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Química Orgânica Avançada · Named reactions

Reações nomeadas que formam ligações carbono–carbono

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O que você vai aprender

  • Push arrows through the ylide and carbanion olefinations and three-membered-ring syntheses (Horner–Wadsworth–Emmons, Julia–Lythgoe, Julia–Kocienski, Corey–Chaykovsky, Darzens) and predict their products and alkene geometry.
  • Use silyl enol ethers, zinc enolates, iminium ions and enolate annulations (Mukaiyama aldol, Reformatsky, Mannich, Robinson, Knoevenagel–Doebner) to make a chosen carbon–carbon bond without self-condensation.
  • Explain nitro-group and umpolung chemistry (Henry, Nef, Morita–Baylis–Hillman, Stetter) in terms of which carbon is made nucleophilic and how the catalyst is regenerated.
  • Trace cationic cyclizations, the Ireland–Claisen rearrangement and the Arndt–Eistert homologation, including their stereochemical consequences.

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Olefination: where the oxygen goes

Every carbonyl olefination swaps C=O for C=C by turning the carbonyl oxygen into part of a leaving group: a phosphate in the Horner–Wadsworth–Emmons reaction, an acetate or a heteroaryl oxide in the Julia reactions. In the Horner–Wadsworth–Emmons reaction a phosphonate carbanion adds to an aldehyde, the alkoxide closes onto phosphorus to an oxaphosphetane, and syn fragmentation releases a water-soluble phosphate. Addition is reversible for stabilised carbanions, so the less hindered anti adduct funnels to the (E)-alkene; electron-poor bis(trifluoroethyl) phosphonates (Still–Gennari) eliminate faster than they equilibrate and give (Z). In the Julia–Lythgoe sequence a phenyl sulfone anion adds to an aldehyde, the alkoxide is acylated, and sodium amalgam reduction removes both groups to give mainly the (E)-alkene. In the Julia–Kocienski version a benzothiazolyl or tetrazolyl sulfone lets the alkoxide attack the heteroaryl ring (a Smiles rearrangement); the resulting sulfinate loses SO₂ and an aryloxide in one pot.

Three-membered rings from ylides and α-halo carbanions

Sulfur ylides add to carbonyl groups but, unlike phosphorus ylides, the betaine closes by intramolecular SN2: the alkoxide displaces a neutral sulfide or sulfoxide. Dimethylsulfonium methylide is reactive and adds irreversibly to the C=O of an enone, giving an epoxide. Dimethylsulfoxonium methylide is more stabilised; its 1,2-addition is reversible, so it ends up adding 1,4 and closing a cyclopropane. Both are Corey–Chaykovsky reactions. The Darzens reaction follows the same logic with an α-halo ester enolate: aldol-type addition, then the alkoxide displaces chloride to give a glycidic ester. The Mukaiyama aldol replaces the enolate with a silyl enol ether that is too weak a nucleophile to react until a Lewis acid activates the aldehyde, so crossed aldols work without self-condensation.

Nitro groups, zinc enolates and iminium ions

Nitroalkanes (pKa ≈ 10 in water) are deprotonated by amines; the nitronate adds to aldehydes in the reversible Henry (nitroaldol) reaction. The β-nitro alcohol can be dehydrated (mesylation, then E1cB) to a nitroalkene, and a Nef reaction (nitronate added to strong aqueous acid) converts the nitro carbon into a ketone, releasing HNO. Reformatsky reagents, zinc enolates made by inserting zinc into an α-bromo ester, add to aldehydes and ketones through a six-membered zinc-chelated transition state but do not attack esters. Mannich reactions use an iminium ion as the electrophile; with Eschenmoser's salt, quaternisation and elimination turn the Mannich base into an α-methylene carbonyl. The Robinson annulation is a Michael addition to methyl vinyl ketone followed by an intramolecular aldol condensation that closes a cyclohexenone; with 2-methylcyclohexane-1,3-dione it gives the Wieland–Miescher ketone. In the Knoevenagel–Doebner reaction malonic acid condenses with an aldehyde in pyridine with a little piperidine, and decarboxylation gives the (E)-cinnamic acid.

