What Is Michael Addition?
The Miehael addition reaction classically refers to the 1,4-addition of enolates or other stable carbanion nucleophiles, such as organocopperlithium reagents, to α,β-unsaturated ketones, aldehydes, nitriles, nitro compounds, and hydroxy acid derivatives, resulting in the formation of new carbon-carbon bonds. The Michael addition reaction is named after the American scientist Arthur Michael, who contributed to this reaction.
Michael addition is one of the most broadly applicable carbon-carbon bond forming reactions, and in particular a method for carbon chain elongation in chemical synthesis. In its most basic form, a nucleophile (an enolate, malonate, nitroalkane, thiolate, amine, etc.) adds to the β-position of an α,β-unsaturated acceptor (enone, enoate, acrylonitrile, nitroalkene, etc.) to give a 1,4-adduct. The trend of expanding the use of the term "Michael addition", such as aza-Michael addition and oxa-Michael addition has also been reported.
- Reagents:
a) Base Catalyst: Commonly alkoxides (e.g., NaOEt), carbonates (e.g., K2CO3), or organic bases (e.g., DBU).
b) Solvent: Typically polar aprotic solvents like THF, DMF, or acetonitrile. - Michael Acceptors
a) α,β-Unsaturated carbonyls: enones, enals, acrylates, acrylamides, vinyl ketones.
b) Electron-poor alkenes: nitroalkenes, vinyl sulfones, maleimides, acrylonitrile.
c) Activated heteroatom-substituted alkenes (e.g., vinyl phosphonates, vinyl sulfones). - Michael Donors (Nucleophiles)
a) Carbon nucleophiles: stabilized enolates (β-dicarbonyls, malonates, cyanoacetates), nitroalkanes, alkylidene malonates (vinylogous variants), organometallic reagents (organocuprates, organozinc reagents in conjugate additions).
b) Heteroatom nucleophiles: thiols (thiol–Michael), amines (aza-Michael), alcohols (oxa-Michael under strong activation), and phosphines (phosphine-mediated umpolung reactions). - Products: 1,4-conjugate (Michael) adducts.
- Reaction Type: A conjugate addition reaction.
- Related Reactions: Aldol Reaction, Robinson Annulation.
Fig 1. Miehael addition reaction and its mechanism. [1]
Mechanism of Michael Addition
- Deprotonation and Nucleophile Generation: The Michael donor (Nu-H), with an acidic α-proton, is deprotonated by a base to form a stabilized nucleophilic anion.
- Nucleophilic Attack: The nucleophile attacks the electrophilic β-carbon of the Michael acceptor. This step forms a resonance-stabilized enolate intermediate. The β-carbon is electrophilic due to the electron-withdrawing nature of the conjugated carbonyl, which delocalizes the electron density.
- Protonation: The resulting enolate anion is protonated by a proton source in the workup step to yield the saturated 1,5-difunctionalized product.
Experimental Tips:
Its broad scope, mild conditions, and compatibility with many catalytic modes (base, Lewis acid, organocatalysis, transition-metal catalysis, photochemical and radical variants) make it central to complex molecule construction, cascade/tandem sequences, and polymer chemistry (e.g., thiol–Michael "click" reactions).
Michael additions of α,β-unsaturated carbonyl compounds with ethyl acetoacetate or diethyl malonate produce 1,5-dicarbonyl compounds after hydrolysis and thermal decarboxylation.
Michael additions are also commonly used to prepare 1,7-difunctional compounds.
This reaction is regioselective, and the hydroxyl group is always located on the more heavily substituted carbon.
Application Examples of Michael Addition
- Example 1: Xin-Meng Chen et al. developed an organocatalytic asymmetric dearomatization method for the reaction of 3-nitroindoles and 3-nitrobenzothiophenes with ethyl 4-mercapto-2-butenoate. This method obtained a series of chiral tetrahydrothiophene indoles and tetrahydrothiophene benzothiophenes with three adjacent stereocenters in high yields, good diastereoselectivity and excellent enantioselectivity. [2]
- Example 2: Yana A. Naumovich et al. used the Michael addition reaction of phosphorus-containing compounds (diphenylphosphine oxide, diisopropyl phosphite, phosphine–borane complexes, and triphenylphosphonium bromide) with unstable conjugated nitrosoolefins to synthesize various α-phosphorus-substituted oximes (β-oximinoalkyl-substituted phosphonates, phosphine oxides, phosphine–borane complexes, and phosphonium salts). [3]
Fig 2. Synthetic examples via Miehael addition reaction.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 348-351.
- Chen, Xin-Meng, et al. Organic Letters 21.14 (2019): 5452-5456.
- Naumovich, Yana A., et al. The Journal of Organic Chemistry 84.11 (2019): 7244-7254.
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