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, ...
, the Michael reaction or Michael addition is a reaction between a Michael donor (an
enolate
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.
Bonding and structure
Enolate anions are electr ...
or other
nucleophile) and a Michael acceptor (usually an
α,β-unsaturated carbonyl) to produce a Michael adduct by creating a carbon-carbon bond at the acceptor's
β-carbon
In the nomenclature of organic chemistry, a locant is a term to indicate the position of a functional group or substituent within a molecule.
Numeric locants
The International Union of Pure and Applied Chemistry (IUPAC) recommends the use of n ...
.
It belongs to the larger class of
conjugate addition
Nucleophilic conjugate addition is a type of organic reaction. Ordinary nucleophilic additions or 1,2-nucleophilic additions deal mostly with additions to carbonyl compounds. Simple alkene compounds do not show 1,2 reactivity due to lack of polari ...
s and is widely used for the mild formation of carbon-carbon bonds.
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The Michael addition is an important atom-economical method for diastereoselective
In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...
and enantioselective C–C bond formation, and many asymmetric variants exist
:
In this general Michael addition scheme, either or both of R and R' on the nucleophile (the Michael donor) represent electron-withdrawing
In chemistry, an electron-withdrawing group (EWG) is a substituent that has some of the following kinetic and thermodynamic implications:
*with regards to electron transfer, electron-withdrawing groups enhance the oxidizing power tendency of th ...
substituents such as acyl
In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an alkyl group (). In organic chemistry, the acyl group (IUPAC ...
, cyano
Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms.
In chemistry, a cyanide () is a chemical compound that contains a functional group. This group, known as the cyano group, consists of a ...
, nitro, or sulfone
In organic chemistry, a sulfone is a organosulfur compound containing a sulfonyl () functional group attached to two carbon atoms. The central hexavalent sulfur atom is double-bonded to each of two oxygen atoms and has a single bond to each of ...
groups, which make the adjacent methylene hydrogen acidic
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a ...
enough to form a carbanion when reacted with the base, ''B:''. For the alkene
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
(the Michael acceptor), the R" substituent is usually 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 containi ...
, which makes the compound an α,β-unsaturated carbonyl compound
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 ...
(either an enone or an enal), or R" may be any electron withdrawing group.
Definition
As originally defined by Arthur Michael Arthur Michael (August 7, 1853 – February 8, 1942) 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, we ...
, the reaction is the addition of an enolate
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.
Bonding and structure
Enolate anions are electr ...
of a ketone or aldehyde to an α,β-unsaturated carbonyl compound at the β carbon. The current definition of the Michael reaction has broadened to include nucleophiles other than enolate
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.
Bonding and structure
Enolate anions are electr ...
s. Some examples of nucleophiles include doubly stabilized carbon nucleophiles such as beta-ketoesters, malonate
The conjugate acids are in :Carboxylic acids.
{{Commons category, Carboxylate ions, Carboxylate anions
Carbon compounds
Oxyanions ...
s, and beta-cyanoesters. The resulting product contains a highly useful 1,5-dioxygenated pattern. Non-carbon nucleophiles such as water, alcohols, 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
Hydrogen is the chemical element wi ...
s, and enamine
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
:
The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and t ...
s can also react with an α,β-unsaturated carbonyl in a 1,4-addition.
Some authors have broadened the definition of the Michael addition to essentially refer to any 1,4-addition reaction of α,β-unsaturated carbonyl compounds. Others, however, insist that such a usage is an abuse of terminology, and limit the Michael addition to the formation of carbon–carbon bonds through the addition of carbon nucleophiles. The terms ''oxa-Michael reaction'' and ''aza-Michael reaction'' have been used to refer to the 1,4-addition of oxygen and nitrogen nucleophiles, respectively. The Michael reaction has also been associated with 1,6-addition reactions.
Mechanism
In the reaction mechanism, there is 1 (with R an alkoxy
In chemistry, the alkoxy group is an alkyl group which is singularly bonded to oxygen; thus . The range of alkoxy groups is vast, the simplest being methoxy (). An ethoxy group () is found in the organic compound ethyl phenyl ether (, also ...
group) as the nucleophile:
:
Deprotonation
Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju. ...
of 1 by a base leads to carbanion 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
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.
Bonding and structure
Enolate anions are electr ...
ions. This nucleophile reacts with the electrophilic alkene 3 to form 4 in a conjugate addition reaction. Finally, enolate 4 abstracts a proton from protonated base (or solvent) to produce 5.
The reaction is dominated by orbital, rather than electrostatic, considerations. The HOMO
''Homo'' () is the genus that emerged in the (otherwise extinct) genus '' Australopithecus'' that encompasses the extant species ''Homo sapiens'' ( modern humans), plus several extinct species classified as either ancestral to or closely relat ...
of stabilized enolate
In organic chemistry, enolates are organic anions derived from the deprotonation of carbonyl () compounds. Rarely isolated, they are widely used as reagents in the synthesis of organic compounds.
