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Síntese Avançada · Modern methods

Oxidações e reduções seletivas

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O que você vai aprender

  • Draw chromium-free alcohol oxidations (Dess–Martin, TEMPO/bleach, activated DMSO) as O–X bond formation followed by loss of the carbinol C–H, and choose the oxidant that stops at the aldehyde or tolerates the rest of the molecule.
  • Predict which carbon and which face a hydride reagent attacks (NaBH₄, Luche conditions, L- and K-Selectride, DIBAL-H, LiAlH₄ with Weinreb amides) and quantify diastereoselectivity.
  • Draw the polar mechanisms that place oxygen next to a carbonyl group or an alkene (Rubottom, Davis oxaziridine, SeO₂ allylic oxidation, selenoxide elimination) and predict ozonolysis products from the workup used.
  • Explain dissolving-metal reductions (Birch, Na/NH₃ on alkynes) as electron and proton transfers, predict Birch regiochemistry, and contrast them with Lindlar, diimide and silane reductions.

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Oxidising alcohols without chromium

Every modern alcohol oxidation follows the same two-stage plan. First the alcohol oxygen bonds to an electron-poor atom: iodine(V) in Dess–Martin periodinane (DMP, drawn), the nitrogen of a TEMPO-derived oxoammonium ion, or the sulfur of activated DMSO (Swern with oxalyl chloride, Parikh–Doering with SO₃·pyridine). Then a base removes the hydrogen on the carbinol carbon; that C–H pair becomes the C=O π bond and the O–X pair returns to X, which is reduced by two electrons (I(V) → I(III), DMSO → Me₂S). A tertiary alcohol has no carbinol C–H and is not oxidised. Primary alcohols stop at the aldehyde because an aldehyde is oxidised further only through its hydrate, which has a new O–H and a new carbinol C–H: DMP, Swern and Parikh–Doering oxidations are run without water, and TEMPO/bleach is run in a buffered two-phase CH₂Cl₂/water mixture with one equivalent of NaOCl, where the aldehyde, kept mainly in the organic layer, is hydrated and oxidised only slowly. To reach the carboxylic acid without chromium, oxidise the aldehyde in a second step with NaClO₂ (Pinnick), adding 2-methylbut-2-ene to destroy the HOCl formed. DMP works at room temperature under neutral conditions. TEMPO with bleach (NaOCl, KBr, NaHCO₃) is catalytic in TEMPO and, through its crowded nitrogen adduct, oxidises primary alcohols much faster than secondary ones. Swern oxidations must be kept near −78 °C until the base is added; on warming, the sulfonium intermediates give methylthiomethyl ethers (R–O–CH₂SCH₃) instead. Parikh–Doering runs at 0 °C. TPAP (Pr₄N⁺ RuO₄⁻) is used catalytically with NMO as the stoichiometric oxidant and molecular sieves to remove water. The Oppenauer oxidation transfers hydride from an aluminium alkoxide to acetone; it is the reverse of the Meerwein–Ponndorf–Verley reduction and needs excess acetone to drive the equilibrium.

Hydride reductions: which carbon, which face

A hydride reagent chooses among carbonyls by electrophilicity (aldehyde > ketone > ester > amide), and among faces by size. On a locked cyclohexanone such as 4-tert-butylcyclohexanone, small NaBH₄ or LiAlH₄ attacks mainly from the axial direction, which avoids torsional strain with the neighbouring axial C–H bonds, and gives mostly the trans alcohol with an equatorial OH. Bulky L-Selectride (LiBH(s-Bu)₃) is blocked from the axial face by the axial hydrogens at C3 and C5, attacks equatorially and gives the cis alcohol with an axial OH (left and right in the drawing: trans, cis). A diastereomer ratio converts to a diastereomeric excess, de = (major − minor)/(major + minor) × 100%, and under kinetic control to an energy difference, ΔΔG‡ = RT ln(major/minor). On cyclohex-2-en-1-one, NaBH₄ with CeCl₃ in methanol (Luche conditions) attacks the carbonyl carbon and gives the allylic alcohol, whereas K-Selectride adds hydride to the β-carbon and gives an enolate. Luche conditions also reverse the usual aldehyde/ketone selectivity, because the aldehyde is tied up as its methanol (hemi)acetal while the ketone is reduced. Stopping at the aldehyde level needs an intermediate that cannot collapse while hydride is present: DIBAL-H at −78 °C turns a lactone into an aluminium-bound hemiacetal that is released as the lactol only on workup, and LiAlH₄ turns a Weinreb amide into a metal-chelated tetrahedral intermediate that gives the aldehyde only after acid workup. Count oxidation levels to check the stopping point: +1 for each bond from carbon to oxygen and −1 for each bond to hydrogen gives +3 for a lactone carbonyl carbon, +1 for a lactol or aldehyde carbon and −1 for a CH₂OH carbon.

