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Birch Reduction Without Tears. Or Ammonia. Or Metals.

The Birch reduction is pretty interesting to run, especially the first time you do it. Liquid ammonia is not a typical reaction solvent, and condensing it off a cold finger always looks a bit like a magic trick. You’ll be standing there with a beaker of sodium or lithium metal pieces (sitting under solvent!), which were likely carved off with a knife from a larger piece that lives its life in a jar of mineral oil. Sodium metal itself looks like a grey lump or cylinder under those conditions, but as you dig into it (the stuff has a consistency in between cold butter and a hard salami), the fresh surface is brilliantly shiny and metallic, as if somebody had invented spreadable chrome for car fenders. But only for an instant; it tarnishes while you watch. Robert Frost was surely right that nothing gold can stay, but nothing silver hangs around for long either in that column of the periodic table, not if there’s any oxygen or water around.

Or any ammonia. As you add your alkali metal to the solution, you get a startling blue color that forms around each piece of dissolving metal – actual solvated electrons – and at least at first, the blue probably dissipates as it heads out into the solution and meets your substrate. We’re taught in chemistry that reduction is the addition of electrons to a substance, and here you are, reducing your starting material by dunking it in a literal bath of electrons. Eventually, though, it holds on, and you have a frosty blue reaction flask that looks like a very refreshing drink for an alien on a hot day. (Any lab that you’d care to work in would be a hot day for liquid-ammonia-drinking aliens – I always figured that the different additives and substrates in the Birch reactions I’ve run over the years would be like different cocktail recipes for them. . .) Note: more laboratory blue candidates here.

The final part of the workup is simple, anyway: you just pull the flask out of the cold bath and come back in a while when all the ammonia has boiled away. The reason you go to all this trouble, of course, is that the electron-dunk provides you with transformations and structures that can be hard to realize any other way. There aren’t too many good options for taking down an aromatic ring by one double bond’s worth of oxidation state, for example. But no one wants to do this on large scale, which can present a real impasse. Here’s what happens when there’s no way out and you have to do the Birch on an industrial scale: significant time, expense, and effort.

There’s a new paper from the Baran lab, though, that tries to get around these problems. I’ve written about Birch alternatives before, and there have been many, but they all suffer from some of the defects of the original (or add new ones). When you’re talking about pumping electrons directly into your substrate, though, electrochemistry should come to mind. There have been many reports of this sort of thing, naturally, going back to Arthur Birch himself, but electrochemistry itself has generally been an unattractive proposition for synthetic organic chemists, with its own reputation for wonky unscalability. Baran’s group has been trying to change that, and this paper is another step in that process.

The paper really shows you how tricky such optimization can be. Along the way, they noticed a metallic substance plating out on the cathode, and realized that this was lithium metal itself. This was a problem in the early lithium-ion battery days, so the group turned to the sorts of methods that have been used in the battery industry to keep this from happening, specifically tris(pyrrolidino)phosphoramide (TPPA), a (nontoxic) phosphoramide that’s also been used as an HMPA replacement in organic synthesis. The proton source for the reaction needed optimization (dimethylurea worked the best), as did the material of the anode (magnesium instead of aluminum), and the cathode itself needed to be made physically smaller (to increase the current density). That’s the sort of electrochemical thinking that has to be learned; if you’ve never done this stuff before it could be a while before that last one occurs to you.

In the end (after detailed study of the reaction), it doesn’t appear that lithium metal itself or any solvated electrons are the active species in this reaction – rather, the substrates are getting reduced directly on the cathode surface, and that the flow of electrons from that surface is the rate-limiting step. Overall, the reaction looks like a single-electron reduction, then a protonation, then both steps again. A lithium cation/dimethylurea complex is a key part of system, probably sitting right next to the radical anion intermediate, which helps explain the dependence on the proton donor component.

