Oxidation of Alcohols

1 alcohol:

2 alcohol:

H OH
R

O
H

H OH
R

3 alcohol:

H OH

No Reaction

OH

A. Chromium Based Reagents

General Mechanism: !

!
:B

H H
R

OH

H H

O CrLn

H3O

OH

H OH
R

slow

O
Cr Ln-1

OH

- 1 alcohols: under anhydrous conditions (Collins, PCC, PDC) will stop at aldehyde
- in presence of aqueous acid (Jones), see further (rapid) oxidation to carboxylic acid
- oxidation of 2 alcohols give ketones
- these processes generate chromium waste (toxic)

A. Chromium Based Reagents

1. CrO3/H2SO4 (aq): Jones Oxidation

preparation
O
O
HO Cr O Cr OH
O
O

CrO3 + H2O + H2SO4

H2O

O
HO Cr OH
O
(dilute)

(concentrated)

- reagent is shelf stable

reactivity
O

CrO3, H2SO4
O

OH

acetone
85%

OH

- 1 alcohol CO2H
- rapid reaction
- strongly acidic; not useful for acid sensitive substrates
- reaction can effectively be run as a titration

Yamamoto Tetrahedron
1990, 46, 4595.

A. Chromium Based Reagents

mechanism
R H
R'

OH

R H

H2CrO4
acetone
CrVI (red)

R'

O
Cr

slow
OH

+
R

R'

H2CrO3

CrIII (green)

R2CH-OH + Cr(VI)

R2C=O + Cr(IV) + 2 H+

R2CH-OH + Cr(IV)

R2C=O + Cr(II) + 2 H+

Cr(II) + Cr(VI)
R2CH-OH + Cr(V)

HOCrO

Cr(III) + Cr(V)
R2C=O + Cr(III) + 2 H+

- stoichiometry: 3 R2CHOH + 2 CrO3 + 6 H+ 3 R2C=O + 2 Cr3+ + 6 H2O

A. Chromium Based Reagents

2. CrO3pyridine: Collins reagent

preparation
N O
O Cr
O
N

CrO3 + 2 pyridine

hygroscopic
red crystalline
solid

H2O

(Cr2O7)2-(pyrH+)2
(yellow)

- important: add CrO3 to pyridine (reverse results in strong exotherm!)

- Sarett: in situ generation in pyridine
- Collins: isolated solid; reaction in CH2Cl2
- Radcliff: in situ generation in CH2Cl2
reactivity
OH

O
CrO3, pyr
CH2Cl2

95%

Ratcliffe JOC 1970, 35, 4000.

- 1 alcohol CHO
- neutral to slighlty basic; good for acid sensititve substrates
- requires large excess of reagent; anhydrous conditions

A. Chromium Based Reagents

3. Pyridinium Chlorochromate (PCC): Corey-Suggs Oxidation

preparation
N
H

CrO3 + HCl + pyridine

O
Cr
O
Cl
O

orange solid

- stable; commercially available

- chloride facilitates formation of chromate ester
reactivity
O
O

OH

PCC
4 MS, CH2Cl2

O
O

94%

Nicolaou J. Am. Chem. Soc.

1988, 110, 4672

- 1 alcohol CHO
- can use in near stoichiometric amounts (ca. 1.5 equiv)
- mild conditions; slightly acidic can buffer with NaOAc
- add powd MS or Celite to facilitate product isolation
- addition of MS can accelerate rxn rate
- can promote allylic rearrangements

A. Chromium Based Reagents

4. Pyridinium Dichromate (PDC): Corey-Schmidt Oxidation

preparation
orange solid

CrO3 + pyridine + H2O

N
H

Cr2O72-

- stable; commercially available

reactivity

PDC
O

CH2Cl2

PDC
OH

DMF

CO2H
Corey Tetrahedron Lett.
1970, 20, 399.

- product of reaction depends on solvent used

CH2Cl2: 1 alcohol CHO
DMF: 1 alcohol CO2H (allylic alcohols give CHO)
- oxidizes more slowly than other Cr-based reagents
- mild conditions; less acidic than PCC

B. Manganese Based Reagents

1. Manganese Dioxide (MnO2)

reagent
- dark brown or black solid

- structure/activity depends on preparation

- non-stoichiometric material containes Mn(II) and Mn(III) oxides and hydrated
species
reactivity
OH
MeO

O
OH

MeO

MnO2
acetone

MeO

OH

MeO

- selective oxidation of allylic and benzylic alcohols; significant rate difference!

