers that (maybe?) should be more JOC and Org. Lett. papers (still valuable transformations, just not conceptually ground-breaking). This is my perception, for what it’s worth.

    1. Leadbelly says:

      From what I’ve heard, MacMillan is a hard dude to work for, so I apologize if a commentator is a disgruntled former student of his. But to trivialize the massive amount of work that his students do to develop these broadly useful reactions is insulting. He is a big name, and thus a big target, but his group has made huge impacts on how practicing medicinal chemists tear apart molecules.
      I absolutely disagree that the utility of photoredox is being over-hyped… how many papers have you read on clever transformations that have no substrate scope or clear utility to med Chemists? Speaking as a med chemist, we lust for reactions that don’t need a glove box. We yearn after reactions where you can buy the ligands from Aldrich. We do reactions that we think will work.

      1. Aqua regia says:

        A major reason his group has made “huge impacts” on the reactions of medicinal chemistry is because he has packed the pharma ranks with his disciples that know little beyond the group chemistry they were indoctrinated with.

        The reason his students have to do a “massive amount of work” is because they are, by and large, mindlessly screening reaction conditions to fill in the next table instead of trying to think critically about small details like mechanism.

        It’s laughable to bring up the idea of substrate scope when it comes to MacMillan; the group is notorious for screening innumerable compounds until they find enough substrates that beat the yield/ee cutoff, irrespective of how informative the substrates might be of actual reaction performance. I certainly never would have guessed that methyl to ethyl 10 Angstroms away from the site of reactivity would be tolerated…

        1. Keep It Classsssssy says:

          This just reeks of scorn. Did you ask a MacMillan group member to prom and get turned down?

          1. CR says:

            Funny, but this is the same thing I hear every time Buchwald’s name comes up. Running thousands of reactions and only picking the ones that work best for that great publication – regardless of interest/utility. There is probably some truth to the scorn and probably some fake truths.

          2. Aqua regia says:

            Lead, you’re right, Classy’s ad hominem was not an excuse to double down.

        2. Davecat says:

          That’s totally unfair. You’re not counting all the time spent screening the computational basis sets until you get enough kcals to confirm that trendy mechanism the lab down the hall is working on.

          1. I'll take it says:

            Hey, at least someone is trying to look at mechanism!

        3. Leadbelly says:

          Aqua… please enlighten us as to what you actually consider to be valuable to MedChemists? Amide couplings?
          Based on what you have written, one could assume that everything is derivative of Knoevenagel and Diels and Alder. I would argue that mechanistically there is a bigger difference between imminium and enamine catalysis than there is between a Stille and Kumada.
          Based on your comments, it is extremely insulting to say that pharma people from MacMillan group know little beyond their training. Try and keep it classy. I have interacted with many of them… for some reason they think it is worthwhile to know useful information. Odd.
          But more to the point Aqua… If there is a blade of grass is in an otherwise empty lot, would you call it a field? For all the vitriol against MacMillan, can anyone say that his group hasn’t fundamentally changed how we make molecules in Pharma?

          1. Aqua regia says:

            Honestly, I see a lot more amide bonds in biology than I do aldehydes, so amide couplings are probably a good start on the list.

            The question you asked was who had worked on organocatalysis before MacMillan. Even disregarding the Knoevenagel work, you can conclude that there were several people that worked on organocatalysis before and/or contemporaneously.

            It simply does not follow from that comment to assume everything is a derivative of Knoevenagel and Diels–Alder and enamine/iminium vs. Kumada/Stille is a false equivalence. To use the “standard” parlance, enamine and iminium catalysis are different activation modes, Kumada and Stille are effectively the same overarching activation mode.

            I think you know that the “blade of grass” metaphor is a quote proffered by DWCM in one of the more glaring displays of self-aggrandizing at a seminar in the last decade, it should have proper attribution. It was has been discussed and ridiculed ad nauseum in any setting it has come up. In any case, it is a strawman argument because there certainly existed more than one blade of organocatalysis grass before the MacMillan group.

            Perhaps they have changed how medicinal chemistry is done, but that is in no way proof that it is inherently a good thing…

          2. Ir(DTF)bpy says:

            All the professors in the field know it’s a house of cards waiting to fall. Why do you think they blackballed Yoon so hard on that chain paper? When he showed these fancy special sauce catalysts to just be chain initiators the bottom almost fell out of the bubble.

        4. Jack yeaston says:

          Guys it’s not photoredox anymore it’s called mellatio redox.

