Organic Chemistry 2 · Carbonyl and enolate chemistry
Enolates: alkylation, condensations and conjugate additions: practice problems
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- Acetoacetic ester alkylation with allyl bromide
- Self-aldol condensation of butanal
- Decarboxylation of butylmalonic acid to hexanoic acid
- Crossed Claisen of cyclohexanone with diethyl oxalate
- Dieckmann cyclisation of diethyl heptanedioate
- Directed aldol of cyclohexanone with benzaldehyde
- Claisen condensation of ethyl propanoate
- Intramolecular aldol condensation of hexane-2,5-dione
- Kinetic enolate alkylation of 3-methylbutan-2-one with benzyl bromide
Draw the mechanism 38
- Acetoacetic ester alkylation with allyl bromideDeprotonate ethyl acetoacetate with the matching alkoxide and alkylate the enolate on carbon with allyl bromide.
- Self-aldol condensation of butanalDraw the hydroxide-catalysed aldol addition of two butanal molecules and the E1cB dehydration that gives (E)-2-ethylhex-2-enal.
- Decarboxylation of butylmalonic acid to hexanoic acidDraw the cyclic loss of CO₂ from a substituted malonic acid and the acid-catalysed tautomerisation of the enol to hexanoic acid.
- Crossed Claisen of cyclohexanone with diethyl oxalateDraw the ethoxide-mediated acylation of cyclohexanone by diethyl oxalate, the deprotonation of the 1,3-dicarbonyl product that drives the reaction, and the acid workup.
- Dieckmann cyclisation of diethyl heptanedioateDraw the intramolecular Claisen (Dieckmann) condensation of diethyl heptanedioate to the six-membered cyclic β-keto ester, including the deprotonation that drives it and the acid workup.
- Directed aldol of cyclohexanone with benzaldehydePreform the cyclohexanone enolate with LDA, add it to benzaldehyde, and protonate the alkoxide at workup to give the β-hydroxy ketone.
- Claisen condensation of ethyl propanoateDraw the Claisen condensation of ethyl propanoate: enolate formation, addition to a second ester, loss of ethoxide, the deprotonation that drives the reaction, and acid workup.
- Intramolecular aldol condensation of hexane-2,5-dioneDraw the hydroxide-catalysed ring closure of hexane-2,5-dione onto its own second ketone and the E1cB dehydration that gives 3-methylcyclopent-2-en-1-one.
- Kinetic enolate alkylation of 3-methylbutan-2-one with benzyl bromideDraw the LDA deprotonation of 3-methylbutan-2-one at its methyl group and the SN2 benzylation of the kinetic enolate.
- Methylation of methyl phenylacetate through its LDA enolateForm an ester enolate quantitatively with LDA and alkylate it with iodomethane by an SN2 reaction.
- Malonic ester alkylation with 1-bromobutaneDeprotonate diethyl malonate with ethoxide, show how both ester groups share the negative charge, and alkylate the enolate with 1-bromobutane.
- Diethyl malonate and 1,4-dibromobutane close a cyclopentaneUse two successive malonate alkylations, the second one intramolecular, to build diethyl cyclopentane-1,1-dicarboxylate.
- Michael addition of pentane-2,4-dione to cyclohex-2-en-1-oneDraw the base-catalysed conjugate addition of the pentane-2,4-dione enolate to the β-carbon of cyclohex-2-en-1-one and the proton transfer that regenerates ethoxide.
- Michael addition of ethyl 2-oxocyclopentane-1-carboxylate to acrylonitrileDraw the conjugate addition of a cyclic β-keto ester enolate to acrylonitrile and the proton transfer that regenerates the ethoxide catalyst.
- Robinson annulation of 2-methylcyclohexanone with methyl vinyl ketoneDraw the Michael addition of the more substituted 2-methylcyclohexanone enolate to methyl vinyl ketone, the intramolecular aldol addition that closes a six-membered ring, and the E1cB dehydration to the bicyclic enone.
- 4-Phenylbutan-2-one by acetoacetic ester synthesisDraw 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.
- (E)-4-(Furan-2-yl)but-3-en-2-one from furfural and acetoneDraw the hydroxide-promoted crossed aldol condensation of acetone with furfural: enolate formation, addition to the aldehyde, protonation and E1cB dehydration to (E)-4-(furan-2-yl)but-3-en-2-one.
- 1,1,1-Trifluoropentane-2,4-dione by crossed ClaisenDraw the crossed Claisen of acetone with ethyl trifluoroacetate: enolate addition, loss of ethoxide, deprotonation of the β-diketone and the acidic workup to 1,1,1-trifluoropentane-2,4-dione.
- 2-Oxocyclopentane-1-carbaldehyde by crossed ClaisenDraw the ethoxide-promoted crossed Claisen of cyclopentanone with ethyl formate: enolate addition to the formate, loss of ethoxide, deprotonation of the 1,3-dicarbonyl product and the acidic workup to 2-oxocyclopentane-1-carbaldehyde.
