Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Protocol
  • Published:

Lab-scale production of anhydrous diazomethane using membrane separation technology

Nature Protocols volume 12, pages 2138–2147 (2017)Cite this article

Subjects

Abstract

Diazomethane is among the most versatile and useful reagents for introducing methyl or methylene groups in organic synthesis. However, because of its explosive nature, its generation and purification by distillation are accompanied by a certain safety risk. This protocol describes how to construct a configurationally simple tube-in-flask reactor for the in situ on-demand generation of anhydrous diazomethane using membrane separation technology and thus avoiding distillation methods. The described reactor can be prepared from commercially available parts within ∼1 h. In this system, solutions of Diazald and aqueous potassium hydroxide are continuously pumped into a spiral of membrane tubing, and diazomethane is generated upon mixing of the two streams. Pure diazomethane gas diffuses out of the reaction mixture through the membrane tubing (made of gas-permeable Teflon AF-2400). As the membrane tubing is immersed in a flask filled with the substrate solution, diazomethane is instantly consumed, which minimizes the risk of diazomethane accumulation. For this protocol, the reaction of diazomethane with benzoic acid on a 5-mmol scale has been selected as a model reaction and is described in detail. Methyl benzoate was isolated in an 88–90% yield (597–611 mg) within ∼3 h.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2: Schematic overview of the tube-in-flask reactor and reaction scheme.
Figure 3: Parallelization of the tube-in-flask reactor for scale-up.
Figure 4
Figure 5: Construction of a nut–ferrule assembly (fitting).
Figure 6: Bringing the AF-2400 tubing into shape.
Figure 7: Assembly of the tube-in-flask reactor.
Figure 8: Sealing of the safety cap ports.
Figure 9
Figure 10
Figure 11: Diazomethane generation and consumption.

Similar content being viewed by others

References

  1. Black, T.H. The preparation and reactions of diazomethane. Aldrichimica Acta 16, 3–10 (1983).

    CAS  Google Scholar 

  2. Zavozin, A.G., Ignat'ev, N.V., Schulte, M. & Zlotin, S.G. Synthesis of novel tridentate pyrazolebipyridine ligands for co-complexes as redox-couples in dye-sensitized solar cells. Tetrahedron 71, 8551–8556 (2015).

    Article  CAS  Google Scholar 

  3. Pace, V., Verniest, G., Sinisterra, J.-V., Alcántara, A.R. & De Kimpe, N. Improved Arndt-Eistert synthesis of α-diazoketones requiring minimal diazomethane in the presence of calcium oxide as acid scavenger. J. Org. Chem. 75, 5760–5763 (2010).

    Article  CAS  Google Scholar 

  4. Candeias, N.R., Paterna, R. & Gois, P.M.P. Homologation reaction of ketones with diazo compounds. Chem. Rev. 116, 2937–2981 (2016).

    Article  CAS  Google Scholar 

  5. Schjøth-Eskesen, C. & Jensen, H.H. Efficient Arndt–Eistert synthesis of selective 5-HT7 receptor antagonist SB-269970. Synth. Commun. 39, 3243–3253 (2009).

    Article  Google Scholar 

  6. Belderrain, T.R. & Nicasio, M.C. Cyclopropanation of alkenes with C-1. in Science of Synthesis, C-1 Building Blocks in Organic Synthesis 1 (ed. Van Leeuwen, P.W.N.M.) 259–280 (Georg Thieme Verlag, 2014).

    Google Scholar 

  7. Fustero, S., Sánchez-Roselló, M., Barrio, P. & Simón-Fuentes, A. From 2000 to mid-2010: a fruitful decade for the synthesis of pyrazoles. Chem. Rev. 111, 6984–7034 (2011).

    Article  CAS  Google Scholar 

  8. Schoental, R. Carcinogenic action of diazomethane and of nitroso-N-methyl urethane. Nature 188, 420–421 (1960).

    Article  CAS  Google Scholar 

  9. Lewis, C.E. Diazomethane poisoning: report of a case suggesting sensitization reaction. J. Occup. Med. 6, 91–92 (1964).

