Oxidation and Reduction in Organic Synthesis
1. Oxidation of alcohols: chromium, manganese, DMSO and hypervalent iodine
| Reagent | Primary alcohol gives | Notes |
|---|---|---|
| Jones (CrO₃, aqueous H₂SO₄, acetone) | carboxylic acid (via the aldehyde hydrate) | secondary → ketone; strongly acidic, aqueous |
| PCC, PDC (CH₂Cl₂), Collins (CrO₃·2py) | aldehyde | anhydrous, so no hydrate forms and oxidation stops |
| KMnO₄ | carboxylic acid | also cleaves alkenes when hot; oxidises benzylic C–H to ArCOOH |
| MnO₂ | aldehyde, only if allylic or benzylic | chemoselective; saturated alcohols untouched |
| Swern ((COCl)₂, DMSO, Et₃N, −78 °C) | aldehyde | via an alkoxysulfonium ylide; by-products Me₂S, CO, CO₂; related Moffatt (DCC) and Parikh–Doering (SO₃·py) |
| Dess–Martin periodinane, IBX | aldehyde | hypervalent iodine(V); neutral, room temperature, fast |
With chromium(VI) the alcohol first forms a chromate ester, and the rate-determining step is removal of the α-C–H with loss of Cr(IV) (a primary kinetic isotope effect of about 6 is observed); overall each Cr(VI) accepts three electrons on the way to Cr(III), so two CrO₃ oxidise three molecules of a secondary alcohol. The DMSO methods and the periodinanes avoid heavy metals and acidic water, which is why they are preferred for sensitive substrates; tertiary alcohols, having no α-H, resist all of them.
2. Peracids, dihydroxylation, ozonolysis and hydroboration
Peracids (mCPBA, peracetic acid) transfer an oxygen atom to an alkene in one concerted, "butterfly" step (Prilezhaev), so epoxidation is syn and stereospecific — a cis-alkene gives a cis-epoxide — and faster for electron-rich (more substituted) alkenes. An allylic OH directs the peracid to its own face by hydrogen bonding. Peracids also oxidise ketones in the Baeyer–Villiger reaction, inserting O between the carbonyl carbon and the group best able to carry positive charge in the Criegee intermediate. The migratory aptitude is tertiary alkyl > secondary alkyl ≈ cyclohexyl ≈ benzyl ≈ phenyl > primary alkyl > methyl; the migrating group keeps its configuration; cyclic ketones give lactones and aldehydes usually give acids.
Alkenes to diols. OsO₄ adds through a cyclic osmate ester, so the two OH groups are delivered syn; it is used catalytically with a co-oxidant (NMO in the Upjohn procedure, K₃Fe(CN)₆ in the Sharpless method). Cold, dilute, alkaline KMnO₄ also gives syn diols through a cyclic manganate ester but over-oxidises easily. Anti diols come from epoxidation followed by acid-catalysed ring opening. So cis-2-butene gives meso-2,3-butanediol with OsO₄ and the racemic diol via the epoxide. Ozonolysis cleaves C=C completely: O₃ adds to give a molozonide, which fragments and recombines (the Criegee mechanism) to the ozonide; a reductive work-up (Me₂S, PPh₃ or Zn/AcOH) gives aldehydes and ketones, an oxidative work-up (H₂O₂) turns the aldehydes into acids, and NaBH₄ gives alcohols. Hydroboration–oxidation adds H and B syn across the alkene with boron on the less substituted carbon (steric and electronic reasons, through a four-centre transition state); alkaline H₂O₂ then replaces B by OH with retention, giving the anti-Markovnikov alcohol with no rearrangement. Bulky boranes (9-BBN, disiamylborane) raise the regioselectivity and convert terminal alkynes into aldehydes.