Bonding and structure
Enolate anions are electr ...
s has a large coefficient on the central carbon atom while the LUMO of many alpha, beta unsaturated carbonyl compounds has a large coefficient on the beta carbon. Thus, both reactants can be considered soft. These polarized frontier orbital
A frontier is the political and geographical area near or beyond a boundary. A frontier can also be referred to as a "front". The term came from French in the 15th century, with the meaning "borderland"—the region of a country that fronts o ...
s 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
In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The t ...
, 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 end to an organosilicon group. They are important intermediates in organic synthesis.
Sy ...
in the Mukaiyama–Michael addition, or more usually, enolate nucleophile. In the latter case, the stabilized carbonyl compound is deprotonated
Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju.ed ...
with a strong base (hard enolization) or with a Lewis acid and a weak base (soft enolization). The resulting enolate attacks the activated olefin with 1,4-regioselectivity
In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction 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 ...
, forming a carbon–carbon bond. This also transfers the enolate to the 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 carrie ...
. 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 () 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 ...
in base. In most cases, the reaction is irreversible at low temperature.
History
The research done by Arthur Michael in 1887 at Tufts University
Tufts University is a private research university on the border of Medford and Somerville, Massachusetts. It was founded in 1852 as Tufts College by Christian universalists who sought to provide a nonsectarian institution of higher learning. ...
was prompted by an 1884 publication by Conrad & Kuthzeit on the reaction of ''ethyl 2,3-dibromopropionate'' with ''diethyl sodiomalonate'' forming a cyclopropane 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 (IUPAC: propenoic acid) is an organic compound with the formula CH2=CHCOOH. It is the simplest unsaturated carboxylic acid, consisting of a vinyl group connected directly to a carboxylic acid terminus. This colorless liquid has a ...
. He then confirmed this assumption by reacting 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. It is also used to synthesize other compounds su ...
and the ethyl ester of cinnamic acid
Cinnamic acid is an organic compound with the formula C6H5-CH=CH- COOH. It is a white crystalline compound that is slightly soluble in water, and freely soluble in many organic solvents. Classified as an unsaturated carboxylic acid, it occurs na ...
forming the first Michael adduct:
:
In the same year Rainer Ludwig Claisen
Rainer Ludwig Claisen (; 14 January 1851 – 5 January 1930) was a 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 u ...
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 (IUPAC systematic name: propanedioic acid) is a dicarboxylic acid with structure CH2(COOH)2. The ionized form of malonic acid, as well as its esters and salts, are known as malonates. For example, diethyl malonate is malonic acid' ...
with aldehyde
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 ...
s. However, according to biographer Takashi Tokoroyama, this claim is without merit.
Asymmetric Michael reaction
Researchers have expanded the scope of Michael additions to include elements of chirality via asymmetric versions of the reaction. The most common methods involve 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 i ...
phase transfer catalysis, such as quaternary ammonium salt
In chemistry, quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure , R being an alkyl group or an aryl group. Unlike the ammonium ion () and the primary, secondary, or tertiary ammonium cation ...
s derived from the Cinchona alkaloid
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 ...
s; or organocatalysis, which is activated by enamine
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
:
The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and t ...
or 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 ...
with chiral secondary amines, usually derived from proline.
In the reaction between cyclohexanone and β-nitrostyrene sketched below, the base proline is derivatized and works in conjunction with a protic acid such as ''p''-toluenesulfonic acid:
:
Syn addition is favored with 99% ee. In the transition state
In chemistry, 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 potential energy along this reaction coordinate. It is often marked ...
believed to be responsible for this selectivity, the enamine
An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.
:
The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and t ...
(formed between the proline nitrogen and the cycloketone) and β-nitrostyrene are co-facial with the nitro group hydrogen bonded to the protonated amine in the proline side group.
:
A well-known Michael reaction is the synthesis of warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
from 4-hydroxycoumarin and benzylideneacetone first reported by Link in 1944:
:
Several asymmetric versions of this reaction exist using chiral catalysts.
Examples
Classical examples of the Michael reaction are the reaction between 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. It is also used to synthesize other compounds su ...
(Michael donor) and diethyl fumarate
In organic chemistry, an ethyl group (abbr. Et) is an alkyl substituent with the formula , derived from ethane (). ''Ethyl'' is used in the International Union of Pure and Applied Chemistry's nomenclature of organic chemistry for a saturated t ...
(Michael acceptor), that of diethyl malonate and mesityl oxide
Mesityl oxide is a α,β-unsaturated ketone with the formula CH3C(O)CH=C(CH3)2. This compound is a colorless, volatile liquid with a honey-like odor.
Synthesis
It is prepared by the aldol condensation of acetone to give diacetone alcohol, whic ...
, that of diethyl malonate and methyl crotonate, that of 2-nitropropane and methyl acrylate
Methyl acrylate is an organic compound, more accurately the methyl ester of acrylic acid. It is a colourless liquid with a characteristic acrid odor. It is mainly produced to make acrylate fiber, which is used to weave synthetic carpets. It is al ...
