Enolatos: alquilação, condensações e adições conjugadas

Alkylation and the malonic and acetoacetic ester syntheses

• Acetoacetic ester alkylation with allyl bromideDeprotonate ethyl acetoacetate with the matching alkoxide and alkylate the enolate on carbon with allyl bromide.
• 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.
• 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.
• 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.

Aldol, Claisen and Dieckmann condensations

• 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.
• 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.
• 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.
• Benzylidenemalononitrile by Knoevenagel condensationDraw the piperidine-catalysed Knoevenagel condensation of malononitrile with benzaldehyde: carbanion formation, addition, proton transfers and E1cB loss of hydroxide.

Making enolates

• 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.
• 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.
• 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.

Michael additions and Robinson annulation

• 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.
• 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.
• 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.

Alquilação e sínteses dos ésteres malônico e acetoacético

• 4-Fenilbutan-2-ona pela síntese do éster acetoacéticoDesenhe a síntese da 4-fenilbutan-2-ona pelo éster acetoacético: SN2 do enolato no brometo de benzila, hidrólise ácida do éster etílico, descarboxilação do β-cetoácido e tautomerização do enol.
• Descarboxilação do ácido 2-oxociclo-hexano-1-carboxílicoDesenhe a descarboxilação cíclica de seis átomos do ácido 2-oxociclo-hexano-1-carboxílico ao enol e CO2, e a tautomerização do ciclo-hex-1-en-1-ol a ciclo-hexanona mediada por ácido.

Condensações aldólica, de Claisen e de Dieckmann

• (E)-4-(Furan-2-il)but-3-en-2-ona a partir de furfural e acetonaDesenhe a condensação aldólica cruzada da acetona com furfural promovida por hidróxido: formação do enolato, adição ao aldeído, protonação e desidratação E1cB à (E)-4-(furan-2-il)but-3-en-2-ona.
• 1,1,1-Trifluoropentano-2,4-diona por Claisen cruzadaDesenhe a Claisen cruzada da acetona com trifluoroacetato de etila: adição do enolato, perda de etóxido, desprotonação da β-dicetona e tratamento ácido até a 1,1,1-trifluoropentano-2,4-diona.
• 2-Oxociclopentano-1-carbaldeído por Claisen cruzadaDesenhe a Claisen cruzada da ciclopentanona com formiato de etila promovida por etóxido: adição do enolato ao formiato, perda de etóxido, desprotonação do produto 1,3-dicarbonílico e tratamento ácido até o 2-oxociclopentano-1-carbaldeído.
• Condensação aldólica intramolecular da octano-2,7-dionaDesenhe o fechamento de anel da octano-2,7-diona promovido por hidróxido, via seu enolato interno em C3, e a desidratação E1cB que forma a 1-(2-metilciclopent-1-en-1-il)etan-1-ona.

Formação de enolatos

• Contração de anel de Favorskii da 2-clorociclo-heptanonaDesenhe o rearranjo de Favorskii da 2-clorociclo-heptanona com metóxido, do enolato α′, passando pela ciclopropanona bicíclica, até o ciclo-hexanocarboxilato de metila.
• Ciclo-hexanocarboxilato e bromofórmio pela reação do halofórmioDesenhe as três bromações do grupo metila da 1-ciclo-hexiletan-1-ona promovidas por hidróxido, a adição de hidróxido, a perda do ânion tribromometila e a transferência de próton que fornece ciclo-hexanocarboxilato e bromofórmio.
• α-Bromação HVZ do ácido 3-fenilpropanoicoDesenhe a sequência HVZ no ácido 3-fenilpropanoico: formação do brometo de acila com PBr3, enolização, α-bromação por Br2 e hidrólise a ácido 2-bromo-3-fenilpropanoico.
• 2-Metil-1-fenilpropan-1-ona por metilação com LDADesenhe a desprotonação da propiofenona pelo LDA em seu CH2 α e a metilação SN2 do enolato de lítio pelo iodometano, formando a 2-metil-1-fenilpropan-1-ona.

Alquilação e as sínteses malônica e acetoacética

• Ciclopropano-1,1-dicarboxilato de dietila a partir do malonato de dietilaDesenhe as duas desprotonações do malonato de dietila por etóxido, a SN2 intermolecular no 1,2-dibromoetano e a SN2 intramolecular que fecha o ciclopropano-1,1-dicarboxilato de dietila.
• Ácido pent-4-enoico pela síntese malônicaDesenhe a síntese malônica do ácido pent-4-enoico: SN2 do enolato do malonato no brometo de alila, hidrólise ácida dos dois ésteres, descarboxilação e tautomerização do enol.

