Mannich reaction
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In
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J.; ...
, the Mannich reaction is a three-component
organic reaction Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, Mechanistic Organ ...
that involves the amino alkylation of an acidic proton next to a
carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...
()
functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
by
formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
() and a primary or secondary
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
() or
ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...
(). The final product is a β-amino-carbonyl compound also known as a Mannich base. Reactions between
aldimine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
s and α-methylene carbonyls are also considered Mannich reactions because these
imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
s form between amines and
aldehydes In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
. The reaction is named after Carl Mannich. center, 500px, 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 In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions di ...
of an amine to a carbonyl group followed by dehydration to the
Schiff base In organic chemistry, a Schiff base (named after Hugo Schiff) is a compound with the general structure ( = alkyl or aryl, but not hydrogen). They can be considered a sub-class of imines, being either secondary ketimines or secondary aldimine ...
. The Schiff base is an
electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries ...
which reacts in a second step in an
electrophilic addition In organic chemistry, an electrophilic addition reaction is an addition reaction where a chemical compound containing a double or triple bond has a π bond broken, with the formation of two new σ bonds.March, Jerry; (1985). Advanced Organic Che ...
with an enol formed from a carbonyl compound containing an acidic alpha-proton. The Mannich reaction is a
condensation reaction In organic chemistry, a condensation reaction is a type of chemical reaction in which two molecules are combined to form a single molecule, usually with the loss of a small molecule such as water. If water is lost, the reaction is also known as a ...
. In the Mannich reaction, primary or secondary
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
s 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 (
nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...
s) that include carbonyl compounds,
nitrile In organic chemistry, a nitrile is any organic compound that has a functional group. The prefix ''cyano-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including met ...
s,
acetylene Acetylene (systematic name: ethyne) is the chemical compound with the formula and structure . It is a hydrocarbon and the simplest alkyne. This colorless gas is widely used as a fuel and a chemical building block. It is unstable in its pure ...
s, aliphatic
nitro compound In organic chemistry, nitro compounds are organic compounds that contain one or more nitro functional groups (). The nitro group is one of the most common explosophores (functional group that makes a compound explosive) used globally. The nitr ...
s, α-alkyl-
pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a d ...
s or
imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
s. It is also possible to use activated
phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
groups and electron-rich heterocycles such as
furan Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as furans. Furan is a colorless, flammable, highly ...
,
pyrrole Pyrrole is a heterocyclic aromatic organic compound, a five-membered ring with the formula C4 H4 NH. It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., ''N''-meth ...
, and
thiophene Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extensive substitution reactions. It is a colorless liquid with a benzene-like odor. In most of its reacti ...
.
Indole Indole is an aromatic heterocyclic organic compound with the formula C8 H7 N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indole is widely distributed in the natural environmen ...
is a particularly active substrate; the reaction provides
gramine Gramine (also called donaxine) is a naturally occurring indole alkaloid present in several plant species. Gramine may play a defensive role in these plants, since it is toxic to many organisms. Occurrence Gramine has been found in the giant reed, ...
derivatives. The Mannich reaction can be considered to involve a mixed-
aldol reaction The aldol reaction is a means of forming carbon–carbon bonds in organic chemistry. Discovered independently by the Russian chemist Alexander Borodin in 1869 and by the French chemist Charles-Adolphe Wurtz in 1872, the reaction combines two carb ...
, dehydration of the alcohol, and conjugate addition of an amine (
Michael reaction In organic chemistry, the Michael reaction or Michael addition is a reaction between a Michael donor (an enolate or other nucleophile) and a Michael acceptor (usually an α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon ...
) all happening in "
one-pot In chemistry a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy separ ...
". Double Mannich reactions can also occur.


Reaction mechanism

The mechanism of the Mannich reaction starts with the formation of an
iminium In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology. Structure Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with al ...
ion from the amine and formaldehyde. center, 567px The compound with the carbonyl functional group (in this case a
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
) will tautomerize to the enol form, after which it attacks the iminium ion. center, 436px center, 650px On methyl ketones, the enolization and the Mannich addition can occur twice, followed by an β-elimination to yield β-amino enone derivatives.