- Decarboxylation of 2-oxocyclohexane-1-carboxylic acidDraw the cyclic six-atom decarboxylation of 2-oxocyclohexane-1-carboxylic acid to the enol and CO2, and the acid-relayed tautomerization of cyclohex-1-en-1-ol to cyclohexanone.
- Favorskii ring contraction of 2-chlorocycloheptanoneDraw the Favorskii rearrangement of 2-chlorocycloheptanone with methoxide, from the α′-enolate through the bicyclic cyclopropanone to methyl cyclohexanecarboxylate.
- Cyclohexanecarboxylate and bromoform by haloform reactionDraw the three hydroxide-promoted brominations of the methyl group of 1-cyclohexylethan-1-one, hydroxide addition, loss of the tribromomethyl anion and the proton transfer that gives cyclohexanecarboxylate and bromoform.
- HVZ α-bromination of 3-phenylpropanoic acidDraw the HVZ sequence on 3-phenylpropanoic acid: acyl bromide formation with PBr3, enolization, α-bromination by Br2 and hydrolysis to 2-bromo-3-phenylpropanoic acid.
- 2-Bromobutanoic acid by the Hell–Volhard–Zelinsky reactionDraw the HVZ sequence on butanoic acid: conversion to the acyl bromide with PBr3, enolization, α-bromination by Br2 and hydrolysis to 2-bromobutanoic acid.
- 3-Methylcyclohex-2-en-1-one by intramolecular aldol condensation of heptane-2,6-dioneDraw the hydroxide-promoted ring closure of heptane-2,6-dione through its terminal-methyl enolate and the E1cB dehydration that gives 3-methylcyclohex-2-en-1-one.
- Intramolecular aldol condensation of octane-2,7-dioneDraw the hydroxide-promoted ring closure of octane-2,7-dione through its internal C3 enolate and the E1cB dehydration that gives 1-(2-methylcyclopent-1-en-1-yl)ethan-1-one.
- Propanoate and iodoform from butan-2-one (haloform reaction)Draw the base-promoted triple iodination of the methyl group of butan-2-one, hydroxide attack and loss of the triiodomethyl anion, and the proton transfer that gives propanoate and iodoform.
- 2-Allyl-6-methylcyclohexanone by kinetic enolate allylationDraw LDA deprotonation of 2-methylcyclohexanone at the less substituted α-carbon and SN2 allylation of that kinetic enolate by allyl bromide.
- Benzylidenemalononitrile by Knoevenagel condensationDraw the piperidine-catalysed Knoevenagel condensation of malononitrile with benzaldehyde: carbanion formation, addition, proton transfers and E1cB loss of hydroxide.
- 2-Methyl-1-phenylpropan-1-one via LDA methylationDraw LDA deprotonation of propiophenone at its α-CH2 and SN2 methylation of the lithium enolate by iodomethane to give 2-methyl-1-phenylpropan-1-one.
- Diethyl cyclopropane-1,1-dicarboxylate from diethyl malonateDraw both ethoxide deprotonations of diethyl malonate, the intermolecular SN2 on 1,2-dibromoethane and the intramolecular SN2 that closes diethyl cyclopropane-1,1-dicarboxylate.
- Pent-4-enoic acid by malonic ester synthesisDraw the malonic ester synthesis of pent-4-enoic acid: malonate enolate SN2 on allyl bromide, acid hydrolysis of both esters, decarboxylation and tautomerization of the enol.
- 4-Methylpentanoic acid by malonic ester synthesis with 1-bromo-2-methylpropaneDraw the malonic ester synthesis of 4-methylpentanoic acid: malonate enolate SN2 on 1-bromo-2-methylpropane, acid hydrolysis of both esters, decarboxylation and tautomerization.
- Michael addition of diethyl malonate to chalconeDraw ethoxide deprotonation of diethyl malonate, conjugate addition of the malonate enolate to the β-carbon of chalcone, and protonation of the resulting enolate by ethanol.
- 5-Nitrohexan-2-one by Michael addition of nitroethane to methyl vinyl ketoneDraw the DBU-catalysed Michael addition of the nitroethane nitronate to methyl vinyl ketone, ending with proton return that gives 5-nitrohexan-2-one.
- Hajos–Parrish ketone by Robinson annulation with MVKDraw the Robinson annulation of 2-methylcyclopentane-1,3-dione with methyl vinyl ketone: Michael addition, protonation of the enolate, intramolecular aldol ring closure and E1cB dehydration to the Hajos–Parrish ketone.
- Stork enamine Michael of cyclopentanone with methyl acrylateDraw pyrrolidine enamine formation from cyclopentanone, conjugate addition of the enamine to methyl acrylate, protonation of the ester-stabilized carbanion, and hydrolysis of the iminium ion.
- 3-(2-Oxocyclohexyl)propanenitrile by Stork enamine Michael additionDraw pyrrolidine enamine formation from cyclohexanone, conjugate addition of the enamine to acrylonitrile, protonation of the nitrile-stabilized carbanion, and hydrolysis of the iminium ion.
Predict the product 9
- Predict a crossed aldol condensationPredict the product of a crossed aldol condensation between an enolisable aldehyde and a non-enolisable aldehyde.
