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 (−NH2).[1] The final product is a β-amino-carbonyl compound also known as a Mannich base. The reaction is named after Carl Mannich.[2][3]
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.[4]:140
Reaction mechanism
The mechanism of the Mannich reaction starts with the formation of an iminium ion from the amine and aldehyde.[4]:140
Arrow pushing for the formation of an iminium ion
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.
Asymmetric Mannich reactions
If the enolizable ketone or aldehyde has a substituent at the α-position, proline and similar-amino acid organocatalysts may be used to achieve the Mannich reaction stereoselectively (in regard to the relative stereochemistry of α-substituent and the resulting amino functionality at the β-position of the product).
An (S)-prolinecatalyzed Mannich reaction favors the formation of the product in which the substituent and amino functionalities are syn relative to one another.[5] 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.[6] 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.
1 2 3 Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5thed.). New York: Springer. pp.140–142. ISBN978-0387683546.
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