Michael reaction, Michael addition or conjugate addition of an enolate to conjugated carbonyl compound is an organic reaction, where a conjugated unsaturated carbonyl compound is alkylated, to produce a larger molecule with a larger carbon skeleton. It is an alkylation of an electrophilic alkene, belonging a larger class of reactions of conjugate additions.

Definition

As originally defined by 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 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 result is a 1,5-dioxygenated pattern.

Mechanism

Simply put, the double-single-double bond system of the acceptor conducts electricity, allowing the carbonyl oxygen to receive the electrons of the attacking nucleophile via the double bond system, as opposed to direct attack to the carbonyl. The oxygen will become an alkoxide ion, which very rapidly reverts to something else.

Like the aldol addition, the Michael reaction may proceed via an enol, silyl enol ether (Mukaiyama-Michael), or more usually, enolate nucleophile. In the latter case, a carbonyl compound with acidic alpha-hydrogens is treated with either a base (hard enolization) or with a Lewis acid and a weak base (soft enolization). This produces the enolate nucleophile, which then adds with 1,4-regioselectivity to an appropriate activated olefin. The result is C-C bond formation with the enolate being transferred to the electrophile. Since, in some cases, the enolate may be transferred back to unreacted nucleophile precursors, the reaction may be catalytic in base. In other cases, the enolate may be trapped by further reactions, such as aldol addition, or simply quenched by water on workup. In most cases, the reaction is irreversible.

Significance

Michael addition is an important method for alkylation. An α,β-unsaturated carbonyl compound which can undergo a Michael addition is called a Michael acceptor. Michael addition is often easier than the corresponding direct addition to carbonyl, giving selectivity.

Michael acceptors are generally poisonous and carcinogenic, since they accept attacks from vital enzymes, such as DNA polymerase, which are then alkylated and thus inactivated. Even acrylates are cancer suspect agents.⁴

Robinson annulation is a sequence of Michael addition and aldol reaction to yield a cyclic compound (annulus).

References

1. Michael, Arthur. J. Prakt. Chem. 1887, 36, 349-356; ibid., 1894, 49, 20
2. Kohler. (J. Am. Chem. Soc., 1907, 37, 385; ibid., 1935, 57, 1316.
3. http://www.chem.ucalgary.ca/courses/351/Carey5th/Ch18/ch18-4-3.html.
4. Clayden et al, Organic Chemistry

Organic reactions

Michael-Addition | マイケル付加 | Reakcja Michaela