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Pushing Electrons

A few years back here on this site when I would write about synthetic photochemical methods, the reaction in the comments section was, well, mixed. There would be interest, but there was always a strain of “Bunch of academic publications that will never amount to anything in the real world” as well. The amount of blue light that I see coming from fume hoods these days, though, seems to indicate that photoredox chemistry has indeed found a home, because it can do things that are very hard to accomplish by other means.

Another method in that category is electrochemistry, and although I have done a fair amount of photochemistry (sensitized and not) over the years, I (like most synthetic organic chemists) had never really done much with the electrodes. The field had a reputation (pretty well-deserved, too) of being very finicky and hard to reproduce. You would see some interesting reaction done with an electrochemical rig and think “Yeah, that would be pretty useful if it weren’t electrochemistry”. That’s what led the Baran group a couple of years back to try to standardize and popularize such techniques. The jury is still out on that one – it’s not like the journals have filled up with electrochemical synthesis, but at the same time you do see more of it than you used to, and colleagues of mine have had some success with it in the med-chem labs. That’s certainly due to the commercially available equipment, which (as was the plan) has lowered the barrier to trying such things out. Indeed, photoredox chemistry and electrochemistry have some synthetic overlap, since they’re fundamentally based on oxidation and reduction potentials.

Inevitably, we’re now seeing more crossovers between these two. Here’s a new paper on electrophotochemical substitution of aryl fluorides. These are reactions that you would draw out as classic nucleophilic aromatic substitutions, heating them up in DMSO or something with base. And there are a number of reactions here that would probably work out fine that way, since the reaction goes best with electron-deficient fluoroaryls, but there are several that would be hard to realize the classic way, too. Similarly, here’s a recent paper on trifluoromethylation and a look at two other such transformations.

It’s not for nothing that drawing organic chemistry mechanisms is referred to as “pushing electrons”, because that’s what we do as we break and form bonds. These newer methods are getting down to that as directly as possible – there is no more “atom-efficient” reaction possible than shoveling electrons directly into a molecule (or better yet, a specific bond). Those electrons can be coming right out of an electrode, or the “electron shovel” can be some catalytically generated species that turns around to deliver another load. But either way, it does make you wonder if organic synthesis is setting out on a different path than the classical reactions have taken. I don’t know if the combination of photochemistry and electrochemistry is going to take off on its own. Neither do its practitioners, of course. It’s a new enough field, though, for there to be some really useful reactions hiding in it that no one has yet come across.

That’s not to say that all the older reactions are going to go away, and especially not any time soon. They’re already being augmented, though, and I would be willing to bet that in the coming decades there will be more and more of these direct electron-pushing processes used. You’d expect to see them especially in process chemistry and specialty chemicals, where some particular molecule’s preparation needs to be optimized and it’s worth spending the time and effort to come up with bespoke conditions. That’s still the reputation that photochemical (and especially electrochemical) methods have, that they need too much tweaking and dinking of conditions to get them to work well, but that’s what the synthesis of high-volume high-value materials is all about. . .

22 comments on “Pushing Electrons”

  1. lfert says:

    I ran some hydrodechlorination reactions on polychloro aromatic systems 20 years ago using Zn/Acetic acid. It would be interesting to revisit some of these to see if it could work electrochemically w.r.t. the selectivity we saw initially. I also worked on the preparation of parylenes which involved the dimeric coupling of para di-benzyl bromides under similar conditions (with low yields). Again, wondering if electrochemical methods would be superior.

  2. Jake O says:

    My Monday morning brain read the title as “Pushing Elections.” Really glad that’s not what it says.

  3. John Wayne says:

    I’d like to suggest that the criticism these methods tend to gather appears to be from a general lack of comparison of the new method to other ways of making things. Derek, you brought up a perfect example: why would you use electrochemistry to substitute an aryl fluoride if SnAr chemistry would work? If the authors of these papers show yields from known methods and focus on the reactions that work poorly (e.g. electron rich systems in the example,) then they would really have something.*

    If I was a PI in this area, I would have my students run the routine reactions and get a yield so you could do the real comparison. Running controls is good science; plus, any reaction you find that works poorly via the known method and better with the new method is immediately valuable and publishable.

    * To take this example further, you could also look for pendant functionality that doesn’t like being heated above 100 degrees in base. Having lots of orthogonal options to do a specific transformation is always useful, and sometimes critical for success.

  4. Albert says:

    My colleagues are about to manufacture 1.5 tons of material using a photoredox reaction this spring. Not that you absolutely couldn’t do it another way, but photoredox option gave a higher yield and quality plus likely will be chepar in the long run. That’s all the arguments a process chemist needs.

    1. Derek Lowe says:

      That would seem to answer most objections about running photoredox on scale! I’ve heard of a couple of other things along this line as well. It’s real.

    2. chemist says:

      Is that by flow or do you put an LED rod in the tank?

  5. Ffghhszxfggg says:

    On the Baran point, the former TSRI has never been known as a bastion of honesty. They will lie, steel, even kill to get another company. Not much to say about that crazy hole as a former “grad student”.