        5. Passerby says:

          “A major reason his group has made “huge impacts” on the reactions of medicinal chemistry is because he has packed the pharma ranks with his disciples that know little beyond the group chemistry they were indoctrinated with.”

          That may be true, but how is it any different from Buchwald’s or Jacobsen’s or Grubbs’s or Baran’s students? Statistically speaking very few people end up in faculty positions, so most are going to end up in industry and push chemistry that they were “indoctrinated” with. I fail to see how McMillan’s students would be an exception here.

          On a side note, there is little doubt that his students get stellar offers. One recent McMillan grad I am familiar with just started at a big east coast pharma company with a salary that would usually be appropriate for someone working for 6-8 years after grad school.

      2. Mlct says:

        To quote someone… “no one cares how hard you worked”

    2. boronsaur says:

      I see your point old timer, however, your argument comes down to a simplistic point: where the science ends up published. I my opinion there is an unhealthy obsession by many PI’s-> postdocs -> grad students, to get their work in science/JACS and not in the the stinky Org. Lett/JOC. Unfortunately this is encouraged by for example, employers both in academia and industry. This is a serious problem we should try to fight.

  2. Rubpy3Cl2 says:

    Photo redox is great, and I have successfully applied it!

    However, what’s not so great is that Prof. MacMillan can get incremental results published in Nature, while other researchers, who not seem to have such a nice review cartel (e.g. Xiao, Koenig, Stephenson), do not get the recognition they deserve.

    1. AA says:

      Sadly that’s the case with any big name prof, regardless of which field they publish in. Buchwald gets his incremental Copper Hydride follow-ups bumped up a journal level or two because it’s Buchwald.

      1. Beyond Whig history says:

        Yes, but does Buchwald have the history that dmac does with “inventing” fields? I seem to remember several groups doing good organocatalysis work before he got in front of that parade, and the nickel photoredox was developed in one of his colleague’s labs (and molander’s) before he decided he wanted a piece of the action (and basically annexed the research program). The work is honestly no less turn the crank than cross coupling, like you say. However, the history of its”development” had certainly driven much of the resentment

        1. Leadbelly says:

          Who was doing imminium catalysis before MacMillan? Hajos-Parrish-Weichert is mechanistically very different.

          1. Aqua regia says:

            Insofar as iminium catalysis is different from enamine catalysis, but the overarching argument is still intellectually dishonest.

            Chem. Rev. on Organocatalysis: http://pubs.acs.org/doi/abs/10.1021/cr078412e

            Iminium Catalysis: http://pubs.acs.org/doi/abs/10.1021/cr068388p

            “Perhaps the earliest recorded example of an iminium-catalyzed process is the Knoevenagel condensation[17,23] mediated by primary or secondary amines.”

            What’s the date on that Knoevenagel report? Knoevenagel, E. Chem. Ber. 1894, 27, 2345. In short, plenty of people were doing organocatalysis before King David appeared as our organocatalytic lord and savior.

            The only thing MacMillan has done better than everyone better than others in the area of organocatalysis is control the narrative. The same thing is happening again with photoredox, which is why Old Timer is spot on.

          2. Aqua regia says:

            Insofar as iminium catalysis is different from enamine catalysis, but the overarching argument is still intellectually dishonest.

            Chem. Rev. on Organocatalysis: 10.1021/cr078412e

            Iminium Catalysis: 10.1021/cr068388p

            “Perhaps the earliest recorded example of an iminium-catalyzed process is the Knoevenagel condensation[17,23] mediated by primary or secondary amines.”

            What’s the date on that Knoevenagel report? Knoevenagel, E. Chem. Ber. 1894, 27, 2345. In short, plenty of people were doing organocatalysis before King David appeared as our organocatalytic lord and savior.

            The only thing MacMillan has done better than everyone better than others in the area of organocatalysis is control the narrative. The same thing is happening again with photoredox, which is why Old Timer is spot on.

  3. anon says:

    Can someone (maybe even Derek?) write up a brief history of photoredox so we know how, when and with whom it started?

    1. Bill says:

      There is an almost 1:1 ratio of reviews to papers in this field, so take try searching the literature.

  4. Li Zhi says:

    While it’s understandable to despise the fact that, by and large, we are pack animals who show (or should I say “display”?) inordinate respect for alphas (and there *can* be more than one!), to rail at human nature is tantamount to howling at the Moon. It’s the world we live in, spend your energy on productive avenues – you’ll be better served (and that ain’t one). (IMHO)

  5. InfMP says:

    It is interesting that people hate photoredox online…but you don’t find them saying it in person.
    It’s kind of like people that voted for Trump…they did it in private, but you won’t find them saying anything out loud.