Adições de Michael e anelação de Robinson

• Adição de Michael do malonato de dietila à chalconaDesenhe a desprotonação do malonato de dietila pelo etóxido, a adição conjugada do enolato do malonato ao carbono β da chalcona e a protonação do enolato resultante pelo etanol.
• Cetona de Hajos–Parrish por anelação de Robinson com MVKDesenhe a anelação de Robinson da 2-metilciclopentano-1,3-diona com a metil vinil cetona: adição de Michael, protonação do enolato, fechamento de anel por aldólica intramolecular e desidratação E1cB até a cetona de Hajos–Parrish.
• Michael via enamina de Stork: ciclopentanona e acrilato de metilaDesenhe a formação da enamina de pirrolidina a partir da ciclopentanona, a adição conjugada da enamina ao acrilato de metila, a protonação do carbânion estabilizado pelo éster e a hidrólise do íon imínio.

Aldol, Claisen and Dieckmann condensations

• Predict a crossed aldol condensationPredict the product of a crossed aldol condensation between an enolisable aldehyde and a non-enolisable aldehyde.
• Self-aldol condensationPredict the conjugated product of a ketone self-aldol condensation.
• ClaisenPredict the β-keto ester from an ester self-Claisen condensation.

Michael additions and Robinson annulation

• 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.
• Nitroalkene acceptorPredict the Michael adduct of malonate with a nitroalkene.

Making enolates

• 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.

Alkylation and the malonic and acetoacetic ester syntheses

• Ring via dialkylationPredict the carbocycle formed by double alkylation of malonate with a dihalide.

Adições de Michael e anelação de Robinson

• Anelação de Robinson da 2-metilciclo-hexano-1,3-dionaPreveja a enona bicíclica formada na anelação de Robinson de uma 1,3-diona cíclica.

Aldol, Claisen and Dieckmann condensations

• 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.

Michael additions and Robinson annulation

• 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.

Alkylation and the malonic and acetoacetic ester syntheses

• 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.

Adições de Michael e anelação de Robinson

• Michael ou aldólica: enolato do acetoacetato de etila e MVKClassifique a adição de um enolato estabilizado a uma cetona α,β-insaturada como Michael (1,4) ou aldólica (1,2).

Making enolates

• Rank α-hydrogen acidityRank carbonyl compounds by the acidity of their most acidic C–H bond using the stabilisation of each enolate.
• Rank enol contentRank carbonyl compounds by the fraction present as the enol at equilibrium.

Alkylation and the malonic and acetoacetic ester syntheses

• Rank electrophiles for malonate alkylationRank alkyl halides by how well they alkylate a malonate enolate in an SN2 reaction.

Alkylation and the malonic and acetoacetic ester syntheses

• Mass of CO₂ releasedCalculate the mass of CO₂ lost when a substituted malonic acid decarboxylates completely.

Making enolates

• Count exchangeable hydrogensCount the α-hydrogens of an unsymmetrical ketone that exchange for deuterium through enolate formation.
• 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.

Aldol, Claisen and Dieckmann condensations

• Count the Dieckmann ringCount the ring size produced when a long-chain diester undergoes Dieckmann cyclisation.
• How many products?Count the major Claisen products when one partner cannot form an enolate.

Misto: sínteses de enolatos em várias etapas, espectros, halofórmio

• Hidróxido consumido na reação do iodofórmio da acetofenonaBalanceie a reação do halofórmio de uma metilcetona e conte quanto hidróxido ela consome.

Aldol, Claisen and Dieckmann condensations

• Why no Dieckmann product?Diagnose a failed Dieckmann cyclisation by counting the ring the enolate would have to close.

Making enolates

• Why did the hydroxide alkylation fail?Diagnose why aqueous hydroxide is a poor base for alkylating a simple ketone.

Alkylation and the malonic and acetoacetic ester syntheses

• Why no tert-butylExplain why tertiary halides fail in acetoacetic ester alkylation.

Michael additions and Robinson annulation

• Which compound was isolated?Use IR, ¹H NMR and the molecular formula to tell the Robinson annulation product from its Michael and aldol intermediates.

Misto: sínteses de enolatos em várias etapas, espectros, halofórmio

• RMN de 1H do acetoacetato de etila: o simpleto em 3,4 ppmAtribua um sinal de RMN de ¹H de um β-cetoéster a partir do deslocamento, da integração e do desdobramento.

Aldol, Claisen and Dieckmann condensations

• 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.

Alkylation and the malonic and acetoacetic ester syntheses

• 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.

Michael additions and Robinson annulation

• 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.

Alkylation and the malonic and acetoacetic ester syntheses

• Plan an acetoacetic ester synthesisChoose the two alkylation steps of an acetoacetic ester synthesis that build an α-branched methyl ketone.

Making enolates

• 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.

Misto: sínteses de enolatos em várias etapas, espectros, halofórmio

• 2-Etil-hexan-1-ol a partir do butanal: ordene as etapasOrdene as etapas de uma rota aldólica que dobra a cadeia de carbonos até um álcool primário ramificado.

Aldol, Claisen and Dieckmann condensations

• 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.

Alkylation and the malonic and acetoacetic ester syntheses

• Why do β-keto acids lose CO₂ so easily?Explain why a carbonyl group β to a carboxylic acid allows decarboxylation on gentle heating.