, that of ethyl phenylcyanoacetate and acrylonitrile
Acrylonitrile is an organic compound with the formula and the structure . It is a colorless, volatile liquid although commercial samples can be yellow due to impurities. It has a pungent odor of garlic or onions. In terms of its molecula ...
and that of nitropropane and methyl vinyl ketone.
A classic tandem
Tandem, or in tandem, is an arrangement in which a team of machines, animals or people are lined up one behind another, all facing in the same direction.
The original use of the term in English was in ''tandem harness'', which is used for two ...
sequence of Michael and aldol additions is the Robinson annulation
The Robinson annulation is a chemical reaction used in organic chemistry for ring formation. It was discovered by Robert Robinson in 1935 as a method to create a six membered ring by forming three new carbon–carbon bonds. The method uses a keto ...
.
Mukaiyama-Michael addition
In the Mukaiyama–Michael addition, the nucleophile is a 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 end to an organosilicon group. They are important intermediates in organic synthesis.
Sy ...
and the catalyst is usually titanium tetrachloride
Titanium tetrachloride is the inorganic compound with the formula . It is an important intermediate in the production of titanium metal and the pigment titanium dioxide. is a volatile liquid. Upon contact with humid air, it forms thick clouds ...
:
1,6-Michael reaction
The 1,6-Michael reaction proceeds via nucleophilic attack on the 𝛿 carbon of an α,β-,𝛿-diunsaturated Michael acceptor. The 1,6-addition mechanism is similar to the 1,4-addition, with one exception being the nucleophilic attack occurring at the 𝛿 carbon of the Michael acceptor. However, research shows that organocatalysis often favours the 1,4-addition. In many syntheses where 1,6-addition was favoured, the substrate contained certain structural features. Research has shown that catalysts can also influence the regioselectivity
In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction 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 ...
and enantioselectivity of a 1,6-addition reaction.
For example, the image below shows the addition of ethylmagnesium bromide
Ethylmagnesium bromide is a Grignard reagent with formula C2H5MgBr. It is widely used in the laboratory synthesis of organic compounds.
Reactions
Apart from acting as the synthetic equivalent of an ethyl anion synthon for nucleophilic addition, ...
to ethyl sorbate 1 using a copper catalyst with a reversed josiphos (''R,S'')-(–)-3 ligand. This reaction produced the 1,6-addition product 2 in 0% yield, the 1,6-addition product 3 in approximately 99% yield, and the 1,4-addition product 4 in less than 2% yield. This particular catalyst and set of reaction conditions led to the mostly regioselective and enantioselective 1,6-Michael addition of ethyl sorbate 1 to product 3.
Applications
Pharmaceuticals
A Michael reaction is used as a mechanistic step by many covalent inhibitor drugs. Cancer drugs such as ibrutinib, osimertinib, and rociletinib have an acrylamide functional group as a Michael acceptor. The Michael acceptor on the drug reacts with a Michael acceptor in the active site of an enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
. This is a viable cancer treatment because the target enzyme is inhibited following the Michael reaction.
Polymerization reactions
Mechanism
All polymerization reactions have three basic steps: initiation, propagation, and termination. The initiation step is the Michael addition of the nucleophile to a monomer
In chemistry, a monomer ( ; '' mono-'', "one" + ''-mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
...
. The resultant species undergoes a Michael addition with another monomer, with the latter acting as an acceptor. This extends the chain by forming another nucleophilic species to act as a donor for the next addition. This process repeats until the reaction is quenched by chain termination. The original Michael donor can be a neutral donor such as 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
Hydrogen is the chemical element wi ...
s, thiol
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
s, and alkoxides, or alkyl ligands bound to a metal.
Examples
Linear step growth polymerizations are some of the earliest applications of the Michael reaction in polymerizations. A wide variety of Michael donors and acceptors have been used to synthesize a diverse range of polymers. Examples of such polymers include poly(amido amine), poly(amino ester), poly(imido sulfide), poly(ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...
sulfide), poly(aspartamide), poly(imido 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 ...
), poly(amino quinone), poly(enone sulfide) and poly(enamine ketone).
For example, linear step growth polymerization produces the redox active poly(amino quinone), which serves as an anti-corrosion
In chemistry, a corrosion inhibitor or anti-corrosive is a chemical compound that, when added to a liquid or gas, decreases the corrosion rate of a material, typically a metal or an alloy, that comes into contact with the fluid. The effectiveness ...
coatings on various metal surfaces. Another example includes network polymer
In materials science, a thermosetting polymer, often called a thermoset, is a polymer that is obtained by irreversibly hardening (" curing") a soft solid or viscous liquid prepolymer (resin). Curing is induced by heat or suitable radiation and ...
s, which are used for drug delivery, high performance composites, and coatings. These network polymers are synthesized using a dual chain growth, photo-induced radical and step growth Michael addition system.
References
{{DEFAULTSORT:Michael Reaction
Addition reactions
Carbon-carbon bond forming reactions
Name reactions