Synthetically, this reaction seems to behave very similarly to the classic Birch, but with no ammonia and no alkali metals, of course. A wide range of substituted aryls react just the way that they’re supposed to, and the carbocyclic rings of heteraryls react preferentially, too, as they should. Very interestingly, it appears that a range of other synthetic transformations that depend on dissolving-metal conditions (ketone reduction, McMurry coupling, reductive cyclizations and ring openings of various kinds) can also run under the same conditions – which is not true of the Birch reaction itself, nor of any of its alternatives.

And finally, the whole thing seems to be easily scaled up. The paper demonstrates this by just stacking more electrochemical modules together and running them in either batch or flow mode. This take it from milligram scale, to 10 grams, to 100-gram scale with virtually identical yields, which makes me think that a commercial Birchomatic machine (Baranomatic?) is in our futures. I wouldn’t mind that at all, and I suspect that there are many other chemists who would be happy to never roll out an ammonia tank again. . .

33 comments on “Birch Reduction Without Tears. Or Ammonia. Or Metals.”

  1. Isidore says:

    “Synthetically, this reaction seems to behave very similarly to the classic Birch, but with no ammonia and no alkali metals, of course.”
    I can’t access the paper but its tile and your description above of lithium deposit on the cathode in the Baran group experiment, as well as the formation of the lithium cation/dimethylurea complex, suggest that there is, in fact, some alakali metal required for this electrochemical reduction, is this not co?

    1. Derek Lowe says:

      They actually keep the lithium from depositing by use of the TPPA additive – the lithium comes in in the form of lithium bromide added to the mixture.

  2. Old Timer says:

    What are solvated electrons? Shouldn’t there be some Cerenkov radiation if that were true?

    1. McChemist says:

      You only get Cerenkov radiation with very high speed electrons (that is, electrons that are moving faster than the speed of light in that particular medium). Radioactive decay generally produces electrons with this sort of speed, but you aren’t going to see this with an electron that is simply sitting in solvent.

    2. b says:

      https://en.wikipedia.org/wiki/Electride

      Lots of cool work on this area from the Dye group out of Michigan State.

  3. Anonymous says:

    Birch Reduction, aka, The Ty-D-Bol Reaction. 🙂

    Paywall on the Baran paper. For me, the rate limiting step in doing electrochem on my synthesis projects was PI resistance, way off the megaohms scale on my PI resistance meter.

    When it comes to synthesis, I am generally in favor of whatever works, be it Birch or electrochem.

    1. Design Monkey says:

      Technically, if you yourself understand electronics stuff, and depending on, how fancy you needs are, hardware for basic small scale electrochemistry costs on order of 0$-10$-100$ (used phone charger from trashcan, cheap chinese bare bones power supply module, ready made lab power supply). Now, if you start to need platinum electrodes, then, yes, that will cost arm, leg and kidney.

  4. Wavefunction says:

    One of my favorite activities in the college lab was to cut up sodium pieces from a larger piece for use in all kinds of reactions including Birch reductions.

  5. steve says:

    Great to hear. I love Birch beer.

    1. RM says:

      Diet Birch Beer – a (literally) reduced calorie beverage.

  6. Hap says:

    One of the TAs in grad school started a small fire in undergrad lab when he threw the ethanol (with cut-up sodium pieces in it from a Birch setup) in the waste jug – someone noticed when flames were coming out the top. I think the Birch reductions worked, though, other than that.

    1. KazooChemist says:

      Ah, yes. Chopping up sodium/potassium/lithium. Always time for a minor fire. An undergrad researcher in the lab when I was in grad school opened a brand new can of sodium metal and proceeded to start cutting into it to get fresh slices for a Bouveault-Blanc reduction. The knife slipped, the chunk flipped away, and a tennis ball sized lump of sodium tumbled into the nearby sink! Fortunately for all in the lab the sink was dry. Fresh underwear all around that day.

      1. Anonymous says:

        Kazoo, “Chopping up sodium/potassium/lithium. Always time for a minor fire.” — I think I may have posted this to Pipeline previously, but I can’t find it. (Re-make Pipeline using real open source “forum” software so we can more easily follow, search and reply to topics!)

