Start with methyl vinyl ketone (MVK, but-3-en-2-one, CH2=CH–CO–CH3) and the anion of pentane-2,4-dione. MVK has two electrophilic carbons: the carbonyl carbon, and the CH2 at the far end of the C=C, called the β carbon. The anion bonds to the β carbon. Count the oxygen as atom 1 and that carbon is atom 4, so this is a 1,4-addition, also called conjugate addition.
Which of the two carbons a nucleophile picks depends mainly on the nucleophile, and much less on the enone. You met that rule with cuprates in Cuprates and conjugate addition. Here the nucleophile is an enolate, the anion left when a hydrogen is removed from the α carbon of a carbonyl compound, and its 1,4-addition has its own name.
The Michael reaction
A Michael addition is the 1,4-addition of a stabilized enolate, or a similar stabilized carbanion, to an α,β-unsaturated carbonyl, a compound whose C=C sits between the α and β carbons, right next to the C=O. Two names come with it:
- The donor is the compound that gets deprotonated and becomes the nucleophile. Above, that is pentane-2,4-dione.
- The acceptor is the unsaturated carbonyl, also called a Michael acceptor. Above, that is MVK.
The mechanism takes three moves, drawn in the first three panels of the figure below:
- Deprotonate. Ethoxide takes a hydrogen from the CH2 between the two C=O groups. The anion is stable because its charge spreads onto both oxygens.
- Add. The anion’s carbon bonds to the acceptor’s β carbon. What forms first is a new enolate, not yet a ketone.
- Protonate. The new enolate takes a proton from ethanol. A proton on carbon gives the ketone directly. A proton on oxygen gives an enol, which tautomerizes (moves the H from O to C) to the same ketone.
Which donors and acceptors work
The donor is almost always a compound whose α hydrogen sits between two electron-withdrawing groups, groups such as C=O, C≡N or NO2 that pull electron density toward themselves. The common ones are 1,3-diketones, β-keto esters and malonates. Their pKa values are about 9–13, far below the 20 of a simple ketone.
Their anions are soft. A soft nucleophile has its charge spread over several atoms instead of packed onto one. It reacts where orbitals overlap best, not where the positive charge is largest.
On an enone those are two different carbons. The carbonyl carbon carries the larger positive charge. The β carbon carries the larger share of the LUMO, the lowest-energy empty orbital, which is the orbital that takes in a nucleophile’s electrons. So a soft enolate adds at the β carbon: 1,4, not 1,2.
| Common donors (α pKa) | Common acceptors |
|---|---|
| 1,3-diketone, e.g. pentane-2,4-dione (~9) | α,β-unsaturated ketone, an enone |
| β-keto ester, e.g. ethyl acetoacetate (~11) | α,β-unsaturated aldehyde |
| malonate, e.g. diethyl malonate (~13) | α,β-unsaturated ester |
| nitroalkane, e.g. nitromethane (~10) | α,β-unsaturated nitrile |
| malononitrile and α-cyano esters (cyanoacetates) | nitroalkene |
| enamine (C=C–N), the neutral option | methyl vinyl ketone, the workhorse |
Read down the left column: each donor except the enamine has a C–H next to a group that can take the charge, usually two such groups (nitromethane has one, the strongly withdrawing NO2). The enamine’s carbon is nucleophilic without losing a proton, because nitrogen’s lone pair pushes into the C=C. Read down the right: each acceptor has a C=C conjugated to an electron-withdrawing group, and that group is the only reason the β carbon is electrophilic at all.
Thiols and amines add 1,4 to enones too. That is how cysteine and lysine side chains in proteins get modified in the body. For exam work, the carbon donors in the table are the list to know.
Why a doubly stabilized donor
There are two reasons, and both matter in practice.
The first is control. A simple ketone enolate made with LDA (lithium diisopropylamide, a strong and bulky base) at −78 °C is hard: its charge is concentrated, and it forms irreversibly. It is more prone to add 1,2, at the carbonyl carbon, giving an alkoxide and then an alcohol. A doubly stabilized enolate is soft (above) and adds 1,4.
