Química Orgânica 2 · Condensação de Claisen e adição conjugada
Annulate a ketone with methyl vinyl ketone
Condições: Cyclopentanone and but-3-en-2-one (methyl vinyl ketone) with sodium ethoxide in ethanol, then heat. One ethanol/ethoxide molecule transfers protons throughout the reaction; Na⁺ is a spectator. Follow the path to the fused bicyclic enone 1,2,3,6,7,7a-hexahydro-5H-inden-5-one. Competing self-aldol reactions and polymerization of the enone are not modeled; the new stereocenter at the ring carbon that forms the first C–C bond is not assessed.
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Form the ketone enolate
A ketone α C–H (pKa approximately 19 to 20) is less acidic than ethanol (pKa approximately 16), so only a small fraction of enolate is present at any moment. It is replenished as it reacts.
As setas curvas
- An ethoxide lone pair takes an α proton from cyclopentanone.
- The α C–H pair stays on carbon, giving the enolate (drawn as its carbon contributor).
Michael addition to the enone
Conjugation makes the terminal carbon of methyl vinyl ketone electrophilic. Attack there (1,4-addition) keeps the product anion stabilized as an enolate.
As setas curvas
- The enolate carbon lone pair bonds to the β carbon of the enone.
- The enone C=C π pair forms a π bond between the α carbon and the carbonyl carbon.
- The enone carbonyl π pair becomes a lone pair on oxygen, giving a new enolate.
Protonate the new enolate on carbon
Ethanol (pKa approximately 16) is a stronger acid than a ketone α C–H (pKa approximately 19 to 20), so protonating this enolate is favorable. The product is a 1,5-diketone.
As setas curvas
- A lone pair on the negatively charged oxygen rebuilds the carbonyl π bond.
- The enolate π pair bonds the α carbon to the ethanol proton.
- The O–H pair stays on oxygen, regenerating ethoxide.
Form the enolate that can close a ring
Several α carbons can be deprotonated reversibly. Only the enolate at the side-chain methyl carbon can reach the ring carbonyl carbon while making a six-membered ring, which is the ring size that forms most easily.
Nota: Remove a hydrogen from the methyl group of the side-chain ketone. Its hydrogens are equivalent.
As setas curvas
- Ethoxide takes a proton from the methyl carbon of the side-chain ketone.
- The methyl C–H pair stays on carbon.
Close the six-membered ring
An intramolecular aldol addition. The new six-membered ring contains the four side-chain carbons and the two adjacent carbons of the original ring.
As setas curvas
- The side-chain enolate carbon lone pair bonds to the ring carbonyl carbon.
- The ring carbonyl π pair becomes a lone pair on oxygen.
Protonate the alkoxide
An alkoxide and ethoxide are bases of similar strength (their alcohols have pKa values of approximately 16 to 18), so proton exchange with ethanol is fast. The product is a β-hydroxy ketone.
As setas curvas
- An alkoxide oxygen lone pair takes a proton from ethanol.
- The O–H pair stays on the ethanol oxygen, regenerating ethoxide.
Deprotonate between the ketone and the alcohol
With heat, the aldol product loses water by the E1cB route, which starts from an enolate.
As setas curvas
- Ethoxide takes a proton from the α carbon between the ketone and the new C–OH carbon.
- The α C–H pair stays on carbon as an enolate.
Expel hydroxide
Hydroxide is normally a poor leaving group, but here it leaves from an anion next to a carbonyl, and the new C=C bond is conjugated with the ketone. Heat drives this step.
As setas curvas
- The enolate carbon lone pair forms a π bond to the neighboring carbon bearing OH.
- The C–O pair leaves with oxygen as hydroxide.
Fused cyclohexenone
A new six-membered ring is fused to the original five-membered ring. Its new C=C double bond is conjugated with the ketone: 1,2,3,6,7,7a-hexahydro-5H-inden-5-one. All four carbons of methyl vinyl ketone ended up in the new ring. The cyclopentanone oxygen left as hydroxide, and ethoxide ended up as ethanol.
O que você vai praticar
Carry a ketone enolate through Michael addition, intramolecular aldol addition and E1cB dehydration to a fused cyclohexenone (a Robinson annulation).
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