        I’ve done a lot of microscale synthesis to avoid burning up (heh, heh – double entendre) high value intermediates. That includes using Li/Na/K, not just for Birch. When I needed tiny amounts of fresh, clean metal, I’d tare a capillary tube (or cut off the tip of a Pasteur pipette), slice a clean face on the metal block, and jab / dig out a tiny amount of silvery, shiny metal. Back to the balance to get the mass. (I never really trust sub-mg weighings very much, but I was “comfortable” with ~mg amounts of metal.) Depending on the reaction, the metal reacts slowly from the open end of the capillary or aggressive stirring (or jabbing with a glass rod or spatula) can break the capillary glass and release the metal entirely.

        (I’ve also done lots of reactions in capillary tubes, a trick I learned from a 4th year grad student when I was a first year. He went off to a teaching position at a small college.)

      2. Paul D. says:

        Probably this has been posted before: disposal of war surplus sodium in 1947.

        https://www.youtube.com/watch?v=OBm8fM8sV0w

        1. My parents got to have all the fun.

          They claim it was an alkaline lake. It certainly is now.

  7. Synthon says:

    I enjoyed doing the lithium/ ethylamine Birch. Lithium is less reactive than sodium and harder,, so you but the lump with a hammer until it’s a foil and cut strips with scissors which were then dunked in ethylamine.. Worked well.

    1. Steve says:

      Thats how I did my Birch reactions too, but too reactive for most reductions

  8. Tocrat says:

    Yet another ‘rite of passage’ reaction on its way to the organic chemistry dustbin. Mixed feelings myself. Nothing like the terror of condensing liquid ammonia from a rusty old cylinder (as was typical in most university labs in the 80s/90s) to focus the mind and force one to grow up! Progress is good as long as we don’t then become too frightened of the mundane

    1. AQR says:

      If you had a rusty cylinder, it’s best to redistill the ammonia from the first flask into another for the reaction. Otherwise the iron contaminants can blow into the flask with the ammonia and it catalyzes the formation of lithium amide, which serves as a base rather than a reducing agent.

  9. chris says:

    Birch reduction was one of the reactions I used to love to do, the colour was great. Also like Sandmeyer reaction, beautiful yellow crystals emerging from black mixture.

  10. loupgarous says:

    “Laboratory-scale photoredox catalysis using hydrated electrons sustainably generated with a single green laser”, in issue 11, 2017, Chemical Science (pub. by the Royal Society), Robert Naumann, Christoph Kerziga and Martin Goez describes an alternative to Birch reduction –

    “The ruthenium-tris-bipyridyl dication as catalyst combined with the ascorbate dianion as bioavailable sacrificial donor provides the first regenerative source of hydrated electrons for chemical syntheses on millimolar scales. This electron generator is operated simply by illumination with a frequency-doubled Nd:YAG laser (532 nm) running at its normal repetition rate.”

    The chemist’s toolbox for reactions with solvated electrons is gaining new tools. Photo redox isn’t super hot news, but Vitamin C as a sacrifical donon in a photoredox reaction seems cool to me, not to mention it’s part of a laser-pumped photoredox set-up.

  11. loupgarous says:

    Once more, with correct HTML…

    “Laboratory-scale photoredox catalysis using hydrated electrons sustainably generated with a single green laser”, in issue 11, 2017, Chemical Science (pub. by the Royal Society), Robert Naumann, Christoph Kerziga and Martin Goez describes an alternative to Birch reduction –

    “The ruthenium-tris-bipyridyl dication as catalyst combined with the ascorbate dianion as bioavailable sacrificial donor provides the first regenerative source of hydrated electrons for chemical syntheses on millimolar scales. This electron generator is operated simply by illumination with a frequency-doubled Nd:YAG laser (532 nm) running at its normal repetition rate.”

    The chemist’s toolbox for reactions with solvated electrons is gaining new tools. Photo redox isn’t super hot news, but Vitamin C as a sacrifical donon in a photoredox reaction seems cool to me, not to mention it’s part of a laser-pumped photoredox set-up.