Nucleophilic catalysis and umpolung

A nucleophilic catalyst can create a carbanion where none existed. In the Morita–Baylis–Hillman reaction DABCO adds to an acrylate, the enolate attacks an aldehyde, a proton transfer follows (usually rate-limiting), and E1cB elimination returns DABCO, leaving an allylic alcohol on the α-carbon of the acrylate. In the Stetter reaction a thiazolium ylide adds to an aldehyde; proton transfer gives the Breslow intermediate, an enaminol whose former carbonyl carbon is now nucleophilic (an acyl-anion equivalent). Conjugate addition to an enone and release of the catalyst give a 1,4-dicarbonyl compound, a relationship that normal enolate chemistry cannot make directly.

Cations, [3,3] shifts and one-carbon homologation

In the Prins reaction a protonated aldehyde is attacked by an alkene. Styrene and excess formaldehyde give 4-phenyl-1,3-dioxane; a homoallylic alcohol and an aldehyde form an oxocarbenium ion that cyclises six-endo through a chair, and chloride captures the 4-position cation to give the 2,4-cis tetrahydropyran. The Ireland–Claisen rearrangement converts an allyl ester into its silyl ketene acetal (LDA, then a silyl chloride); the [3,3] shift then runs near room temperature and gives a γ,δ-unsaturated acid with allylic transposition. The chair transition state translates the ketene acetal geometry into relative configuration; HMPA switches that geometry. The Arndt–Eistert homologation turns an acid chloride into a diazoketone (diazomethane with a base to remove HCl); the Wolff rearrangement then gives a ketene, with the migrating group keeping its configuration, and water traps it as the acid that is one CH₂ longer.

What to carry forward

For each named reaction, ask three questions: which carbon has been made nucleophilic (enolate, silyl enol ether, ylide, nitronate, Breslow intermediate), what activates the electrophile (Lewis acid, iminium, protonation), and what irreversible event pulls the sequence forward (phosphate or SO₂ loss, ring closure, dehydration, N₂ loss). The answers predict the product, the stereochemistry and what goes wrong when the conditions change.

Problemas de prática (40)

Praticar é grátis com uma conta.

Desenhe o mecanismo 19

Cations, [3,3] shifts and homologation

  • Arndt–Eistert homologation: benzoyl chloride to phenylacetic acidDraw diazoketone formation from benzoyl chloride and diazomethane, the Wolff rearrangement to phenylketene and the addition of water that completes the one-carbon homologation to phenylacetic acid.
  • Ireland–Claisen rearrangement of allyl 2-methylpropanoateDraw enolate formation and O-silylation of allyl 2-methylpropanoate, the [3,3]-sigmatropic shift of the silyl ketene acetal and hydrolysis of the silyl ester to 2,2-dimethylpent-4-enoic acid, which has a new quaternary carbon.
  • Prins cyclization of but-3-en-1-ol with 2-methylpropanalDraw hemiacetal and oxocarbenium-ion formation from a homoallylic alcohol and an aldehyde, the six-endo cation cyclization and chloride capture that give a 4-chlorotetrahydropyran.
  • Prins reaction of styrene with two formaldehydesDraw the acid-catalysed Prins reaction of styrene with two molecules of formaldehyde that builds 4-phenyl-1,3-dioxane.

