Michael addition reaction

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Contents

Michael Addition
Reaction type Addition reaction
Reaction
Michael Donor
+
Michael Acceptor
+
(H3O+)
↓
Michael adduct
Identifiers
Organic Chemistry Portal michael-addition
RSC ontology ID RXNO:0000009

In organic chemistry, the Michael reaction or Michael 1,4 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-carbon bond at the acceptor's β-carbon. [1] [2] It belongs to the larger class of conjugate additions and is widely used for the mild formation of carbon-carbon bonds. [3]

Michael 1,4 reaction equation.svg

The Michael addition is an important atom-economical method for diastereoselective and enantioselective C–C bond formation, and many asymmetric variants exist [4] [5] [6]

In this general Michael addition scheme, either or both of R and R' on the nucleophile (the Michael donor) represent electron-withdrawing substituents such as acyl, cyano, nitro, or sulfone groups, which make the adjacent methylene hydrogen acidic enough to form a carbanion when reacted with the base, B:. For the alkene (the Michael acceptor), the R" substituent is usually a carbonyl, which makes the compound an α,β-unsaturated carbonyl compound (either an enone or an enal), or R" may be any electron withdrawing group.

Michael Reaction general.svg

Definition

As originally defined by Arthur Michael, [7] [8] the reaction is the addition of an enolate 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 enolates. [9] Some examples of nucleophiles include doubly stabilized carbon nucleophiles such as beta-ketoesters, malonates, and beta-cyanoesters. The resulting product contains a highly useful 1,5-dioxygenated pattern. Non-carbon nucleophiles such as water, alcohols, amines, and enamines can also react with an α,β-unsaturated carbonyl in a 1,4-addition. [10]

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 [2] 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. [11]

Mechanism

In the reaction mechanism, there is 1 as the nucleophile: [3]

Arrow pushing mechanism of Micheal reaction.png

Deprotonation 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 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 of stabilized enolates 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 orbitals are of similar energy, and react efficiently to form a new carbon–carbon bond. [12]

Like the aldol addition, the Michael reaction may proceed via an enol, silyl enol ether in the Mukaiyama–Michael addition, or more usually, enolate nucleophile. In the latter case, the stabilized carbonyl compound is deprotonated 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, forming a carbon–carbon bond. This also transfers the enolate to the electrophile. 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 in base. In most cases, the reaction is irreversible at low temperature.

History

The research done by Arthur Michael in 1887 at Tufts University was prompted by an 1884 publication by Conrad & Kuthzeit on the reaction of ethyl 2,3-dibromopropionate with diethyl sodiomalonate forming a cyclopropane derivative [13] (now recognized as involving two successive substitution reactions).

Michael reaction Conrad Guthzeit comparison.svg

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. He then confirmed this assumption by reacting diethyl malonate and the ethyl ester of cinnamic acid forming the first Michael adduct: [14]

Original Michael reaction.svg

In the same year Rainer Ludwig Claisen claimed priority for the invention. [15] He and T. Komnenos had observed addition products to double bonds as side-products earlier in 1883 while investigating condensation reactions of malonic acid with aldehydes. [16] However, according to biographer Takashi Tokoroyama, this claim is without merit. [14]

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 phase transfer catalysis, such as quaternary ammonium salts derived from the Cinchona alkaloids; or organocatalysis, which is activated by enamine or iminium with chiral secondary amines, usually derived from proline. [17]

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: [18]

Michael reaction asymmetric.png

Syn addition is favored with 99% ee. In the transition state believed to be responsible for this selectivity, the enamine (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.