    1. Pepe says:

      Photocuck!

    2. LED Prince says:

      There are plenty that do say it out loud, just in the right company.

      Fauxtoredox is just the latest of the hot topic fads but that doesn’t make calling it like it is any less likely to greatly complicate your own career prospects. Fear of retribution by our “leaders in the field” is a fantastic motivator to stay quiet.

      “Upon this, one has to remark that men ought either to be well treated or crushed, because they can avenge themselves of lighter injuries, of more serious ones they cannot; therefore the injury that is to be done to a man ought to be of such a kind that one does not stand in fear of revenge.”

  6. notbob says:

    My biggest issue is scalability. The majority of photoredox reactions in the literature (including the paper you reference) are run at <100 mg scale and are not scalable, even to gram scale, without complex custom engineered setups. That means the practical utility is virtually zero – even in a medchem setting.

    1. MK says:

      I suppose it might be scalable in a flow reactor…

      1. Lora says:

        Not sure how you would do it in a flow cell, but I’ve done fluidized beds in shallow tanks with overhead LEDs and glass tops for a biosynthesis reaction in algae. It was indeed a giant pain in the behind and needed a lot of custom machining; we actually ended up buying a CNC and hiring a machinist, it was cheaper than constantly sending out drawings for fabrication.

        The biggest engineering problem was not, as it turned out, getting enough photons on the things – it was cooling the lights. Even LEDs throw a stupid amount of heat when you’re blasting them.

    2. photoflow says:

      Scalability of these reactions is rapidly changing, and given the novelty of any new field, challenges remain. But the solutions are on paper simple, the engineering just needs to advance to accommodate the chemistry. Photon flux and surface area are the two most important parameters to scalability, and can be adjusted based on light sources and engineering controls. It will all come online in due time IMO.

      1. Brian M says:

        In my experience (as someone whose thesis was on synthetic photochemistry) there is a chicken/egg problem. Industry is always going to be reluctant to accept a synthesis with a photochemical step if it means having to design, engineer and build a brand new type of reactor from scratch.
        Similarly, synthetic photochemistry is never going to get mainstream recognition (and the funding that comes with it) until it has been shown to have practical industrial applications.
        The current challenge is that most photochemical reactions don’t do anything that can’t be done thermally. Sure, the same result may be achieved safer and more efficiently, and maybe even cheaper in some cases but industry is usually going to go with the tried and tested thermal route. The big breakthrough for synthetic photochemistry is when you can use it to make a commercially viable drug that can’t be made thermally.

    3. Leadbelly says:

      Yeah… light. I’ve been annoyed by that too and expect someone will solve it at some future date. My solution is to get 2g of photoredox product is to set up 1 reaction and put it into 5 vials. Not elegant, but it works.

      1. Leadbetter says:

        That’s the definition of scalable right there…

        How much custom-synthesized heteroleptic Ir/Ru complex is does that work out to?

        1. Leadbelly says:

          Leadbetter… As a medchemist, if I need to make more than 2g I hand it to someone else. You are highlighting an engineering / process problem, which is different from my goal to rapidly make compounds I care about. Similar to how the conditions from original RCM papers are NOT the conditions for large scale, I am confident someone will make a flow reactor for large scale synthesis. Not my problem.

          1. BTDT says:

            your job is to make what is required to push the project forward
            I slammed chemist who couldn’t do scale

  7. Chemperor says:

    As an inorganic chemist, I’m glad that photoredox is getting its–ahem–day in the sun. It gives me one more potential application to list in papers and grant proposals:
    “These new (insert exceedingly rare and expensive transition metal) complexes could also have applications in photoredox processes (insert 20 MacMillan references).”

  8. odonovdh says:

    There are plenty of blue lights shining in the fumehoods here at my own Big Pharma company. As with Derek, we have adopted this new technology with enthusiasm, if not always success. Methodology development seems to come in waves (Organocatalysis, Gold, CH activation, Photoredox…) and oftentimes those not working on The Next Big Thing miss out on funding in favour of the current vogue. Maybe that’s one of the reasons for all the vitriol?