Asymmetric Mannich reactions

Mannich reactions can employ (''S'')-proline
chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from ...
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
. The reaction take place between
propionaldehyde Propionaldehyde or propanal is the organic compound with the formula CH3CH2CHO. It is the 3-carbon aldehyde. It is a colourless, flammable liquid with a slightly fruity odour. It is produced on a large scale industrially. Production Propionalde ...
and an
imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...
derived from
ethyl glyoxylate Glyoxylic acid or oxoacetic acid is an organic compound. Together with acetic acid, glycolic acid, and oxalic acid, glyoxylic acid is one of the C2 carboxylic acids. It is a colourless solid that occurs naturally and is useful industrially. ...
. By modification of the proline catalyst to it is also possible to obtain anti-Mannich adducts.


Applications

The Mannich reaction is used in many areas of organic chemistry, Examples include: *
alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloalk ...
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
s *
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...
s,
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
s,
antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...
s, and
alkaloids Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar st ...
(e.g.
tropinone Tropinone is an alkaloid, famously synthesised in 1917 by Robert Robinson as a synthetic precursor to atropine, a scarce commodity during World War I. Tropinone and the alkaloids cocaine and atropine all share the same tropane core structure. It ...
) *
agrochemical An agrochemical or agrichemical, a contraction of ''agricultural chemical'', is a chemical product used in industrial agriculture. Agrichemical refers to biocides ( pesticides including insecticides, herbicides, fungicides and nematicides) an ...
s, such as plant growth regulators *
polymer A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...
s *
catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
s *
Formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
tissue crosslinking *
Pharmaceutical drug A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
s (e.g. rolitetracycline (the Mannich product of
tetracycline Tetracycline, sold under various brand names, is an oral antibiotic in the tetracyclines family of medications, used to treat a number of infections, including Acne vulgaris, acne, cholera, brucellosis, plague (disease), plague, malaria, and sy ...
and pyrrolidine), fluoxetine (antidepressant),
tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an ...
and
tolmetin Tolmetin is a nonsteroidal anti-inflammatory drug (NSAID) of the heterocyclic acetic acid derivative class. It is used primarily to reduce hormones that cause pain, swelling, tenderness, and stiffness in conditions such as osteoarthritis and rh ...
(anti-inflammatory drug). * soap and detergents. These compounds are used in a variety of cleaning applications, automotive fuel treatments, and
epoxy Epoxy is the family of basic components or cured end products of epoxy resins. Epoxy resins, also known as polyepoxides, are a class of reactive prepolymers and polymers which contain epoxide groups. The epoxide functional group is also coll ...
coatings * polyetheramines from substituted branched chain alkyl
ether In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
s * α,β- unsaturated
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
s by the thermal degradation of Mannich reaction products (e.g.
methyl vinyl ketone Methyl vinyl ketone (MVK, IUPAC name: butenone) is the organic compound with the formula CH3C(O)CH=CH2. It is a reactive compound classified as an Alpha-beta Unsaturated carbonyl compounds, enone, in fact the simplest example thereof. It is a co ...
from 1-diethylamino-butan-3-one)


See also

* Betti reaction * Kabachnik–Fields reaction * Pictet–Spengler reaction *
Stork enamine alkylation The Stork enamine alkylation involves the addition of an enamine to a Michael acceptor (e.g, an enone, α,β -unsaturated carbonyl compound) or another electrophilic alkylation reagent to give an alkylated iminium product, which is hydrolyzed by d ...
*
Nitro-Mannich reaction The nitro-Mannich reaction (or ''aza-Henry reaction'') is the nucleophilic addition of a nitroalkane (or the corresponding nitronate anion) to an imine, resulting in the formation of a beta-nitroamine. With the reaction involving the addition of an ...


References


External links

* {{Authority control Carbon-carbon bond forming reactions Multiple component reactions Name reactions