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Síntese Avançada · Modern methods

Cadeias radicalares e catálise fotorredox

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O que você vai aprender

  • Draw initiation and propagation steps of radical chain reactions with fishhook arrows, and explain why a catalytic amount of initiator is enough.
  • Use bond dissociation energies and rate constants to predict the outcome of tin hydride reductions, 5-exo-trig cyclizations and radical additions.
  • Design Barton–McCombie deoxygenations, atom-transfer radical additions and Giese additions, separating their polar and radical steps.
  • Analyse photoredox quenching cycles: calculate excited-state redox potentials and electron-transfer free energies, and interpret quenching and quantum-yield data.

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Ler a aula gratuita (7 partes)

Radical chains: initiate, propagate, terminate

A radical chain needs only a trickle of radicals to start. AIBN (azobisisobutyronitrile, drawn) has two weak C–N bonds; at about 60–80 °C both break and a molecule of N₂ is expelled, leaving two 2-cyano-2-propyl radicals. Losing N₂ makes the decomposition irreversible, and the radicals are tertiary and conjugated with the nitrile. For reactions that must run cold, triethylborane with a trace of air is used instead: O₂ attacks boron and releases ethyl radicals even at −78 °C. An initiator radical then abstracts H from tributyltin hydride, Bu₃SnH, to make the chain carrier Bu₃Sn•. In the propagation steps one radical is consumed and another is made, so each initiation event turns over many substrate molecules: 0.05–0.2 equiv of initiator is enough. Termination combines two radicals (Bu₃Sn• + Bu₃Sn• → Bu₃Sn–SnBu₃) and removes them. Radical intermediates are detected with traps such as TEMPO, a persistent nitroxide radical that captures carbon radicals, and with radical clocks (below). Dissolved O₂ also traps carbon radicals, so radical reactions are run under argon. Draw every radical event with fishhooks: each half-arrow moves one electron, and a bond forms where two half-arrows meet.

Tin hydride reductions follow bond strengths

Two propagation steps reduce an alkyl halide R–X with Bu₃SnH. First Bu₃Sn• abstracts the halogen atom, because the Sn–X bond formed is stronger than the C–X bond broken; the rate falls in the order R–I > R–Br > R–Cl, and C–F bonds are not touched. Then the carbon radical takes a hydrogen atom from Bu₃SnH. The Sn–H bond is weak (about 310 kJ/mol) while an alkyl C–H bond is strong (about 410–420 kJ/mol), so this transfer releases roughly 100 kJ/mol and regenerates Bu₃Sn•. A carbon radical reacts with Bu₃SnH with a rate constant near 2 × 10⁶ M⁻¹ s⁻¹ at 25 °C. Any faster unimolecular step, such as a ring closure, competes with it, and the tin hydride concentration decides which wins. Tin residues are toxic. They are removed by stirring the crude product with aqueous KF, which precipitates insoluble Bu₃SnF. Tris(trimethylsilyl)silane is a tin-free H donor with a somewhat stronger Si–H bond (≈ 350 kJ/mol).

5-exo-trig cyclization

The hex-5-enyl radical closes onto its own alkene at about 2 × 10⁵ s⁻¹ at 25 °C, attacking the internal alkene carbon so that a five-membered ring forms and the radical ends up on an exocyclic CH₂. About 98% of the product is the five-membered ring, although 6-endo closure would give a more stable secondary radical and a less strained ring. The selectivity is kinetic: in the chair-like transition state the radical can reach the internal alkene carbon at the required angle of attack with little strain, but not the terminal one. Because the preference is kinetic, a methyl group on the internal alkene carbon, which hinders attack there, lets 6-endo closure win. Substituents elsewhere follow the Beckwith guidelines: a substituent on the radical carbon, or on the middle carbon of the chain, favours a cis-disubstituted ring, and one on either of the other two chain carbons favours trans. The ratio of ring to open-chain product is k_c / (k_H[Bu₃SnH]), so a cyclization of known rate works as a radical clock. To favour cyclization, keep the Bu₃SnH concentration low, for example by adding it slowly with a syringe pump; at high concentration the open-chain radical is reduced before it closes. Aryl radicals, α-alkoxy radicals from bromoacetals (the Ueno–Stork reaction) and vinyl radicals formed by 5-exo-dig closure onto alkynes all behave the same way.