  9. Anon2178 says:

    Derek: pick any field you’ve covered, look at the comments, and you’ll see vehement hostility. Go look at any discussion about fragments (aggregators! junk! where are the drugs?!), cancer cell lines (irreproducible! contaminated!), company performance (idiot managers! short sellers!), computational techniques (overfitting! not even wrong!) on here. I think you only noticed for photochemistry because you’re a fan of it, rather than a skeptic.

    1. Some idiot says:

      I disagree completely… As a long-term reader of this blog, I’m with Derek on this one… I was really surprised to see the intensity of comments the first time it was really mentioned, and this has not receded. Yes, people commenting in this blog have a tendency to say what they mean (happily so!!! (-: ), but I can honestly say that I cannot recall a single other topic (apart from politics; I am staying _way_ out of that one… :-/ ) which has consistently lead to so much acidity in the comments.

      I feel that at first it was due to a real or perceived grievance that the McMillan group appeared to have it a lot easier publishing stuff than the rest of us mere mortals (e.g. the first comment in this thread). I have no axe in this fight, so I am not claiming whether or not it is “real” or only “perceived”. I have not tried the chemistry myself either. But since then topic seems to have become a good whipping post generally, possibly because there was so much momentum in trashing the significance of the work.

      But yes, the phenomenon is definitely real… To rehash the old NY taxi horn/red light joke, it feels like “Q: What is the definition of a millisecond? A: The time between the mention of photoredox and the first negative comment…”

      1. Yet another idiot says:

        I picked one area from the list (in silico, since it has its own category over there on the right of the screen). Here are quotes from comments to posts in that category. Judge for yourself whether the comments are vehement:

        “Fully automated shit generation. And that’s putting it nicely.”

        “Big Data- it is Scheisse!”

        “Well, hopefully they will try their ‘cure’ on themselves first. That way we’ll solve two problems in one sitting. They need to stop inhaling whatever they are smoking.”

        “staggering unrepentant dirt-merchants playing buzzword bingo for the big payoff.
        Sorry, but what you are proposing has absolutely no basis in any reality- ‘it’s not even wrong.’ It’s just smoke, mirrors and manure.”

        “[…] the new head of MD Anderson spouting off about how they were going to find cures for cancer using computational methods. I was disappointed but was forced to write him off as a moron. ”

        “Watson is crap, it can only tell you what you first specifically feed it, like some retarded parrot. Garbage in, garbage out, and then some.”

        “waste of time.”

        “It would be sad if it wasn’t laughable.”

        “I think it’s charitable of you to characterize this as hubris. It’s downright stupid.
        It reflects such a magnitude of ignorance and arrogance that it’s hard to believe this person isn’t deliberately misleading investors.”

        “Roll it up, light it up, smoke it up Inhale, exhale”

        “I’ll paraphrase: Computational chemistry, the cure of the future, and always will be.”

        “I guess I should stipulate that you’re also young, extremely well-paid, and ferociously good-looking, and that Stripebutt, your rainbow-colored pet unicorn, is looking over your shoulder and whinnying appreciatively while you get all this done. Because sometimes it looks like Stripey’s going to make an appearance before that software ever does, pesky unicorn droppings and all – we’ve been trying to realize something like this for decades, and anyone who tells you that we’re there is trying to sell you something.”

        1. Some idiot says:

          Good to see I have company…! (-;

          I probably didn’t make my point clearly enough… Yes, these comments are vehement, but I never suggested otherwise. I agree that this blog is (happily!!!) full of, ahem, robust comments (and yes, in-silico is one of the areas, and there are many others; I agree with some of the hosings, and disagree with some other of the hosings, but that is also irrelevant). However, I still consider this to criticism of the work, and discussion of the validity of the work reported. Which is fine, natural, and (on the whole) constructive.

          In the case of the photoredox, there is relatively little debate as to whether or not it works (although generally discussions on scaleability), but more (as Derek pointed out in his article) comments along the lines that it is obvious, trivial, or at the very least that (e.g.) incremental improvements have no right to be published in major journals, and certainly not as a “publication machine” (I am an not arguing one way or the other here, just stating what I perceive). Which more comes down to, again, the perception (real or otherwise) that there is one set of rules for some (e.g. McMillan) and another set of rules for the rest of us. I don’t see this in other areas (e.g. in-silico).

          1. Yet another idiot says:

            Your name is accurate, shit-for-brains, if you think the objections relevant for one area will be the same as for another! Obviously the rants on in silico posts won’t be about MacMillan’s publishing, since he doesn’t publish in the field; only a moron without the most basic understanding of science would think otherwise. Good thing for you that bench chemistry doesn’t require basic literacy, or you would have realized that Derek is talking about the hostility in the tone of the comments and that the exact objections raised are irrelevant. The original poster was pointing out that this happens for *all* topics of discussion, but people only notice when they (or their favored subjects) are the ones under attack. Otherwise, if you agree with the comment’s sentiment, it just seems like the commentator is correct – if overly emphatic in making the point.

