organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...

, 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 with the formula , composed of a carbon atom double bond, double-bonded to an oxygen atom, and it is divalent at the C atom. It is common to several classes of organic compounds (such a ...

()

functional group In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...

formaldehyde Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...

() and a primary or secondary

amine In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

() or

ammonia Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...

(). The final product is a β-amino-carbonyl compound also known as a

Mannich base A Mannich base is a beta- amino-ketone, which is formed in the reaction of an amine, formaldehyde (or an aldehyde) and a carbon acid. The Mannich base is an endproduct in the Mannich reaction, which is nucleophilic addition reaction of a non-en ...

. 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 bo ...

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 bon ...

s form between amines and

aldehydes In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

. The reaction is named after Carl Mannich. Mannich Reaction V

The Mannich reaction starts with the

nucleophilic addition In organic chemistry, a nucleophilic addition (AN) 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 addit ...

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 aldim ...

. 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 Electric charge, charged, have an ...

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 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

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 name of the compound is composed of a base, which includes the carbon of the , suffixed with "nitrile", so for example is called " propionitrile" (or pr ...

acetylene Acetylene (Chemical nomenclature, systematic name: ethyne) is a 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 u ...

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 nit ...

s, α-alkyl-

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, 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, weak ...

s or

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 , and is often represented by the symbol Ph (archaically φ) or Ø. The phenyl group is closely related to benzene and can be viewed as a benzene ...

groups and electron-rich heterocycles such as

furan Furan is a Heterocyclic compound, heterocyclic organic compound, consisting of a five-membered aromatic Ring (chemistry), ring with four carbon Atom, atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as f ...

pyrrole Pyrrole is a heterocyclic, aromatic, organic compound, a five-membered ring with the formula . It is a colorless volatile liquid that darkens readily upon exposure to air. Substituted derivatives are also called pyrroles, e.g., ''N''-methylpyrrol ...

, 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 organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...

is a particularly active substrate; the reaction provides gramine derivatives. The Mannich reaction can be considered to involve a mixed-

aldol reaction The aldol reaction (aldol addition) is a Chemical reaction, reaction in organic chemistry that combines two Carbonyl group, carbonyl compounds (e.g. aldehydes or ketones) to form a new β-hydroxy carbonyl compound. Its simplest form might invol ...

, 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 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 a ...

ion from the amine and formaldehyde. Mannichreactionmech1

The compound with the carbonyl functional group (in this case a

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

) will tautomerize to the enol form, after which it attacks the iminium ion. Mannichreactionmech2

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

(''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. A substituted proline can instead catalyze the (''R'', ''S'') ''anti'' adduct. Asymmetric Mannich RXN

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 group is derived from a cy ...

s *

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

nucleotide Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy ...

s, and

alkaloids Alkaloids are a broad class of naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large variety of organisms i ...

(e.g. tropinone) *

agrochemical An agrochemical or agrichemical, a contraction of ''agricultural chemical'', is a chemical product used in industrial agriculture. Agrichemical typically refers to biocides (pesticides including insecticides, herbicides, fungicides and nematicide ...

s, such as plant growth regulators *

polymer A polymer () is a chemical substance, substance or material that consists of very large molecules, or macromolecules, that are constituted by many repeat unit, repeating subunits derived from one or more species of monomers. Due to their br ...

s *

catalyst Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

s *

Formaldehyde Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...

tissue crosslinking *

Pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, 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 ...

s (e.g. rolitetracycline (the Mannich product of

tetracycline Tetracycline, sold under various brand names, is an antibiotic in the tetracyclines family of medications, used to treat a number of infections, including acne, cholera, brucellosis, plague, malaria, and syphilis. It is available in oral an ...

and pyrrolidine),

fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

(antidepressant),

tramadol Tramadol, sold under the brand name Tramal among others, is an opioid analgesic, pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release form ...

and tolmetin (anti-inflammatory drug). * soap and detergents, especially with application to automotive fuel * Polyetheramines from substituted branched chain alkyl

ether In organic chemistry, ethers are a class of compounds that contain an ether group, a single oxygen atom bonded to two separate carbon atoms, each part of an organyl group (e.g., alkyl or aryl). They have the general formula , where R and R� ...

s. * α,β- unsaturated

s by the thermal degradation of Mannich reaction products (e.g. methyl vinyl ketone from 4-(diethylamino)butan-2-one)

References

External links

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

Reaction mechanism

Asymmetric Mannich reactions

Applications

See also

References

External links