Mannich reaction
Reaction in organic chemistry From Wikipedia, the free encyclopedia
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]
 | It has been suggested that Betti reaction be merged into this article. (Discuss) Proposed since January 2025. |
| Mannich reaction | |
|---|---|
| Named after | Carl Mannich |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | mannich-reaction |
| RSC ontology ID | RXNO:0000032 |
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 an asymmetric 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]
See also
References
External links
Wikiwand - on
Seamless Wikipedia browsing. On steroids.