- 1 alcohol CHO
- slow reaction, requires large excess of reagent
- H bonding solvents show strong deactivating effect; non-polar solvents best
- mild; no isomerization of double bonds upon oxidiation of allylic alcohols

B. Manganese Based Reagents

2. Manganese Dioxide, ROH, NaCN: Corey-Gilman-Ganem Oxidation
!
reagent

- modified MnO2 oxidation

reactivity

MnO2, NaCN
MeOH, AcOH

O
OH

CO2Me

- direct oxidation of 1 allylic/benzylic alcohols to esters

- more commonly used for the conversion of conjugated aldehydes to esters

B. Manganese Based Reagents

3. Potassium Permanganate (KMnO4)
reactivity
O

CN

CN

KMnO4, NaH2PO4
CHO
N
Boc

tBuOH, H2O
94%

CO2H
N
Boc

Joulli J. Am. Chem. Soc.

1992, 114, 10181.

- 1 alcohol CO2H; also useful for the oxidation of aldehydes

- powerful oxidant; over oxidation/side reactions may be a problem
also oxidizes alkenes, 1,2-diols, etc.
- insoluble in organic solvents
- may be successful when other oxidants fail (Jones, AgO, NaOCl).
- R4NMnO4 shows similar reactivity and is soluble in organics

C. Ruthenium Based Reagents

1. Ruthenium Tetraoxide (RuO4)
reagent
- toxic

- catalytic procedures use 1-5% Ru metal with a stoichiometric oxidant

reactivity
O

O
RuCl3-NaIO4
MeCN, CCl4, H2O

OBz

60%

HO

OBz
HO O

Overman J. Am. Chem. Soc.

1997, 119, 12031.

- 1 alcohol CO2H
- powerful, non-selective oxidant; will also attack multiple bonds,1,2-diols,
ethers, aromatic rings, etc.

C. Ruthenium Based Reagents

2. Tetra-n-propylammonium Perruthenate (Pr4N+RuO4-): TPAP
reagent
- developed by Steve Ley (Imperial College Cambridge)
- catalytic; used in conjunction with a stoichiometric oxidant (NMO)
- perruthate salts with a large counterion are mild and selective oxidants
reactivity

N
HO

CBz
TPAP, NMO
4 MS, CH2Cl2

N
O

CBz

Jacobsen J. Am. Chem. Soc.

2004, 126, 706.

- 1 alcohol CHO
- mild oxidant; no over oxidation, does not react with multiple bonds
- use of MS required to remove water and achieve high catalyst turnover
- modified conditions allow for oxidation of 1 alcohol to carboxylic acid
(Stark Org. Lett. 2011, 13, 4164)

C. Ruthenium Based Reagents

2. Tetra-n-propylammonium Perruthenate (Pr4N+RuO4-): TPAP
mechanism

http://www.synarchive.com/named-reactions/Ley-Griffith_Oxidation

D. DMSO Based Reagents

General Mechanism: !

OH

E
S O

S O

H
R

B
E

CH2
O S
Me

H
CH2
O S
Me

Me
S
Me

- mild class of reagents

- dont have environmental issues associated with use of Cr based reagents
- no over oxidation oxidation of 1 alcohols give aldehydes
- oxidation of 2 alcohols give ketones

D. DMSO Based Reagents

1. DMSO, (COCl)2; Et3N: Swern Oxidation !

activation:
Cl

O
S O

Cl

Cl

O
S

Me
Cl S
Me

Cl
O

+ CO2 + CO + Cl-

- also TFAA, Ac2O, SOCl2, Cl2, P2O5

reactivity
O

O
DMSO, (COCl)2
CH2Cl2; then Et3N
OH

CHO

Funk J. Org. Chem.

1987, 52, 3173.

- 1 alcohol CHO
- most common of DMSO based reagents
- very mild run at low temp (-78 to -60C)
- low sensitivity to steric factors
- preparation of -alkoxy carbonyl derivatives may be problematic use Et2NiPr

D. DMSO Based Reagents

2. DMSO, DCC, TFA, pyridine: Moffatt Oxidation

activation: DMSO + DCC

S
O
+

S O

N C N

N C N

reactivity
OBz

OBz
OH

MeO

OBPS

DMSO, EDC
TFA, pyr
94%

O
MeO

OBPS

Hannessian Can. J. Chem.

1981, 59, 870.

