Mannich reaction
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The '''Mannich reaction''' is an [[organic reaction]] and consists of an '''amino alkylation''' of an acidic proton placed next to a [[carbonyl]] [[functional group]] with [[formaldehyde]] and [[ammonia]] or any primary or secondary [[amine]]. The final product is a β-amino-carbonyl compound <ref>Original translated from German Wiki</ref>. Reactions between [[aldimine]]s and α-methylene carbonyls are also considered Mannich reactions because these imines form between amines and aldehydes.
[[image:Mannich.png|center|500px|Scheme 1. Ammonia or an amine reacts with formaldehyde and an alpha acidic proton to a beta amino carbonyl compound]]
The reaction is named after [[Chemist]] [[Carl Mannich]] <ref>{{cite journal| author = Mannich, C.; Krosche, W.| title = Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak und Antipyrin| journal = Archiv der Pharmazie| year = 1912| volume = 250| pages = 647–667| doi = 10.1002/ardp.19122500151}}</ref>.
The Mannich reaction is an example of [[nucleophilic addition]] of an amine to a [[carbonyl]] group followed by [[elimination reaction|elimination]] of a [[hydroxyl]] anion to the [[Schiff base]]. The Schiff base is an [[electrophile]] which reacts in step two in a second [[nucleophilic addition]] with a [[carbanion]] generated from a compound containing an acidic proton. Therefore the Mannich reaction contains both an electrophilic and a nucleophilic nature. The Mannich reaction is also considered a [[condensation reaction]].
In the Mannich reaction [[ammonia]] or primary or secondary [[amine]]s are employed for the activation of [[formaldehyde]]. Tertiary amines and [[aryl]] amines stop at the Schiff base because it lacks a proton to form the intermediate [[imine]]. α-CH-acidic compounds ([[Nucleophile]]s) are [[Carbonyl]] compounds, [[Nitrile]] compounds, [[Acetylene]] compounds, aliphatic [[Nitro]] compounds, α- alkyl-[[pyridine]] compounds or [[Imine]] compounds. It is also possible to use heterocycles such as [[furan]], [[pyrrole]], and [[thiophene]], as their structure simulates the enol form of a carbonyl quite nicely.
This reaction yields β-amino carbonyl compounds and [[Mannich base]] compounds. See for example [[tropinone]].
The Mannich reaction requires high reaction temperatures, long reaction times and a protic solvent. Formation of undesired reaction by-product is a common phenomenon.
==Reaction mechanism==
The mechanism of the Mannich reaction starts with the formation of an [[iminium]] ion from the amine and the formaldehyde.
[[image:Mannichreactionmech1.svg|center|567px]]
Because the reaction takes place under acidic conditions, the compound with the carbonyl functional group (in this case a [[ketone]]) can [[Keto-enol tautomerism|tautomerize]] to the enol form, after which it can attack the iminium ion.
[[image:Mannichreactionmech2.svg|center|436px]]
[[image:Mannichreactionmech3.svg|center|650px]]
==Asymmetric Mannich reactions==
Progress has been made towards [[chiral synthesis|asymmetric]] Mannich reactions. When properly functionalized the newly formed ethylene bridge in the Mannich adduct has two [[prochiral]] centers giving rise to two diastereomeric pairs of enantiomers. The first asymmetric Mannich reaction with an unmodified aldehyde was carried with [[proline|(S)-proline]] as a naturally occurring [[optical isomerism|chiral]] [[catalyst]] <ref>{{cite journal| author = Cordova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F., III| title = A Highly Enantioselective Route to Either Enantiomer of Both α- and β-Amino Acid Derivatives| journal = [[Journal of the American Chemical Society]]| year = 2002| volume = 124| issue = 9| pages = 1866–1867| doi = 10.1021/ja017833p}}</ref>.