3. Sharpless and Jacobsen epoxidations and Sharpless asymmetric dihydroxylation
The Sharpless asymmetric epoxidation oxidises allylic alcohols with tert-butyl hydroperoxide, Ti(Oi-Pr)₄ and a diethyl tartrate (DET). The allylic OH binds to titanium, so only allylic alcohols react, and the tartrate chirality fixes the face: with the alcohol drawn at the lower right of the alkene in the plane of the page, (−)-D-DET delivers oxygen from the top face and (+)-L-DET from the bottom, predictably and with ee usually above 90%. With a racemic secondary allylic alcohol the same catalyst epoxidises one enantiomer much faster — a kinetic resolution. The Jacobsen epoxidation uses a chiral Mn(III)–salen complex with NaOCl as the oxidant, needs no directing group, and works best for cis-disubstituted and trisubstituted unfunctionalised alkenes, through a Mn(V)=O species approaching along a pathway set by the bulky salen substituents.
The Sharpless asymmetric dihydroxylation adds two OH groups syn with catalytic OsO₄ (as K₂OsO₂(OH)₄), K₃Fe(CN)₆ as the stoichiometric oxidant, K₂CO₃ and a cinchona-alkaloid ligand. The commercial mixtures are AD-mix-α, with (DHQ)₂PHAL from dihydroquinine, and AD-mix-β, with (DHQD)₂PHAL from dihydroquinidine; the two pseudo-enantiomeric ligands give opposite enantiomers of the diol, and a mnemonic based on the sizes of the alkene substituents predicts which. Unlike the epoxidation, it needs no allylic alcohol and works for most alkene classes.
4. Catalytic hydrogenation, homogeneous and heterogeneous
Heterogeneous catalysts — Pd/C, PtO₂ (Adams), Raney Ni, Rh/Al₂O₃ — adsorb H₂ and the alkene on the metal surface and deliver both hydrogens from the same face: syn addition, from the less hindered face. Ease of reduction runs roughly alkyne > alkene > C=O > arene; arenes need Rh or high pressure. Lindlar’s catalyst (Pd on CaCO₃ poisoned with lead acetate and quinoline) stops at the alkene and gives cis-alkenes from alkynes. Hydrogenolysis with Pd/C also cleaves benzyl ethers and Cbz groups. Homogeneous catalysts dissolve: Wilkinson’s RhCl(PPh₃)₃ reduces unhindered alkenes selectively and leaves C=O, NO₂ and esters; chiral catalysts such as Noyori’s Ru–BINAP hydrogenate functionalised alkenes and β-keto esters with very high ee, and cationic Rh or Ir complexes can be directed by a nearby OH group.
5. Dissolving-metal and metal-based reductions: Li/Na–NH₃, Mg, Zn, Ti and Sm
Alkali metals dissolve in liquid ammonia to give solvated electrons, which reduce by single-electron transfer. The Birch reduction converts benzene rings to 1,4-cyclohexadienes (Na or Li, NH₃, an alcohol as proton source): the arene radical anion is protonated, reduced again and protonated again, the two new hydrogens ending up 1,4 to each other. Electron-donating substituents (OMe, alkyl) stay on a remaining double bond — anisole gives 1-methoxycyclohexa-1,4-diene, which hydrolyses to cyclohex-2-enone — while electron-withdrawing groups (COOH) end up on an sp³ carbon. The same conditions reduce internal alkynes to trans-alkenes, complementing Lindlar, and reduce α,β-unsaturated ketones to enolates.
- Magnesium: Mg or Mg(Hg) couples ketones to pinacols (1,2-diols) through ketyl radicals; Mg in methanol reduces α,β-unsaturated esters and nitriles at the C=C.
- Zinc: the Clemmensen reduction (Zn(Hg), conc. HCl) reduces aryl ketones to CH₂ in acid, the complement of the basic Wolff–Kishner reduction; Zn in acetic acid removes α-heteroatoms from carbonyl compounds and reduces nitro groups; Zn also reduces ozonides and drives the Reformatsky reaction.
- Titanium: low-valent Ti (TiCl₃ or TiCl₄ with LiAlH₄, Zn or Zn–Cu) couples carbonyls reductively to pinacols at low temperature and to alkenes on heating (the McMurry reaction), the oxophilic titanium removing both oxygens.
- Samarium: SmI₂ (Kagan’s reagent), a mild, soluble one-electron reductant made stronger by HMPA or water, forms ketyl radicals for pinacol couplings, Barbier-type additions of alkyl halides to carbonyls and ketyl–olefin cyclisations, and reductively cleaves α-heterosubstituents from ketones.
