Michael reaction
Overview
 
The Michael reaction or Michael addition is the nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....

 of a carbanion
Carbanion
A carbanion is an anion in which carbon has an unshared pair of electrons and bears a negative charge usually with three substituents for a total of eight valence electrons. The carbanion exists in a trigonal pyramidal geometry. Formally a carbanion is the conjugate base of a carbon acid.where B...

 or another nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...

 to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds. Many asymmetric variants exist.


In this scheme the R and R' substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...

s on the nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...

 (a Michael donor) are electron-withdrawing groups such as acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...

 and cyano making the methylene hydrogen acidic forming the carbanion on reaction with base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 B:.
Discussions
Encyclopedia
The Michael reaction or Michael addition is the nucleophilic addition
Nucleophilic addition
In organic chemistry, a nucleophilic addition reaction is an addition reaction where in a chemical compound a π bond is removed by the creation of two new covalent bonds by the addition of a nucleophile....

 of a carbanion
Carbanion
A carbanion is an anion in which carbon has an unshared pair of electrons and bears a negative charge usually with three substituents for a total of eight valence electrons. The carbanion exists in a trigonal pyramidal geometry. Formally a carbanion is the conjugate base of a carbon acid.where B...

 or another nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...

 to an alpha, beta unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C-C bonds. Many asymmetric variants exist.


In this scheme the R and R' substituent
Substituent
In organic chemistry and biochemistry, a substituent is an atom or group of atoms substituted in place of a hydrogen atom on the parent chain of a hydrocarbon...

s on the nucleophile
Nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...

 (a Michael donor) are electron-withdrawing groups such as acyl
Acyl
An acyl group is a functional group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids.In organic chemistry, the acyl group is usually derived from a carboxylic acid . Therefore, it has the formula RCO-, where R represents an alkyl group that is...

 and cyano making the methylene hydrogen acidic forming the carbanion on reaction with base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 B:. The substituent on the activated alkene
Alkene
In organic chemistry, an alkene, olefin, or olefine is an unsaturated chemical compound containing at least one carbon-to-carbon double bond...

, also called a Michael acceptor, is usually a ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...

 making it an enone
Enone
An enone is an unsaturated chemical compound or functional group consisting of a conjugated system of an alkene and a ketone. The simplest enone is methyl vinyl ketone or CH2=CHCOCH3....

, but it can also be a nitro
Nitro
-Chemistry:*Nitroglycerin, an explosive chemical compound*Nitromethane, the simplest organic nitro compound; also used to fuel high-performance internal-combustion engines*Nitrous oxide, "laughing gas", used in some dental procedures as an anaesthetic...

 group.

Definition

As originally defined by Arthur Michael
Arthur Michael
Arthur Michael was an American organic chemist who is best known for the Michael reaction.- Life :Arthur Michael was born into a wealthy family in Buffalo, New York in 1853, the son of John and Clara Michael, well-off real-estate investor...

, the reaction is the addition of an enolate of a ketone or aldehyde to an α,β-unsaturated carbonyl compound at the β carbon. A newer definition, proposed by Kohler, is the 1,4-addition of a doubly stabilized carbon nucleophile to an α,β-unsaturated carbonyl compound. Some examples of nucleophiles include beta-ketoesters, malonate
Malonate
The malonate or propanedioate ion is CH222− . Malonate compounds include salts and esters of malonic acid, such as*diethyl malonate, 2,*dimethyl malonate, 2,...

s, and beta-cyanoesters. The resulting product contains a highly useful 1,5-dioxygenated pattern.

Classical examples of the Michael reaction are the reaction between diethyl malonate
Diethyl malonate
Diethyl malonate, also known as DEM, is the diethyl ester of malonic acid. It occurs naturally in grapes and strawberries as a colourless liquid with an apple-like odour, and is used in perfumes...