Barton–McCombie deoxygenation

An alcohol C–O bond is too strong to be cleaved by Bu₃Sn•, so the alcohol is first converted into a thiocarbonyl derivative by polar steps. For a xanthate: NaH makes the alkoxide, the alkoxide adds to CS₂, and the resulting dithiocarbonate anion is S-methylated by MeI. The radical chain follows. Bu₃Sn• adds to the weak C=S π bond, and the carbon radical formed fragments: its C–O bond to the alkyl group breaks, a strong C=O bond forms, and the alkyl radical is released. That radical takes H from Bu₃SnH. Thionocarbonates and thiocarbonyl imidazolides react the same way, while an ordinary ester has no C=S bond and is untouched. Secondary alcohols work best. Primary alkyl radicals are released more slowly, and tertiary xanthates are prone to elimination. Carboxylic acids are removed in the same spirit by the Barton decarboxylation: Bu₃Sn• adds to the C=S sulfur of an N-hydroxypyridine-2-thione ester, the weak N–O bond breaks as the ring becomes an aromatic pyridine, and the acyloxyl radical loses CO₂ to give an alkyl radical with one carbon fewer.

Atom-transfer and Giese additions

In an atom-transfer radical addition (ATRA, the Kharasch reaction) Cl₃C• adds to the less hindered terminal CH₂ of an alkene, giving the more stable secondary radical. That radical takes a halogen atom from the next Cl₃C–X, releasing Cl₃C• again. BrCCl₃ transfers bromine rather than chlorine because the C–Br bond is the weaker one. In a Giese addition a nucleophilic alkyl radical, generated by tin from an alkyl iodide or bromide, adds to the β-carbon of an electron-poor alkene such as methyl acrylate. The α-carbonyl radical formed then takes H from Bu₃SnH. Polarity matching makes this work: alkyl radicals have a high-energy SOMO and add much faster to acrylates and acrylonitrile than to electron-rich or unactivated alkenes. Allyltributylstannane (the Keck allylation) delivers an allyl group instead of H: the adduct radical expels Bu₃Sn• by β-scission.

Photoredox quenching cycles

A photoredox catalyst such as Ru(bpy)₃²⁺ absorbs visible light (λmax ≈ 452 nm) in a metal-to-ligand charge-transfer band, which most organic substrates do not absorb. Its excited state Ru(II)* lives about 1 μs, long enough to meet a quencher in solution, and is both a better oxidant and a better reductant than the ground state. Its potentials follow from the ground-state couples and the excited-state energy E₀,₀ (≈ 2.10 eV): E(II*/I) = E(II/I) + E₀,₀ = −1.33 + 2.10 = +0.77 V vs SCE, and E(III/II*) = E(III/II) − E₀,₀ = +1.29 − 2.10 = −0.81 V. In oxidative quenching Ru(II)* gives an electron to an acceptor and becomes Ru(III), which later takes an electron back from a donor. In reductive quenching Ru(II)* takes an electron from a donor, often an amine or a Hantzsch ester, and becomes Ru(I) (−1.33 V), which then reduces the substrate. An electron transfer is favourable when ΔG = −F[E(acceptor) − E(donor)] is negative (F = 96.485 kJ mol⁻¹ V⁻¹). Substrates that are harder to reduce need a more strongly reducing catalyst such as fac-Ir(ppy)₃, whose excited state reaches −1.73 V. These single-electron transfers change charges and cannot be drawn with fishhooks; the radicals they create then react by ordinary radical steps. Stern–Volmer experiments (I₀/I = 1 + k_qτ₀[Q]) show which component quenches the excited state. The quantum yield Φ (product molecules per photon absorbed) is at most 1 for a closed photoredox cycle, so Φ above 1 proves that a radical chain operates: each photogenerated radical goes on to make more than one product molecule. Oxygen quenches excited states and traps radicals, so photoredox reactions are degassed.