The conditions matter as much as the donor. With a catalytic amount of alkoxide at room temperature, every step is reversible. Even a simple ketone enolate then ends up as the 1,4 product, because that product is more stable and the reaction has time to reach it. That is why cyclohexanone, an ordinary ketone, works as the donor in the classic Robinson annulation below. A doubly stabilized donor makes conjugate addition reliable; it is not what makes it possible.
The second is clean deprotonation. At pKa 9–13 the donor uses up the alkoxide essentially completely, so no free strong base is left to attack the acceptor’s carbonyl.
Recognize the product by counting
Go back to the product in panel 4 of the mechanism figure. Number it from one C=O carbon to the other, across the new bond: 1 is a donor C=O carbon, 2 the donor’s α carbon, 3 the old β carbon, 4 the old α carbon and 5 the acceptor’s C=O carbon.
The other two enolate reactions leave their own spacings. An aldol’s nucleophile hits a C=O carbon and the oxygen stays as an OH, so it gives a β-hydroxy carbonyl, with the C=O and the C–OH at 1,3. A Claisen’s nucleophile hits an ester carbon and the alkoxide leaves, so it gives a 1,3-dicarbonyl, with two C=O groups at 1,3. So count the gap first, then check whether the second oxygen is a C=O or an OH. Count from the C=O carbon and the other chain carbon bonded to oxygen (a second C=O carbon, or the C–OH carbon); an ester’s O–CH2CH3 is not part of the count.
The count works backwards too. A disconnection is a bond you imagine breaking to see which starting materials could have made the molecule. A structural feature that points to one reaction is that reaction’s retron. The 1,5-dicarbonyl is the Michael retron: break the bond between carbons 2 and 3, which is α to one carbonyl and β to the other, and you get the enolate donor and the enone acceptor back.
The Robinson annulation
Mix cyclohexanone, methyl vinyl ketone and ethoxide, and a second six-membered ring grows onto the first, carrying an enone (a C=C conjugated with a C=O). This is the Robinson annulation. Annulation means building a new ring onto a molecule, and this is the standard way to build a six-membered ring that bears an enone.
Three reactions run one after another in the same flask. The figure numbers the six atoms of the new ring 1 to 6, and the list uses the same numbers:
- Michael. Ring carbon 2, the α carbon of cyclohexanone, adds to carbon 3, the β carbon of MVK. The product is a 1,5-dicarbonyl, with its C=O carbons at 1 and 5.
- Intramolecular aldol. Base makes an enolate at carbon 6, the methyl at the end of the new side chain. Carbon 6 attacks the ring’s C=O carbon, 1, and closes the new ring. The Aldol reactions section covers aldols that close rings.
- Dehydration. The β-hydroxy ketone loses water by E1cb: base removes a hydrogen from carbon 6, then hydroxide leaves carbon 1. A C=C forms between 1 and 6.
The dehydration drives the sequence. The Michael addition and the aldol are both reversible. Losing water gives a C=C conjugated with the C=O, which is more stable, and in practice that step does not run back. It pulls the earlier equilibria forward.
The product is a cyclohexenone in every case you will meet. Methyl vinyl ketone is the classic acceptor, because it is cheap and the ring it builds is the one steroid synthesis needed. Steroids are the four-ring compounds such as cholesterol and the sex hormones.
Why the new ring has six atoms
Take the simplest 1,5-dicarbonyl, heptane-2,6-dione, CH3CO(CH2)3COCH3. Number it the same way: C=O carbons at 1 and 5, carbons 2, 3 and 4 between them, and carbon 6 the methyl beyond carbonyl 5.
An aldol joins an α carbon to a carbonyl carbon, never two carbonyl carbons to each other. So the possible nucleophiles are the α carbons. Carbons 2 and 4 are inner α carbons: they sit between the two carbonyls. Carbon 6 sits on the far side of carbonyl 5. An α carbon on the far side of a carbonyl, away from the other carbonyl, is an α′ (“alpha prime”) carbon. The methyl beyond carbonyl 1 is one too, and by symmetry it gives the same ring.
