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Diazomethane Without Tears. Or Explosions.

Here’s a neat paper from Oliver Kappe’s group on diazomethane flow chemistry. They’re using the gas-permeable tube-in-tube technique (as pioneered by Steve Ley’s group). Flow systems have been described for using diazomethane before, but this looks like a convenient lab-scale method.
Diazomethane is the perfect reagent to apply flow chemistry to. It’s small, versatile, reactive, does a lot of very interesting and useful chemistry (generally quickly and in high yields). . .and it’s also volatile, extremely toxic, and a really significant explosion hazard. Generating it as you use it (and reacting it quickly) is a very appealing thought. In this system, the commercial diazomethane precursor Diazald is mixed with a KOH flow in one tube, while a THF solution of the reactants flows past it on the other side of a gas-permeable membrane. Methyl ester formation, cyclopropanation, and Arndt–Eistert reactions all worked well.
Aldrich or someone should work this up into a small commercial apparatus, a bespoke diazomethane generator for general use. I think it would sell. I suggest, free of charge, the brand name “Diazoflow”.

18 comments on “Diazomethane Without Tears. Or Explosions.”

  1. A Nonny Mouse says:

    Phoenix Chemicals (now defunct) based near Liverpool used to make an alpha-diazo ketone on tonnage scale using diazomethane.
    Their technique was to to distil out the diazomethane solution through a 1 metre tube into the reaction vessel. No serious accidents, but the tube used to blow up on a regular basis (which is what they expected and why they designed to process that way).

  2. Rhenium says:

    I’d buy a “Diazpflow” is they were commercially available.
    I’ve been wanting to do a one carbon ring expansion on benzene compounds to get access to substituted cycloheptatrienes for a long time.
    Can any one in the comments suggest a group that does such chemistry successfully and regularly and who might be open to teaching an interested academic?

  3. Anonymous says:

    Of interest to Rhenium?
    Buchner and Beyond: Arene Cyclopropanation as Applied to Natural Product Total Synthesis. Reisman, S. E.; Nani, R. R., Levin, S. Synlett, 2011, 17, 2437. DOI: 10.1055/s-0031-128952.

  4. Jean Grey says:

    It’s kinda ironic that they named the company Phoenix but it can’t rise from the ashes

  5. Rhenium says:

    Thanks anon (#3), I’ll check it out.

  6. Harry says:

    I seem to recall that Aerojet worked with diazomethane at large scale, but I may be misremembering (and I’m too lazy to try to check).

  7. Anonymous says:

    I put this technology along the same category as H-cube. You can always tell a nice story if it works good luck trying to use it to trouble shoot a specific transformation.

  8. gippgig says:

    Speaking of flow chemistry, this looks interesting:
    End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation, doi: 10.1002/anie.201305429.
    Wonder how long it will take to develop a general-purpose version and eventually revolutionize the pharmacy business.

  9. A Nonny Mouse says:

    Quite correct; they were the other company in addition to Phoenix that were making the alpha diazo ketone (for an HIV drug).

  10. Nick K says:

    Very nice paper indeed. Wish I’d thought of it.

  11. Iridium says:

    H-cube works very well.
    Although it is true that from time to time some stability issues might appear, it is great on small scale (5-50mg scale).

  12. anon says:

    @11 IMHO the H-cube gives terribly irreproducible results. You can’t trust the catalyst cartridge once you’ve done one reaction.

  13. cliffintokyo says:

    Who was it that said there is no room left for significant improvements in basic techniques? Nice work, and excellent awareness-raising post.

  14. Chimaera says:

    Am I the only one who saw the title and was disappointed that it wasn’t a “Things I Won’t Work With” post?

  15. a says:

    Whatever happened to Phoenix ? Looks like they had an interesting setup….was their lunch eaten by china/india, or were there other issues?

  16. Vader says:

    I looked it up on Wikipedia (all hail the font of all human knowage) and there are comments like “Use of a blast shield is highly recommended while using this compound.”
    Must be really useful for Derek not to have this on his list of “Compounds I won’t work with.”

  17. MarkyB says:

    This is great for medchem, but the main problem with examples of this approach using gases in flow in this way is that people actually start taking it seriously as a scale up method, which it’s not.
    Phoenix used diazomethane in flow as part of their core business for years. Aerojet did it in batch. The former’s failing was not erosion from the East but other issues. Their technical methodology was sound.

  18. Anonymous says:

    I used diazomethane for esterification, and it would be my first choice to make methyl esters from acids. No distillation, I just separated the yellow ethereal layer from the aqueous KOH and used it to titrate the acid in ether at 0C (until effervescence stopped and yellow color remained, then destroy excess with AcOH).

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