  12. Scott says:

    I’d be very concerned about the fire hazard, same as with lithium batteries.

    1. NotAChemist says:

      I have a hard time thinking it’d be more of a fire hazard than big solid lumps of sodium metal.

  13. Ted says:

    Hi all:

    Nice to see some familiar names in the shout-out to the old Upjohn process (“Pfizer API”) group. From large scale ozonolysis, stoichiometric osmolyations to the infamous Sitosterol pile, that place had serious old school chemistry credibility…

    I had a process a few years back that involved repeated washes of a toluene solution with 9M sulfuric acid (at >70°C – “these are the times that try men’s souls” chemistry) in order to pull out the residual copper. We followed the washes in the first scale-ups colorimetrically – I just set up a dilution series of copper sulfate in scintillation vials… Definitely a top 3 in the most aesthetic reactions I’ve run.

    -t

  14. Barry says:

    Benkeser showed that Calcium metal works (albeit with vigorous scouring) in lieu of Sodium or Lithium and if you use ethyl amine or ethylene diamine, or a mixture thereof, you don’t need as much cooling as for liquid ammonia.
    And Kowalski showed in the Bouvealt-Blanc reduction on the way to cimetidine that dissolving metal reductions (with whole ingots of sodium, in hundreds of liters of ammonia) can be quite cost effective on scale (when the world’s supply of LAH wouldn’t be enough)
    Overall, this is a solution to an invented problem

    1. Thomas McEntee says:

      Barry is right. Relatively speaking, sodium and ammonia are dirt-cheap, At a plant where I was worked as a process chemist in the 1970s, in a ferrocene process, I watched old plant hands picking up 5-lb blocks of sodium and slinging them into the reactor manhole.

  15. Hanno Wertal says:

    A colleague in uni did a birch on a 1L scale and the whole department came to see the beautiful blue colour – now, after 20 years of scale-up I can only think that the liter of liquid ammonia could have easily killed us all…
    How did we survive university?

    1. Barry says:

      The Process and Manufacturing groups at Smith-Klein ran the BouvealtBlanc reduction of an ester to an alcohol for cimetidine on tons of material in hundreds (if not thousands) of liters of ammonia for years. That ammonia was distilled out of one reactor upon completion into a second. And back and forth, year after year. Ammonia is cheap, and biodegradeable. Clean chemistry, cheap, unproblematic waste-stream. Not in need of re-invention.

  16. Scott Harried says:

    We reductively removed a benzyl ether in the presence of an alkene in route to a total synthesis of discodermolide (J. Org. Chem., 2003, 68 (17), pp 6646–6660). Classic Birch with Na or Li in NH3 resulted in the over reduction of the alkene to the corresponding alkane. In a set of reaction conditions similar to the Benkeser reaction, but with Li metal instead of Ca metal, and no sand required. So, Li metal with ethylenediamine in 2:1 TEA to THF at zero degrees for 2 hours on 35 mmol scale, about 10 grams. It was a performed on any scale we tried and very mild. Slow enough to TLC and monitor. Aqueous ammonium chloride work up.

  17. Barry says:

    parts of the conversation seem ludicrously miscalibrated. Ammonia is cheap, and biodegradable, and easily recaptured/recycled if you’re using in on scale. It doesn’t for peroxides like ether or THF. It doesn’t evolve phosgene like chloroform. It doesn’t persist in the environment like benzene. Hundreds of pounds of liquid ammonia are routinely used in big refrigeration units.Thousands of pounds of liquid ammonia are routinely injected into farmlands (where it presumably kills nematodes as well as providing fixed nitrogen to the crops to follow). Sure, the farmhands doing that application should have more training and more protective equipment to satisfy a chemist. But the stuff’s just not THAT dangerous.
    Efforts to avoid using ammonia are efforts that could be better spent.

  18. Luke says:

    I wonder if we’re going to start seeing electrochemical ammonia-free methamphetamine?

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