Now count each loop. Carbon 6 attacking carbon 1 closes the loop 1-2-3-4-5-6: six atoms. Carbon 2 attacking carbon 5 closes 2-3-4-5: four atoms. So does carbon 4 attacking carbon 1. A four-membered ring is badly strained and does not compete with a six.
A ring donor can offer a second α′ carbon. In cyclohexanone’s Michael product, the ring CH2 on the other side of carbonyl 1 could attack carbonyl 5, and that loop also has six atoms. The worked example below shows why that closure goes nowhere.
Working backwards from a cyclohexenone
Take 3-methylcyclohex-2-en-1-one. Number its ring the build way: the C=O carbon is 5, the C=C runs between 6 and 1, and the methyl sits on 1. Then undo the three steps, last step first:
- Undo the dehydration. Add water back across the C=C: H on 6, OH on 1. That gives a β-hydroxy ketone.
- Undo the aldol. Break the bond between the α carbon and the carbinol carbon (the carbon carrying the OH): bond 6–1. The ring opens to heptane-2,6-dione, a 1,5-dicarbonyl.
- Undo the Michael. Break bond 2–3. The pieces are acetone, the donor (carbons 1 and 2, plus the methyl on 1), and methyl vinyl ketone, the acceptor (carbons 3 to 6).
Run this check on every cyclohexenone in an exam question. If the ring opens to a 1,5-dicarbonyl, a Robinson annulation can make it. If carbon 1 carries an H instead of a carbon group, the donor was an aldehyde.
2-Methylcyclohexane-1,3-dione and methyl vinyl ketone give the Wieland–Miescher ketone, where a great deal of steroid synthesis starts. The numbers below are the new ring’s, as before.
1. Find the donor carbon. C2 of the dione sits between both C=O groups, so an alkoxide deprotonates it. It already carries the methyl. After the Michael addition it has four carbon neighbors, which is why that methyl ends up on a quaternary carbon.
2. Michael. C2 (number 2) adds to the β carbon of MVK, its CH2 end (number 3). The product is 2-methyl-2-(3-oxobutyl)cyclohexane-1,3-dione: the ring plus a –CH2CH2COCH3 arm on C2.
3. Find the two six-atom loops. The fused loop: the arm’s methyl (6) attacks a ring C=O carbon (1), closing 6-5-4-3-2-1. The new ring shares one bond, 1–2, with the old ring. Rings that share one bond are fused.
The bridged loop: the ring CH2 next to the other ring C=O (marked x) attacks the arm’s C=O carbon (5). That loop has six atoms too, but it shares three atoms and two bonds with the old ring. Rings that share more than one bond are bridged. This one is named bicyclo[3.3.1], for the 3, 3 and 1 atoms in its three bridges.
The bridged aldol product cannot dehydrate. Its C=C would have to start at x, a bridgehead (an atom where the rings join), and a C=C at the bridgehead of so small a bridged ring is too strained to form (Bredt’s rule). That aldol runs backward instead, and the material ends up on the fused path.
4. Dehydrate. The fused aldol product loses water. The new C=C runs between 1, the old ring C=O carbon, and 6, in conjugation with the arm’s C=O at 5. Carbon 1 belongs to both rings, so the C=C sits at the ring fusion.
5. Read the product. Two fused rings: an enone in the new ring, an untouched ketone in the old one, and an angular methyl (a methyl on a ring-fusion carbon) on carbon 2. Run the three backward steps on it and the dione and MVK come back out. That checks that you built it right.
What carries forward
A Michael addition is conjugate addition with an enolate donor, and it leaves a 1,5-dicarbonyl. A Robinson annulation is a Michael addition followed by an intramolecular aldol condensation, and it leaves a cyclohexenone. You recognize both by the spacing in the product, not by memorized conditions, and that is the way to hold every condensation in this chapter.