    CAS  PubMed  Google Scholar 

  10. de Boer, Th.J. & Backer, H.J. Diazomethane. Org. Synth. 36, 16–19 (1956).

    Article  CAS  Google Scholar 

  11. National Institute for Occupational Safety and Health. Diazomethane http://www.cdc.gov/niosh/ipcsneng/neng1256.html (1995; accessed 21 August 2017).

  12. Carlson, E., Duret, G., Blanchard, N. & Tam, W. Synthesis of cyclopropanated [2.2.1] heterobicycloalkenes: an improved procedure. Synth. Commun. 46, 55–62 (2016).

    Article  CAS  Google Scholar 

  13. Barkawi, L.S. & Cohen, J.D. A method for concurrent diazomethane synthesis and substrate methylation in a 96-sample format. Nat. Protoc. 5, 1619–1626 (2010).

    Article  CAS  Google Scholar 

  14. Cohen, J.D. Convenient apparatus for the generation of small amounts of diazomethane. J. Chromatogr. 303, 193–196 (1984).

    Article  CAS  Google Scholar 

  15. Morandi, B. & Carreira, E.M. Iron-catalyzed cyclopropanation in 6 M KOH with in situ generation of diazomethane. Science 335, 1471–1474 (2012).

    Article  CAS  Google Scholar 

  16. Dallinger, D. & Kappe, C.O. Enabling technologies for diazomethane generation and transformation. Aldrichimica Acta 49, 57–66 (2016).

    CAS  Google Scholar 

  17. Deadman, B.J., Collins, S.G. & Maguire, A.R. Taming hazardous chemistry in flow: the continuous processing of diazo and diazonium compounds. Chem. Eur. J. 21, 2298–2308 (2015).

    Article  CAS  Google Scholar 

  18. Müller, S.T.R. & Wirth, T. Diazo compounds in continuous-flow technology. ChemSusChem 8, 245–250 (2015).

    Article  Google Scholar 

  19. Gutmann, B., Cantillo, D. & Kappe, C.O. Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. Angew. Chem. Int. Ed. Engl. 54, 6688–6729 (2015).

    Article  CAS  Google Scholar 

  20. Proctor, L.D. & Warr, A.J. Development of a continuous process for the industrial generation of diazomethane. Org. Process Res. Dev. 6, 884–892 (2002).

    Article  CAS  Google Scholar 

  21. Archibald, T.G., Barnard, J.C. & Reese, H.F. Continuous process for diazomethane from an N-methyl-N-nitrosoamine and from methylurea through N-methyl-N-nitrosoureas. US Patent 5854405 (1998).

  22. Struempel, M., Ondruschka, B., Daute, R. & Stark, A. Making diazomethane accessible for R&D and industry: generation and direct conversion in a continuous micro-reactor set-up. Green Chem. 10, 41–43 (2008).

    Article  CAS  Google Scholar 

  23. Rossi, E., Woehl, P. & Maggini, M. Scalable in situ diazomethane generation in continuous-flow reactors. Org. Process Res. Dev. 16, 1146–1149 (2012).

    Article  CAS  Google Scholar 

  24. Maurya, R.M., Park, C.P., Lee, L.H. & Kim, D.-P. Continuous in situ generation, separation, and reaction of diazomethane in a dual-channel microreactor. Angew. Chem. Int. Ed. Engl. 50, 5952–5955 (2011).

    Article  CAS  Google Scholar 

  25. Mastronardi, F., Gutmann, B. & Kappe, C.O. Continuous flow generation and reactions of anhydrous diazomethane using a Teflon AF 2400 tube-in-tube reactor. Org. Lett. 16, 5590–5593 (2013).

    Article  Google Scholar 

  26. Brzozowski, M., O'Brien, M., Ley, S.V. & Polyzos, A. Flow chemistry: intelligent processing of gasliquid transformations using a tube-in-tube reactor. Acc. Chem. Res. 48, 349–362 (2015).

