Zincke reaction

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The Zincke reaction is an organic reaction in which a pyridine is transformed into a pyridinium salt by reaction with 2,4-dinitro-chlorobenzene and a primary amine.^[1]

The Zincke reaction should not be confused with the Zincke-Suhl reaction or the Zincke nitration.

1 Reaction mechanism
2 Applications
3 Zincke aldehydes
4 References

[edit] Reaction mechanism

The first reaction is the formation of the N-2,4-dinitrophenyl-pyridinium salt (2). This salt is typically isolated and purified by recrystallization.

Upon heating a primary amine with the N-2,4-dinitrophenyl-pyridinium salt (2), the addition of the amine leads to the opening of the pyridinium ring. A second addition of amine leads to the displacement of 2,4-dinitroaniline (5) and formation of the König salt ^[2] (6a and 6b). The trans-cis-trans isomer of the König salt (6a) can react by either sigmatropic rearrangement or nucleophilic addition of a zwitterionic intermediate to give cyclized intermediate (7).^[3] This has been suggested to be the rate-determining step.^[4]^[5] After proton transfer and amine elimination, the desired pyridinium ion (9) is formed.

This mechanism can be referred to as an instance of the ANRORC mechanism: nucleophilic addition (A_N), ring opening and ring closing.

[edit] Applications

In one solid-phase synthesis application, the amine is covalently attached to Wang resin.^[6]

Another example is the synthesis of a chiral isoquinolinium salt.^[7]

[edit] Zincke aldehydes

With secondary amines and not primary amines the Zincke reaction takes on a different shape forming so-called Zincke aldehydes in which the pyridine ring is ring-opened with the terminal imine group hydrolyzed to an aldehyde ^[8] :

This variation has been applied in the synthesis of novel indoles ^[9] :

with cyanogen bromide mediated pyridine activation.

[edit] References

^ (a) Zincke, Th.; Heuser, G.; Moller, W. Justus Liebigs Ann. Chem. 1904, 333, 296. (b) Zincke, Th. Justus Liebigs Ann. Chem. 1903, 330, 361. (c) Zincke, T. H.; Weisspfenning, G. Justus Liebigs Ann. Chem. 1913, 396, 103.
^ König, W. J. Prakt. Chem. 1904, 69, 105.
^ Kunugi, S.; Okubo, T.; Ise, N. J. Am. Chem. Soc. 1976, 98, 2282-2287. (DOI:10.1021/ja00424a047)
^ Marvell, E. N.; Caple, G.; Shahidi, I. J. Am. Chem. Soc. 1970, 92, 5641-5645. (DOI:10.1021/ja00722a016)
^ Marvell, E. N.; Shahidi, I. J. Am. Chem. Soc. 1970, 92, 5646-5649. (DOI:10.1021/ja00722a017)
^ "The Solid-Phase Zincke Reaction: Preparation of -Hydroxy Pyridinium Salts in the Search for CFTR Activation" Eda, M.; Kurth, M. J.; Nantz, M. H. J. Org. Chem. 2000, 65(17), 5131 - 5135. (DOI:10.1021/jo0001636)
^ New Chiral Isoquinolinium Salt Derivatives from Chiral Primary Amines via Zincke Reaction Denis Barbier, Christian Marazano, Bhupesh C. Das, and Pierre Potier J. Org. Chem.; 1996; 61(26) pp 9596 - 9598; (Note) DOI:10.1021/jo961539b
^ T. Zincke, W. Wurker, Justus Liebigs Ann. Chem. 1905, 338, 107 – 141;
^ Synthesis of Nitrogen Heterocycles by the Ring Opening of Pyridinium Salts Aaron M. Kearney, Christopher D. Vanderwal Angew. Chem. Int. Ed. 2006, 45, 7803 –7806 DOI:10.1002/anie.200602996