9.10: Conjugate Carbonyl Additions - The Michael Reaction

Predicting the Product of a Michael Reaction

During the reaction the C=C pi bond of the α, β-unsaturated carbonyl is broken. An C-H bond is formed on the carbon in the α-position from the carbonyl. An acidic hydrogen is removed from the nucleophile and then it is used to form a C-C bond with the carbon in the beta position from the carbonyl.

1. In the first step, remove the double bond and add two single bonds
2. Add hydrogen to the bond adjacent to the carbonyl
3. Add the nucleophile to the other end of the double bond (remember to remove a hydrogen from the nucleophile)

Michael Acceptors and Michael Donors

The Michael reaction can be performed with a wide variety of α, β-unsaturated carbonyl electrophilic acceptors and enolate donors. Michael acceptors such as α, β-unsaturated ketones, aldehydes, esters, amides, and nitro compounds can all participate in this reaction. Michael donors with particularly acidic α-hydrogens, such as β-diketones, β-keto esters, β-keto nitriles, α-nitro ketones, malonic esters, and nitro compounds can be used.

Table \(\PageIndex{1}\): Some Michael Acceptors and Michael Donors

Michael acceptors		Michael donors
CH2=CH-CH=O	Propenal α,β-unsaturated aldehyde		β-Diketone
	3-Buten-2-one α,β-unsaturated ketone		β-Keto ester
	Ethyl propenoate α,β-unsaturated ester		Diethyl malonate
	Propenamide α,β-unsaturated amide		β-Keto nitrile
	Propenenitrile α,β-unsaturated nitrile		Nitro compound
	Nitroethylene

Planning a Synthesis Using a Michael Reaction

The true utility of the Michael reaction is seen when considering it use in a synthesis. The reaction can be used to prepare aldehydes, ketones, esters, amides, nitriles, and nitro compounds. A target molecule can possibly be made using a Michael reaction if it contains one of these functional groups and an alkyl chain at least three carbons long. The key bond cleavage is a C-C bond between β and gamma carbons from a carbonyl-like group. The fragment with the Y group loses an α-hydrogen and then forms a C=C bond between the α and beta carbon. The carbon of the other fragment gains a hydrogen. This fragment should possess an acidic α-hydrogen and should be made up of Michael donor fragments such as those listed in Table \(\PageIndex{1}\). In some cases, there may be more than one fragmentation variation. Each variation should be investigated and the possible starting materials compared for viability.

Worked Example \(\PageIndex{2}\): Using the Michael Reaction

How might you obtain the following compound using a Michael reaction?

Strategy

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an α,β-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a β-diketone, β-keto ester, malonic ester, or similar compound. The C–C bond formed in the conjugate addition step is the one between the α carbon of the acidic donor and the β carbon of the unsaturated acceptor.

Solution

In combination with alkylations and condensations, the Michael reaction may be used to construct a wide variety of complex molecules from relatively simple starting materials. The carbon nucleophiles used in the following examples include cyanide ion, sodium diethylmalonate and the conjugate base of cyclohexane-1,3-dione. These anions are sufficiently stable that their addition reactions may be presumed reversible. If this is so, the thermodynamic argument used for hetero-nucleophile additions would apply here as well, and would indicate preferential formation of 1,4-addition products. Cyanide addition does not always follow this rule, and aldehydes often give 1,2-products (cyanohydrins). In each case the initial reaction is a Michael addition, and the new carbon-carbon bond is colored magenta. Any subsequent bonds that are formed by other reactions are colored orange.