Tscherniac-Einhorn reaction

What is Tscherniac-Einhorn reaction?

In 1901, Tscherniac reported the first instance of a reaction involving the condensation of N-hydroxymethylphthalimide with various aromatic compounds, such as o-nitrotoluene. In 1905, Einhorn expanded upon Tscherniac’s work by demonstrating the condensation between N-hydroxymethylchloroacetinide and benzoic or cinnamic acid. Tscherniac-Einhorn reaction is now commonly referred to as the Tscherniac-Einhorn amidomethylation, Tscherniac-Einhorn aromatic amidoalkylation, or Tscherniac-Einhorn synthesis, and the N-hydroxymethylamide and N-hydroxymethylimide are known as Tscherniac-Einhorn reagents.

Tscherniac-Einhorn reaction - general reaction scheme
Tscherniac-Einhorn reaction

Typically, Tscherniac-Einhorn reaction is catalyzed by a strong acid, such as CH3SO3H, H2SO4, H2SO4-AcOH, p-TsOH, or CF3CO2H / CH2Cl2. The resulting N-arylmethyl amides or imides can then be hydrolyzed to produce arylmethylamines. Strong H2SO4 can convert N-hydroxymethylphthalimide into a highly nucleophilic intermediate that can even react with nitrobenzene or 2,4-dinitrophenol.

To achieve mono-amidoalkylation products, the stoichiometry and reaction conditions must be carefully controlled due to the high nucleophilicity of the carbocation intermediate.

For example, the amidoalkylation of aromatic compounds with electron-donating groups should be carried out in H2SO4/AcOH, while compounds with electron-withdrawing groups require concentrated H2SO4. The dehydration of N-hydroxymethylamides remains the common method for forming N-acyliminium ions.