Chemical Sciences: A Manual for CSIR-UGC National Eligibility Test for Lectureship and JRF/Named Reactions/Michael Reaction

The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile doi:10.1016/j.progpolymsci.2006.03.001 Mather 2006 reprint 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. Chapter 18: Enols and Enolates — The Michael Addition reaction Ian Hunt University of Calgary http://www.chem.ucalgary.ca/courses/351/Carey5th/Ch18/ch18-4-3.htmlClayden et al., Organic Chemistry 400px|Michael Reaction general mechanism 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. Definition As originally defined by Arthur Michael, Ueber die Addition von Natriumacetessig- und Natriummalonsäureäthern zu den Aethern ungesättigter Säuren Arthur Michael Journal für Praktische Chemie 35 1 349–356 1887 http://gallica.bnf.fr/ark:/12148/bpt6k907989/f356.chemindefer 10.1002/prac.18870350136 Ueber die Addition von Natriumacetessig- und Natriummalonsäureäther zu den Aethern ungesättigter Säuren Arthur Michael Journal für Praktische Chemie 49 1 20–29 1894 http://gallica.bnf.fr/ark:/12148/bpt6k90814q/f29.table 10.1002/prac.18940490103 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,Kohler. (J. Am. Chem. Soc., 1907, 37, 385; ibid., 1935, 57, 1316. 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), 1,1,2,3-Propanetetracarboxylic acid, tetraethyl ester H. T. Clarke and T. F. Murray 1 272 1941 cv1p0272 that of mesityl oxide and diethyl malonate, 1,3-Cyclohexanedione, 5,5-dimethyl- R. L. Shriner and H. R. Todd 2 200 1943 cv2p0200 that of diethyl malonate and methyl crotonate, 4 630 1963 β-Methylglutaric anhydride James Cason cv4p0630 that of 2-nitropropane and methyl acrylate, 4 652 1963 Methyl γ-Methyl-γ-nitrovalerate R. B. Moffett cv4p0652 that of ethyl phenylcyanoacetate and acrylonitrile 4 776 α-Phenyl-α-carbethoxyglutaronitrile E. C. Horning and A. F. Finelli 1963 cv4p0776 and that of nitropropane and methyl vinyl ketone. Conversion of Nitro to Carbonyl by Ozonolysis of Nitronates: 2,5-Heptanedione 6 648 1988 cv6p0648 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. Mechanism The reaction mechanism is 1 (with R an alkoxy residue) as the nucleophile: 500px|Michael reaction mechanism 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. Asymmetric Michael reaction 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: 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 9624–9625 10.1021/ja062701n 400px|Michael reaction asymmetric 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. 200px|Asymmetric Michael Transition State A well-known Michael reaction is the synthesis of warfarin from 4-hydroxycoumarin and benzylideneacetone first reported by Link in 1944 doi:10.1021/ja01234a019: Warfarin synthesis Several asymmetric versions of this reaction exist using chiral catalysts doi:10.1002/anie.200352136 doi:10.1021/ol062000v doi:10.1021/ol062718a doi:10.1002/ejoc.200900664 doi:10.1002/ejoc.200900831 doi:10.1021/ed800040m . Mukaiyama-Michael Addition In the Mukaiyama-Michael Addition the nucleophile is an silyl ether and the catalyst usually titanium tetrachloride: Mukaiyama, T. Titanium Tetrachloride in Organic Synthesis [New synthetic methods (21)] Angew. Chem., Int. Ed. Engl. 1977 16 817–826 10.1002/anie.197708171 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 14738–14739 10.1021/ja063900 center|400px|Mukaiyama-Michael addition History The research done by Arthur Michael in 1887 was prompted by an 1884 publication by Conrad & Kuthzeit on the reaction of diethyl 2,3-dibromopropionate with diethyl sodiomalonate forming a cyclopropane derivative doi:10.1002/cber.188401701314 (now recognized as involving two successive substitution reactions). File:Michael reaction Conrad Guthzeit comparison.svg Michael was able to obtain the same product by replacing the propionate by 2-bromacrylic acid ethylester and realized that this reaction could only work by assuming an addition reaction to the double bond of the acrylic acid. He then confirmed this assumption by reacting diethyl malonate and the ethyl ester of cinnamic acid forming the very first Michael adduct doi:10.1002/ejoc.200901130: The Original 1887 Michael reaction In the same year Rainer Ludwig Claisen claimed priority for the invention doi:10.1002/prac.18870350144. He and T. Komnenos had observed addition products to double bonds as side-products earlier in 1883 while investigating condensation reactions of malonic acid with aldehydes doi:10.1002/jlac.18832180204 However, according to biographer Takashi Tokoroyama this claim is without merit. References