Nitro groups, umpolung and nucleophilic catalysis

  • Morita–Baylis–Hillman reaction of methyl acrylate with benzaldehydeDraw the DABCO-catalysed Morita–Baylis–Hillman reaction: conjugate addition of the amine, aldol addition of the enolate, proton transfer and E1cB release of the catalyst.
  • Nitroalkene from a Henry adduct: mesylation and E1cB eliminationDraw mesylation of the Henry adduct and the E1cB elimination through a nitronate that gives (E)-β-nitrostyrene.
  • Henry reaction of nitromethane with cyclohexanecarbaldehydeDraw the amine-catalysed Henry reaction: nitronate formation, addition to the aldehyde and proton return that regenerates triethylamine.
  • Nef reaction: nitrocyclohexane to cyclohexanoneDraw the acid-mediated Nef reaction of the nitronate of nitrocyclohexane: double O-protonation, addition of water at carbon, loss of water from nitrogen and cleavage to cyclohexanone and HNO.
  • Stetter reaction of benzaldehyde with methyl vinyl ketoneDraw the thiazolium-catalysed Stetter reaction: ylide formation, addition to benzaldehyde, formation of the Breslow intermediate, conjugate addition to methyl vinyl ketone and release of the catalyst from the 1,4-diketone.

Olefinations and ylide reagents

  • Corey–Chaykovsky cyclopropanation of cyclohex-2-en-1-oneDraw formation of dimethylsulfoxonium methylide, its conjugate addition to cyclohex-2-en-1-one and the enolate ring closure that expels DMSO to give bicyclo[4.1.0]heptan-2-one.
  • Corey–Chaykovsky epoxidation of 4-tert-butylcyclohexanoneDraw formation of dimethylsulfonium methylide, its addition to 4-tert-butylcyclohexanone and the intramolecular displacement of dimethyl sulfide that closes the spiro epoxide.
  • Darzens condensation of cyclohexanone with ethyl chloroacetateDraw the deprotonation of ethyl chloroacetate, the aldol-type addition of the chloro enolate to cyclohexanone and the intramolecular SN2 that closes the glycidic ester.
  • Masamune–Roush Horner–Wadsworth–Emmons olefination of benzaldehydeDraw the DBU/LiCl deprotonation of triethyl phosphonoacetate, its addition to benzaldehyde and the oxaphosphetane fragmentation that gives ethyl (E)-cinnamate.
  • Julia–Kocienski olefination with a benzothiazolyl sulfoneDraw the one-pot Julia–Kocienski olefination: sulfone deprotonation, addition to the aldehyde, Smiles rearrangement of the benzothiazolyl group from sulfur to oxygen, and elimination of SO2 and the aryloxide.
  • Julia–Lythgoe olefination: the ionic steps to the β-acetoxy sulfoneDraw the deprotonation of propyl phenyl sulfone, its addition to benzaldehyde and the in-situ acetylation that gives the β-acetoxy sulfone substrate for the Julia–Lythgoe reduction.

Enol, enolate and zinc nucleophiles

  • Mannich α-methylenation of γ-butyrolactone with Eschenmoser's saltDraw enolate formation, Mannich addition to Eschenmoser's salt, N-methylation and the E1cB elimination of trimethylamine that installs an exocyclic methylene on γ-butyrolactone.
  • Mukaiyama aldol of acetophenone silyl enol ether with 2-methylpropanalDraw the Lewis-acid-activated Mukaiyama aldol: BF3 activates 2-methylpropanal, the silyl enol ether forms the C–C bond, and the silyl group moves to the new alkoxide oxygen.
  • Reformatsky reaction of ethyl bromoacetate with acetophenoneDraw the zinc enolate of ethyl bromoacetate adding to acetophenone through a six-membered cyclic transition state, then the acidic workup that gives the β-hydroxy ester.
  • Robinson annulation: 2-methylcyclohexane-1,3-dione and methyl vinyl ketone to the Wieland–Miescher ketoneDraw the Michael addition of the 1,3-dione enolate to methyl vinyl ketone, the intramolecular aldol that closes the new six-membered ring, and the E1cB dehydration to the Wieland–Miescher ketone.

Preveja o produto 6

Nitro groups, umpolung and nucleophilic catalysis

  • MBH product from methyl vinyl ketonePredict the Morita–Baylis–Hillman adduct of an enone and an aromatic aldehyde.
  • Nef reaction of a nitro esterPredict the carbonyl compound formed when a secondary nitroalkane undergoes a Nef reaction.

