Nierenstein reaction

What is Nierenstein reaction?

The synthesis of α-chloromethyl ketone through the reaction of an aliphatic or aromatic acyl chloride with diazomethane was first discovered by Staudinger in 1914, and subsequently studied by Clibbens and Nierenstein in 1915, and extensively by Nierenstein. This reaction is commonly referred to as the Nierenstein reaction, although it is also sometimes called the Clibbens-Nierenstein reaction or Nierenstein chloromethylation.

Nierenstein reaction - general reaction scheme - Clibbens-Nierenstein reaction - Nierenstein chloromethylation
Nierenstein reaction

In addition to α-chloromethyl ketones, this reaction can also be used to create other reactive halides containing different elements, such as mercury, and even molecules with halogen-sensitive groups like the Si-H link.

It’s worth noting that the direct product of the reaction between an acyl chloride and diazomethane is actually a diazoketone, rather than α-chloromethyl ketone. For example, benzoyl chloride quickly transforms into diazoacetophenone when reacted with diazomethane, with the evolution of nitrogen. The diazoketones generated in situ can then decompose to produce a range of products, such as ethylenic compounds coupled from two diazoketone molecules under catalytic decomposition. When acyl chloride is added to more than two equivalents of diazomethane, the diazoketone can be obtained, purified, and further converted into corresponding acid, ester, amide or substituted amide.

However, when α-chloromethyl ketone is the desired product, the reversed process should be used, and the total amount of diazomethane restricted to the minimum needed. Excess amounts of diazomethane should be quickly added into the acyl chloride solution. It’s important to note that Nierenstein reaction is not suitable for preparing α-bromomethyl ketone as the bromine atom is less mobile. Under certain conditions, dihalogenated dioxanes can be produced, such as in the reaction between benzoyl bromide and diazomethane. In this case, 62 % 2,5-dibromo-2,5-diphenyl-1,4-dioxane is obtained while only 28 % ω-bromoacetophenone is yielded.

Similarly, when the mobility of the chlorine atom is reduced, the yield of the corresponding α-chloromethyl ketone also decreases. Examples of this include the reactions between diazomethane and phenylacetyl chloride, diphenylacetyl chloride, or triphenylacetyl chloride. The former two acetyl chlorides give 87 % and 82 % of the corresponding α-chloro-γ-phenyl-acetone and α-chloro-γ,γ-diphenyl-acetone, respectively, while the latter yields 92 % dioxane derivative. The Nierenstein reaction has been extended to a one-pot preparation of terminal olefins.

References

  • Staudinger, H., Chem. Ztg., 1914, 758
  • Clibbens, D. A. and Nierenstein, M., J. Chem. Soc., Trans., 1915, 107, 1491
  • Nierenstein, M., J. Chem. Soc., 1920, 117, 1153
  • Nierenstein, M.; Wang, D. G. and Warr, J. C., J. Am. Chem. Soc., 1924, 46, 2551
  • Nierenstein, M.; Wang, D. G. and Warr, J. C., J. Am. Chem. Soc., 1924, 46, 2554
  • Kahil, A. I. M. and Nierenstein, M., J. Am. Chem. Soc., 1924, 46, 2556
  • Lewis, H. H.; Nierenstein, M. and Rich, E. M., J. Am. Chem. Soc., 1925, 47, 1728
  • Nierenstein, M. (1928). The Nierenstein Reaction. Nature, 122(3070), 313. https://doi.org/10.1038/122313a0
  • Malkin, T. and Nierenstein, M., J. Am. Chem. Soc., 1952, 74, 1504
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