6. Hydride reagents: NaBH₄, Selectrides, Luche, LiAlH₄ and DIBAL-H
| Reagent | Reduces | Leaves alone / special feature |
|---|---|---|
| NaBH₄ | aldehydes, ketones, acid chlorides (to alcohols) | esters, acids, amides, nitriles, nitro groups; used in alcohols or water |
| Luche: NaBH₄ + CeCl₃ in MeOH | enones selectively 1,2 to allylic alcohols; ketones in the presence of aldehydes (which are protected as acetals in situ) | hard methoxyborohydrides and Ce³⁺ activation of C=O favour 1,2-attack |
| L-Selectride (Li), K-Selectride (K): M[HB(sec-Bu)₃] | ketones, very stereoselectively; enones 1,4 | bulky, so attack from the less hindered (equatorial) face gives the axial alcohol |
| LiAlH₄ | aldehydes, ketones, esters, acids (to 1° alcohols); amides and nitriles (to amines); epoxides; halides | isolated C=C; reacts violently with water, so used in dry ether or THF |
| DIBAL-H | esters and lactones to aldehydes and lactols at −78 °C; nitriles to aldehydes after hydrolysis; enones 1,2 | a neutral Lewis-acidic hydride; the tetrahedral intermediate survives at low temperature, so reduction stops at the aldehyde |
Each LiAlH₄ can deliver four hydrides. An ester needs two: the first gives a tetrahedral intermediate that expels alkoxide to an aldehyde, which is more reactive than the ester and takes the second at once. So, in principle, half a mole of LiAlH₄ reduces a mole of ester, and only DIBAL-H at low temperature, or conversion to a Weinreb amide, stops at the aldehyde. For cyclohexanones the stereochemistry turns on size: small hydrides (NaBH₄, LiAlH₄) attack axially to give mainly the equatorial alcohol (about 90% trans for 4-tert-butylcyclohexanone), while L-Selectride attacks equatorially and gives mainly the axial (cis) alcohol.
Key takeaways
- PCC, PDC, Swern and Dess–Martin stop primary alcohols at the aldehyde; Jones and KMnO₄ go to the acid; MnO₂ oxidises only allylic and benzylic alcohols; each Cr(VI) takes three electrons.
- Peracid epoxidation is syn and stereospecific; Baeyer–Villiger migrates the group best at carrying positive charge (3° > 2° ≈ Ph > 1° > Me) with retention; OsO₄ and cold KMnO₄ give syn diols; ozonolysis cleaves C=C; hydroboration is syn, anti-Markovnikov, with retention on oxidation.
- Sharpless AE: allylic alcohols, Ti(Oi-Pr)₄, TBHP, DET sets the face; Jacobsen: Mn-salen for cis-alkenes; Sharpless AD: OsO₄ with (DHQ)₂PHAL (AD-mix-α) or (DHQD)₂PHAL (AD-mix-β).
- Heterogeneous hydrogenation is syn; Lindlar gives cis-alkenes, Na/NH₃ trans-alkenes; Birch gives 1,4-dienes (donors on the double bond); Clemmensen, McMurry and SmI₂ chemistry are Zn, Ti and Sm reductions.
- NaBH₄: aldehydes and ketones only; LiAlH₄: esters, acids, amides, nitriles too; DIBAL-H at −78 °C: ester → aldehyde; Luche: 1,2 on enones; Selectrides: bulky, give axial alcohols.
Practice questions (19)
Attempt each one before opening the answer. Every explanation names the tempting wrong option as well as the right one, because that is where marks are lost.
Secondary alcohols are oxidised to ketones by Cr(VI), which is reduced to Cr(III). How many moles of CrO₃ are needed to oxidise 1.0 mol of propan-2-ol to acetone? Give the answer to two decimal places.
Numerical answer — type the value.
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Answer: 0.67
Alcohol → ketone is a two-electron oxidation, and Cr(VI) → Cr(III) accepts three electrons, so 2 CrO₃ oxidise 3 alcohols: 2/3 = 0.667 mol, i.e. 0.67. Assuming one CrO₃ per alcohol ignores the electron balance.In acidic solution MnO₄⁻ is reduced to Mn²⁺. How many moles of permanganate are needed to oxidise 1.0 mol of ethanol to acetic acid? Give the answer to one decimal place.
