Michael Addition is a useful reaction for adding a carbon-carbon bond between an alkene and an electron-depleted carbon.
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Overview of the Michael Addition
Michael additions are a very useful reaction in the toolbox of organic chemists because these reactions very easily add a c-c single bond in a predictable manner with little side effects. Discovered at Tufts University by Arthur Michael in 1887, Michael additions were the target of much research. Thus, chemists have characterized this reaction extensively. An overall Michael reaction adds a carbon-carbon bond between an electropositive carbon atom (electrophile) and an alkene conjugated to a carbonyl:
The Michael donor is an alkene with two very electronegative functional groups (e.g. cyanides, esters, amides, sulphones, and nitro groups) separated by just one carbon. Because these groups help pull the electrons off of the carbon in-between, this forms a more readily reactive electrophile.
The Michael acceptor consists of two very important parts: an alkene and a carbonyl, separated by only one carbon atom. This makes the molecule conjugated and thus a good nucleophile, as well as an appealing target for the electrophilic donor. The alkene is where the Michael donor donates an electron pair to, which additionally is the same pair which reforms the base catalyst. The carbonyl serves as a parking lot for an electron pair to allow the other electrons to move more freely during the reaction.
Base catalyzes Michael additions. Typically, strong Arrhenius bases such as NaOH or KOH or alkoxide bases are best, but weaker organic bases allow for more gentle reactions to limit the amount of undesired product. If parts of the Michael donor and acceptor are sensitive to base, then Michael additions are not a good option.
Ions can interfere with the reaction, so aprotic solvents are best. These solvents may be polar or nonpolar solvents, however, most Michael acceptors and donors are soluble in protic ones. Green chemistry research is seeking to replace these solvents for less toxic ones.
Michael Addition Mechanism
1. A base donates an electron to a hydrogen on the Michael donor (an electrophile). An electron pair moves from the C-H bond to the Michael donors slightly positive carbon because the R groups are very electron withdrawing.
2. This creates a carbanion and a protonated molecule of base.
3. The extra electron pair from the carbanion is donated to the furthest carbon on the alkene of the Michael acceptor (nucleophile) from the carbonyl. Later, the C-C pi bond migrates closer to the carbonyl and the C-O pi bond migrates to the oxygen atom to create an enolate. R1 represents any groups of any electronegativity.
4. The electron pair from the enolate is returned to the carbon to create a ketone as the C-C pi bond attacks the extra proton on the base to reestablish the alkene.
5. The reactants successfully underwent Michael addition and the base molecule is restored.
Michael additions will be racemic if there are no steric or electrical factors influencing the Michael donor or acceptor. However, research into creating an enantiopure bond is an important area as many medicinal molecules feature this type of carbon bonds. If the product is racemic, immediately half of the drug is unusable. Most stereochemical catalysts are expensive and metal based, but a group of researchers discovered that an abundant and cheap amino acid, proline, can be added to coax the bond into the desired orientation. This is so significant that it won the Nobel Prize in chemistry in 2021.
Examples of the Michael Addition
Michael addition is commonly used in the synthesis of medicinal molecules; significantly, intramolecular Michael additions are a common choice to close rings in molecules with electronegative substituents. Also, some drugs react in a Michael addition with amino acids and nucleotides to form irreversible bonds, permanently disabling broken cell machinery.