In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of an acidic proton next to a carbonyl (C=O) functional group by formaldehyde (H−CHO) and a primary or secondary amine (−NH₂) or ammonia (NH₃).^[1] The final product is a β-amino-carbonyl compound also known as a Mannich base. Reactions between aldimines and α-methylene carbonyls are also considered Mannich reactions because these imines form between amines and aldehydes. The reaction is named after Carl Mannich.^[2][3]

The Mannich reaction starts with the nucleophilic addition of an amine to a carbonyl group followed by dehydration to the Schiff base. The Schiff base is an electrophile which reacts in a second step in an electrophilic addition with an enol formed from a carbonyl compound containing an acidic alpha-proton. The Mannich reaction is a condensation reaction.^[4]: 140

In the Mannich reaction, primary or secondary amines or ammonia react with formaldehyde to form a Schiff base. Tertiary amines lack an N–H proton and so do not react. The Schiff base can react with α-CH-acidic compounds (nucleophiles) that include carbonyl compounds, nitriles, acetylenes, aliphatic nitro compounds, α-alkyl-pyridines or imines. It is also possible to use activated phenyl groups and electron-rich heterocycles such as furan, pyrrole, and thiophene. Indole is a particularly active substrate; the reaction provides gramine derivatives.

The Mannich reaction can be considered to involve a mixed-aldol reaction, dehydration of the alcohol, and conjugate addition of an amine (Michael reaction) all happening in "one-pot". Double Mannich reactions can also occur.

Reaction mechanism

The mechanism of the Mannich reaction starts with the formation of an iminium ion from the amine and formaldehyde.^[4]: 140

The compound with the carbonyl functional group (in this case a ketone) will tautomerize to the enol form, after which it attacks the iminium ion.

On methyl ketones, the enolization and the Mannich addition can occur twice, followed by an β-elimination to yield β-amino enone derivatives.^[5][6]

Asymmetric Mannich reactions

(S)-proline catalyzes a chiral Mannich reaction. It diastereoselects the syn adduct, with greater effect for larger aldehyde substituents; and enantioselects the (S, S) adduct.^[7] A substituted proline can instead catalyze the (R, S) anti adduct.^[8]

Applications

The Mannich reaction is used in many areas of organic chemistry, Examples include:

• alkyl amines
• peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone^[4]: 142)
• agrochemicals, such as plant growth regulators^[9]
• polymers
• catalysts
• Formaldehyde tissue crosslinking
• Pharmaceutical drugs (e.g. rolitetracycline (the Mannich product of tetracycline and pyrrolidine), fluoxetine (antidepressant), tramadol and tolmetin (anti-inflammatory drug).
• soap and detergents, especially with application to automotive fuel^[10]
• Polyetheramines from substituted branched chain alkyl ethers.^[11][12]
• α,β-unsaturated ketones by the thermal degradation of Mannich reaction products (e.g. methyl vinyl ketone from 1-diethylamino-butan-3-one)^[13][14]