Michael reaction
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The Michael reaction or Michael addition is the nucleophilic addition of an carbanion to an alpha, beta 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.[1][2]
In this scheme the R and R' substituents on the nucleophile 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 is usually a ketone making it an enone but it can also be a nitro group.
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[edit] Definition
As originally defined by Michael,[3] 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,[4] 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.
[edit] Mechanism
The reaction mechanism is outlined below with a 1,3-dicarbonyl compound 1 (with R an alkoxy residue) 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.
Like the aldol addition, the Michael reaction may proceed via an enol, silyl enol ether in the Mukaiyama-Michael addition, or more usually, enolate nucleophile. In the latter case, the stabilized carbonyl compound is deprotonated with a strong Base (hard enolization) or with a Lewis acid and a weak base (soft enolization). The resulting enolate attacks the activated olefin with 1,4-regioselectivity, forming a carbon-carbon bond. This also transfers the enolate to the electrophile. Since the electrophile is much less acidic than the nucleophile, rapid proton transfer usually transfers the enolate back to the nucleophile if the product is enolizable; however, one may take advantage of the new locus of nucleophilicity if a suitable electrophile is pendant. Depending on the relative acidities of the nucleophile and product, the reaction may be catalytic in base. In most cases, the reaction is irreversible at low temperature, due to least-motion arguments.
[edit] Significance
Classical examples of the Michael reaction are the reaction between diethyl malonate (Michael acceptor) and diethyl fumarate,[5] that of mesityl oxide and diethyl malonate,[6] that of diethyl malonate and methyl crotonate,[7] that of 2-nitropropane and methyl acrylate,[8] that of ethyl phenylcyanoacetate and acrylonitrile[9] and that of nitropropane and methyl vinyl ketone.[10]
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. More recent research has focused on expanding the scope of asymmetric Michael additions. The most common methods involve chiral phase transfer catalysis, involving chiral quaternary ammonium salts derived from the Cinchona alkaloids, and organocatalysis, which uses enamine or iminium activation with chiral secondary amines, usually derived from proline.
In the reaction between cyclohexanone and nitrostyrene sketched below, the base proline is derivatized and works in conjunction with a protic acid such as P-Toluenesulfonic acid:[11]
Syn addition is favored with 99% ee. In the transition state believed to be responsible for this selectivity, the enamine (formed between the proline nitrogen and the cycloketone) and nitrostyrene are co-facial with the nitro group hydrogen bonded to the protonated amine in the proline side group.
[edit] Variations
[edit] Mukaiyama-Michael Addition
In the Mukaiyama-Michael Addition the nucleophile is an silyl ether and the catalyst usually titanium tetrachloride:[12][13]
[edit] References
- ^ http://www.chem.ucalgary.ca/courses/351/Carey5th/Ch18/ch18-4-3.html.
- ^ Clayden et al, Organic Chemistry
- ^ Michael, Arthur. J. Prakt. Chem. 1887, 36, 349-356; ibid., 1894, 49, 20
- ^ Kohler. (J. Am. Chem. Soc., 1907, 37, 385; ibid., 1935, 57, 1316.
- ^ 1,1,2,3-Propanetetracarboxylic acid, tetraethyl ester Organic Syntheses, Coll. Vol. 1, p.272 (1941); Vol. 4, p.29 (1925). Article
- ^ 1,3-Cyclohexanedione, 5,5-dimethyl- Organic Syntheses, Coll. Vol. 2, p.200 (1943); Vol. 15, p.14 (1935) Link
- ^ Organic Syntheses, Coll. Vol. 4, p.630 (1963); Vol. 38, p.52 (1958). Link
- ^ Organic Syntheses, Coll. Vol. 4, p.652 (1963); Vol. 32, p.86 (1952) Link.
- ^ Organic Syntheses, Coll. Vol. 4, p.776 (1963); Vol. 30, p.80 (1950) Link.
- ^ Organic Syntheses, Coll. Vol. 6, p.648 (1988); Vol. 56, p.36 (1977) Link.
- ^ Simple Diamine- and Triamine-Protonic Acid Catalysts for the Enantioselective Michael Addition of Cyclic Ketones to Nitroalkenes Sunil V. Pansare and Keyur Pandya J. Am. Chem. Soc.; 2006; 128(30) pp 9624 - 9625; (Communication) DOI:10.1021/ja062701n
- ^ Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977, 16, 817-826. DOI:10.1002/anie.197708073
- ^ Synthesis of Oligosubstituted Bullvalones: Shapeshifting Molecules Under Basic Conditions Alex R. Lippert, Juthanat Kaeobamrung, and Jeffrey W. Bode J. Am. Chem. Soc.; 2006; 128(46) pp 14738 - 14739; (Communication) DOI:10.1021/ja063900+