Numerical answer — type the value.
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Answer: 0.8
Ethanol (C at −1) to acetic acid (C at +3) is a four-electron oxidation; Mn(VII) → Mn(II) takes five. So 4/5 = 0.8 mol MnO₄⁻ per mole of ethanol (4 MnO₄⁻ for 5 EtOH). Treating it as a two-electron oxidation, as for the aldehyde, gives 0.4.Which reagents oxidise a primary alcohol to the aldehyde without significant over-oxidation to the acid?
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Answer: A — PCC in CH₂Cl₂; B — Swern conditions; C — Dess–Martin periodinane
PCC, the Swern oxidation and the Dess–Martin reagent work in the absence of water, so the aldehyde cannot form the hydrate that would be oxidised further. Jones reagent is aqueous acidic Cr(VI) and takes primary alcohols through to carboxylic acids.Which reagent selectively oxidises an allylic alcohol in the presence of a saturated secondary alcohol?
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Answer: A — Activated MnO₂
MnO₂ is a heterogeneous oxidant that reacts through radical intermediates stabilised by the adjacent C=C or arene, so allylic and benzylic alcohols react and saturated ones do not. Jones and Swern oxidise both alcohols, and hot KMnO₄ would also cleave the alkene.Baeyer–Villiger oxidation of cyclohexyl methyl ketone with mCPBA gives mainly
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Answer: A — cyclohexyl acetate
In the Criegee intermediate the group better able to stabilise positive charge migrates to oxygen: secondary cyclohexyl far outranks methyl, so O is inserted between C=O and the ring, giving CH₃COO–C₆H₁₁. Methyl migration, giving the methyl ester, is the least favoured of all.cis-2-Butene is dihydroxylated with catalytic OsO₄ and NMO. How many stereoisomers of 2,3-butanediol are formed?
Numerical answer — type the value.
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Answer: 1
OsO₄ delivers both OH groups syn, so the cis-alkene gives only the meso diol: one achiral stereoisomer. Epoxidation followed by acid hydrolysis (net anti addition) would instead give the racemic pair, counted as 2.1-Methylcyclohexene is ozonised and worked up with dimethyl sulfide. How many carbon atoms does the single product contain?
Numerical answer — type the value.
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Answer: 7
Cleaving the ring C=C of a cyclic alkene keeps every carbon in one chain: 1-methylcyclohexene (C₇H₁₂) gives 6-oxoheptanal, CH₃CO(CH₂)₄CHO, with seven carbons, a ketone at one end and an aldehyde at the other. Oxidative work-up would give 6-oxoheptanoic acid.1-Methylcyclohexene is treated with BH₃·THF and then with H₂O₂/NaOH. The product is
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Answer: A — trans-2-methylcyclohexanol (racemic)
Boron adds to the less substituted C2 and H to C1 on the same face (syn); oxidation replaces B by OH with retention, so OH at C2 and the new H at C1 are cis, which places the OH and the methyl trans. 1-Methylcyclohexanol is the Markovnikov product of acid-catalysed hydration.Which substrate requirement distinguishes the Sharpless asymmetric epoxidation from the Jacobsen epoxidation?
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Answer: A — Sharpless needs an allylic alcohol that binds titanium; Jacobsen works on unfunctionalised cis-alkenes
In the Sharpless system the allylic OH coordinates to the Ti–tartrate catalyst, which is what sets the face and why other alkenes are untouched. The Mn(III)–salen/NaOCl system of Jacobsen needs no directing group and is best for cis-disubstituted alkenes.Which components belong to the Sharpless asymmetric dihydroxylation?
