Conjugate Carbonyl Additions The Michael Reaction

Thomson Click Organic Process to view an animation showing the mechanism of the Michael addition reaction. 

Arthur WIichael (1853-1942) was born to a wealthy family in Buffalo, New York. Although he received no formal university degrees, he studied in Heidelberg, Berlin, and the Ecole de Medecine, Paris. Returning to the United States, he became professor of chemistry at Tufts University (1882-1889, 1894-1907), and then at Harvard University (1912-1936). Perhaps his most important contribution to science was his instrumental role in bringing the European research model of graduate education to the United States. 

We saw in Section 19.13 that certain nucleophiles, such as amines, react with a,/3-unsaturated aldehydes and ketones to give the conjugate addition product, rather than the direct addition product. 

Exactly the same kind of conjugate addition can occur when a nucleophilic enolate ion reacts with an a, 6-unsaturated carbonyl compound—a process known as the Michael reaction. 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /3-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a./3-unsaturated ketone. For example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

O The base catalyst removes an acidic alpha proton from the starting fi-keto ester to generate a stabilized enolate ion nucleophile. 

Q The nucleophile adds to the a,jS-unsaturated ketone electrophile in a Michael reaction to generate a new enolate as product. 

Ethyl 2-oxocyclo-hexa neca rboxy late 

What product would you expect from the following reaction  

Dieckmann cyclization of diethyl 3-methylheptanedioate gives a mixture of two )3-keto ester products. What are their structures, and why is a mixture formed  

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Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

The 1,4-addition of an enolate anion 1 to an o ,/3-unsaturated carbonyl compound 2, to yield a 1,5-dicarbonyl compound 3, is a powerful method for the formation of carbon-carbon bonds, and is called the Michael reaction or Michael addition The 1,4-addition to an o ,/3-unsaturated carbonyl substrate is also called a conjugate addition. Various other 1,4-additions are known, and sometimes referred to as Michael-like additions. 

The previous sections dealt with reactions in which the new carbon-carbon bond is formed by addition of the nucleophile to a carbonyl group. Another important method for alkylation of carbon nucleophiles involves addition to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,(3-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. 

The Michael reaction involves conjugate addition of a nucleophile onto an a,P-unsaturated carbonyl compound, or similar system. Such reactions take place in nature as well, and some can be potentially dangerous to us. For example, the a,P-unsaturated ester ethyl acrylate is a cancer suspect agent. This electrophile can react with biological nucleophiles and, in so doing, bind irreversibly to the nucleophile, rendering it unable to carry out its normal functions. A particularly important enzyme that can act as a nucleophile is DNA polymerase, which is responsible for the synthesis of strands of DNA, especially as part of a DNA repair mechanism (see Section 14.2.2). The nucleophilic centre is a thiol grouping, and this may react with ethyl acrylate as shown. 

The conjugate addition of nucleophiles to a,/3-unsaturated carbonyl compounds at the /3-position was described in Section 18.10. Enolate and related carbanion nucleophiles also add in a conjugate manner to a./Tunsaturated carbonyl compounds in a process known as the Michael reaction or Michael addition. In many of the examples the enolate ion is one that is stabilized by two carbonyl (or similar) groups. The ,/3-unsatura(cd compound is called the Michael acceptor. 

The Michael reaction is the conjugate addition of an enolate to an a,P-unsaturated carbonyl compound. 

The Michael reaction involves the conjugate addition (1,4-addition) of a resonance-stabilized enolate to the p carbon of an a,p-unsaturated carbonyl system. 

All conjugate additions add the elements of H and Nu across the a and P carbons. In the Michael reaction, the nucleophile is an enolate. Enolates of active methylene compounds are particularly common. The a,p-unsaturated carbonyl component is often called a Michael acceptor. 

The Michael reaction is addition of a carbon nucleophile to the /3 position of an a,/3-unsaturated carbonyl compound or its equivalent. It also may be called a 1,4-addition reaction (the carbonyl oxygen is counted as 1 and the )3-carbon as 4). The conjugation of the v bond with thp carbonyl group imparts positive character to the /3 position, making it susceptible to reaction with a nucleophile. The product of this reaction, an enolate ion, also is stabilized by resonance. 

The Michael reaction of sulfonyl carbanions with a,p-unsaturated esters provides a useful preparation of cyclopropane esters, as shown in Scheme 47. In this sequence, the sulfonyl carbanion undergoes conjugate 1,4-addition to the a,p-unsaturated carbonyl compound followed by intramolecular elimination of the benzenesulfinate anion (Scheme 47). 

In an a,P-unsaturated carbonyl system, the addition could be either 1,2 or 1,4, i.e. simple or conjugate. With Grignard reagents, the nucleophilic addition can be either 1,2 or 1,4, and often depends upon any steric factors that are present in the substrate. When an a,P-unsaturated carbonyl compound is treated with a carbanion, particularly one that is stabilised by a carbonyl group, the resultant 1,4-addition with the formation of a new carbon/carbon bond is called the Michael reaction. If the reaction occurs intramolecularly, it is called the Robinson annulation reaction. 

Conjugate additions. Cyclopentaneacetic esters are readily prepared by cyclization of -iodo-a,P-unsaturated esters. The Michael reaction of silyl ketene acetals with enones (and Mukaiyama aldol reaction) can be promoted by Sml,. " However, thermodynamic enolsilylation of carbonyl compounds under similar conditions is noted. 

Compounds with a carbonyl group conjugated to the double bond are conventionally called Michael acceptors. The Michael reaction is a route to a carbon-carbon bond. A nucleophile adds to a Michael acceptor. Together with nucleophilic addition at the carbonyl group, this is the first step of Robinson s cyclization, which is an excellent method for the preparation of medium-sized (and especially six-membered) rings. 

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