[[Image:Asymmetric mannich overview.png|center|500px|Scheme 4. Asymmetric Mannich reactions ref. Cordova (2002)]]
The reaction taking place is between a simple aldehyde such as [[propionaldehyde]] and an [[imine]] derived from [[glyoxylic acid|ethyl glyoxylate]] and [[aniline|para-methoxy-aniline]] (PMP = paramethoxphenyl) catalyzed by (S)-proline in [[dioxane]] at [[room temperature]]. The reaction product is [[Diastereoselectivity|diastereoselective]] with a preference for the syn-Mannich reaction 3:1 when the alkyl substituent on the aldehyde is a [[methyl]] group or 19:1 when the alkyl group the much larger [[pentyl]] group. Of the two possible syn adducts (S,S) or (R,R) the reaction is also [[enantioselective]] with a preference for the (S,S) adduct with [[enantiomeric excess]] larger than 99%. ''Scheme 5'' explains this stereoselectivity.
[[Image:SynMannichAdduct.png|center|500px|Scheme 5. Asymmetric syn-Mannich reactions ref. Cordova (2002)]]
Proline enters a [[catalytic cycle]] by reacting with the aldehyde to form an [[enamine]]. The two reactants (imine and enamine) line up for the Mannich reaction with [[Si face|Si facial]] attack of the imine by the Si-face of the enamine-aldehyde. Relieve of [[steric strain]] dictates that the alkyl residue R of the enamine and the imine group are [[antiperiplanar]] on approach which locks in the syn mode of addition. The enantioselectivity is further controlled by [[hydrogen bonding]] between the proline [[carboxylic acid]] group and the imine. The [[transition state]] for the addition is a nine-membered ring with [[chair conformation]] with partial single bonds and double bonds. The proline group is converted back to the aldehyde and a single S,S isomer is formed.
By modification of the proline catalyst to it is also possible to obtain anti-Mannich adducts <ref>{{cite journal| author = Mitsumori S., Zhang H., Ha-Yeon Cheong P., Houk K. N.,Tanaka F., Barbas III C. F.| title = Direct Asymmetric anti-Mannich-Type Reactions Catalyzed by a Designed Amino Acid| journal = [[Journal of the American Chemical Society]]| year = 2006| volume = 128| issue = 4| pages = 1040–1041| doi = 10.1021/ja056984f}}</ref>
[[Image:Anti Mannich reaction.png|center|500px|Scheme 6. Asymmetric syn-Mannich reactions ref. Mitsumori (2006)]]
An additional methyl group attached to proline forces a specific enamine approach and the transition state now is a 10-membered ring with addition in anti-mode. The diastereoselectivity is at least anti:syn 95:5 regardless of alkyl group size and the S,R [[enantiomer]] is preferred with at least 97% [[enantiomeric excess|ee]].
==Applications==
The Mannich-Reaction is employed in the [[organic synthesis]] of natural compounds like for instance [[Peptide]]s-[[Nucleotide]]s-[[Antibiotic]]s and [[Alkaloids]]. Other applications are in agro chemicals such as plant growth regulators <ref>{{cite journal| author = da Rosa F. A. F., Rebelo R. A., Nascimento II 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 = | pages = 11| url = http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532003000100003}}</ref>, paint- and [[polymer chemistry]], [[catalyst]]s and crosslinking.
The Mannich Reaction is also used in the synthesis of medicinal compounds e.g. Rolitetracycline (Mannich base of Tetracycline), Fluoxetine (Antidepressant) and Tolmetin (Antiinflammatory drug).
==References==
<div class="references-small"><references /></div>
==See also==
*[[Betti reaction]]
*[[Pictet-Spengler reaction]]
[[Category:Carbon-carbon bond forming reactions]]
[[Category:Multiple component reactions]]
[[de:Mannich-Reaktion]]
[[es:Reacción de Mannich]]
[[fr:Réaction de Mannich]]
[[ja:マンニッヒ反応]]
[[pl:Reakcja Mannicha]]
[[Category:Name reactions]]