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Answer: A — Catalytic osmium, as K₂OsO₂(OH)₄; B — K₃Fe(CN)₆ as the stoichiometric oxidant; C — A cinchona-alkaloid ligand such as (DHQD)₂PHAL
AD-mix contains the osmate, ferricyanide, K₂CO₃ and either (DHQ)₂PHAL (α) or (DHQD)₂PHAL (β), which give opposite diol enantiomers. Diethyl tartrate with titanium isopropoxide is the asymmetric epoxidation catalyst, a different reaction.2-Butyne is reduced with H₂ over Lindlar’s catalyst. The product is
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Answer: A — cis-2-butene
The poisoned palladium surface delivers two hydrogens syn and releases the alkene before it can be reduced further, giving the Z-alkene. Na in liquid NH₃ gives trans-2-butene; ordinary Pd/C would continue to butane.How many moles of H₂ are consumed when 1 mol of limonene (which has two C=C double bonds) is fully hydrogenated over PtO₂?
Numerical answer — type the value.
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Answer: 2
Each C=C takes one H₂, so the ring and isopropenyl double bonds together consume 2 mol, giving p-menthane (C₁₀H₂₀). Hydrogen uptake is a classical way of counting double bonds, since rings do not react.Birch reduction of anisole (Na, liquid NH₃, EtOH) gives
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Answer: A — 1-methoxycyclohexa-1,4-diene
With an electron-donating OMe, protonation of the radical anion and then of the carbanion occurs at the positions ortho and meta to it, so OMe remains on a double bond of the non-conjugated 1,4-diene; acid hydrolysis then gives cyclohex-2-enone. An electron-withdrawing COOH would end up on an sp³ carbon instead.Which reagent converts an aryl ketone ArCOCH₃ into ArCH₂CH₃ under strongly acidic conditions?
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Answer: A — Zn(Hg) and concentrated HCl (Clemmensen)
The Clemmensen reduction deoxygenates C=O fully to CH₂ on the zinc amalgam surface in hot acid, and is the acid-side complement of the Wolff–Kishner reduction. NaBH₄ and DIBAL-H stop at the alcohol, and SmI₂ forms ketyls that couple.Which of the following are reduced to a primary alcohol by LiAlH₄ but not by NaBH₄ under ordinary conditions?
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Answer: A — Ethyl acetate; B — Benzoic acid
Esters and carboxylic acids need the stronger LiAlH₄, giving ethanol (two molecules, one from each half of ethyl acetate) and benzyl alcohol. NaBH₄ readily reduces aldehydes such as butanal (to a primary alcohol) and ketones, so those do not meet the "not by NaBH₄" condition — and cyclohexanone gives a secondary alcohol anyway.In principle, how many moles of LiAlH₄ are needed to reduce 1.0 mol of an ester RCOOR′ to RCH₂OH and R′OH? Give the answer to one decimal place.
Numerical answer — type the value.
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Answer: 0.5
The ester takes two hydrides (one to reach the aldehyde, one more to the alkoxide), and each AlH₄⁻ supplies four, so 2/4 = 0.5 mol. In practice an excess is used; answering 2 counts hydrides rather than moles of reagent.Which reagent reduces cyclohex-2-en-1-one selectively to cyclohex-2-en-1-ol?
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Answer: A — NaBH₄ with CeCl₃ in methanol (Luche)
Ce³⁺ activates the carbonyl and the methoxyborohydrides formed are hard, so hydride adds 1,2 and the C=C survives. L-Selectride adds 1,4 (conjugate reduction), H₂/Pd reduces the C=C first, and Li/NH₃ gives the saturated ketone via the enolate.Methyl hexanoate is treated with one equivalent of DIBAL-H in toluene at −78 °C, then aqueous work-up. The main product is
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Answer: A — hexanal
DIBAL-H delivers one hydride to give an aluminium hemiacetal that is stable at −78 °C and collapses to the aldehyde only on work-up, when no hydride remains. With excess reagent or at higher temperature the reduction runs on to hexan-1-ol, as with LiAlH₄.4-tert-Butylcyclohexanone is reduced separately with NaBH₄ and with L-Selectride. Which statement about the major products is correct?
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Answer: A — NaBH₄ gives mainly the trans (equatorial OH) alcohol; L-Selectride gives mainly the cis (axial OH) alcohol
The locked ring presents two faces: small BH₄⁻ prefers axial attack, avoiding torsional strain with the adjacent axial hydrogens, and puts OH equatorial (trans to t-Bu); the very bulky tri-sec-butylborohydride is blocked by the 3,5-axial hydrogens and attacks equatorially, putting OH axial (cis).