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New Electron Tricks in Synthetic Chemistry

One of specialties of Phil Baran’s group at Scripps the last few years has been electrosynthesis, which has a traditional hmm-interesting-turn-the-page reputation among most synthetic chemists that they’re trying to change. Photochemistry was in roughly the same category at one time, and has become much more mainstream (although it always had an advantage with lower barrier to entry). That field has made inroads through the advent of many new reactions, bond-forming processes that are hard to realize any other way, and that is surely the path forward for electrochemistry as well: provide relatively cheap, standardized equipment with easy setup and the promise of being able to do things you’ve never been able to do before.

Here’s a new paper from the group, now on ChemRxiv, that makes such a case. They demonstrate some weird effects of using square-waveform “rapid alternating polarity” instead of the traditional direct-current electrochemistry. These sorts of alternating-current applications have really not been explored much, and from this paper it appears that that neglect may have been a mistake. Take a look at this carbonyl reduction:

Protein degradation fans will recognize the pomalidomide building block at left, but I feel pretty sure that no one has one-shot conditions that will reduce one of the five carbonyls in the molecule selectively.  You’ll note that you can’t even do that with traditional DC electrochemistry. This is one of the more dramatic examples from the paper; some of the other reactions on test molecules work fine either way, while some of them definitely show improved yields with the AC conditions. But this really gets the attention; you feel as if you have a magic wand when something like this works out.

The overall reduction is consistent with a (expected) mechanism that goes through a radical anion intermediate, followed by protonation. Running the reaction in deuterated methanol, for example, installs deuteriums on the reduced carbon. And the selectivities can be largely explained/predicted by the different reduction potentials of the carbonyls, which in turn can be approximated by their LUMO (lowest-unoccupied molecular orbital) coefficients. But when using the standard chemical reagents, we’re not really used to going direct to LUMOs to predict our reactions, because most of the carbonyl reducing agents are Lewis-acidic and complex the carbonyl oxygen as a first step. As the paper points out, synthetic chemists are used to having aldehydes as the fastest, cleanest carbonyl to reduce, but the paper shows an example where the phthalimide gets reduced in the presence of an aldehyde – which makes sense in terms of sheer reduction potential, but seems weird to one’s usual chemical intuition.

What’s weird is that switching to the square-waveform alternating current achieves this, while just plain direct current often doesn’t. The paper shows evidence that changing the frequency of the AC can have an effect on the reactions as well, depending on the kinetics of the possible reaction steps. Switching quickly enough between polarities can make the faster pathway possible before a slower step gets going, in other words. It seems that there are probably a lot of odd reactions waiting in this area, and no doubt folks in Baran’s group are zapping a whole range of molecules as we speak to find some new applications. Bring on the electric voodoo, say I – we need all the help we can get.

35 comments on “New Electron Tricks in Synthetic Chemistry”

  1. John Wayne says:

    Keep the orthogonal tools for synthesis coming!

    1. Jordan says:

      Came here to say the same thing — though what I think electrochemistry still lacks is a broader conceptual framework that can be used to design synthetic routes (rather than “let’s electrocute this compound and see what happens”).

  2. A Nonny Mouse says:

    Interesting the use of pivalic acid; they say that this is the proton source.

    Pivalic undergoes a radical coupling with itself to form a dimer when using peroxide/Fe(III) (which I have done on kilos). Could it be that they are forming the radical of the pivalic acid which is doing the work?

  3. Shazbot says:

    One step closer to getting the desired reaction through shouting at the precursor in question.

    One day.. One day.

    1. John Wayne says:

      I bet you that shouting at a forming Grignard reagent in German can get it to initiate … personal anecdote.

      1. FoodScientist says:

        “mechanical activation of magnesium for Grignard reagent via sonication”

        1. Anon says:

          Of course the holy grail is getting the reaction to run by glaring at it.

  4. Eugene says:

    If an AC field has this effect I wonder if a non-symetrical AC pulse waveform would give different results.

  5. J says:

    Yes, varying the duty cycle should be investigated, in particular a short active pulse and a longer cooling-down period. Also, I wonder whether it needs to be balanced AC, or whether pulsed DC would work as well.