 (Michael donor) and diethyl fumarate (Michael acceptor), that of mesityl oxide
Mesityl oxide
Mesityl oxide is a α,β-Unsaturated ketone with the formula CH3CCH=C2. This compound is a colorless, volatile liquid with a strong peppermint odor.-Synthesis:...

 and diethyl malonate, that of diethyl malonate and methyl crotonate, that of 2-nitropropane and methyl acrylate
Methyl acrylate
Methyl acrylate is a volatile chemical compound classified as a methyl ester. It has a characteristic acrid odor used in the preparation of polyamidoamine dendrimers typically by Michael addition with a primary amine....

, that of ethyl phenylcyanoacetate and acrylonitrile
Acrylonitrile
Acrylonitrile is the chemical compound with the formula C3H3N. This pungent-smelling colorless liquid often appears yellow due to impurities. It is an important monomer for the manufacture of useful plastics. In terms of its molecular structure, it consists of a vinyl group linked to a nitrile...

 and that of nitropropane
Nitro compound
Nitro compounds are organic compounds that contain one or more nitro functional groups . They are often highly explosive, especially when the compound contains more than one nitro group and is impure. The nitro group is one of the most common explosophores used globally...

 and methyl vinyl ketone
Methyl vinyl ketone
Methyl vinyl ketone is a reactive organic compound classified as an enone. It is a colorless, flammable, highly toxic liquid with a pungent odor...

.

The Michael addition is an important atom-economical
Atom economy
Atom economy describes the conversion efficiency of a chemical process in terms of all atoms involved . In an ideal chemical process, the amount of starting materials or reactants equals the amount of all products generated and no atom is wasted...

 method for diastereoselective
Diastereomer
Diastereomers are stereoisomers that are not enantiomers.Diastereomerism occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalent stereocenters and are not mirror images of each other.When two diastereoisomers differ from each other at...

 and enantioselective C-C bond formation. A classical tandem sequence of Michael and aldol additions is the Robinson annulation
Robinson annulation
The Robinson annulation is an organic reaction used to create a six-member ring α,β-unsaturated cyclic ketone, using a ketone and methyl vinyl ketone...

.

Mechanism

The reaction mechanism
Reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...

 is 1 (with R an alkoxy residue) as the nucleophile :


Deprotonation
Deprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...

 of 1 by base leads to carbanion
Carbanion
A carbanion is an anion in which carbon has an unshared pair of electrons and bears a negative charge usually with three substituents for a total of eight valence electrons. The carbanion exists in a trigonal pyramidal geometry. Formally a carbanion is the conjugate base of a carbon acid.where B...

 2 stabilized by its electron-withdrawing groups. Structures 2a to 2c are three resonance structures that can be drawn for this species, two of which have enolate ions. This nucleophile reacts with the electrophilic alkene 3 to form 4 in a conjugate addition reaction. Proton abstraction from protonated base (or solvent) by the enolate 4 to 5 is the final step.

The course of the reaction is dominated by orbital, rather than electrostatic, considerations. The HOMO
Homo
Homo may refer to:*the Greek prefix ὅμο-, meaning "the same"*the Latin for man, human being*Homo, the taxonomical genus including modern humans...

 of stabilized enolates has a large coefficient on the central carbon atom while the LUMO
Lumo
Lumo is a 2007 documentary film about twenty-year-old Lumo Sinai, a woman who fell victim to "Africa's First World War." While returning home one day, Lumo and another woman were gang-raped by a group of soldiers fighting for control of the Democratic Republic of the Congo during the 1994 Rwandan...

 of many alpha, beta unsaturated carbonyl compounds has a large coefficient on the beta carbon. Thus, both reactants can be considered soft
HSAB theory
The HSAB concept is an acronym for 'hard and soft acids and bases. Also known as the Pearson acid base concept, HSAB is widely used in chemistry for explaining stability of compounds, reaction mechanisms and pathways....

. These polarized frontier orbitals are of similar energy, and react efficiently to form a new carbon-carbon bond.

