Arrow Lab

Síntese Avançada · Strategy

Reações em cascata (dominó e tandem)

Uma lição resolvida gratuita e 40 problemas de prática em que você mesmo desenha cada seta curva.

Travou em reações em cascata (dominó e tandem)? 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.

Escaneie sua lição de graça

Prática grátis de setas curvas: escolha um mecanismo

Toque em um para ver cada seta curva, passo a passo. Nas demos, você mesmo as desenha, sem cadastro.

  • Cascata eletrocíclica

    Desenhe grátis2 etapas

O que você vai aprender

  • Define domino, tandem and sequential one-pot processes and judge routes by step count, overall yield and atom economy.
  • Trace anionic and pericyclic cascades: Michael–aldol (Robinson) annulation, conjugate addition with enolate trapping, Knoevenagel–hetero-Diels–Alder, anionic oxy-Cope with enolate alkylation, Claisen–Cope and the endiandric acid electrocyclization cascade.
  • Predict the stereochemistry of cationic cascades from orbital symmetry and chair transition states: the conrotatory Nazarov closure, interrupted Nazarov trapping and polyene cyclizations.
  • Draw and predict radical and metal-mediated cascades: tandem 5-exo radical cyclizations, Heck insertion cascades, the Pauson–Khand reaction and ring-closing or ring-rearrangement metathesis.

Lição gratuita

O texto da lição resolvida. No Arrow Lab, cada etapa vem com as estruturas e as setas desenhadas.

Ler a aula gratuita (5 partes)

What makes a reaction a cascade

A domino (cascade) reaction forms two or more bonds under the same conditions, and each event uses the functionality created by the one before it, so nothing is added once the reaction has started. 'Tandem' is used loosely for the same idea. A sequential one-pot process is different: a second reagent is added to the same flask after the first stage has finished. Cascades save steps, workups and purifications, and they use reactive intermediates (enolates, cations, radicals, organopalladium species) at once instead of isolating them. Overall yield multiplies along a linear route: eight steps at 85% each give 0.85⁸ ≈ 27%, so removing steps matters more than squeezing the last few percent from each one. Atom economy, product mass divided by the summed mass of the reactants, measures waste. The Robinson annulation of cyclohexanone with methyl vinyl ketone loses only water and has an atom economy of about 89%.

Anionic and pericyclic cascades

The Robinson annulation is a Michael–aldol–dehydration cascade: the Michael addition creates a 1,5-diketone, whose methyl-ketone enolate closes a six-membered ring onto the other carbonyl group, and dehydration gives the conjugated cyclohexenone. Conjugate addition of a cuprate to a cyclopentenone gives one enolate regiospecifically. Trapping it with an electrophile in the same flask (a three-component coupling) installs the new group at C2, trans to the group just added at C3. In a Knoevenagel–hetero-Diels–Alder domino, an aldehyde condenses with a 1,3-dicarbonyl compound to give an electron-poor alkylidene 1,3-dicarbonyl (a 1-oxadiene), which adds to a tethered alkene to form a dihydropyran. The potassium alkoxide of a 1,5-dien-3-ol undergoes an anionic oxy-Cope rearrangement 10¹⁰–10¹⁷ times faster than the neutral alcohol. The rearrangement delivers a single enolate regioisomer, which can then be alkylated. When both ortho positions of an allyl aryl ether are blocked, the Claisen dienone cannot tautomerize, so a Cope rearrangement moves the allyl group to the para position, where tautomerization restores the phenol. In the endiandric acid cascade, an (E,Z,Z,E)-tetraene undergoes a thermal 8π conrotatory closure, then a 6π disrotatory closure to a cis-fused bicyclo[4.2.0]octadiene, and finally an intramolecular Diels–Alder reaction.

Cationic cascades: Nazarov and polyene cyclizations

A Lewis or Brønsted acid turns a divinyl ketone into a 3-oxypentadienyl cation. This 4π-electron system closes thermally in a conrotatory sense, so the two terminal substituents of an (E,E)-dienone end up trans in the oxyallyl cation that forms. The cation normally loses a β-proton to give a cyclopentenone. In an interrupted Nazarov reaction a nucleophile, an alkene or a diene ([4+3] cycloaddition) captures the oxyallyl cation first. In a cationic polyene cyclization, an initiator (an acetal or allylic alcohol with a Lewis acid, or an epoxide) generates a cation that is attacked by a chain of trisubstituted alkenes. Each ring closes through a chair-like transition state with Markovnikov regiochemistry, giving a new tertiary cation. (E)-Alkenes give trans ring fusions (the Stork–Eschenmoser rule), so an all-E polyene gives a trans-anti-trans polycycle. A terminator such as an allylsilane ends the cascade cleanly.