Putting oxygen next to a carbonyl or an alkene

An enolate or enol ether is a carbon nucleophile, so an electrophilic oxygen source gives an α-oxygenated ketone. In the Rubottom oxidation, m-CPBA epoxidises a silyl enol ether, the siloxy oxygen pushes the epoxide open to an oxocarbenium ion, and the silyl group migrates to the new alkoxide, giving an α-silyloxy ketone. In the Davis oxidation the enolate attacks the oxygen of an N-sulfonyloxaziridine (drawn), breaking the weak N–O bond; the hemiaminal anion then expels the alkoxide and a sulfonimine. Oxygen always ends on the carbon that was nucleophilic, so the regiochemistry is set when the enolate is made: LDA at −78 °C gives the less substituted (kinetic) enolate, while TMSCl and Et₃N in hot DMF give mainly the more substituted silyl enol ether. Selenium reagents oxidise next to alkenes and carbonyls. SeO₂ undergoes an ene reaction with an alkene and then a [2,3]-sigmatropic shift, so the oxygen ends on the allylic carbon next to the more substituted alkene carbon (CH₂ before CH₃ before CH); with a gem-dimethyl alkene the methyl trans to the chain is oxidised, giving the E allylic alcohol. An α-phenylseleno ketone is oxidised by H₂O₂ to the selenoxide, which removes a syn β-hydrogen through a five-atom cyclic transition state at or below room temperature, giving the enone; sulfoxides react the same way but need heating, because the C–S bond is stronger than C–Se. Ozonolysis cuts a C=C bond to an ozonide, and the workup decides the products: Me₂S or Ph₃P gives aldehydes and ketones, NaBH₄ gives alcohols, and H₂O₂ gives carboxylic acids from the aldehyde fragments.

Electrons from metals: Birch reduction and alkynes

Lithium or sodium in liquid ammonia releases solvated electrons. An arene accepts one electron to give a radical anion, an alcohol (ethanol or t-BuOH) protonates it, a second electron gives a cyclohexadienyl anion, and a second protonation gives the product. Ammonia alone (pKa about 38) is too weak an acid to protonate the radical anion fast enough, so the alcohol is required. Two electrons, and so two equivalents of Li or Na, are consumed per ring reduced. The final protonation occurs at the central carbon of the pentadienyl anion, so the product is the non-conjugated cyclohexa-1,4-diene. Electron-donating groups end on a remaining C=C: anisole gives 1-methoxycyclohexa-1,4-diene (drawn). Electron-withdrawing groups end on an sp³ carbon: benzoic acid gives cyclohexa-2,5-diene-1-carboxylic acid. Internal alkynes are reduced by Na in NH₃ through a vinyl anion that prefers the trans geometry, giving E alkenes; H₂ on Lindlar's catalyst (Pd poisoned with lead and quinoline) adds both hydrogens to one face and stops at the Z alkene.

Reductions without metals or hydride salts

Diimide, HN=NH, generated from p-toluenesulfonyl hydrazide and a base on heating, transfers both of its hydrogens to one face of a C=C bond through a six-atom cyclic transition state and releases N₂. Only the cis isomer of diimide can reach the alkene. Diimide reduces non-polar C=C bonds and leaves nitro groups, halides and O–O bonds alone, which catalytic hydrogenation often does not. Ionic hydrogenation uses a silane and a strong acid: trifluoroacetic acid converts a benzylic, diarylmethyl or tertiary alcohol into a stabilised carbocation, and Et₃SiH delivers a hydride to it. Primary and simple secondary alcohols do not form carbocations under these conditions and are not reduced.

What to carry forward

Find the atom that accepts the electrons. In an oxidation, the alcohol or enolate bonds to an electron-poor I, N, S, Se or O and the carbinol C–H pair leaves toward it; in a reduction, a B–H, Al–H, Si–H or N–H pair, or an electron from a metal, goes to the most electrophilic carbon. Then let the reagent's size, the temperature and the workup decide the face, the oxidation level at which the reaction stops, and the products you isolate.