What to carry forward

Treat every radical reaction as a chain of steps, each of which must be exothermic and faster than its competitors. Weak bonds are broken (Sn–H, C–I, C=S π, N₂ release from AIBN) and strong bonds are made (C–H, Sn–X, C=O). Unimolecular ring closures compete with bimolecular H transfer, so concentration controls the product. In photoredox catalysis, add or subtract the excited-state energy to find the potentials of the excited catalyst, then compare potentials to decide which electron transfers can happen.

Problemas de prática (40)

Praticar é grátis com uma conta.

Desenhe o mecanismo 12

Tin hydride reductions and cyclizations

  • Aryl radical cyclization to 3-methyl-2,3-dihydrobenzofuranDraw the tin hydride chain that turns 1-(allyloxy)-2-iodobenzene into 3-methyl-2,3-dihydrobenzofuran: iodine abstraction to an aryl radical, 5-exo-trig cyclization onto the allyl ether, and hydrogen transfer.
  • 5-exo-trig cyclization of the hex-5-enyl radicalDraw the tin hydride chain that converts 6-bromohex-1-ene into methylcyclopentane: bromine abstraction, 5-exo-trig ring closure and hydrogen transfer to the cyclopentylmethyl radical.
  • Keck radical allylation of iodocyclopentaneDraw the radical chain in which allyltributylstannane transfers an allyl group to iodocyclopentane: iodine abstraction, addition of the cyclopentyl radical to the allylstannane and β-scission that releases Bu₃Sn•.
  • Selective tin hydride reduction of the C–Br bond in 1-bromo-3-chloropropaneDraw the two propagation steps by which one equivalent of tributyltin hydride removes the bromine of 1-bromo-3-chloropropane and leaves the C–Cl bond intact.

Deoxygenation, ATRA and radical additions

  • Barton decarboxylation of a thiohydroxamate esterDraw the radical chain that removes the carboxyl group of 3-phenylpropanoic acid via its Barton ester: tin radical addition to the thione, N–O cleavage with aromatization, loss of CO₂ and hydrogen transfer.
  • Barton–McCombie deoxygenation: the radical chainDraw the radical chain of the Barton–McCombie deoxygenation: addition of Bu₃Sn• to the thiocarbonyl sulfur, β-scission of the C–O bond to release the alkyl radical, and hydrogen transfer from tributyltin hydride.
  • Atom-transfer addition of bromotrichloromethane to styreneDraw the propagation steps of the atom-transfer radical addition of BrCCl₃ to styrene and explain why bromine, not chlorine, is the atom transferred.
  • Giese addition of the cyclohexyl radical to methyl acrylateDraw the tin hydride chain in which the cyclohexyl radical adds to methyl acrylate (a Giese reaction), and explain why the nucleophilic alkyl radical adds faster to the electron-poor alkene than it is reduced.
  • Kharasch addition of carbon tetrachloride to hex-1-eneDraw the two propagation steps of the atom-transfer radical addition of CCl₄ across hex-1-ene, and explain the regiochemistry of the trichloromethyl radical addition.
  • Xanthate formation from 4-phenylbutan-2-olDraw the polar steps that convert 4-phenylbutan-2-ol into its S-methyl xanthate: deprotonation by sodium hydride, addition of the alkoxide to carbon disulfide and S-methylation with methyl iodide.

Radical chains and initiators

  • Tris(trimethylsilyl)silane reduces 1-bromoadamantaneDraw the two propagation steps of the tris(trimethylsilyl)silane chain that replaces the bridgehead bromine of 1-bromoadamantane with hydrogen.
  • Triethylborane and oxygen initiate a tin hydride chainDraw how triethylborane reacts with a trace of oxygen to release an ethyl radical, and how that radical abstracts hydrogen from tributyltin hydride to make the chain carrier Bu₃Sn•.

Preveja o produto 3

Deoxygenation, ATRA and radical additions

  • Product of a BrCCl₃ atom-transfer additionPredict the regiochemistry and the transferred atom in the atom-transfer radical addition of bromotrichloromethane to a terminal alkene.

Tin hydride reductions and cyclizations

  • Stereochemistry of a substituted 5-exo closurePredict the major diastereomer of a 1-substituted hex-5-enyl radical cyclization using the Beckwith guidelines.
  • Radical cyclization onto an alkynePredict the product of a 5-exo-dig radical cyclization onto a terminal alkyne followed by hydrogen transfer.