Radical and metal-mediated cascades

With Bu₃SnH and catalytic AIBN, an alkyl bromide gives a carbon radical. A hex-5-enyl radical closes 5-exo-trig much faster than 6-endo (the Beckwith rules), and the new radical can close again onto a second alkene or alkyne before it takes a hydrogen atom from tin hydride. Tandem 5-exo closures build the cis-fused bicyclo[3.3.0]octanes found in triquinane natural products. In Heck cascades, syn carbopalladation of a 1,1-disubstituted alkene gives a neopentyl alkylpalladium species with no β-hydrogen. It cannot eliminate, so it inserts into a second alkene before β-hydride elimination ends the sequence. The Pauson–Khand reaction is a cobalt-mediated [2+2+1] cycloaddition of an alkyne, an alkene and CO; a 1,6-enyne gives a bicyclo[3.3.0]octenone. Ruthenium carbenes combine ring opening of strained cycloalkenes with ring closure (ring-rearrangement metathesis), and enyne ring-closing metathesis makes 1,3-dienes. Loss of ethylene and relief of ring strain drive these reactions.

What to carry forward

Plan a cascade by asking what each intermediate is poised to do next. The event that ends one step must create the functional group the next step needs, all under one set of conditions. Orbital symmetry, chair transition states, Beckwith ring-closure rules and β-hydride availability then decide the rings and stereocentres. Fewer steps, fewer isolations and less waste make cascades the most efficient way to build polycyclic frameworks.

Problemas de prática (40)

Praticar é grátis com uma conta.

Desenhe o mecanismo 10

Anionic and pericyclic cascades

  • Three-component coupling: cuprate conjugate addition and enolate allylationDraw the conjugate addition of a methyl cuprate to cyclopent-2-en-1-one and the in-situ allylation of the regiospecific enolate that it produces.
  • Tandem Michael–Michael annulation: cyclohexenone dienolate and methyl acrylateDraw the kinetic deprotonation of cyclohex-2-en-1-one, the intermolecular Michael addition of the cross-conjugated dienolate to methyl acrylate, and the intramolecular Michael addition that closes a bicyclo[2.2.2]octanone.
  • Domino Knoevenagel–hetero-Diels–Alder reaction of citronellalDraw the Knoevenagel condensation of citronellal with 1,3-dimethylbarbituric acid and the intramolecular hetero-Diels–Alder reaction of the alkylidene barbiturate that closes a tricyclic dihydropyran.
  • Anionic oxy-Cope rearrangement and enolate methylationDraw the deprotonation of 3-methylhexa-1,5-dien-3-ol, the anionic oxy-Cope [3,3] shift that delivers a single enolate regioisomer, and the C-methylation of that enolate to 3-methylhept-6-en-2-one.
  • Para-Claisen rearrangement: Claisen–Cope cascade of allyl 2,6-dimethylphenyl etherDraw the Claisen rearrangement to the blocked ortho-dienone, the Cope rearrangement that carries the allyl group to the para carbon, and the base-mediated tautomerization to 4-allyl-2,6-dimethylphenol.
  • 8π conrotatory–6π disrotatory electrocyclization cascade of an (E,Z,Z,E)-tetraeneDraw the thermal 8π electrocyclization of an (E,Z,Z,E)-tetraene to a cyclooctatriene and the 6π electrocyclization that follows to a bicyclo[4.2.0]octadiene, and assign each rotation mode.

Radical and metal-mediated cascades

  • Tandem 5-exo-trig/5-exo-dig radical cyclization of an enyneDraw the tin hydride chain in which a primary radical closes 5-exo onto an alkene and the new radical closes 5-exo onto an alkyne, ending with hydrogen transfer to a vinyl radical.
  • Domino intramolecular–intermolecular Heck reactionDraw the Heck cascade in which an arylpalladium species cyclizes onto a 1,1-disubstituted alkene, the neopentyl palladium intermediate inserts methyl acrylate, and β-hydride elimination releases the E-enoate.
  • Tandem 5-exo/5-exo radical cyclization to a bicyclo[3.3.0]octaneDraw the tin hydride chain in which a primary radical closes 5-exo onto one alkene and the new radical closes 5-exo onto the second alkene before hydrogen transfer, building 2-methyloctahydropentalene in one operation.

Cationic cascades: Nazarov and polyene cyclizations

  • Nazarov cyclization of cyclohex-1-enyl vinyl ketoneDraw the acid-promoted Nazarov cyclization of cyclohex-1-enyl vinyl ketone: O-protonation, conrotatory 4π electrocyclization of the hydroxypentadienyl cation, proton loss from the ring-fusion carbon and tautomerization to the fused cyclopentenone.