Problemas de prática (40)

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Desenhe o mecanismo 15

Oxygen next to carbonyls and alkenes

  • Davis oxaziridine α-hydroxylation of propiophenoneDraw enolate formation from propiophenone with NaHMDS, attack of the enolate on the oxygen of the Davis oxaziridine, fragmentation of the hemiaminal anion to the alkoxide and a sulfonimine, and protonation to 2-hydroxy-1-phenylpropan-1-one.
  • Rubottom oxidation of the TMS enol ether of cyclohexanoneDraw epoxidation of 1-(trimethylsilyloxy)cyclohex-1-ene by m-CPBA, opening of the siloxy epoxide to an oxocarbenium ion, and silyl migration to the alkoxide that gives the α-silyloxy ketone.
  • Selenoxide elimination: 2-(phenylselanyl)cyclohexanone to cyclohexenoneDraw oxidation of an α-phenylseleno ketone to the selenoxide by hydrogen peroxide and the syn elimination through a five-atom cyclic transition state that gives cyclohex-2-en-1-one.
  • SeO2 allylic oxidation of 1-methylcyclohexeneDraw the ene reaction of SeO₂ with 1-methylcyclohexene, the [2,3]-sigmatropic shift of the allylseleninic acid and the hydrolysis that gives 2-methylcyclohex-2-en-1-ol.

Hydride reductions: site and face

  • DIBAL-H reduction of δ-valerolactone to the lactolDraw coordination of DIBAL-H to δ-valerolactone, hydride transfer to the aluminium hemiacetal that is stable at −78 °C, and the workup that releases tetrahydro-2H-pyran-2-ol.
  • K-Selectride conjugate reduction of cyclohex-2-en-1-oneDraw hydride delivery from K-Selectride to the β-carbon of cyclohex-2-en-1-one, giving an enolate, and the protonation of that enolate on carbon during workup to give cyclohexanone.
  • L-Selectride reduction of 4-tert-butylcyclohexanone to the cis alcoholDraw equatorial hydride delivery from L-Selectride to 4-tert-butylcyclohexanone and protonation of the axial alkoxide, and explain why the bulky reagent gives cis-4-tert-butylcyclohexan-1-ol.
  • Luche 1,2-reduction of (E)-4-phenylbut-3-en-2-oneDraw hydride delivery from a methoxyborohydride to the carbonyl carbon of (E)-4-phenylbut-3-en-2-one and protonation of the alkoxide by methanol, giving the allylic alcohol with the C=C bond intact.
  • NaBH4 reduction of 4-tert-butylcyclohexanone to the trans alcoholDraw axial hydride delivery from borohydride to 4-tert-butylcyclohexanone and protonation of the equatorial alkoxide by methanol, giving trans-4-tert-butylcyclohexan-1-ol.
  • LiAlH4 reduction of a Weinreb amide to cyclohexanecarbaldehydeDraw hydride addition to a Weinreb amide, and the acidic workup that converts the chelated tetrahedral intermediate into cyclohexanecarbaldehyde and N,O-dimethylhydroxylamine.

Electron-transfer and metal-free reductions

  • Diimide reduction of 1-nitro-4-vinylbenzeneDraw the generation of diimide from p-toluenesulfonyl hydrazide and acetate, and the concerted transfer of both diimide hydrogens to the vinyl group of 1-nitro-4-vinylbenzene with loss of N₂.
  • Ionic hydrogenation of diphenylmethanol with Et3SiH/TFADraw protonation of diphenylmethanol by trifluoroacetic acid, loss of water to the benzhydryl cation and hydride transfer from triethylsilane that gives diphenylmethane.

Oxidising alcohols without chromium

  • Dess–Martin oxidation of 3-phenylpropan-1-olDraw how 3-phenylpropan-1-ol exchanges onto the iodine(V) centre of Dess–Martin periodinane and how removal of the carbinol hydrogen forms 3-phenylpropanal while iodine is reduced to iodine(III).
  • Parikh–Doering oxidation of 4-phenylbutan-2-olDraw activation of DMSO by sulfur trioxide, formation of the alkoxysulfonium ion from 4-phenylbutan-2-ol, ylide formation with triethylamine and the intramolecular hydrogen transfer that gives 4-phenylbutan-2-one and dimethyl sulfide.
  • TEMPO/bleach oxidation of butane-1,3-diol at the primary alcoholDraw the oxoammonium oxidation of the primary alcohol of butane-1,3-diol: addition of the alcohol to the oxoammonium nitrogen, deprotonation, and the intramolecular removal of the carbinol hydrogen that releases 3-hydroxybutanal and the hydroxylamine TEMPO-H.

