In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of the α-position of a ketone or aldehyde with an aldehyde and a nullary, primary, or secondary amine (). The final product is a β-amino-carbonyl compound also known as a Mannich base. The reaction is named after Carl Mannich.
alt= A scheme of the Mannich reaction. A secondary amine, aldehyde and ketone is drawn on the left side of the reaction arrow. Written above the reaction arrow is the text "acid catalyst." To the right of the arrow, the β-amino carbonyl product formed is drawn.|center|500x500px|An acid-catalyzed three component reaction with amine, ketone or aldehyde, and an enolizable carbonyl to yield a β-amino carbonyl.
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 α-proton. The Mannich reaction is a condensation reaction.
Reaction mechanism
The mechanism of the Mannich reaction starts with the formation of an iminium ion from the amine and aldehyde. A modified proline catalyst, such as a methylated pyrrolidinecarboxylic acid, can be used to favor the formation of the product with the substituents anti to one another.
In both cases, the organocatalyst transforms the enolizable aldehyde or ketone to an (E)-enamine. The facial selectivity of the nucleophilic attack is dictated by the preferred conformation adopted by the enamine (e.g., s-cis vs. s-trans) and the relative orientations of the enamine and imine such that the carboxylic acid functionality can protonate the imine nitrogen.
center|658x658px|Scheme 4. Asymmetric Mannich reactions ref. Cordova (2002) and Mitsumori (2006)
Applications
The Mannich reaction is used in many areas of organic chemistry, Examples include:
- alkyl amines
- peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone
- 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
- Polyetheramines from substituted branched chain alkyl ethers.
- α,β-unsaturated ketones by the thermal degradation of Mannich reaction products (e.g. methyl vinyl ketone from 4-(diethylamino)butan-2-one)
See also
- Betti reaction
- Kabachnik–Fields reaction
- Petasis reaction
- Pictet–Spengler reaction
- Stork enamine alkylation
- Nitro-Mannich reaction
- Crabbé reaction
- Aza-Baylis-Hillman reaction – Mannich addition to an enone