Oxidation Reactions

General Mechanism of Alcohol Oxidation

Kornblum Oxidation: (Sulfur-based alcohol oxidation)

Alkyl halide oxidation (or alpha halo-carbonyl)

Only reactive alkyl halides or tosylates will react. 1) DMSO, heat 2) Et3N/Base

Pritzner-Moffatt Oxidation (Sulfur-based alcohol oxidation)

Alcohol Oxidation

DCC, DMSO, TFA

DCC activation by TFA, attack by DMSO

Parikh-Doering Oxidation (Sulfur-based alcohol oxidation)

Alcohol oxidation

Pyr-SO3, DMSO, Et3N

Dump and stir

Corey-Kim Oxidation: (Sulfur-based alcohol oxidation)

Alcohol Oxidation

N-chlorosuccinamide, DMS, Et3N

Swern Oxidation: (Sulfur-based alcohol oxidation)

Alcohol oxidation

1. COCl2, DMSO

2. Et3N

2-iodoxybenzoic acid (IBX) Oxidation

Alcohol oxidation

IBX

Dess-Martin Periodinane

Alcohol oxidation

DMP

N-oxoammonium Mediated Oxidation

Alcohol to ketone/aldehyde

Ley Oxidation

Alcohol oxidation

tetrapropylammonium perruthenate, NMO

in DCM gives aldehyde/ketone,

with H2O gives carboxylic acid

TEMPO Oxidation

PRIMARY alcohol to ketone/aldehyde

TEMPO, NaOCl or PhI(OAc)2

Stahl Oxidation

PRIMARY alcohol to ketone/aldehyde

Cu(I) salt, bpy, TEMPO, imidazole, O2

ABNO Oxidation: Alcohol to Amide

PRIMARY alcohol oxidation, directly to amide

Cu(I), ABNO

Chemoselective Secondary Alcohol Oxidation

Oxidants: NBS, Br2, NaOCl

Pinnick Oxidation

Aldehyde to carboxylic acid

NaClO2, t-BuOH, NaH2PO4

2-Me-2-Butene to suppress hypochlorous acid

Chlorite adds to aldehyde, deprotonates in elimination

Chromium Reagents - alcohol oxidation

Alcohol to carboxylic acid: Jones (CrO3, H2SO4, H2O —→ H2CrO4)

Alcohol to Ketone/aldehyde: Collins (CrO3-pyr2, DCM)

Alcohol to Ketone/aldehyde: Corey (PCC, pyridinium chlorochromate) - slightly acidic

Alcohol to Ketone/aldehyde: PDC (Cr2O7, solvent). Milder PCC. Can be secondary selective based on solvent

Allylic Oxidation with Chromium reagents: Oxidative Transposition

PCC or PDC. Via [3,3] sigmatropic rearrangement

Allylic Oxidation: Oxidative Transposition

Enone from allylic alcohol

3 mechanistic paths: Dissociative, [1,3]-rearrangement, SN2

Use of N-oxoammonium salt

Allylic Oxidation using Chromium reagents

Allylic carbonylation

PCC, PDC, or CrO3 (3-5)-DMP

Mechanistic speculation: Radical pathway

Doyle Oxidation: Allylic carbonylation

Allylic carbonylation

Rh2(cap)4, tBuOOH

Selenium Dioxide Oxidation: Allylic Hydroxylation

Allylic hydroxylation

Selectivity: Tri substituted olefins react at more substituted end of double bond.

Order of reactivity: CH2>CH3>CH

Terminal olefins prefer endocyclic vs exocyclic (i.e inside the cycle versus outside)

Manganese Dioxide Oxidation

Oxidation of allylic alcohol

Corey Modification: Allylic alcohol to methyl ester (NaCN, cat. AcOH, MeOH). Cyanohydrin intermediate, oxidation to carbonyl cyanide, then attack by methanol to form methyl ester)

Can also cleave diols

Selenoxide Elimination: Unsaturation of Carbonyl

Unsaturation of carbonyl compounds

LDA, then PhSeCl

Then, H2O2

PhSeCl reagent. Can use other peroxides instead of H2O2

Mukaiyama’s reagent: Unsaturation of Carbonyl

Unsaturation of carbonyl compounds

Base, Mukaiyama’s reagent

Saegusa-Ito Oxidation: Unsaturation of carbonyl compounds

Unsaturation of carbonyl compounds

Silane + base, then Pd(OAc)2 + Oxidant

Via silyl enol ether intermediate

IBX Unsaturation

Ketone to alpha-beta unsaturated ketone

Halogen Elimination: Unsaturation of carbonyl

Unsaturation of carbonyl compounds

CuX2, NCS, or X2

Mechanism: Bromide formation, elimination

Rubottom Oxidation: Alpha hydroxylation of carbonyl

Alpha hydroxylation of carbonyl compounds

Silane, then mCPBA

Mechanism:

Via silyl enol ether intermediate. Peroxide attack forms epoxide, which forms a ketone + alpha silyl ether intermediate via rearrangement. Protonation yields product.

