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. It belongs to the larger class of conjugate additions and is widely used for the mild formation of carbon–carbon bonds.
center|frameless|427x427pxThe Michael addition is an important atom-economical method for diastereoselective 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 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.
alt=Michael Reaction general|center|550x550px
Definition
As originally defined by Arthur Michael, 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. 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.
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
Mechanism
In the reaction mechanism, there is 1 as the nucleophile:
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 (now recognized as involving two successive substitution reactions).
:File: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:
:The original 1887 Michael reaction
In the same year Rainer Ludwig Claisen 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 with aldehydes. However, according to biographer Takashi Tokoroyama, this claim is without merit.
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:
:400px|Michael reaction asymmetric
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.
:200px|Asymmetric Michael transition state
A well-known Michael reaction is the synthesis of warfarin from 4-hydroxycoumarin and benzylideneacetone first reported by Link in 1944:
:Warfarin synthesis
Several asymmetric versions of this reaction exist using chiral catalysts.
Examples
Classical examples of the Michael reaction are the reaction between diethyl malonate (Michael donor) and diethyl fumarate (Michael acceptor), that of diethyl malonate and mesityl oxide (forming Dimedone), that of diethyl malonate and methyl crotonate, that of 2-nitropropane and methyl acrylate, that of ethyl phenylcyanoacetate and acrylonitrile and that of nitropropane and methyl vinyl ketone.
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:
center|400px|Mukaiyama–Michael addition
1,6-Michael reaction
The 1,6-Michael reaction proceeds via nucleophilic attack on the 𝛿 carbon of an α,β-<math>\gamma</math>,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.
Polymerization reactions
Mechanism
Source: The original Michael donor can be a neutral donor such as amines, thiols, and alkoxides, or alkyl ligands bound to a metal.
center|thumb|861x861px|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. 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.
alt=Poly(amino quinone)|left|thumb|409x409px|Poly(amino quinone)
thumb|412x412px|Poly(amido amine)