            (If it wasn’t clear, this reply was deliberately written to be provocative and hostile, as an example of the trope under discussion, but it is NOT any more “robust” than the earlier quoted examples. Perhaps it’s now more clear why this kind of interaction doesn’t feel “constructive”. I suggest that it’s possible to express skepticism and criticism without name-calling, condescension, and derision. Indeed, most of the content on this blog, both by Derek and the commentators, does! But, the hostility that Derek discussed is in no way unique to photoredox.)

        2. Some idiot says:

          Thanks for your second comment… It clarifies the case for me nicely. In other words, you have misunderstood the point, and have no interest in trying to see things differently. Don’t worry; I can be abusive too, but choose not to be.

          🙂

          And if you consider that condescending, well, I guess that is a problem where you can work it out with yourself privately.

          🙂

          1. Californian Gangsta says:

            Don’t be slinging dope like some project nigger!

    2. tangent says:

      Hi, I’m a neutral bystander — not a chemist, have no horse in any of these races. I’ve definitely noticed the hostile crowd that shows up for photochemistry.

      Not that it’s absent for other subjects. But the statistics do seem different — photochemistry gets a higher rate of comments that are purely grumpiness (little to no content), and of commenters who appear to be single-issue on this, like they have LED snark in their usernames. To be fair, there also is a recurring criticism in the mix, of salami-slicing the Least Publishable Unit.

      But the only other subjects that show similar levels of grumpiness are the ones that tie in to people’s fears of being replaced by foreigners. (directly — H1-B policy — or indirectly — opinions on Chinese ethics)

  10. 💩 says:

    Triggered much? I guess blue leds CAN melt snowflakes.

  11. Former Organicker says:

    From my own perspective, I think a lot of the work is pretty good and interesting. I do have a bit of a caveat, which is that I’d like to see a lot more “we tried a UV light without the metal” type experiments. It’s the same issue I have with a lot of catalysis papers, really, a lack of bench-marking.

    This paper, other than that, seems pretty interesting and the substrate scope is pretty good. Look at all those unprotected basic nitrogens!

    1. Humulonimbus says:

      “Normal” OH and NH bonds are difficult to cleave homolytically – a very nice feature to all types of photo/radical chemistry.

  12. Spurn Volmer says:

    I think it’s great because it allows you to take any Chinese radical mediated paper from the past 15 years and republish it in a better journal by simply adding iridium and thiophenol 💁‍♂️👨‍🔬

  13. Humulonimbus says:

    I also don’t understand the hate for photoredox and (apparently) anyone who is trying to develop it to the point that it’s industrially relevant. It clearly has potential, but also clearly did not appear in the academic literature fully-formed and ready for practical application to every conceivable substrate and scale. Neither did Pd couplings.

    I guess that puts my vote on the “for” side.

    1. processchemist says:

      Pd Couplings found their way to the plant many times, in the last two decades, simply not in the way they are described on most papers

      1. Humulonimbus says:

        So have RCM reactions, also not the way they were described in the original papers.

        That’s like, the whole point of process chemistry.

        1. Huburisnimbus says:

          Exactly…so why are academic chemists trying to “solve” what amounts to a process engineering job?

          1. Humulonimbus says:

            Are you saying you should get to decide what projects academic researchers pursue? Hubris indeed.

          2. Humulonumbus says:

            Also, see Brian M’s thoughtful comment above about the chicken/egg problem.

            http://blogs.sciencemag.org/pipeline/archives/2017/06/05/sensitized-redox-photochemistry-and-some-opinions#comment-282278

            You can’t expect to throw a new method over the fence and have industrial chemists adopt it immediately. Someone has to keep pushing the rock up the hill until it finally rolls down the other side.

  14. ACH says:

    Put me down for another pro-photoredox vote! It’s working great on my current chemical series.

    Question for the crowd: has anyone used ex-US chemistry CROs to perform the new MacMillan-type photoredox chemistry? How reproducible is it? Does the CRO have the commercially-available photoredox setup which Derek linked to in a previous post, or a home rig get-up?