- Predict the Michael adductPredict the product of a Michael addition of a malonate enolate to an α,β-unsaturated ester.
- Put the Robinson annulation in orderOrder the bond-forming and bond-breaking events of a Robinson annulation.
- Which silyl enol ether forms under equilibrating conditions?Predict the major silyl enol ether of an unsymmetrical ketone when the enolates can equilibrate before trapping.
- Self-aldol condensationPredict the conjugated product of a ketone self-aldol condensation.
- ClaisenPredict the β-keto ester from an ester self-Claisen condensation.
- Ring via dialkylationPredict the carbocycle formed by double alkylation of malonate with a dihalide.
- Nitroalkene acceptorPredict the Michael adduct of malonate with a nitroalkene.
- Robinson annulation of 2-methylcyclohexane-1,3-dionePredict the bicyclic enone from a Robinson annulation of a cyclic 1,3-dione.
Classify 5
- Which ester can only be the acceptor?Identify an ester that lacks α-hydrogens and therefore can serve only as the electrophile in a crossed Claisen condensation.
- Which reagent adds at the β-carbon?Classify nucleophiles by whether they add to the β-carbon or to the carbonyl carbon of an α,β-unsaturated ketone.
- Which acid loses CO₂ on gentle heating?Identify a β-keto acid among keto acids with the carbonyl at different positions.
- Which heats off CO2?Identify which keto acid decarboxylates on gentle heating.
- Michael or aldol: ethyl acetoacetate enolate and MVKClassify the addition of a stabilized enolate to an α,β-unsaturated ketone as Michael (1,4) or aldol (1,2).
Compare 3
- Rank α-hydrogen acidityRank carbonyl compounds by the acidity of their most acidic C–H bond using the stabilisation of each enolate.
- Rank electrophiles for malonate alkylationRank alkyl halides by how well they alkylate a malonate enolate in an SN2 reaction.
- Rank enol contentRank carbonyl compounds by the fraction present as the enol at equilibrium.
Calculate 8
- Mass of CO₂ releasedCalculate the mass of CO₂ lost when a substituted malonic acid decarboxylates completely.
- Count exchangeable hydrogensCount the α-hydrogens of an unsymmetrical ketone that exchange for deuterium through enolate formation.
- Count the Dieckmann ringCount the ring size produced when a long-chain diester undergoes Dieckmann cyclisation.
- How much enolate does ethoxide make?Calculate the equilibrium constant for deprotonating a simple ketone with ethoxide and judge whether enolate formation is complete.
- How complete is LDA deprotonation?Calculate the equilibrium constant for deprotonating a ketone with LDA from the two pKa values.
- Count α-HCount the α-hydrogens of an ester to judge how many enolisation events are possible.
- How many products?Count the major Claisen products when one partner cannot form an enolate.
- Hydroxide used in the iodoform reaction of acetophenoneBalance the haloform reaction of a methyl ketone and count the hydroxide it consumes.
Find the error 3
- Why no Dieckmann product?Diagnose a failed Dieckmann cyclisation by counting the ring the enolate would have to close.
- Why did the hydroxide alkylation fail?Diagnose why aqueous hydroxide is a poor base for alkylating a simple ketone.
- Why no tert-butylExplain why tertiary halides fail in acetoacetic ester alkylation.
Interpret the evidence 2
- Which compound was isolated?Use IR, ¹H NMR and the molecular formula to tell the Robinson annulation product from its Michael and aldol intermediates.
- 1H NMR of ethyl acetoacetate: the 3.4 ppm singletAssign a ¹H NMR signal of a β-keto ester from its shift, integration and splitting.
Work backward 4
- Which dione closes to 3-methylcyclohex-2-en-1-one?Work backwards from a cyclic enone to the open-chain dicarbonyl compound that forms it by intramolecular aldol condensation.
- Pick the alkyl halide for a malonic ester synthesisWork backwards from a substituted acetic acid to the alkyl halide needed in a malonic ester synthesis.
- Disconnect a Michael productIdentify the Michael donor and acceptor that build a ketone carrying a 2-cyanoethyl group on its α-carbon.
- Which ketone was annulated?Identify the ketone that, with methyl vinyl ketone, gives a given Robinson annulation product.
Plan a synthesis 4
- Plan an acetoacetic ester synthesisChoose the two alkylation steps of an acetoacetic ester synthesis that build an α-branched methyl ketone.
- Choose the base for complete enolate formationSelect a base that converts a simple ketone completely into its enolate before an alkyl halide is added.
- Pick the baseChoose conditions that form the kinetic enolate of an unsymmetrical ketone.
- 2-Ethylhexan-1-ol from butanal: order the stepsOrder the steps of a two-carbon-doubling aldol route to a branched primary alcohol.
Explain why 2
- Why a full equivalent of ethoxide?Explain why a Claisen condensation consumes a full equivalent of alkoxide while an aldol addition needs only a catalytic amount.
- Why do β-keto acids lose CO₂ so easily?Explain why a carbonyl group β to a carboxylic acid allows decarboxylation on gentle heating.
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