- 1 alcohol CHO
- first reported DMSO based oxidant; less commonly used
- separation of by-pyroduct (dicyclohexylurea) can be difficult use EDC
HClMe2N

N C N

- may result in formation of MTM ethers (side reaction)

D. DMSO Based Reagents

3. SO3pyridine, DMS; Et3N: Parikh-Doehring

activation

S O

O
S

O
S O S O
O

reactivity
H

HO
O

H
H

SO3pyr, DMSO
Br

CH2Cl2; Et3N

O
O

H
H

- 1 alcohol CHO
- easy workup; well suited to large scale reactions

Br

Evans ACIEE 1999,

38, 3175

E. Silver Based Oxidants

1. Ag2CO3/celite: Fetizons reagent

reactivity
MeO

MeO
Ag2CO3

toluene, 110
NMe

84%

HO

NMe
Rappoport - codeine

- 1 alcohol CHO
- original oxidant modified by Fetizon adsorb on celite to increase surface area
- neutral conditions; very sensitive to steric factors
- $$$, must use large excess small scale reactions
- reaction does not proceed through cationic intermediate (no rearrangements, etc.)
- controlled overoxidation possible with some substrates (selective lactol oxidation)

HO

MeO

OH

MOMO

MeO

OBn
Ag2CO3/celite
benzene, 80C

MOMO

OBn

O
O

Kallmerten Tetrahedron Lett. 1990, 31, 4305.

E. Silver Based Oxidants

2. Silver (I) Oxide (Ag2O)

reactivity
CHO
HO

Ag2O
EtOH (aq)

CO2H
HO

80%

Kitching JCSP1 1995, 1309.

- mild method for the conversion of CHO CO2H (in presence of free OH)
- unsaturated aldehydes are problematic (isomerization)
- weak oxidant

F. Other Oxidants
1. Dess-Martin Periodinane

preparation
O

O
CO2H

KBrO3
H2SO4

Ac2O

O
I
O
HO
(IBX) shock
sensitive

O
I OAc
AcO OAc
white
solid

pTsOH, 100C

- can determine quality of reagent by solublity in CH2Cl2

reactivity
O

O
O

MeO

Dess-Martin
CH2Cl2

OH

O
MeO

CHO

Danishefsky J. Am. Chem. Soc.

1991, 113, 3850.

- 1 alcohol CHO
- mild reagent; nearly neutral conditions gives off AcOH, but can buffer
- will not oxidize N or S

F. Other Oxidants
mechanism
AcO O
AcO I
AcO

O
- AcOH

AcO O
AcO I
O

OH
H

O
H

AcO I

- addition of 1 equiv water accelerates reaction (Schreiber)

O
+

2 AcOH

F. Other Oxidants
2. o-Iodoxybenzoic acid (IBX)

preparation
O
CO2H
I

oxone
H2O, 70C

O
I
O
HO

- intermediate in the synthesis of Dess-Martin periodinane; simpler prep

reactivity
OH

O
IBX (2.3 equiv)
toluene, DMSO
88%

Nicolaou J. Am. Chem. Soc.

2000, 122, 7596.

- in excess will oxidize alcohols to ,-unsaturated aldehydes and ketones

(or saturated aldehydes/ketones to ,-unsaturated compounds)
- mild reagent for oxidation of 1,2-diols without oxidative cleavage
- insoluble in most organic solvents, except DMSO or DMSO mixtures

"SIBX"
IBX

F. Other Oxidants
2. o-Iodoxybenzoic acid (IBX)

49%

CO2H

22%

preparation
HO2C

O
CO2H
I

oxone
H2O, 70C

O
I
O
HO

CO2H

Quideau Org. Lett. 2003, 5, 2903.

- intermediate in the synthesis of Dess-Martin periodinane; simpler prep

reactivity
OH

O
IBX (2.3 equiv)
toluene, DMSO
88%

29%

Nicolaou J. Am. Chem. Soc.

2000, 122, 7596.

- in excess will oxidize alcohols to ,-unsaturated aldehydes and ketones

(or saturated aldehydes/ketones to ,-unsaturated compounds)
- mild reagent for oxidation of 1,2-diols without oxidative cleavage
- insoluble in most organic solvents, except DMSO or DMSO mixtures

F. Other Oxidants
mechanism
O

O O
I
HO

- H2O
H
H

OH
H

I
H

- alcohol oxidation: mirrors Dess-Marin periodinane mechanism

O
O
O

O
O I
HO

O
I
O HO

HO

HO I

F. Other Oxidants
3. Al(OiPr)3, acetone: Oppenauer Oxidation
reactivity
OH

Al(OiPr)3
acetone

MeO

MeO

Me

Boger J. Org. Chem.

1984, 49, 4045.