AsymmetricMichaelTransitionState.png

A well-known Michael reaction is the synthesis of warfarin from 4-hydroxycoumarin and benzylideneacetone first reported by Link in 1944: [19]

Warfarin synthesis.svg

Several asymmetric versions of this reaction exist using chiral catalysts. [20] [21] [22] [23] [24] [25]

Examples

Classical examples of the Michael reaction are the reaction between diethyl malonate (Michael donor) and diethyl fumarate (Michael acceptor), [26] that of diethyl malonate and mesityl oxide (forming Dimedone), [27] that of diethyl malonate and methyl crotonate, [28] that of 2-nitropropane and methyl acrylate, [29] that of ethyl phenylcyanoacetate and acrylonitrile [30] and that of nitropropane and methyl vinyl ketone. [31]

A classic tandem sequence of Michael and aldol additions is the Robinson annulation.

Mukaiyama-Michael addition

In the Mukaiyama–Michael addition, the nucleophile is a silyl enol ether and the catalyst is usually titanium tetrachloride: [32] [33]

Mukaiyama-Michael addition Mukaiyama-Michael addition.png
Mukaiyama–Michael addition

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. [34] [35] 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. [35] However, research shows that organocatalysis often favours the 1,4-addition. [34] In many syntheses where 1,6-addition was favoured, the substrate contained certain structural features. [35] Research has shown that catalysts can also influence the regioselectivity and enantioselectivity of a 1,6-addition reaction. [35]

For example, the image below shows the addition of ethylmagnesium bromide to ethyl sorbate 1 using a copper catalyst with a reversed josiphos (R,S)-(–)-3 ligand. [35] 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.

The Michael addition of ethylmagnesium bromide to ethyl sorbate. 1,6-Michael addition of ethylmagnesium bromide to ethyl sorbate.png
The Michael addition of ethylmagnesium bromide to ethyl sorbate.

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 donor on the drug reacts with a Michael acceptor in the active site of an enzyme. This is a viable cancer treatment because the target enzyme is inhibited following the Michael reaction. [36]

Polymerization reactions

Mechanism [2]

All polymerization reactions have three basic steps: initiation, propagation, and termination. The initiation step is the Michael addition of the nucleophile to a monomer. 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. [37] The original Michael donor can be a neutral donor such as amines, thiols, and alkoxides, or alkyl ligands bound to a metal. [38]

Polymerization mechanism of a Michael addition with a thiol nucleophile Thiol Michael polymerisation.png
Polymerization mechanism of a Michael addition with a thiol nucleophile

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 sulfide), poly(aspartamide), poly(imido ether), 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 coatings on various metal surfaces. [39] Another example includes network polymers, 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.

Poly(amino quinone) Poly amino quinone.png
Poly(amino quinone)
Poly(amido amine) Poly(amido amine).png
Poly(amido amine)

Related Research Articles

<span class="mw-page-title-main">Ketone</span> Organic compounds of the form >C=O

In organic chemistry, a ketone is an organic compound 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)−. The simplest ketone is acetone, with the formula (CH3)2CO. Many ketones are of great importance in biology and industry. Examples include many sugars (ketoses), many steroids, and the solvent acetone.

<span class="mw-page-title-main">Aldol reaction</span> Chemical reaction

The aldol reaction is a reaction in organic chemistry that combines two carbonyl compounds to form a new β-hydroxy carbonyl compound. Its simplest form might involve the nucleophilic addition of an enolized ketone to another:

<span class="mw-page-title-main">Enamine</span> Class of chemical compounds

An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.

<span class="mw-page-title-main">Aldol condensation</span> Type of chemical reaction

An aldol condensation is a condensation reaction in organic chemistry in which two carbonyl moieties react to form a β-hydroxyaldehyde or β-hydroxyketone, and this is then followed by dehydration to give a conjugated enone.

<span class="mw-page-title-main">Organolithium reagent</span> Chemical compounds containing C–Li bonds

In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom to the substrates in synthetic steps, through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers. They have also been applied in asymmetric synthesis in the pharmaceutical industry. Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric.

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 ketone and a methyl vinyl ketone to form an α,β-unsaturated ketone in a cyclohexane ring by a Michael addition followed by an aldol condensation. This procedure is one of the key methods to form fused ring systems.

<span class="mw-page-title-main">Enolate</span> Organic anion formed by deprotonating a carbonyl (>C=O) compound

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.