Like the aldol addition, the Michael reaction may proceed via an enol
Enol
Enols are alkenes with a hydroxyl group affixed to one of the carbon atoms composing the double bond. Alkenes with a hydroxyl group on both sides of the double bond are called enediols. Deprotonated anions of enols are called enolates...

, silyl enol ether
Silyl enol ether
Silyl enol ethers in organic chemistry are a class of organic compounds that share a common functional group composed of an enolate bonded through its oxygen terminus to an organosilicon group....

 in the Mukaiyama-Michael addition, or more usually, enolate nucleophile. In the latter case, the stabilized carbonyl compound is deprotonated
Deprotonation
Deprotonation is the removal of a proton from a molecule, forming the conjugate base.The relative ability of a molecule to give up a proton is measured by its pKa value. A low pKa value indicates that the compound is acidic and will easily give up its proton to a base...

 with a strong base (hard enolization) or with a Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...

 and a weak base (soft enolization). The resulting enolate attacks the activated olefin with 1,4-regioselectivity
Regioselectivity
In chemistry, regioselectivity is the preference of one direction of chemical bond making or breaking over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base will abstract from an organic molecule, or where...

, forming a carbon-carbon bond. This also transfers the enolate to the electrophile
Electrophile
In general electrophiles are positively charged species that are attracted to an electron rich centre. In chemistry, an electrophile is a reagent attracted to electrons that participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile...

. Since the electrophile is much less acidic than the nucleophile, rapid proton transfer usually transfers the enolate back to the nucleophile if the product is enolizable; however, one may take advantage of the new locus of nucleophilicity if a suitable electrophile is pendant. Depending on the relative acidities of the nucleophile and product, the reaction may be catalytic
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....

 in base. In most cases, the reaction is irreversible at low temperature, due to least-motion argument
Principle of least motion
In organic chemistry, the principle of least motion is the hypothesis that when multiple species with different nuclear structures could theoretically form as products of a given chemical reaction, the more likely to form tends to be the one requiring the least amount of change in nuclear structure...

s.

Asymmetric Michael reaction

Recent research has focused on expanding the scope of asymmetric Michael additions. The most common methods involve chiral phase transfer catalysis, involving chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 quaternary ammonium salts derived from the Cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...

 alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

s, and organocatalysis
Organocatalysis
In organic chemistry, the term Organocatalysis refers to a form of catalysis, whereby the rate of a chemical reaction is increased by an organic catalyst referred to as an "organocatalyst" consisting of carbon, hydrogen, sulfur and other nonmetal elements found in organic compounds...

, which uses enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...

 or iminium
Iminium
An iminium salt or cation in organic chemistry has the general structure [R1R2C=NR3R4]+ and is as such a protonated or substituted imine. It is an intermediate in many organic reactions such as the Beckmann rearrangement, Vilsmeier-Haack reaction, Stephen reaction or the Duff reaction...

 activation with chiral secondary amines, usually derived from proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

.

In the reaction between cyclohexanone
Cyclohexanone
Cyclohexanone is the organic compound with the formula 5CO. The molecule consists of six-carbon cyclic molecule with a ketone functional group. This colorless oil has an odor reminiscent of peardrop sweets as well as acetone. Over time, samples assume a yellow color due to oxidation...

 and nitrostyrene sketched below, the base proline is derivatized and works in conjunction with a protic acid such as p-toluenesulfonic acid
P-Toluenesulfonic acid
p-Toluenesulfonic acid or tosylic acid is an organic compound with the formula CH3C6H4SO3H. It is a white solid that is soluble in water, alcohols, and other polar organic solvents. The 4-CH3C6H4SO2- group is known as the Tosyl group and is often abbreviated as Ts or Tos...

:


Syn addition
Syn addition
In organic chemistry, syn and anti addition are different ways in which two substituents can be added to a double bond or triple bond. This article will use alkenes as examples....

 is favored with 99% ee
Enantiomeric excess
The enantiomeric excess of a substance is a measure of how pure it is. In this case, the impurity is the undesired enantiomer .-Definition:...

