Mannich reaction

The Mannich reaction is an organic reaction which consists of an amino alkylation of an acidic proton placed next to a carbonyl functional group by formaldehyde and a primary or secondary amine or ammonia. The final product is a β-amino-carbonyl compound also known as a Mannich base.^[1] 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 chemist Carl Mannich.^[2][3]

The Mannich reaction is an example of 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 the second step in an electrophilic addition with a compound containing an acidic proton (which is, or had become an enol). The Mannich reaction is also considered a condensation reaction.

In the Mannich reaction, primary or secondary amines or ammonia, are employed for the activation of formaldehyde. Tertiary amines lack an N–H proton to form the intermediate enamine. α-CH-acidic compounds (nucleophiles) 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.

When rationalizing the Mannich reaction, it can be clearly understood to be a mixed-Aldol reaction, dehydration of the alcohol, and conjugate addition of an amine (Michael reaction) all happening in "one-pot". Double Mannich reactions are also very common to set-up.

Reaction mechanism[]

The mechanism of the Mannich reaction starts with the formation of an iminium ion from the amine and the formaldehyde. Please note, the mechanism shown below is NOT correct. The pKa of the protonated oxygen is approximately -2. The amine base would simply deprotonate the carbonyl and stop the reaction. Consequently, it is imperative that this reaction is performed at a pH of approximately 4-5. The correct mechanism should start with a nucleophilic attack by the nitrogen atom on the carbonyl carbon.

The compound with the carbonyl functional group (in this case a ketone) can tautomerize to the enol form, after which it can attack 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.^[4][5]

Asymmetric Mannich reactions[]

Mannich reactions can employ (S)-proline chiral catalyst.^[6]

The reaction take place between propionaldehyde and an imine derived from ethyl glyoxylate. By modification of the proline catalyst to it is also possible to obtain anti-Mannich adducts.^[7]

Applications[]

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

• alkyl amines
• peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone)
• agrochemicals, such as plant growth regulators^[8]
• 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. These compounds are used in a variety of cleaning applications, automotive fuel treatments, and epoxy coatings
• polyetheramines from substituted branched chain alkyl ethers^[9]
• α,β-unsaturated ketones by the thermal degradation of Mannich reaction products (e.g. methyl vinyl ketone from 1-diethylamino-butan-3-one)^[10][11]

See also[]

• Betti reaction
• Kabachnik–Fields reaction
• Pictet–Spengler reaction
• Stork enamine alkylation
• Nitro-Mannich reaction

References[]

External links[]

• "Mechanism in Motion: Mannich reaction".