Preveja o produto 11

Anionic and pericyclic cascades

  • Follow the crotyl group through two [3,3] shiftsPredict how a crotyl group is attached after the Claisen–Cope (para-Claisen) cascade on a 2,6-disubstituted aryl ether.
  • Order the endiandric acid cascadeSequence the events of the biomimetic electrocyclization–Diels–Alder route to the endiandric acids.
  • Order the Knoevenagel–hetero-Diels–Alder eventsSequence the events of a domino Knoevenagel condensation and intramolecular hetero-Diels–Alder reaction.

Radical and metal-mediated cascades

  • Enyne ring-closing metathesisPredict the 1,3-diene formed by ring-closing enyne metathesis of a 1,6-enyne.
  • Order the steps of a Heck cascadeSequence the organometallic steps of a domino intramolecular–intermolecular Heck reaction.
  • Intramolecular Pauson–Khand productPredict the bicyclic enone formed by an intramolecular Pauson–Khand reaction of a 1,6-enyne.
  • Ring-rearrangement metathesis of a cyclopentenyl etherPredict the product of a ring-opening/ring-closing metathesis cascade of a cycloalkene carrying a tethered alkene.

Cationic cascades: Nazarov and polyene cyclizations

  • Trapping the oxyallyl cation with a dienePredict the new ring formed when a Nazarov oxyallyl cation is intercepted by a 1,3-diene.
  • Order the events of a polyene bicyclizationSequence the ionization, ring-forming and terminating events of a cationic polyene cyclization.
  • Ring fusion from an all-E polyenePredict the ring-fusion stereochemistry of a cationic polyene bicyclization from the alkene geometry and a chair transition state.
  • Change one alkene to ZPredict how replacing an E-alkene by a Z-alkene changes the ring fusion formed in a polyene cyclization.

Classificar 5

Cascade principles and economy

  • Which process is a domino reaction?Distinguish a true domino (cascade) reaction from sequential one-pot procedures and independent parallel reactions.

Cationic cascades: Nazarov and polyene cyclizations

  • What is an interrupted Nazarov reaction?Recognize the interrupted Nazarov reaction as interception of the oxyallyl cation before elimination.
  • Classify the Nazarov ring closureCount the π electrons of the pentadienyl cation in a Nazarov cyclization and assign its thermal rotation mode.

Radical and metal-mediated cascades

  • Pieces of the Pauson–Khand reactionIdentify the three components and the ring formed in a Pauson–Khand reaction.
  • Name the second ring closureClassify a radical ring closure by ring size, exo/endo and trig/dig.

Comparar 1

  • Rank routes by overall yieldRank linear routes of different length and step yield by their overall yield.

Calcular 6

Cascade principles and economy

  • Does a 50% cascade pay off?Compare overall yields when a cascade step replaces several linear steps.
  • Overall yield of a linear routeCalculate the overall yield of a linear sequence from its step count and average step yield.
  • Atom economy of a Robinson annulationCalculate the atom economy of a Michael–aldol–dehydration cascade from molar masses.
  • Count the new C–C σ bondsCount the carbon–carbon σ bonds formed by each event of a Robinson annulation cascade.

Anionic and pericyclic cascades

  • Bonds made in the endiandric cascadeCount the carbon–carbon σ bonds formed in an 8π–6π electrocyclization and intramolecular Diels–Alder cascade.
  • Ring expansion by anionic oxy-CopeCount the size of the ring formed when an anionic oxy-Cope rearrangement breaks a ring bond.

Encontre o erro 1

  • Find the error in a Nazarov stereochemical predictionIdentify the faulty orbital-symmetry reasoning in a predicted Nazarov stereochemical outcome.

Trabalhe de trás para frente 1

  • Which enyne gives this Pauson–Khand product?Work backwards from a bicyclic cyclopentenone to the 1,6-enyne needed for an intramolecular Pauson–Khand reaction.

Planeje uma síntese 1

  • Choose initiator and terminatorChoose an initiator–terminator combination that makes a cationic polyene cyclization start cleanly and end with a single product.

Explique por quê 4

Cascade principles and economy

  • Why chemists design cascadesExplain the practical advantages of combining several bond-forming events into one cascade operation.
  • Why the Robinson annulation runs as one cascadeExplain which features let the Michael addition, aldol addition and dehydration of a Robinson annulation proceed in one flask.

Radical and metal-mediated cascades

  • Why does the palladium keep inserting?Explain why carbopalladation of a 1,1-disubstituted alkene relays into a second insertion instead of β-hydride elimination.
  • What drives a ROM–RCM cascade?Explain the thermodynamic driving forces of ring-opening and ring-closing metathesis cascades.

Travou em reações em cascata (dominó e tandem)? 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.

Escaneie sua lição de graça

Antes deste tópico