Michael reaction

The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C–C bonds. Many asymmetric variants exist. The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C–C bonds. Many asymmetric variants exist. In this scheme the R and R' substituents on the nucleophile (a Michael donor) are electron-withdrawing groups such as acyl and cyano making the methylene hydrogen acidic forming the carbanion on reaction with base B:. The substituent on the activated alkene, also called a Michael acceptor, is usually a ketone making it an enone, but it can also be a nitro group or a sulfonyl fluoride. 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. A newer definition, proposed by Kohler, is the 1,4-addition of a doubly stabilized carbon nucleophile to an α,β-unsaturated carbonyl compound. Some examples of nucleophiles include beta-ketoesters, malonates, and beta-cyanoesters. The resulting product contains a highly useful 1,5-dioxygenated pattern. Classical examples of the Michael reaction are the reaction between diethyl malonate (Michael donor) and diethyl fumarate (Michael acceptor), that of mesityl oxide and diethyl malonate, 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. The Michael addition is an important atom-economical method for diastereoselective and enantioselective C–C bond formation. A classical tandem sequence of Michael and aldol additions is the Robinson annulation. 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 have been used to refer to the 1,4-addition of oxygen and nitrogen nucleophiles, respectively. In the reaction mechanism, there is 1 (with R an alkoxy group) as the nucleophile: Deprotonation of 1 by 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. Proton abstraction from protonated base (or solvent) by the enolate 4 to 5 is the final step. The course of 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.