Wibaut-Arens alkylation

What is Wibaut-Arens alkylation?

In 1921, Dimroth and Heene reported the reductive acylation of pyridine with acetic anhydride and zinc, resulting in the formation of N,N-diacetyl-1,4,1,4-tetrahydro-4,4-dipyridyl. Later on, Wibaut and Arens extended this reaction to the synthesis of 4-ethylpyridine in the early 1940s, and this preparation method is now known as the Wibaut-Arens alkylation or Wibaut-Arens reaction.

Wibaut-Arens alkylation - general reaction scheme - Wibaut-Arens reaction
Wibaut-Arens alkylation

Pyridine is an electron-deficient aromatic compound that typically does not undergo the Friedel-Crafts acylation or Friedel-Crafts alkylation reactions. Instead, it can be used as a solvent for acylation or alkylation, similar to nitrobenzene. Pyridine often reacts with nucleophilic anions, such as NH2− (Chichibabin amination). However, in the presence of zinc, N-acetylated pyridinium can be reduced by zinc through a single electron transfer process, and the resulting radical species dimerizes to form 1,1-diacetyl-1,4,1,4-tetrahydro-bipyridine. Upon further treatment with acetic acid and zinc, this intermediate decomposes to give an equal amount of pyridine and 4-acetylpyridine, and the latter is then reduced to 4-ethylpyridine by zinc.

The theoretical yield of 4-ethylpyridine using this method is 50 %. Various 4-alkylpyridines have been prepared by the use of other acid anhydrides. Additionally, 2-methyl-4-ethylpyridine and 3-methyl-4-ethylpyridine are obtained from 2-picoline and 3-picoline, respectively. However, due to steric hindrance for the potential dimerization of 2-position radical, 2-ethylpyridine has not been obtained from this reaction.

It is worth noting that a comparable yield of 4-ethylpyridine can be obtained from the reaction with either an activated zinc or regular zinc powder. Although the reaction can be improved by the use of iron rather than zinc, the iron filings and impure iron powder usually lead to a lower yield of 4-ethylpyridine than that from pure iron powder. Interestingly, the iron-mediated reaction is more readily controllable at higher temperatures (e.g., 80–100 ºC) by the addition of iron than the one performed at 35–40 ºC. Using platinum oxide and acetic anhydride, 4,4-bipiperidyl was obtained from pyridine.

The use of this reaction is significant in the synthesis of pyridine derivatives, particularly in the production of isonicotinic acid derivatives.

References

Dimroth, O. and Heene, R., Ber., 1921, 54, 2934

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