    Article  CAS  Google Scholar 

  27. Pinho, V.D., Gutmann, B., Miranda, L.S.M., de Souza, R.O.M.A. & Kappe, C.O. Continuous flow synthesis of α-haloketones: essential building blocks of antiretroviral agents. J. Org. Chem. 79, 1555–1562 (2014).

    Article  CAS  Google Scholar 

  28. Koolman, H.F. et al. Automated library synthesis of cyclopropyl boronic esters employing diazomethane in a tube-in-tube flow reactor. Org. Biomol. Chem. 14, 6591–6595 (2016).

    Article  CAS  Google Scholar 

  29. Dallinger, D., Pinho, V.D., Gutmann, B. & Kappe, C.O. Laboratory-scale membrane reactor for the generation of anhydrous diazomethane. J. Org. Chem. 81, 5814–5823 (2016).

    Article  CAS  Google Scholar 

  30. Garbarino, S., Guerra, J., Poechlauer, P., Gutmann, B. & Kappe, C.O. One-pot synthesis of α-haloketones employing a membrane-based semi batch diazomethane generator. J. Flow Chem. 6, 211–217 (2016).

    Article  CAS  Google Scholar 

  31. O'Brien, M., Baxendale, I.R. & Ley, S.V. Flow ozonolysis using a semipermeable Teon AF-2400 membrane to effect gas-liquid contact. Org. Lett. 12, 1596–1598 (2010).

    Article  CAS  Google Scholar 

  32. Greene, J.F., Preger, Y., Stahl, S.S. & Root, T.W. PTFE-membrane flow reactor for aerobic oxidation reactions and its application to alcohol oxidation. Org. Process Res. Dev. 19, 858–864 (2015).

    Article  CAS  Google Scholar 

  33. Hartman, R.L. Managing solids in microreactors for the upstream continuous processing of fine chemicals. Org. Process Res. Dev. 16, 870–887 (2012).

    Article  CAS  Google Scholar 

  34. Cantillo, D. et al. Sequential nitration/hydrogenation protocol for the synthesis of triaminophloroglucinol: safe generation and use of an explosive intermediate under continuous-flow conditions. Org. Process Res. Dev. 18, 1360–1366 (2014).

    Article  CAS  Google Scholar 

  35. Horie, T. et al. Photodimerization of maleic anhydride in a microreactor without clogging. Org. Process Res. Dev. 14, 405–410 (2010).

    Article  CAS  Google Scholar 

  36. Sedelmeier, J., Ley, S.V., Baxendale, I.R. & Baumann, M. KMnO4-mediated oxidation as a continuous flow process. Org. Lett. 12, 3618–3621 (2010).

    Article  CAS  Google Scholar 

  37. de Boer, Th.J. & Backer, H.J p-Tolylsulfonylmethylnitrosamide. Org. Synth. 34, 96–100 (1954).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Gutmann for help with the assembly of the tube-in-flask reactor and the workshop of the Institute of Chemistry at the University of Graz for constructing parts of the reactor (adaptions of the safety cap and production of the screw cap).

Author information

Authors and Affiliations

  1. Institute of Chemistry, University of Graz, NAWI Graz, Graz, Austria

    Doris Dallinger & C Oliver Kappe

  2. Research Center Pharmaceutical Engineering GmbH (RCPE), Graz, Austria

    C Oliver Kappe

Authors
  1. Doris Dallinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Oliver Kappe
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.D. and C.O.K. designed the experiments. D.D. carried out the experiments. Both authors contributed to the writing of the manuscript.

Corresponding author

Correspondence to C Oliver Kappe.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dallinger, D., Kappe, C. Lab-scale production of anhydrous diazomethane using membrane separation technology. Nat Protoc 12, 2138–2147 (2017). https://doi.org/10.1038/nprot.2017.046

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nprot.2017.046

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing