| Michael Addition | |||||||||||
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| Reaction type | Addition reaction | ||||||||||
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| Organic Chemistry Portal | michael-addition | ||||||||||
| RSC ontology ID | RXNO:0000009 | ||||||||||
Inorganic chemistry, theMichael reaction orMichael 1,4 addition is a reaction between aMichael donor (anenolate or othernucleophile) and aMichael acceptor (usually anα,β-unsaturated carbonyl) to produce aMichael adduct by creating a carbon-carbon bond at the acceptor'sβ-carbon.[1][2] It belongs to the larger class ofconjugate additions and is widely used for the mild formation of carbon–carbon bonds.[3]
The Michael addition is an importantatom-economical method fordiastereoselective andenantioselective C–C bond formation, and manyasymmetric variants exist[4][5][6]
In this general Michael addition scheme, either or both of R and R' on the nucleophile (the Michael donor) representelectron-withdrawingsubstituents such asacyl,cyano,nitro, orsulfone groups, which make the adjacentmethylene hydrogenacidic enough to form acarbanion when reacted with thebase,B:. For thealkene (the Michael acceptor), the R" substituent is usually acarbonyl, which makes the compound anα,β-unsaturated carbonyl compound (either anenone or anenal), or R" may be any electron withdrawing group.
As originally defined byArthur Michael,[7][8] the reaction is the addition of anenolate 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 thanenolates.[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, andenamines 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 termsoxa-Michael reaction andaza-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]
In thereaction mechanism, there is1 as the nucleophile:[3]
Deprotonation of1 by a base leads tocarbanion2, stabilized by its electron-withdrawing groups. Structures 2a to 2c are threeresonance structures that can be drawn for this species, two of which haveenolate ions. This nucleophile reacts with the electrophilic alkene3 to form4 in aconjugate addition reaction. Finally, enolate4 abstracts a proton from protonated base (or solvent) to produce5.
The reaction is dominated by orbital, rather than electrostatic, considerations. TheHOMO of stabilizedenolates 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 consideredsoft. These polarizedfrontier orbitals are of similar energy, and react efficiently to form a new carbon–carbon bond.[12]
Like thealdol addition, the Michael reaction may proceed via anenol,silyl enol ether in theMukaiyama–Michael addition, or more usually, enolate nucleophile. In the latter case, the stabilized carbonyl compound isdeprotonated with a strong base (hard enolization) or with aLewis acid and a weak base (soft enolization). The resulting enolate attacks the activatedolefin with 1,4-regioselectivity, forming a carbon–carbon bond. This also transfers the enolate to theelectrophile. 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 becatalytic in base. In most cases, the reaction isirreversible at low temperature.
The research done by Arthur Michael in 1887 atTufts University was prompted by an 1884 publication by Conrad & Kuthzeit on the reaction ofethyl 2,3-dibromopropionate withdiethyl sodiomalonate forming acyclopropane derivative[13] (now recognized as involving two successive substitution reactions).
Michael was able to obtain the same product by replacing the propionate by2-bromacrylic acid ethylester and realized that this reaction could only work by assuming an addition reaction to the double bond of theacrylic acid. He then confirmed this assumption by reactingdiethyl malonate and the ethyl ester ofcinnamic acid forming the first Michael adduct:[14]
In the same yearRainer 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 ofmalonic acid withaldehydes.[16] However, according to biographer Takashi Tokoroyama, this claim is without merit.[14]
Researchers have expanded the scope of Michael additions to include elements of chirality viaasymmetric versions of the reaction. The most common methods involvechiralphase transfer catalysis, such asquaternary ammonium salts derived from theCinchonaalkaloids; ororganocatalysis, which is activated byenamine oriminium with chiral secondary amines, usually derived fromproline.[17]
In the reaction betweencyclohexanone andβ-nitrostyrene sketched below, the base proline is derivatized and works in conjunction with a protic acid such asp-toluenesulfonic acid:[18]
Syn addition is favored with 99%ee. In thetransition state believed to be responsible for this selectivity, theenamine (formed between the proline nitrogen and the cycloketone) andβ-nitrostyrene are co-facial with thenitro grouphydrogen bonded to the protonated amine in the proline side group.
A well-known Michael reaction is the synthesis ofwarfarin from4-hydroxycoumarin andbenzylideneacetone first reported by Link in 1944:[19]
Several asymmetric versions of this reaction exist using chiral catalysts.[20][21][22][23][24][25]
Classical examples of the Michael reaction are the reaction betweendiethyl malonate (Michael donor) anddiethyl fumarate (Michael acceptor),[26] that of diethyl malonate andmesityl oxide (formingDimedone),[27] that of diethyl malonate andmethyl crotonate,[28] that of2-nitropropane andmethyl acrylate,[29] that of ethyl phenylcyanoacetate andacrylonitrile[30] and that ofnitropropane andmethyl vinyl ketone.[31]
A classictandem sequence of Michael and aldol additions is theRobinson annulation.
In theMukaiyama–Michael addition, the nucleophile is asilyl enol ether and the catalyst is usuallytitanium tetrachloride:[32][33]
The 1,6-Michael reaction proceeds via nucleophilic attack on the𝛿 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 the𝛿 carbon of the Michael acceptor.[35] However, research shows thatorganocatalysis 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 theregioselectivity andenantioselectivity of a 1,6-addition reaction.[35]
For example, the image below shows the addition ofethylmagnesium bromide to ethyl sorbate1 using a copper catalyst with a reversedjosiphos (R,S)-(–)-3 ligand.[35] This reaction produced the 1,6-addition product2 in 0% yield, the 1,6-addition product3 in approximately 99% yield, and the 1,4-addition product4 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 sorbate1 to product3.
A Michael reaction is used as a mechanistic step by many covalentinhibitor drugs.Cancer drugs such as ibrutinib, osimertinib, and rociletinib have anacrylamide functional group as a Michael acceptor. The Michael donor on the drug reacts with a Michael acceptor in theactive site of anenzyme. This is a viable cancer treatment because the target enzyme is inhibited following the Michael reaction.[36]
Source:[2]
All polymerization reactions have three basic steps: initiation, propagation, and termination. The initiation step is the Michael addition of the nucleophile to amonomer. 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 asamines,thiols, andalkoxides, or alkyl ligands bound to a metal.[38]
Linearstep 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(imidosulfide), poly(ester sulfide), poly(aspartamide), poly(imidoether), poly(aminoquinone), poly(enone sulfide) and poly(enamineketone).
For example, linear step growth polymerization produces the redox active poly(amino quinone), which serves as ananti-corrosion coatings on various metal surfaces.[39] Another example includesnetwork 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.
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