Classificar 3

Radical chains and initiators

  • Classify a step of the tin hydride chainClassify a radical step as initiation, propagation or termination by counting the radicals consumed and formed.

Photoredox catalysis

  • Name the quenching cycleClassify a photoredox catalytic cycle as oxidative or reductive quenching from the order of its electron transfers.

Deoxygenation, ATRA and radical additions

  • Which cyclohexanol derivative survives?Classify alcohol derivatives as Barton–McCombie substrates by the presence of a thiocarbonyl group.

Comparar 3

Deoxygenation, ATRA and radical additions

  • Pick the Giese acceptorChoose the alkene that a nucleophilic alkyl radical adds to fastest, using polarity matching.

Radical chains and initiators

  • Rank hydrogen-atom donors by driving forceRank hydrogen-atom donors by the exothermicity of hydrogen transfer to a primary alkyl radical using bond dissociation energies.
  • Rank 1-halobutanes toward Bu₃Sn•Rank alkyl halides by their rate of halogen-atom abstraction by the tributyltin radical from carbon–halogen bond strengths.

Calcular 7

Photoredox catalysis

  • Is the electron transfer downhill?Calculate the free energy of a photoinduced electron transfer from the excited catalyst to an acceptor using redox potentials.
  • How reducing is excited Ru(bpy)₃²⁺?Calculate the potential of the excited photocatalyst acting as an electron donor in oxidative quenching.
  • How oxidizing is excited Ru(bpy)₃²⁺?Calculate the excited-state reduction potential of a photocatalyst from its ground-state potential and excited-state energy.
  • Energy of a mole of blue photonsCalculate the molar energy of visible photons from their wavelength.
  • Quantum yield of a photoredox reactionCalculate a reaction quantum yield and use it to judge whether a radical chain operates.

Tin hydride reductions and cyclizations

  • Use the hex-5-enyl radical clockCalculate the ratio of cyclized to reduced product from competing first-order cyclization and second-order hydrogen transfer.

Radical chains and initiators

  • Enthalpy of hydrogen transfer from Bu₃SnHCalculate the enthalpy change of hydrogen-atom transfer from tributyltin hydride to a carbon radical from bond dissociation energies.

Encontre o erro 2

Photoredox catalysis

  • Why did the open-flask run fail?Diagnose the effect of dissolved oxygen on a photoredox reaction.

Radical chains and initiators

  • Find the evidence against a hydride SN2Identify the experimental observation that rules out a polar SN2 hydride-transfer mechanism for tin hydride reductions.

Interprete as evidências 3

Photoredox catalysis

  • Order the events of a reductive quenching cyclePut the electron-transfer and radical events of a reductive quenching photoredox cycle in their correct sequence.
  • Who quenches the excited catalyst?Interpret Stern–Volmer luminescence-quenching data to decide between oxidative and reductive quenching.

Radical chains and initiators

  • Read a radical-trapping experimentInterpret a TEMPO trapping experiment as evidence for a carbon-radical intermediate.

Trabalhe de trás para frente 1

  • Choose the bromoacetal for a Ueno–Stork cyclizationWork backwards from a substituted tetrahydrofuran to the bromoacetal that gives it by a 5-exo radical cyclization.

Planeje uma síntese 3

Photoredox catalysis

  • Pick a photocatalyst strong enough to reduce the substrateChoose a photocatalyst species capable of reducing a substrate by comparing excited-state and ground-state redox potentials.

Tin hydride reductions and cyclizations

  • Favour the ring over the reduced chainChoose reaction conditions that favour a radical cyclization over premature hydrogen transfer from tin hydride.
  • Remove the tin by-productsChoose a workup that removes toxic tributyltin by-products from a radical reduction.

Explique por quê 3

Radical chains and initiators

  • Why a little AIBN is enoughExplain why AIBN fragments at moderate temperature and why only a catalytic amount is needed to run a tin hydride chain.

Tin hydride reductions and cyclizations

  • When 6-endo closure winsExplain how a substituent on the internal alkene carbon reverses the usual 5-exo preference of hex-5-enyl radical cyclization.

Photoredox catalysis

  • Why visible light and a photocatalyst?Explain why photoredox catalysts allow selective radical chemistry with visible light.

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