    1. Chris Phoenix says:

      Maybe also stepped voltages, or differently oriented electrodes with different waveforms and phases – one part of the cycle to align the molecules, another to power the reaction.

  6. Sandor says:

    The first thing that sprung to mind when I saw this was how asymmetrical AC waveforms get the job done in TIG-welding aluminum where DC does not. It might be interesting to collaborate with the NMR people and their weird pulse sequences.

    1. Graham says:

      With NMR you can certainly make the spins dance to your desired tune, but only because because relaxation of nuclear spin states is incredibly slow compared to electronic relaxation (by ~10-15 orders of magnitude).

  7. Marko says:

    Could such advancements be further accelerated by using an “electron trick” directly on the synthetic chemists? Like with a cattle prod?

    1. dqwerf says:

      You are joking, but transcranial direct current stimulation is something neurobiologists are experimenting with, along with transcranial magnetic stimulation.

      1. Marko says:

        Yes, those methods would be more readily accepted, I’d imagine.

        Voice-to-skull 5G technology might be another way to boost the chemists’ productivity.

  8. luysii says:

    Back to the basics. There is more energy in high frequency light than low frequency because the electric and magnetic fields are changing more rapidly. Similarly there should be more energy in rapidly changing polarity (e.g. changing electric fields) than in constant electric fields. Issues of resonance with the frequency of the polarity change should make possible distinguishing the 5 carbonyls.

    1. power triangle says:

      This turns out not to be how AC power delivery works. For a pure resistive load, the frequency doesn’t matter, it’s just plain old volts * amps. With a reactive load, the transfer of energy decreases as voltage and current get out of phase; the phase angle will depend on AC frequency and the transfer function of the system.

      (I doubt sheer power dissipation is much of a player in this electrochemistry.)

  9. 123 says:

    Is this really new? could any other types of more meaningful reactions be applied?

  10. David Edwards says:

    electrosynthesis, which has a traditional hmm-interesting-turn-the-page reputation among most synthetic chemists that they’re trying to change.

    In a way, it’s not surprising that electrochemistry has been an extremely niche part of organic chemistry. Students are usually introduced to electrochemistry via inorganic chemistry classes, where ionic compounds pretty much rule the roost, and passing electric currents through said compounds yields readily observable results quickly – zinc galvanising being probably the most common use thereof.

    Organic chemistry in its early days was pretty much centred upon nonpolar molecules with covalent bonds, which are not intuitively regarded as suitable for electrochemical reactions. For that matter, “introduce different molecular species to each other and watch them react” was historically the process that launched chemistry as a whole as an empirical discipline, not least because it proved to be both successful and useful in short order. The tendency to continue using a method that demonstrably works is pretty strong among those who want to achieve results.

    Anyway, back to organic molecules … though there are organic molecules that exhibit at least partial ionic character in the right circumstances (low molecular weight carboxylic acids reacting with alkali metal hydroxides spring to mind here), organic electrochemistry is somewhat avant-garde to put it lightly. Even though biologists are aware that electrochemistry is a significant player in the central nervous system, I’m not aware of efforts to transplant that chemistry elsewhere on a large scale. I could, of course, have missed an entire library of papers in this field, but any such papers tend not to leap out at me when I pay visits to JACS or Angew.

    For that matter, I suspect using AC currents in electrochemistry is also “niche”. So Baran and his colleagues deserve an award of some sort for putting together two niche areas of chemistry, and coming up with something that has some very interesting potential!

    I’m now wondering if they’re going to have some fun with sawtooth waves, just to see if those produce unexpectedly useful results. My inner mental velcro jumper is already pondering the possibilities of feeding the output of a synthesiser into a reaction mixture to see what happens – a musical version of Belousiv-Zhabotinsky, perchance?

    1. Barry says:

      How long can organic electrochemistry stay “avant garde”?
      Gil Stork published Onocerin via Kolbe coupling in 1963

      https://pubs.acs.org/doi/10.1021/ja00904a027

      1. John Wayne says:

        Taking an old reaction that works and expanding both its scope and awareness in the community is a classic way professors make their mark on chemistry. I would list all the famous people who have done this, but it would be more than half of everybody. Such an exercise may also look like a criticism; it isn’t – this is the way.