. In the transition state
Transition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...

 believed to be responsible for this selectivity, the enamine
Enamine
An enamine is an unsaturated compound derived by the reaction of an aldehyde or ketone with a secondary amine followed by loss of H2O.The word "enamine" is derived from the affix en-, used as the suffix of alkene, and the root amine. This can be compared with enol, which is a functional group...

 (formed between the proline nitrogen and the cycloketone) and nitrostyrene are co-facial with the nitro
Nitro
-Chemistry:*Nitroglycerin, an explosive chemical compound*Nitromethane, the simplest organic nitro compound; also used to fuel high-performance internal-combustion engines*Nitrous oxide, "laughing gas", used in some dental procedures as an anaesthetic...

 group hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

ed to the protonated amine in the proline side group.


A well-known Michael reaction is the synthesis of warfarin
Warfarin
Warfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...

 from 4-hydroxycoumarin and benzylideneacetone
Benzylideneacetone
Benzylideneacetone is the organic compound described by the formula C6H5CH=CHCCH3. Although both cis- and trans-isomers are possible for the α,β-unsaturated ketone, only the trans isomer is observed...

 first reported by Link in 1944 :


Several asymmetric versions of this reaction exist using chiral catalysts.

Mukaiyama-Michael Addition

In the Mukaiyama-Michael Addition the nucleophile is an silyl ether
Silyl ether
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis...

 and the catalyst usually titanium tetrachloride
Titanium tetrachloride
Titanium tetrachloride is the inorganic compound with the formula TiCl4. It is an important intermediate in the production of titanium metal and the pigment titanium dioxide. TiCl4 is an unusual example of a metal halide that is highly volatile...

:

History

The research done by Arthur Michael in 1887 was prompted by an 1884 publication by Conrad & Kuthzeit on the reaction of diethyl 2,3-dibromopropionate with diethyl sodiomalonate forming a cyclopropane
Cyclopropane
Cyclopropane is a cycloalkane molecule with the molecular formula C3H6, consisting of three carbon atoms linked to each other to form a ring, with each carbon atom bearing two hydrogen atoms...

 derivative (now recognized as involving two successive substitution reactions).


Michael was able to obtain the same product by replacing the propionate by 2-bromacrylic acid ethylester and realized that this reaction could only work by assuming an addition reaction to the double bond of the acrylic acid
Acrylic acid
Acrylic acid is an organic compound with the formula CH2=CHCO2H. It is the simplest unsaturated carboxylic acid, consisting of a vinyl group connected directly to a carboxylic acid terminus. This colorless liquid has a characteristic acrid or tart smell. It is miscible with water, alcohols,...

. He then confirmed this assumption by reacting diethyl malonate
Diethyl malonate
Diethyl malonate, also known as DEM, is the diethyl ester of malonic acid. It occurs naturally in grapes and strawberries as a colourless liquid with an apple-like odour, and is used in perfumes...

 and the ethyl ester of cinnamic acid
Cinnamic acid
Cinnamic acid is a white crystalline organic acid, which is slightly soluble in water.It is obtained from oil of cinnamon, or from balsams such as storax. It is also found in shea butter and is the best indication of its environmental history and post-extraction conditions...

 forming the very first Michael adduct:


In the same year Rainer Ludwig Claisen
Rainer Ludwig Claisen
Rainer Ludwig Claisen was a famous German chemist best known for his work with condensations of carbonyls and sigmatropic rearrangements. He was born in Cologne as the son of a jurist and studied chemistry at the university of Bonn , where he became a member of K.St.V. Arminia...

 claimed priority for the invention. He and T. Komnenos had observed addition products to double bonds as side-products earlier in 1883 while investigating condensation reactions of malonic acid
Malonic acid
Malonic acid is a dicarboxylic acid with structure CH22. The ionised form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid's ethyl ester...

 with aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....

s. However, according to biographer Takashi Tokoroyama this claim is without merit.
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