Zincke reaction

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.



The Zincke reaction should not be confused with the Zincke-Suhl reaction or the Zincke nitration. Furthermore, the Zincke reaction has nothing to do with the chemical element zinc.

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 (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). This has been suggested to be the rate-determining step. 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 (AN), ring opening and ring closing.

Applications
In one solid-phase synthesis application, the amine is covalently attached to Wang resin.



Another example is the synthesis of a chiral isoquinolinium salt.



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 :



This variation has been applied in the synthesis of novel indoles :



with cyanogen bromide mediated pyridine activation.