Organic Chemistry 2 · Enolates: alkylation, condensations and conjugate additions
4-Phenylbutan-2-one by acetoacetic ester synthesis
Conditions: NaOEt, EtOH; then H3O⁺, Δ
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The mechanism, step by step
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Ethoxide forms the stabilized enolate
The CH2 between the ketone and the ester carbonyl of ethyl acetoacetate is unusually acidic (pKa ≈ 11) because the anion is delocalized onto both oxygens. Ethoxide (ethanol pKa ≈ 16) removes one of those hydrogens essentially completely.
The curved arrows
- The ethoxide lone pair takes the doubly activated α-proton.
- The C–H pair stays on the central carbon, shared with both carbonyls.
SN2 benzylation
The central carbon attacks the CH2 of benzyl bromide from the back side and bromide leaves. Benzylic halides are excellent SN2 substrates because the benzene ring stabilizes the transition state.
The curved arrows
- The carbanion lone pair forms the new C–C bond to the benzylic carbon.
- The C–Br bond breaks and bromide leaves.
Protonate the ester carbonyl
In the acidic workup, hydronium protonates the ester carbonyl oxygen of ethyl 2-benzyl-3-oxobutanoate, activating it toward attack by water.
The curved arrows
- The carbonyl oxygen lone pair takes a proton from hydronium.
- The O–H pair returns to oxygen, releasing water.
Water adds to the ester
Water attacks the activated ester carbonyl carbon and the C=O⁺ π pair moves onto the protonated oxygen.
The curved arrows
- A water lone pair bonds to the carbonyl carbon.
- The π pair moves onto the protonated oxygen.
Deprotonate the added water
Water removes a proton from the oxonium oxygen, giving the neutral tetrahedral intermediate.
The curved arrows
- A water lone pair takes the proton.
- The O–H pair stays on oxygen.
Protonate the ethoxy oxygen
Hydronium protonates the ethoxy oxygen so that it can leave as neutral ethanol rather than as ethoxide.
The curved arrows
- The ethoxy oxygen lone pair takes the proton.
- The O–H pair returns to water.
Ethanol leaves
An OH lone pair re-forms the carbonyl and ethanol departs, completing the hydrolysis of the ester.
The curved arrows
- The oxygen lone pair re-forms the C=O bond.
- The C–O bond breaks and ethanol leaves.
Form the β-keto acid
Water removes the proton from the protonated carbonyl, giving 2-benzyl-3-oxobutanoic acid, a β-keto acid.
The curved arrows
- Water takes the proton.
- The O–H pair stays on the carbonyl oxygen.
Decarboxylation through a cyclic transition state
On heating, the β-keto acid loses CO2 through a six-membered cyclic transition state: the ketone oxygen takes the acid O–H proton while the C–C bond to the carboxyl carbon breaks. The products are carbon dioxide and the enol of the ketone.
The curved arrows
- The ketone oxygen lone pair takes the carboxylic acid proton.
- The O–H pair forms the second C=O bond of carbon dioxide.
- The C–C bond pair becomes the C=C π bond of the enol.
- The C=O π pair moves onto oxygen, which keeps its new O–H.
Enol to ketone: protonate carbon
In acid the enol tautomerizes: hydronium protonates the carbon of the C=C while the O–H lone pair forms C=O⁺.
The curved arrows
- An oxygen lone pair pushes toward carbon to form C=O⁺.
- The C=C π pair takes a proton from hydronium at carbon.
- The O–H pair returns to water.
Deprotonate the oxygen
Water removes the proton from the protonated ketone, giving neutral 4-phenylbutan-2-one and regenerating hydronium.
The curved arrows
- Water takes the proton from oxygen.
- The O–H pair stays on the ketone oxygen.
4-Phenylbutan-2-one
The product is 4-phenylbutan-2-one: the CH3CO–CH2 unit comes from ethyl acetoacetate and the benzyl group from benzyl bromide, so the acetoacetic ester acts as an acetone enolate equivalent. Ethanol, CO2 and bromide are by-products.
What you'll practice
Draw the acetoacetic ester synthesis of 4-phenylbutan-2-one: enolate SN2 on benzyl bromide, acid hydrolysis of the ethyl ester, decarboxylation of the β-keto acid and tautomerization of the enol.
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