Mannich reaction
Named after Carl Mannich
Reaction type Coupling reaction
Identifiers
Organic Chemistry Portal mannich-reaction
RSC ontology ID RXNO:0000032

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]

Scheme 1 – Ammonia or an amine reacts with formaldehyde and an alpha acidic proton of a carbonyl compound to a beta amino carbonyl compound.
Scheme 1 – Ammonia or an amine reacts with formaldehyde and an alpha acidic proton of a carbonyl compound to a beta amino carbonyl compound.

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]

Scheme 4. Asymmetric Mannich reactions ref. Cordova (2002) and Mitsumori (2006)
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:

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. 1 2 3 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.; Collective Volume, vol. 4, p. 281
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