Me

- classical method for alcohol oxidation

- takes advantage of reversible reaction between ketones and metal alkoxides
- mild conditions, infrequently used; does not work well with 1 alcohols
mechanism
OH

Al(OiPr)3

OiPr
O Al OiPr
H O

H OiPr
O Al OiPr
OiPr

H+ transfer

- HOiPr

OiPr

O Al
OiPr

OiPr
Al OiPr
O
H

- use of acetone solvent drives reaction to the right

F. Other Oxidants
4. Sodium Chlorite (NaClO2): Pinnick Oxidation
reactivity
CHO
NaClO2
OH

tBuOH, H2O

CHO

CO2H
NaClO2
tBuOH, H2O

OH
CO2H

- useful method for oxidation of sensitive CHO CO2H, esp. ,-unsaturated CHO
- use hampered by formation of chlorine dioxide
- suppressed by addition of chlorine scavenger (alkene)
5. Sodium Hypochlorite (NaOCl): Stevens Oxidation
reactivity
OH

OH

NaOCl
AcOH
86%

OH

Corey J. Am. Chem. Soc.

1998, 120, 12777.

- selective oxidation of 2 alcohols

- modified procedure uses calcium hypochlorite a stable solid

F. Other Oxidants
6. TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy):
reactivity
Boc
N
O

OH

TEMPO, NaOCl, NaBr

EtOAc:toluene:H2O (1:1:0.15)

Boc
N
O

90%

- 1 alcohol CHO
- used in presence of stoichimetric oxidant (mCPBA, NaOCl, PhI(OAc)3, oxone, etc.
- works best in simple systems
- selective oxidation of alcohols in presence of S or Se
mechanism
[O]

[O]

N
O

N
O

N
OH

RCH2OH + B
RCHO

N
O O
H

BH
R

Oxidation of Ketones

O
O

O
OH

Ketone Enone
1. IBX
!
reactivity
O

!
O

H
TIPS
H

IBX (2 equiv)
tol/DMSO

TIPS
H

87%

- Nicolaou J. Am. Chem. Soc. 2002, 124, 2245.

2. Saegusa Oxidation!

reactivity
OTMS

Pd(OAc)2
MeCN, rt
O

Danishefsky J. Am. Chem. Soc.

2008, 130, 13765.

- Saegusa J. Org. Chem. Soc. 1978, 43, 1011.

- most often stoichimetric in Pd, but use of cat Pd in presence of stoichimetric
oxidant is known (see, for example: Lebel JOC 2013, 78, 776)

Ketone Enone
2. Saegusa Oxidation!
mechanism

Ketone Enone
3. Selenoxide Elimination

reactivity
O

O
LDA;
PhSeBr

O
SePh

H2O2

- other oxidants include NaIO4, O3, mCPBA, etc.

Ketones Esters/Lactones
1. Baeyer Villager Oxidation

reactivity

mCPBA

Me
O

mCPBA

Me
H

- reaction of ketone with peracids (mCPBA, trifluoroperacetic acid, peracetic acid)

- migration occurs at more highly substituted (more electron rich) position:
- migratory aptitude: 3 > 2 > benzyl > Ph > 1 > cyclopropyl > Me > H
- stereochemistry is retained
- note peracids react with other functionality (alkenes, amines, sulfides, etc.)

Alpha Hydroxylation
1. Rubottom Oxidation

reactivity
OTMS

O
OR

mCPBA
CH2Cl2

R = H, TMS

- Rubottom Tetrahedron Lett. 1974, 15, 4319.

- epoxidation of silyl enol ether, followed by silyl migration
- dimethydioxirane (DMDO) can also be used for epoxidation
2. MoOPh Oxidation !

reactivity
O

O
LDA;
MoOPh

OH

OO
O Mo O
(Me2N)3P O N O
MoOPh

- MoOPh = MoO5pryHMPA
- attack of enolate at peroxyl oxygen atom leads to O-O bond cleavage

Alpha Hydroxylation
3. Davis Oxaziridine !
preparation
Ph
N
PhSO2

!
mCPBA or
oxone

O Ph
N
PhSO2

- N-sulfonyloxaziridines prepared by oxidation of corresponding sulfonimine

- chiral reagents are known
reactivity
OTBS

OTBS
HO

KHMDS;
Davis oxaziridine
O

O
H
OTMS
O
Ph

Me

68%

1. NaHMDS
2.

Ph
Cl
N
O S
O
O

O
OTMS

Me
OH

Cl

61%, 95% ee

- nucleophilic attack of enolate on electrophilic oxaziridine oxygen

- potassium enolates tend to work best