Mannich reaction

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]

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 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]

See also

References
  1. Smith, Michael B.; March, Jerry (2007). March's Advanced Organic Chemistry (6th ed.). John Wiley & Sons. pp. 1292–1295. ISBN 978-0-471-72091-1.
  2. Carl Mannich; Krösche, W. (1912). "Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin". Archiv der Pharmazie (in German). 250 (1): 647–667. doi:10.1002/ardp.19122500151. S2CID 94217627.
  3. Blicke, F. F. (2011). "The Mannich Reaction". Organic Reactions. 1 (10): 303–341. doi:10.1002/0471264180.or001.10. ISBN 978-0471264187.
  4. Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. pp. 140–142. ISBN 978-0387683546.
  5. Cromwell, Norman H.; Soriano, David S.; Doomes, Earl (November 1980). "Mobile keto allyl systems. 18. Synthesis and chemistry of N-substituted and N,N-disubstituted 2-benzoyl-1-amino-3-propenes". The Journal of Organic Chemistry. 45 (24): 4983–4985. doi:10.1021/jo01312a034.
  6. Girreser, Ulrich; Heber, Dieter; Schütt, Martin (May 1998). "A Facile One-Pot Synthesis of 1-Aryl-2-(dimethylaminomethyl)prop-2-en-1-ones from Aryl Methyl Ketones". Synthesis. 1998 (5): 715–717. doi:10.1055/s-1998-2056.
  7. Córdova, A.; Watanabe, S.-I.; Tanaka, F.; Notz, W.; Barbas, C. F. (2002). "A highly enantioselective route to either enantiomer of both α- and β-amino acid derivatives". Journal of the American Chemical Society. 124 (9): 1866–1867. doi:10.1021/ja017833p. PMID 11866595.
  8. Mitsumori, S.; Zhang, H.; Cheong, P. H.-Y.; Houk, K.; Tanaka, F.; Barbas, C. F. (2006). "Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid". Journal of the American Chemical Society. 128 (4): 1040–1041. doi:10.1021/ja056984f. PMC 2532695. PMID 16433496.
  9. da Rosa, F. A. F.; Rebelo, R. A.; Nascimento, M. G. (2003). "Synthesis of new indolecarboxylic acids related to the plant hormone indoleacetic acid" (PDF). Journal of the Brazilian Chemical Society. 14 (1): 11–15. doi:10.1590/S0103-50532003000100003.
  10. Aradi, Allen A.; Colucci, William J.; Scull, Herbert M.; Openshaw, Martin J. (19–22 June 2000). A Study of Fuel Additives for Direct Injection Gasoline (DIG) Injector Deposit Control. CEC/SAE Spring Fuels & Lubricants Meeting & Exposition. Warrendale, PA: CEC and SAE International. doi:10.4271/2000-01-2020. ISSN 0148-7191. 2000-01-2020. Retrieved 20 August 2023.
  11. Wang, Wenying; Wang, Wei; Zhu, Zhongpeng; Hu, Xiaoming; Qiao, Fulin; Yang, Jing; Liu, Dan; Chen, Pu; Zhang, Qundan (15 April 2023). "Quantitation of polyetheramines as the active components of detergent additives in gasoline by the ninhydrin reaction". Fuel. 338: 127275. doi:10.1016/j.fuel.2022.127275. ISSN 0016-2361.
  12. Kuo, Chung-Hao; Smocha, Ruth; Loeper, Paul; Mukkada, Nicholas; Simpson Green, Felicia (30 August 2022). "Aftermarket Fuel Additives and their Effects on GDI Injector Performance and Particulate Emissions". SAE Technical Paper Series. 400 Commonwealth Drive, Warrendale, PA, United States: SAE International. doi:10.4271/2022-01-1074.{{cite journal}}: CS1 maint: location (link)
  13. Siegel, H.; Eggersdorfer, M. "Ketones". Ullmann's Encyclopedia of Industrial Chemistry. Weinheim: Wiley-VCH. doi:10.1002/14356007.a15_077. ISBN 978-3527306732.
  14. Wilds, A. L.; Nowak, R. M.; McCaleb, K. E. (1957). "1-Diethylamino-3-butanone (2-Butanone, 4-diethylamino-)". Organic Syntheses. 37: 18. doi:10.15227/orgsyn.037.0018; Collected Volumes, vol. 4, p. 281.
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