Preveja o produto 6

Electron-transfer and metal-free reductions

  • Birch reduction of anisolePredict the Birch reduction product of an arene with an electron-donating substituent.
  • Birch reduction of benzoic acidPredict the Birch reduction product of an arene carrying an electron-withdrawing group.

Hydride reductions: site and face

  • L-Selectride and 2-methylcyclohexanonePredict the relative configuration of the alcohol formed when a bulky hydride reduces a 2-substituted cyclohexanone.
  • Reduce the ketone, keep the aldehydePredict the chemoselectivity of a Luche reduction on a substrate containing both an aldehyde and a ketone.

Oxygen next to carbonyls and alkenes

  • Ozonolysis with a borohydride workupPredict the product of ozonolysis of a cycloalkene followed by a reductive borohydride workup.
  • SeO₂ and a trisubstituted alkenePredict the regiochemistry and alkene geometry of SeO₂ allylic oxidation of a trisubstituted alkene.

Classificar 1

  • Which alcohol does Et₃SiH/TFA reduce?Classify alcohols by whether they undergo ionic hydrogenation with a silane and trifluoroacetic acid.

Comparar 2

Hydride reductions: site and face

  • Which carbonyl takes hydride first?Rank carbonyl compounds by electrophilicity toward a hydride donor.
  • Oxidation levels along a lactone reductionRank related compounds by the oxidation level of the carbon that is reduced in a lactone reduction.

Calcular 4

Electron-transfer and metal-free reductions

  • How much lithium for a Birch reduction?Calculate the minimum mass of lithium for a Birch reduction from the number of electrons transferred.

Oxidising alcohols without chromium

  • Weigh out Dess–Martin periodinaneCalculate the mass of Dess–Martin periodinane needed for a stated number of equivalents.

Hydride reductions: site and face

  • Energy gap behind a 96:4 ratioCalculate the difference in activation free energy that corresponds to a kinetically controlled diastereomer ratio.
  • Diastereomeric excess from a ratioConvert a measured diastereomer ratio into a diastereomeric excess.

Encontre o erro 2

Hydride reductions: site and face

  • A DIBAL-H reduction that gave alcohol and esterDiagnose why a DIBAL-H ester reduction gave alcohol and recovered ester instead of the aldehyde.

Oxidising alcohols without chromium

  • A Swern oxidation that was allowed to warmIdentify the methylthiomethyl ether formed when a Swern oxidation is warmed before the base is added, and name the error.

Interprete as evidências 1

  • Identify the Birch product of benzeneUse ¹H NMR and UV data to identify the non-conjugated diene formed by Birch reduction.

Trabalhe de trás para frente 1

  • Which alkene gave this keto acid?Work back from an oxidative ozonolysis product to the cyclic alkene that formed it.

Planeje uma síntese 3

Oxidising alcohols without chromium

  • A chromium-free route to a carboxylic acidPlan a two-step chromium-free oxidation of a primary alcohol to the carboxylic acid that leaves an alkene untouched.

Oxygen next to carbonyls and alkenes

  • Hydroxylate the more substituted α-carbonChoose enol-derivative conditions and an oxygen source that hydroxylate the more substituted α-carbon of an unsymmetrical ketone.

Electron-transfer and metal-free reductions

  • Make leaf alcohol from an alkyneChoose the alkyne reduction that gives a Z alkene.

Explique por quê 5

Electron-transfer and metal-free reductions

  • Why the Birch reduction needs an alcoholExplain the role of the alcohol in a Birch reduction in terms of electron and proton transfer.
  • How Lindlar's catalyst stops at the Z alkeneExplain why hydrogenation over Lindlar's catalyst stops at the alkene and gives the Z isomer.

Oxidising alcohols without chromium

  • Why so much acetone?Explain why an Oppenauer oxidation uses a large excess of acetone.
  • Why TPAP needs NMOExplain the role of the co-oxidant in a catalytic perruthenate oxidation.

Oxygen next to carbonyls and alkenes

  • Why selenoxides eliminate so easilyExplain why selenoxide eliminations proceed at much lower temperature than sulfoxide eliminations.

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