In organic chemistry, the Knoevenagel condensation reaction is a type of chemical reaction named after German chemist Emil Knoevenagel. It is a modification of the aldol condensation.

<span class="mw-page-title-main">Nucleophilic conjugate addition</span> Organic reaction

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 polarity, unless the alkene is activated with special substituents. With α,β-unsaturated carbonyl compounds such as cyclohexenone it can be deduced from resonance structures that the β position is an electrophilic site which can react with a nucleophile. The negative charge in these structures is stored as an alkoxide anion. Such a nucleophilic addition is called a nucleophilic conjugate addition or 1,4-nucleophilic addition. The most important active alkenes are the aforementioned conjugated carbonyls and acrylonitriles.

In organic chemistry, umpolung or polarity inversion is the chemical modification of a functional group with the aim of the reversal of polarity of that group. This modification allows secondary reactions of this functional group that would otherwise not be possible. The concept was introduced by D. Seebach and E.J. Corey. Polarity analysis during retrosynthetic analysis tells a chemist when umpolung tactics are required to synthesize a target molecule.

<span class="mw-page-title-main">Darzens reaction</span>

The Darzens reaction is the chemical reaction of a ketone or aldehyde with an α-haloester in the presence of a base to form an α,β-epoxy ester, also called a "glycidic ester". This reaction was discovered by the organic chemist Auguste Georges Darzens in 1904.

In organosilicon chemistry, silyl enol ethers are a class of organic compounds that share the common functional group R3Si−O−CR=CR2, composed of an enolate bonded to a silane through its oxygen end and an ethene group as its carbon end. They are important intermediates in organic synthesis.

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Vicinal difunctionalization refers to a chemical reaction involving transformations at two adjacent centers. This transformation can be accomplished in α,β-unsaturated carbonyl compounds via the conjugate addition of a nucleophile to the β-position followed by trapping of the resulting enolate with an electrophile at the α-position. When the nucleophile is an enolate and the electrophile a proton, the reaction is called Michael addition.

Carbonyl oxidation with hypervalent iodine reagents involves the functionalization of the α position of carbonyl compounds through the intermediacy of a hypervalent iodine(III) enolate species. This electrophilic intermediate may be attacked by a variety of nucleophiles or undergo rearrangement or elimination.

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α,β-Unsaturated carbonyl compound Functional group of organic compounds

α,β-Unsaturated carbonyl compounds are organic compounds with the general structure (O=CR)−Cα=Cβ−R. Such compounds include enones and enals, but also carboxylic acids and the corresponding esters and amides. In these compounds, the carbonyl group is conjugated with an alkene. Unlike the case for carbonyls without a flanking alkene group, α,β-unsaturated carbonyl compounds are susceptible to attack by nucleophiles at the β-carbon. This pattern of reactivity is called vinylogous. Examples of unsaturated carbonyls are acrolein (propenal), mesityl oxide, acrylic acid, and maleic acid. Unsaturated carbonyls can be prepared in the laboratory in an aldol reaction and in the Perkin reaction.

In organic chemistry, the Conia-ene reaction is an intramolecular cyclization reaction between an enolizable carbonyl such as an ester or ketone and an alkyne or alkene, giving a cyclic product with a new carbon-carbon bond. As initially reported by J. M. Conia and P. Le Perchec, the Conia-ene reaction is a heteroatom analog of the ene reaction that uses an enol as the ene component. Like other pericyclic reactions, the original Conia-ene reaction required high temperatures to proceed, limiting its wider application. However, subsequent improvements, particularly in metal catalysis, have led to significant expansion of reaction scope. Consequently, various forms of the Conia-ene reaction have been employed in the synthesis of complex molecules and natural products.

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Jiro Tsuji was a Japanese chemist, notable for his discovery of organometallic reactions, including the Tsuji-Trost reaction, the Tsuji-Wilkinson decarbonylation, and the Tsuji-Wacker reaction.

References

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