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Mannich Reaction

The Mannich reaction is a nucleophilic addition of an amine to a carbonyl group to form an imine intermediate. This intermediate then reacts with an electrophilic α-carbon atom, typically from an enolizable carbonyl compound, to form a β-amino-carbonyl product. The reaction requires an amine, formaldehyde, and a compound containing an acidic proton and carbonyl group. It is a versatile reaction used in the synthesis of natural products, medicines, agrochemicals, polymers, and more. Recent advances allow for asymmetric Mannich reactions with high diastereo- and enantioselectivity using chiral proline-based catalysts.

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786 views4 pages

Mannich Reaction

The Mannich reaction is a nucleophilic addition of an amine to a carbonyl group to form an imine intermediate. This intermediate then reacts with an electrophilic α-carbon atom, typically from an enolizable carbonyl compound, to form a β-amino-carbonyl product. The reaction requires an amine, formaldehyde, and a compound containing an acidic proton and carbonyl group. It is a versatile reaction used in the synthesis of natural products, medicines, agrochemicals, polymers, and more. Recent advances allow for asymmetric Mannich reactions with high diastereo- and enantioselectivity using chiral proline-based catalysts.

Uploaded by

Sirisha Narapalli
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© Attribution Non-Commercial (BY-NC)
We take content rights seriously. If you suspect this is your content, claim it here.
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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 with formaldehyde and ammonia or
any primary or secondary amine. The final product is a β-amino-carbonyl compound also
known as aMannich 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 a nucleophilic addition with a compound containing an acidic proton. The
Mannich reaction is also considered a condensation reaction.In the Mannich
reaction, ammonia or primary or secondary amines are employed for the activation
of formaldehyde. Tertiary amines lack an N-H proton to form the intermediate imine. α-CH-
acidic compounds (nucleophiles) include carbonyl compounds, nitriles, acetylenes,
aliphaticnitro 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.

[edit]Reaction mechanism
The mechanism of the Mannich reaction starts with the formation of an iminium ion from the
amine and the formaldehyde.

Because the reaction takes place under acidic conditions, the compound with the carbonyl
functional group (in this case a ketone) cantautomerize to the enol form, after which it can
attack the iminium ion.
[edit]Asymmetric Mannich reactions
Progress has been made towards 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 (S)-proline as a
naturally occurring chiral catalyst.[4]

The reaction taking place is between a simple aldehyde such as propionaldehyde and
an imine derived from ethyl glyoxylate and p-methoxyaniline (PMP = paramethoxphenyl)
catalyzed by (S)-proline in dioxane at room temperature. The reaction product
is diastereoselectivewith 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%. This stereoselectivity is explained in the scheme below.
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 facial attack of the
imine by the Si-face of the enamine-aldehyde. Relief 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.[5]
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% ee.

[edit]Applications

The Mannich-Reaction is employed in the organic synthesis of natural compounds such


as peptides, nucleotides, antibiotics, and alkaloids(e.g. tropinone). Other applications are in
agro chemicals such as plant growth regulators,[6] paint- and polymer
chemistry, catalysts and crosslinking.

The Mannich reaction is also used in the synthesis of medicinal compounds


e.g. rolitetracycline (Mannich base of tetracycline), fluoxetine(antidepressant), tramadol,
and tolmetin (anti-inflammatory drug).

[eference

1. ^ Original translated from German Wiki

2. ^ Mannich, C.; Krösche, W. (1912). "Ueber ein Kondensationsprodukt aus Formaldehyd,


Ammoniak und Antipyrin". Archiv der Pharmazie 250:
647. doi:10.1002/ardp.19122500151. edit

3. ^ Blicke, F. F. Org. React. 1942, 1.

4. ^ Córdova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas Cf, 3. (2002). "A highly
enantioselective route to either enantiomer of both alpha- and beta-amino acid
derivatives". Journal of the American Chemical Society 124 (9): 1866–
1867. doi:10.1021/ja017833p. PMID 11866595. edit

5. ^ Mitsumori, S.; Zhang, H.; Ha-Yeon Cheong, P.; Houk, K.; Tanaka, F.; Barbas Cf, 3.
(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.PMID 16433496. edit
6. ^ da Rosa F. A. F., Rebelo R. A., Nascimento II M. G. (2003). "Synthesis of new
indolecarboxylic acids related to the plant hormone indoleacetic acid". Journal of the
Brazilian Chemical Society 14: 11. doi:10.1590/S0103-50532003000100003.

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