Mannich reaction
{{merge from|Betti reaction|discuss=Talk:Mannich_reaction#Merge proposal|date=January 2025}}
{{Short description|Reaction in organic chemistry}}
{{Use dmy dates|date=April 2023}}
{{Reactionbox
| Name = Mannich reaction
| Type = Coupling reaction
| NamedAfter = Carl Mannich
| Section3 = {{Reactionbox Identifiers
| OrganicChemistryNamed = mannich-reaction
| RSC_ontology_id = 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 ({{chem2|C\dO}}) functional group by formaldehyde ({{chem2|H\sCHO}}) and a primary or secondary amine ({{chem2|\sNH2}}) or ammonia ({{chem2|NH3}}).{{cite book | first1 = Michael B. | last1 = Smith | first2 = Jerry | last2 = March | title = March's Advanced Organic Chemistry | publisher = John Wiley & Sons | year = 2007 | edition=6th | isbn = 978-0-471-72091-1 | pages = 1292–1295 }} 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.{{Cite journal| author1 = Carl Mannich| author-link = Carl Mannich| last2 = Krösche| first2 = W.| title = Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin| journal = Archiv der Pharmazie| volume = 250| issue= 1| pages = 647–667| year = 1912| doi = 10.1002/ardp.19122500151| s2cid = 94217627| language = German| url = https://zenodo.org/record/1424583}}{{cite journal|last = Blicke|first = F. F.|journal = Organic Reactions|year = 2011|title = The Mannich Reaction|volume = 1|issue = 10|pages = 303–341|doi = 10.1002/0471264180.or001.10|isbn = 978-0471264187}}
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.{{cite book |ref=Carey |year=2007 |title=Advanced Organic Chemistry: Part B: Reactions and Synthesis |edition=5th |publisher=Springer |place=New York |author1=Carey, Francis A. |author2=Sundberg, Richard J. |isbn=978-0387683546|pages=140–142}}{{rp|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.{{rp|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.{{cite journal |last1=Cromwell |first1=Norman H. |last2=Soriano |first2=David S. |last3=Doomes |first3=Earl |title=Mobile keto allyl systems. 18. Synthesis and chemistry of N-substituted and N,N-disubstituted 2-benzoyl-1-amino-3-propenes |journal=The Journal of Organic Chemistry |date=November 1980 |volume=45 |issue=24 |pages=4983–4985 |doi=10.1021/jo01312a034}}{{cite journal |last1=Girreser |first1=Ulrich |last2=Heber |first2=Dieter |last3=Schütt |first3=Martin |title=A Facile One-Pot Synthesis of 1-Aryl-2-(dimethylaminomethyl)prop-2-en-1-ones from Aryl Methyl Ketones |journal=Synthesis |date=May 1998 |volume=1998 |issue=5 |pages=715–717 |doi=10.1055/s-1998-2056}}
Asymmetric Mannich reactions
(S)-proline catalyzes an asymmetric Mannich reaction. It diastereoselects the syn adduct, with greater effect for larger aldehyde substituents; and enantioselects the (S, S) adduct.{{Cite journal | last1 = Córdova | first1 = A. | last2 = Watanabe | first2 = S.-I. | last3 = Tanaka | first3 = F. | last4 = Notz | first4 = W. | last5 = Barbas | first5 = C. F.| title = A highly enantioselective route to either enantiomer of both α- and β-amino acid derivatives | journal = Journal of the American Chemical Society | volume = 124 | issue = 9 | pages = 1866–1867 | year = 2002 | pmid = 11866595 | doi = 10.1021/ja017833p| bibcode = 2002JAChS.124.1866C }} A substituted proline can instead catalyze the (R, S) anti adduct.{{Cite journal |last1=Mitsumori |first1=S. |last2=Zhang |first2=H. |last3=Cheong |first3=P. H.-Y. |last4=Houk |first4=K. |last5=Tanaka |first5=F. |last6=Barbas |first6=C. F. |year=2006 |title=Direct asymmetric anti-Mannich-type reactions catalyzed by a designed amino acid |journal=Journal of the American Chemical Society |volume=128 |issue=4 |pages=1040–1041 |doi=10.1021/ja056984f |pmc=2532695 |pmid=16433496|bibcode=2006JAChS.128.1040M }}