        1. Just another Mandalorian. says:

          This is the way.

  11. anon says:

    I believe AC waveforms, in particular square waves, have been found effective in reduction of anions, since the ions have the same charge sign as the electrode. The idea is to use the positive portion time to transport the anions up to the electrode.

    That doesn’t look like the explanation here.

    Since the reaction happens in the in the electrode-solution interface, where the electric field is high (due to short length scale), I’m wondering if part of the effect is due to orienting the molecular in favorable ways by modifying the field with the AC waveform. Or, if the reactants adsorb to the electrode, the orientation effect plays out there?

  12. Dennis says:

    I love that they involve industry scientists in selecting substrates for testing their chemistry – it really puts the new reactivity in good context. I’m sure drug discovery scientists everywhere did a double-take seeing the pthalidomide->lenalidomide example, definitely looks useful for late-stage degrader SAR nowadays =)

    1. Edison says:

      I’m sure it’s the other way around. Industry tells them what they are interested in and they go and do their edisonian approach by running thousands of experiments to produce papers with nice colorful boxes.

  13. Wilhelm Cody says:

    the ratio in Lowe’s blog of such articles to articles on dealing with SARS-CoV-2 and COVID-19 is a great indicator to how close we are to returning to life after the pandemic.

    1. Anon says:

      Yeah I can finally read the blog again. It turned into biotech/pharma-hype mixed with vaccine news for a year. I am sure he enjoyed his increasing popularity in media and Twitter bloggers though..so i won’t blame him. Hopefully it’s over.

      1. Derek Lowe says:

        No one is happier than me about a fading of the pandemic craziness around here, believe me!

  14. gooberizer says:

    https://chemistry-europe.onlinelibrary.wiley.com/doi/full/10.1002/celc.202000648

    Just wanted to highlight that these AC processes can be extremely dicey for engineering reasons not related to the underlying electrochemistry. Not paying critical attention to the underlying EE stuff – a main motivation for buying an IKA ElectraSyn or related gizmo – can significantly distort one’s odds of finding new preparative electrochemistry or being able to generalize the idea behind a newly developed method.

    1. gooberizer says:

      IIRC IKA have fixed this specific problem with a software update but in echem, more such issues can always be lurking in the wings

  15. Mike D. says:

    EE here. This is some really interesting stuff, and I don’t really understand the chemistry side of things much, beyond using a 9V battery, aluminum foil, and a weak salt-in-deionized-water solution to clean (weak, brown-colored) oxides off copper plated fiberglass a couple decades ago. (Seemed to work well enough, so long as you washed the copper immediately after before it formed the colorful oxides.)

    One thing that should be nice about using AC (or basically anything with no DC component) is it should help the electrodes last longer, if you don’t give the waveform enough time to rip atoms off the surface.

    Since they’re seeing results with square waves, there’s a bunch of stuff to try: sine waves instead of square waves (i.e. is it the frequency, or the dv/dt, that’s doing the work), spread-spectrum (i.e. varying pulse width) waveforms instead of CW (constant frequency), seeing what relation there is to frequency (i.e. if the edge is doing the work, doubling the frequency should double the reactions, up to a point), and as several others have suggested, non-continuous waveforms with sharp edges in one direction followed by exponential decays in the other direction.

  16. RuBarf says:

    Screen the waveform library

  17. gippgig says:

    Has anyone tried combining electrochemistry & photochemistry? It seems to me that there might be some way to direct electrochemical oxidation or reduction to a specific bond by exposing the reaction to light with a frequency equal to the vibrational frequency of the desired bond.

    1. gooberizer says:

      Many have tried, this is a whole field in its own right. Photoelectrochemistry is commonly studied at semiconductor electrodes and also through the lens of photoredox chemistry.

      Outside of very special cases, attempts at manipulating bond-specific vibrational excitation fail in promoting specific reactivity because of rapid intramolecular vibrational energy redistribution (called IVR in this field). In the liquid phase collisions with solvent make this even worse.

      1. gippgig says:

        One obvious thing to try is pulsing the voltage & light simultaneously.
        Totally different thought – any chance of getting enantioselectivity by using more than 2 electrodes and applying pulses clockwise vs. counterclockwise? (At least this is getting me to think!)

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