  15. KOH says:

    As an academic chemist, I have avoided using photoredox in my lab with the hesitation that I would be seen as jumping on the bandwagon. I now have a post-doc in my group from Koenig’s lab and he rightfully pointed out that shining some blue LED light on one of our reactions would be a great way to probe the mechanism. I have been pleasantly surprised how quickly we have gotten results and how many more (academically) interesting questions we have generated. I still have not fully shifted my group to photoredox chemistry, but I sure am glad that the tool is out there.

  16. DRP says:

    I think the chemistry is nice, but the repeated science papers grating. What I don’t understand is why people don’t think the same about palladium couplings? Yes, transformed chemistry, yes, well worthy of the Nobel Prize, but I don’t understand how so many of them still get in JACS

  17. CoxTH says:

    As someone without an extensive academic background (currently in the process of getting my BSc), I do not understand the hostility towards specific fields of chemistry or medchem.
    I do understand that people are frustrated about some people getting preferential treatment when it comes to publishing, however I am not in any place to judge if that’s actually true or not.
    Anyways, the point I want to make is that I believe that many fields are unrightfully sold as the “cure-all” of all problems in medchem. In silico simulations of protein folding and substrate binding have the potential to be useful tools to find potential new targets and drug candidates. They can also be useful for weeding out potential failures, but in the end the only way to actually verify the results of such computation is old-fashioned experimental evidence.
    The same goes for photochemistry. There might be some misconduct when it comes to Publishing in this field (see above), but nonetheless it might provide chemists with new and interesting ways to form bonds and if this new chemistry helps to get rid of some of the nastier chemicals, that’s all the better.

  18. Leadbelly says:

    Long time reader first time commentator. I agree, whenever the subject of photo redox comes up feathers get ruffled. Haters gonna hate.
    I’d like to give a different perspective though. Reading through the comments it seems split between people who have tried the chemistry and find value, and those who are frustrated by what journal the papers end up in.
    As a practicing medicinal chemist, I would like to address the people who are frustrated by what they see as incremental improvements. If a singular transformation, with minimal substrate scope, unknown functional group compatibility and a low yield was published in Chem. Ber. 1955… how likely is it that a med chemist is going to use it to make SAR? Unlikely. You may consider the improved yield, substrate scope etc. to be incremental from a scientific standpoint… but it makes a huge difference to people like me who are actually practicing in the field.
    On two separate projects we retooled our synthetic routes directly after MacMillan publications. Project A) the SAR position was step 1 of a 5 step synthesis… this was converted to a step 2 of a 2 step process. Did it work for every substrate? No, but ~40/50 isn’t bad. Project B) after scoping out all the easy SAR, we decided that we would have to change one particular part of the molecule at step 1 of 7. A talented associate pointed out that we might be able to use photo redox at the last step of a 3 step synthesis. It worked 13/15 times. I haven’t seen any new technology that is the ridiculously easy to implement.
    Love photoredox… could give a crap which journal it appears in.

    1. Design Monkey says:

      > I haven’t seen any new technology that is the ridiculously easy to implement.

      Um, Baran’s decarboxylative RAE couplings? About the same schtuff from synthetical point, but without LEDs and iridiums.

  19. Pharma 2Cents says:

    As long as we’re cataloguing criticism – one other aspect that might be nice to know are the demographics of the naysayers. Specfically – academic vs. industrial. Grad student/postdoc vs. junior PI. I am in my 6th year as a medicinal chemist at a typical Big Pharma company and will provide details of my experience. My impression is that objections to photoredox chemistry have come from people who have a problem with MacMillan for one reason or another and project that onto the utility of the chemistry. I’ve heard from several people (at conferences or symposia) in graduate school or early in their tenure as PIs – who have admittedly never turned on a blue LED – that photoredox reactions do not work beyond the published scope. That criticism is broadly applied – MacMillan along with Stephenson, Yoon, Molander, etc. In my organization, we have about 80 chemists. At any given time, about 6 hoods here are bright blue. We have aspects of our SAR that utilize photoredox amination (published with Buchwald) and alkyl aryl couplings run as the last step in a complex molecule synthesis. These reactions are providing greater than 50% success rates now – as defined by the reaction providing enough material for assays. I run Buchwald-Hartwig aminations and Suzuki reactions side by side and find that sometimes one works better than the other. My point is this – it’s being used quite extensively in pharma. If you’re in pharma and not using it because you don’t like the professor that published it – tell your manager that you’re arbitrarily limiting your ability to make compounds and test hypotheses for a petty reason.

