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Lab-scale production of anhydrous diazomethane using membrane separation technology

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.

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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.

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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).

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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.

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Correspondence to C Oliver Kappe.

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The authors declare no competing financial interests.

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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

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