Cations, [3,3] shifts and homologation

  • Ireland–Claisen with allylic transpositionPredict the constitution of an Ireland–Claisen product, including allylic transposition.

Enol, enolate and zinc nucleophiles

  • Knoevenagel–Doebner productPredict the product of a Knoevenagel–Doebner condensation, including decarboxylation and alkene geometry.
  • Reformatsky reagent with a keto esterPredict the chemoselectivity of a Reformatsky reagent toward a ketone in the presence of an ester.

Olefinations and ylide reagents

  • Sulfoxonium ylide and chalconePredict whether a sulfur ylide gives an epoxide or a cyclopropane from an enone.

Comparar 2

Enol, enolate and zinc nucleophiles

  • Rank carbon pronucleophiles by acidityRank the carbon acids used in named C–C bond-forming reactions by their pKa in DMSO.

Olefinations and ylide reagents

  • Julia–Lythgoe versus Julia–KocienskiContrast the two Julia olefinations by what removes the sulfur and oxygen functions.

Calcular 3

Cations, [3,3] shifts and homologation

  • How much diazomethane?Calculate the minimum diazomethane needed to convert an acid chloride into a diazoketone without added base.

Enol, enolate and zinc nucleophiles

  • Atom economy of the Doebner reactionCalculate the atom economy of a Knoevenagel–Doebner condensation from molar masses.

Nitro groups, umpolung and nucleophilic catalysis

  • Can triethylamine deprotonate nitromethane?Calculate the equilibrium constant for deprotonation of a nitroalkane by an amine from two pKa values.

Encontre o erro 1

  • A chloromethyl ketone instead of a diazoketoneDiagnose why an Arndt–Eistert diazoketone step gave an α-chloro ketone.

Interprete as evidências 2

Olefinations and ylide reagents

  • Which glycidic ester diastereomer?Assign the relative configuration of a Darzens glycidic ester from the epoxide H–H coupling constant.

Enol, enolate and zinc nucleophiles

  • Order the events of a Robinson annulationSequence the bond-forming and proton-transfer events of a base-catalysed Robinson annulation.

Trabalhe de trás para frente 2

Nitro groups, umpolung and nucleophilic catalysis

  • Disconnect a β-nitro alcoholIdentify the aldehyde and nitroalkane that give a β-nitro alcohol by a Henry reaction.

Enol, enolate and zinc nucleophiles

  • Three components of a Mannich baseIdentify the ketone, aldehyde and amine that combine in a Mannich reaction to give a β-amino ketone.

Planeje uma síntese 2

Cations, [3,3] shifts and homologation

  • Switching Ireland–Claisen diastereoselectivityChoose the change in enolisation conditions that reverses the diastereoselectivity of an Ireland–Claisen rearrangement.

Olefinations and ylide reagents

  • Choose conditions for a (Z)-enoateSelect the olefination conditions that give a (Z)-α,β-unsaturated ester from an aldehyde.

Explique por quê 3

Nitro groups, umpolung and nucleophilic catalysis

  • Why DABCO?Explain why an unhindered nucleophilic amine, rather than a stronger hindered base, catalyses the Morita–Baylis–Hillman reaction.
  • Why the 1,4-diketone and not benzoin?Explain how reversibility lets a thiazolium catalyst funnel an aldehyde into the Stetter product rather than the benzoin.

Cations, [3,3] shifts and homologation

  • Why is the Prins product 2,4-cis?Explain the 2,4-cis stereochemistry of a Prins cyclization with the chair transition-state model.

Travou em reações nomeadas que formam ligações carbono–carbono? Escaneie o problema.

Tire uma foto da reação da sua lista ou do livro e desenhe o mecanismo com cada seta corrigida. 1 scan grátis agora, sem cadastro; mais 1 com uma conta gratuita.

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