The Mannich reaction is a chemical reaction in organic chemistry and is a amino alkylation of an acidic proton placed next to a carbonyl functional group with formaldehyde and ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl compound

History

The reaction is named after Chemist Carl Mannich.

Classification

The Mannich reaction is an example of nucleophilic addition of an amine to a carbonyl group followed by elimination of a hydroxyl anion to the Mannich base. The Mannich base is an electrophile which reacts in step two in a second nucleophilic addition with a carbanion generated from a compound containing a acidic proton. The Mannich reaction is also considered a condensation reaction.

Reactants

In the Mannich reaction ammonia or primary or secondairy amines are employed for the activation of formaldehyde. Tertairy amines and aryl amines stop at the Mannich base because it lacks a proton to form the intermediate imine. α-CH-acidic compounds (Nucleophiles) are Carbonyl compounds, Nitrile compounds, Acetylene compounds, aliphatic Nitro compounds, α- alkyl-pyridine compounds or Imine compounds.

Products

This reaction yields β-amino carbonyl compounds and Mannich-Base compounds. See for example tropinone.

Reaction conditions

The Mannich reaction requires high reaction temperatures, long reaction times and a protic solvent. Formation of undesired reaction by-product is a common phenomenon.

Reaction mechanism

The Mannich Reaction has a two part reaction mechanism

1. Formation of the Mannich base electrophile in a nucleophilic addition
2. amino alkylation of an acidic hydrogen containing compound

In the second step of the reaction a carbanion is generated from a CH acidic compound (in the example below malonic acid) under the influence of a base which then attacks the iminium salt in a second nucleophilic addition.

Applications

The Mannich-Reaction is employed in the organic synthesis of natural compounds like for instance Peptides-Nucleotides-Antibiotics und Alkaloids. Other applications are in agro chemicals, paint- and polymer chemistry, catalysts and crosslinking.

References

• Original translated from German Wiki
• Recent practical example: synthesis of new indolecarboxylic acids related to the plant hormone indoleacetic acid Flávia A. F. da RosaI, Ricardo A. RebeloI, Maria G. NascimentoII J. Braz. Chem. Soc. vol.14 p. 11 2003[1] open access publication