    1. Sean says:

      I’ve generally heard good things about the Baran lab (aside from being workaholics)… was the work culture toxic?

  6. Ir(wtf)ppy says:

    Based on the lack of comments on this blog looks like the fad has passed

  7. Anonymous says:

    I don’t know if others share my experience, but sometimes the biggest barrier to trying electrochemistry (for synthesis) or any other new technique is the PI. (I was able to borrow parts from a P Chem group and to try e-chem on a very difficult step in the sequence but the PI did NOT appreciate the effort.)

    Commoditization of relatively inexpensive pre-fab set-ups has lowered the barrier (I’d say “lowered the resistance” but that could create confusion) to trying some newer techniques. Sheesh … biologists can buy a kit for almost anything they need to do. (Anybody remember Pierce Chemical silylation kits for biologists? A 1 mL vial of TMSCl and a 1 mL vial of pyridine and an instruction sheet for about 20x – 50x the cost of bulk reagents from Sigma-Aldrich.)

  8. Barry says:

    Maybe I’m being dense, but I don’t see that electrochemistry done at an electrode is that different from single electron transfer from SmI3, or from Li/NH3, or from Ca/EtNH2, or from Fe(0)/HOAc, or from Mg(0)/MeOH…

    1. anonymous says:

      The most obvious difference I see is that the examples given are homogeneous reductions, whereas electrochemical reductions in a cell are heterogeneous, with all the attendant differences that entails. The other difference is of course the source of the electrons, which is ultimately whatever oxidation reaction occurs at the counter electrode in the electrochemical cell.

      1. Barry says:

        Sure, SmI3 and Birch are homogeneous. But surely a substrate molecule can’t tell the Corey/Chaykovsky amalgamated Aluminum reagent from an electrochemical cell (albeit at fixed voltage)

        1. Anonymous says:

          Well, what I had in mind regarding the heterogeneous vs. homogeneous distinction is that with heterogeneous systems, the rate of conversion scales with the area/volume ratio (since the electron transfer occurs at the electrode-solution interface). Of course, this may not be useful for a given system, but it’s something to think about, especially if there is interest in scaling up.

          The other thing is, as long as the electrolyte is not exhausted, the anode reaction keeps supplying electrons. The most obvious complication of this is there are going to be byproducts of the anode reaction, which could result in unwanted side reactions, but a divided cell can be used (unfortunately, this does increase the cell resistance).

          I assume that the tiny bit of electrochemistry that I received in undergraduate chemistry (essentially, the Nernst equation) is typical, at least in the States, so I understand why there’s a lot of reluctance to use it. The investment to gain the necessary background might not pay off. I’m not a synthetic chemist (I work in electrochemistry), so I can understand taking a wait and see approach or working with the methods that one knows will get the job done.

    2. Student says:

      You do have the ability to finely tune the potential of the and it is much cheaper on scale. Other methods e.g. SmI2 is too expensive for scale up and too toxic if you have to add HMPT to increase the redoxpotential.

      1. Barry says:

        Sure, we’ve been drooling over the potential of dialing in the voltage since the 70s to discriminate between functionality. But if I want to reduce a nitro-arene to an aniline in the presence of a aryl bromide, my best friend is still Iron dust in Acetic acid, no an electrochemical cell.

        1. new and impruved says:

          Lol, ok b00mer good luck publishing Fe/AcOH in JACS

          1. Barry says:

            If you propose to publish a “new selective reduction” protocol where an older one exists, neither JACS nor anyone else will take you paper without benchmarking on that older protocol. Whether you find that protocol sexy or not is not relevant.

    3. Hap says:

      Waste would be the difference, maybe, if you don’t have to use a lot of electrolyte to run the electrochemical reaction. You don’t have to clean out the salts if they’re not there. There’s lots of ways to get electrons, while (depending on the reductant) there’s only so much of an element in the world.

      Having a simpler system where there’s less intellectual complexity (less things that a person performing the reaction has to worry about) would help with adoption of electrochem – the stoichiometric reactions are known knowns while the electrochemical reactions are not so known.

  9. loupgarous says:

    This may not, strictly speaking, be electrochemistry – the electrons are solvated when the laser ionizes the ascorbate. But it might be of interest here, since Albert mentioned a photoredox reaction at the 1.5 ton scale:

    “Sustainable, inexpensive and easy-to-use access to the super-reductant e˙−aq through 355 nm photoionization of the ascorbate dianion—an alternative to radiolysis or UV-C photochemistry” Marcel Brautzsch, Christoph Kerzig and Martin Goez, Green Chem., 2016, 18, 4761-4771

  10. B says:

    I expect disagreement on this…oh well. A few years ago, I correlated an electrochemical mechanism paper out of Howard University to an organic chemistry transformation successfully buuuut I am an organic chemist with a very good physical chemistry background as well as friends with former coworkers who were process chemists or electrochemists. I am guessing to successfully go in the opposite direction (what is attempted with these photoredox reactions), it would help to get input or work with people that have expertise in these (and possibly other) multiple fields.

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