Upjohn and Sharpless Hydroxylation: Alpha hydroxylation of carbonyl compounds

Nonselective (Upjohn) or stereoselective (Sharpless) Alpha hydroxylation of carbonyl compounds

Davis Oxaziridine: Alpha hydroxylation of carbonyl compounds

Alpha hydroxylation of carbonyl compounds

Base, then Davis oxaziradine

Enantioselective variant possible

MoOPH Oxidation: Alpha hydroxylation of carbonyl

Alpha hydroxylation of carbonyl compounds

Mechanism: Via Metal-enol ether adduct. Oxygen is from MoOPH. 

Modifications: 

From nitrile compound: Ketone formed

From Sulfone: Ketone formed 

From alkene: enantioselective hydroxylation from borane intermediate (from hydroboration)

Alpha Hydroxylation with Oxygen

Alpha hydroxylation of carbonyl compounds

Reductant required

Mechanism: Via Metal-enol ether adduct. Oxygen is from MoOPH. Peroxide intermediate via radical recombination (triplet oxygen). Reductant cleaves hydroperoxo intermediate.

Baeyer-Villiger Oxidation

Ester synthesis

tBuOOH

Large group (RL) needs to be anti periplanar to O-O bond.

More subsittuted group migrates (tertiary>secondary>allyl>primary>methyl)

Prilezhaev Epoxidation

Nucleophillic epoxidation

“Butterfly mechanism”

More acidic peroxyacid = faster reaction

DMDO or TFDO Epoxidation

TFDO can also do C-H bond hydroxylation

Henbest Epoxidation

Required allylic alcohol

Stereoselective, directed by H-bonding between alcohol and peracid

Henbest Epoxidation Mechanism/TS

120 degree dihedral angle between alcohol directing group and alkene (minimize A1,3 interactions)

In cyclic case, half-chair formation dictates disfavored vs favored face (by whether half chair is stable or not)

Sharpless Directed Epoxidation

Allylic alcohol required

Stereoselective, directed by chelation. 

Sharpless Epoxidation Mechanism/TS

50 degree angle between alcohol and alkene, determines which face is most favorable (minimize A1,3 interactions). Top face or bottom face favored

Sharpless Asymmetric Epoxidation

Allylic alcohol required

Ti(OiPr)4, tBuOOH, Diethyltartrate (+ or -)

Alcohol in top right corner, (+)-DET attacks from top face

Jacobsen Epoxidation

Best for conjugated systems (alpha-beta unsaturated ketones, styrenes, etc.)

Mn catalyst, NaOCl (bleach) oxidant

Shi Epoxidation

Best for non-conjugated, non-allylic alcohols

Oxone, Fructose, Potassium carbonate base

Nucleophilic Epoxidation

Activated alkene required (EWG)
Hydroxide, peroxide, water

Upjohn Dihydroxylation

Syn dihydroxylation.

OsO4, NMO

In cyclic case, dependent on current ring conformation/substituents

If NaIO4 after, Lemieux-Johnson Oxidation (Oxidative cleavage of diols)

Upjohn Dihydroxylation Mechanism/TS

120 degree dihedral angle required that minimized A1,3 interaction. However, OsO4 approached from OPPOSITE face of preferred conformer.

Sharpless Asymmetric Dihydroxylation

AD Mix: K2CHO3, K3[Fe(CN)6], K2OsO4-H2O

Jacobson Epoxidation Stereochemistry

((S,S) TOP, (R,R) BOTTOM) for BOTH cases—> 

For tri-sub olefins: H in lower right corner 

For Cis-sub olefins: Aryl, alkenyl, or alkynyl group in top left corner

Sharpless Asymmetric Dihydroxylation Stereochemistry

H in lower right corner, Large group in lower left.

Alpha bottom, Beta top

Ruthenium Tetroxide Oxidative Cleavage

Stronger oxidative cleavage. Will oxidize aldehydes to carboxylic acids

Alpha hydroxy ketones/aldehydes are also cleaved

Lead Tetraacetate Oxidative Cleavage

Oxidative cleavage of diols

Ozonolysis

Oxidative cleavage of Olefins

O3

Lemieux-Johnson Oxidative Cleavage

Ozonolysis-Schreiber’s Modifications

O3, MeOH, p-tsOH

then NaHCO3, DMS: Acetal + ketone/aldehyde

then Ac2O, Et3N: Acetal + ester

O3, MeOH, NaHCO3

then Ac2O, Et3N: Aldehyde + ester

Schenk Ene Photooxygenation

Allylic alcohol from alkene

O2, photosensitizer, then reductant

Dehydration step gives alkene (need alpha proton available in one of the alkene substiuents)

Oxidation of Olefins via Singlet Oxygen

[4+2] cycloaddition, reductant forms 1,4- allylic diol

[2+2] cycloaddition, reductant forms 1,2 diol

Kornblum-DeLaMare gives a gamma-hydroxy alpha-beta unsaturated ketone

Kornblum-DeLaMare + Furan gives alpha-beta unsaturated hydroxy lactone