    1. I'll Second That says:

      This is an excellent a point! I believe the number of negative comments here are not representative of the opinion of the Pharma community. Rather academics or grad students with an axe to grind. Why do I believe this? Well the adoption of a lot of these methods is quite robust at the Big Pharma that I work at. Specifically, the Aryl-Br Alkyl-Br coupling method is a complete game changer.

      Moreover, I have background in organometallic chemistry, working with some of the top groups in the country. I always wondered what it must have been like to be working at the basic scientific level when palladium catalyzed cross coupling where being developed and how exciting it must have been. This is what we are witnessing, a completely paradigm shifting technology. These methods will become more robust over time, like anything else. Either you get on the ship now or you will be left at the dock.

    2. TLLOM says:

      I completely agree. I have been working in pharma for about 5 years and the number of chemists applying photoredox reactions to medchem problems has increased exponentially – not only at my own company but also across the industry in general. If a disconnection exists that will make your route shorter…use it…regardless of who wrote the paper.

      When it comes to scalability, there are a number of publications already in the literature reporting medium to large scale photoredox reaction (recent kilogram-scale trifluoromethylation from Stephenson/Lilly collaboration: http://www.sciencedirect.com/science/article/pii/S2451929416301048). With more and more companies investing in the medchem/process interface, issues of scalability and scope can be rapidly address within the context of a given project.

  20. anon says:

    @ CoxTH…looks like a rookie! You have some ways to go before you get frustrated and rant like the rest. When things does not happen for you (at the right time and the right place) despite giving the best the only thing that is left is to rant, be impassioned and sound off. That way we got rid of the steam that is building inside. Like I said, you have ways to go before you realize what I just said on behalf of others. Kapish?

    1. Xiao Bu says:

      What are you talking about? CoxTH said they are an undergrad in their first sentence, so obviously they are a rookie. Their post was seemingly an outpouring of their interest in chemistry/in silico docking, more than a substantive contribution to the topic, but I don’t quite understand why you are taking aim at them. Let them get involved.

  21. Mike says:

    The comments above pretty much help pinpoint the answer Derek’s question directed at the people who are “set off” by photoredox: Dave MacMillan. There are no less than 15 (at last count) mentions of his name above, many of them associated with some form of ad hominem vitriol. Some do take the time to address the scope and utility of this field of synthesis (many very thoughtfully), but many do not. Rather they sink down to the level of venting some pent-up personal attacks that only the commenter knows the cause of, revealing more about themselves than the subject of their derision. I’ve met many graduates of his program and the slander here is completely uncalled for. They are overall very thoughtful, smart and creative folks who are broadly trained in the field of organic chemistry and synthesis. And to attack MacMillan personally does nothing to change that or to diminish the contributions he and his group have made to that field and many others. You wish to label him as a salesman? Don’t attend his lectures. Want to denigrate his chemistry? Don’t use it (and add many more steps to your work in the process). Packed the Pharma ranks with his disciples? Yeah, who wants well-trained chemists working alongside them anyway. Think his papers are just incremental improvements in the work of others? Then why didn’t you think of it yourself, get a few papers and a promotion in the process? The reality is that the excellent work coming out of his lab and the great chemists he is training will live on long past your retirement, so keep tilting at windmills until your keyboard wears out. No one will remember you for your carpal tunnel.

    1. Leadbelly says:

      Beautiful rebuttal “Mike”…

  22. milkshaken says:

    Since there were quite a few ad hominem comments here about MacMillan overselling his results, I would add personal note too. I got the chance to know Dave when he was finishing his postdoc, we worked on related projects, and he showed me his research proposals as was preparing for tenure track professor job interviews. (I was very junior at the time). I remember some sigmatropic rearrangements of iminiums in his proposal but organocatalysis definitely wasn’t there. I remember him as very motivated, productive, not a douchebag (unlike some other people there), with wry sense of humor.

    Hajosh-Parrish has been in every freshman organic chemistry textbook, but it took MacMillan to bring the attention to it, expand the scope, and it grew it into a new trend. I remember a senior Corey student playing with C2 symmetrical bicyclic guanidines related to Levamisole, for asymmetric Strecker, and Jacobsen group doing the same with tert-leucine-diaminocyclohexane derived thioureas right before MacMillan, so the renaissance of organocatalysis was in the air, but he grasped the idea and showed how general and powerful it can be.
    Now the photoredox. One has to appreciate that he has had a keen sense and a pretty good style. (I am saying this even as I am not completely sold on the general merits of photoredox yet, simply because the stuff is hard to scale up and some of the Ir catalysts are very dear.)