Applications
The Mannich reaction is used in many areas of organic chemistry, Examples include:
- alkyl amines
- peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone{{rp|142}})
- agrochemicals, such as plant growth regulators{{cite journal| doi = 10.1590/S0103-50532003000100003| doi-access = free| last1 = da Rosa| first1 = F. A. F.| last2 = Rebelo| first2 = R. A.| last3 = Nascimento| first3 = M. G.| title = Synthesis of new indolecarboxylic acids related to the plant hormone indoleacetic acid| journal = Journal of the Brazilian Chemical Society| year = 2003| volume = 14| issue = 1| pages = 11–15| url = http://www.scielo.br/pdf/jbchs/v14n1/a03v14n1.pdf}}
- 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{{cite conference|url=http://papers.sae.org/2000-01-2020/|title=A Study of Fuel Additives for Direct Injection Gasoline (DIG) Injector Deposit Control|first1=Allen A.|last1=Aradi|first2=William J.|last2=Colucci|first3=Herbert M.|last3=Scull|first4=Martin J.|last4=Openshaw|date=June 19–22, 2000|conference=CEC/SAE Spring Fuels & Lubricants Meeting & Exposition|publisher=CEC and SAE International|location=Warrendale, PA|id=2000-01-2020|issn=0148-7191|doi=10.4271/2000-01-2020|access-date=20 August 2023}}
- Polyetheramines from substituted branched chain alkyl ethers.{{Cite journal |last1=Wang |first1=Wenying |last2=Wang |first2=Wei |last3=Zhu |first3=Zhongpeng |last4=Hu |first4=Xiaoming |last5=Qiao |first5=Fulin |last6=Yang |first6=Jing |last7=Liu |first7=Dan |last8=Chen |first8=Pu |last9=Zhang |first9=Qundan |date=2023-04-15 |title=Quantitation of polyetheramines as the active components of detergent additives in gasoline by the ninhydrin reaction |url=https://www.sciencedirect.com/science/article/pii/S0016236122040996 |journal=Fuel |volume=338 |pages=127275 |doi=10.1016/j.fuel.2022.127275 |bibcode=2023Fuel..33827275W |issn=0016-2361}}{{Cite journal |last1=Kuo |first1=Chung-Hao |last2=Smocha |first2=Ruth |last3=Loeper |first3=Paul |last4=Mukkada |first4=Nicholas |last5=Simpson Green |first5=Felicia |date=2022-08-30 |title=Aftermarket Fuel Additives and their Effects on GDI Injector Performance and Particulate Emissions |url=https://doi.org/10.4271/2022-01-1074 |journal=SAE Technical Paper Series |volume=1 |language=en |location=400 Commonwealth Drive, Warrendale, PA, United States |publisher=SAE International |doi=10.4271/2022-01-1074}}
- α,β-unsaturated ketones by the thermal degradation of Mannich reaction products (e.g. methyl vinyl ketone from 1-diethylamino-butan-3-one){{Ullmann| last1 = Siegel| first1 = H.|last2 = Eggersdorfer| first2 = M.| title = Ketones| doi = 10.1002/14356007.a15_077}}{{OrgSynth|last1 = Wilds|first1 = A. L.|last2 = Nowak|first2 = R. M.|last3 = McCaleb|first3 = K. E.|title = 1-Diethylamino-3-butanone (2-Butanone, 4-diethylamino-)|year = 1957|volume = 37|pages = 18|doi=10.15227/orgsyn.037.0018|collvol = 4|collvolpages = 281|prep = CV4P0281}}
See also
References
{{Reflist}}
External links
- {{cite web | url = https://www.youtube.com/watch?v=HUVQ3SNz7m0 | title = Mechanism in Motion: Mannich reaction| date = 20 August 2010| via = YouTube}}
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Category:Carbon-carbon bond forming reactions