  23. anon says:

    If there’s something that comments here and in some other chemistry blogs tell us, it’s that chemists are unusually unhappy and grudge-bearing people.

  24. another med chemist says:

    As a med chemist in Big Pharma who spends a sizable amount of time at the bench, I thought I’d throw my hat into the ring. At our company, photoredox is being employed quite frequently and having noticeable impacts on several projects. I’ve used it myself and been pretty satisfied with the results – some of the Ni/photoredox transformations have been game-changers! I think one of the issues here that perhaps gives photoredox chemistry a bad rep is the bizarre expectation that it must work every single time for every substrate. That’s ridiculous and any seasoned med chemist should know better. I’ve certainly run my fair share of Buchwald-Hartwig couplings and Suzuki’s that failed… Considering most of the standard photocats are commercial and reaction set-up is a breeze with those Kessil lamps, I can see this chemistry getting adopted more and more (certainly in my department, and likely industry-wide).

  25. md chmst says:

    I will add another vote in favor of the utility of photoredox chemistry. I work as a med chemist at a typical Big Pharma company and have been fascinated by the shift in opinions that have taken place here. Not long ago the majority of chemists here were reluctant to try out this type of chemistry but now there are blue lights shining in hoods around the clock. We are looking at bond disconnections that we never thought were practical or possible only a couple of years ago. I don’t care who writes the papers- if the chemistry makes my job easier and allows me to construct molecules in ways that saves a tremendous amount of time and effort, I am all for it. And as for the negativity toward who is publishing the chemistry and in what journals, it really comes across as petty jealousy.

  26. tommysdad says:

    OK, hate on one of the PIs if you want. I like the guy personally as well as professionally, but YMMV.

    But photoredox & other CH activation methods are fundamentally changing how (good) medicinal chemists are strategically designing LO campaigns. How many times have you heard a colleague lament “if I could only put a methyl group here . . .”? How many good ways did you know how to install difluoromethyl groups 4 years ago?

    Scalability? Do it in flow to make grams. And didn’t I see a picture of a room-sized photoredox flow reactor in C&E News last year?

    1. Design Monkey says:

      Honey, photoredox is only one of ways of doing radical chemistry, sometimes sort of convenient, sometimes not at all so. It’s a silly exaggerated buzzword now, because, you know, blue LEDs look cute.

  27. Curt F. says:

    Most of the angry folks seem to view the scientific literature as a means to anoint kings and queens, while most of the happy folks seem to view the scientific literature as a way to learn new chemistry. Food for thought.

    1. Mutations says:

      R3N

    2. MoMo says:

      That’s exactly right, as those who create, are well funded to do science and add to scientific progress don’t give a rat’s anus what Blogs and the anonymous say about them. But this is why the 20-80 rule is operative, and especially in Pharma, where the insecure and functionally uncreative ride the coattails of the 20% and come here to complain.

      All the miscreants wish they could be as successful as those pushing the limits of chemistry, and you are bothering and hindering the ones that do.

  28. kriggy says:

    can someone link me a good general review about photochem? None at my department does that so I have only very limited idea whats going on.

    THanks

  29. oliver says:

    Hi Derek,
    Regarding the scalability problem, has anyone looked at the merry-go-round
    photoreactor setups, that have been used by ppl like Hammond?
    They seem to do a good job at getting enough material to react at the same time.

  30. Xiao Bu says:

    Just adding my 5 cents, and I am not employed in industry so I could have it totally wrong. But it seems clear that photoredox has aided discovery chemists to afford useful quantities of compounds at the preclinical stage. Scale up and engineering issues are a separate thing, and it makes no sense to forgo a 1 mmol photoredox reaction because one day in the distant future it might not be easy to scale up. The point is to get the compounds, test them, and see if they warrant a closer look by process chemists, isn’t it?

  31. Chris Phoenix says:

    “The real problem — as my first harasser described — was that others were beginning to pay attention to me. He wrote as if mere exposure to my work was harming his world.”
    “From the hater’s POV, you (the Koolaid server) do not “deserve” that attention. You are “stealing” an audience. From their angry, frustrated point of view, the idea that others listen to you is insanity. From their emotion-fueled view you don’t have readers you have cult followers. That just can’t be allowed.”
    https://www.wired.com/2014/10/trolls-will-always-win/

Leave a Reply

Your email address will not be published. Required fields are marked *

Time limit is exhausted. Please reload CAPTCHA.