Oxidation of Alcohols

H OH O O
1° alcohol:
R H R H R OH

H OH O
2° alcohol:
R H R R

H OH
3° alcohol: No Reaction
R H
A. Chromium Based Reagents
General Mechanism: ! ! !

:B
H H H H slow O
+ O CrLn O
R OH R O Cr Ln-1 R H

H OH O
H3O
R OH R 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 H2O O
CrO3 + H2O + H2SO4 HO Cr O Cr OH 2 HO Cr OH
O O O

(concentrated) (dilute)

- reagent is shelf stable

• reactivity

CrO3, H2SO4 O

O OH acetone O OH Yamamoto Tetrahedron

85% 1990, 46, 4595.

- 1° alcohol  CO2H
- rapid reaction
- strongly acidic; not useful for acid sensitive substrates
- reaction can effectively be run as a titration
A. Chromium Based Reagents

• mechanism

R H R H slow O
H2CrO4 O + H2CrO3 HOCrO
R' OH acetone R' O Cr OH R R'
CrVI (red) O 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) Cr(III) + Cr(V)

R2CH-OH + 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. CrO3•pyridine: Collins reagent ! ! !

• preparation
N O
hygroscopic H2O
CrO3 + 2 pyridine O Cr red crystalline (Cr2O7)2-(pyrH+)2
O
N solid
(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
H 95% H
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
CrO3 + HCl + pyridine H O orange solid
Cr
O Cl
O
- stable; commercially available
- chloride facilitates formation of chromate ester

• reactivity

O O
PCC
O OH 4Å MS, CH2Cl2 O O Nicolaou J. Am. Chem. Soc.
1988, 110, 4672
94%

- 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 2 Cr2O72-

- stable; commercially available

• reactivity

PDC PDC
CO2H
O CH2Cl2 OH DMF
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 O
MeO MnO2 MeO
OH OH
acetone
MeO 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
O MeOH, AcOH O
CO2Me
OH

- 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 O CN
KMnO4, NaH2PO4
CHO tBuOH, H2O CO2H
N N Joullié J. Am. Chem. Soc.
94% 1992, 114, 10181.
Boc Boc

- 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
H H
OBz 60% OBz Overman J. Am. Chem. Soc.
HO HO O 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

CBz CBz
N N
TPAP, NMO
HO 4Å MS, CH2Cl2 O
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: ! ! !

R OH B
H
E CH2
E
S O S O R O S
Me

H
CH2 Me
R O + S
R O S
Me Me

- mild class of reagents

- don’t 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:
O Cl O Me
S O + Cl S Cl Cl S
Cl O
Me
O O

+ CO2 + CO + Cl-
- also TFAA, Ac2O, SOCl2, Cl2, P2O5

• reactivity

O O
DMSO, (COCl)2
CH2Cl2; then Et3N
Funk J. Org. Chem.
OH CHO 1987, 52, 3173.

- 1° alcohol  CHO
- most common of DMSO based reagents
- very mild  run at low temp (-78 to -60°C)
- low sensitivity to steric factors
- preparation of β-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 DMSO, EDC O

OBPS TFA, pyr OBPS Hannessian Can. J. Chem.

MeO O MeO O 1981, 59, 870.
94%

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

N C N
HCl•Me2N

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

D. DMSO Based Reagents
3. SO3•pyridine, DMS; Et3N: Parikh-Doehring ! !

• activation

O O
S O + S S O S O
O O
O

• reactivity

H H H H
O O
SO3•pyr, DMSO
HO CH2Cl2; Et3N O
H H Evans ACIEE 1999,
O O
H Br H Br 38, 3175

- 1° alcohol  CHO
- easy workup; well suited to large scale reactions
E. Silver Based Oxidants
1. Ag2CO3/celite: Fetizon’s reagent ! !
• reactivity
MeO MeO

Ag2CO3
O toluene, 110° O
NMe 84% NMe
Rappoport - codeine
HO O

- 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 MOMO OBn MeO MOMO OBn

Ag2CO3/celite
benzene, 80°C O
OH
O

Kallmerten Tetrahedron Lett. 1990, 31, 4305.

E. Silver Based Oxidants
2. Silver (I) Oxide (Ag2O) ! !
• reactivity

CHO Ag2O CO2H

EtOH (aq)
HO 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 Ac2O
O O
H2SO4 I pTsOH, 100°C I OAc
I O
HO AcO OAc
(IBX) shock white
sensitive solid

- can determine quality of reagent by solublity in CH2Cl2

• reactivity
O O

O Dess-Martin O
CH2Cl2
MeO MeO CHO Danishefsky J. Am. Chem. Soc.
1991, 113, 3850.
OH

- 1° alcohol  CHO
- mild reagent; nearly neutral conditions  gives off AcOH, but can buffer
- will not oxidize N or S
F. Other Oxidants

• mechanism

O O O
AcO O AcO O O
- AcOH O
AcO I AcO I + AcO I + 2 AcOH
AcO O H R
OH
H R
H R H
H

- addition of 1 equiv water accelerates reaction (Schreiber)

F. Other Oxidants
2. o-Iodoxybenzoic acid (IBX) ! !
• preparation
O
CO2H
oxone
O
H2O, 70°C I
I O
HO

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

• reactivity

OH O
IBX (2.3 equiv)
toluene, DMSO
Nicolaou J. Am. Chem. Soc.
88% 2000, 122, 7596.

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

(or saturated aldehydes/ketones to α,β-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 49%
F. Other Oxidants
CO2H
2. o-Iodoxybenzoic acid (IBX) ! ! 22%

• preparation
O HO2C CO2H
29%
CO2H
oxone
O
H2O, 70°C I
I O Quideau Org. Lett. 2003, 5, 2903.
HO

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

• reactivity

OH O
IBX (2.3 equiv)
toluene, DMSO
Nicolaou J. Am. Chem. Soc.
88% 2000, 122, 7596.

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

(or saturated aldehydes/ketones to α,β-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
O O O
O O
I - H2O I O
+ HO I
HO
H O H R
OH
H
R
H R
H

- alcohol oxidation: mirrors Dess-Marin periodinane mechanism

O
O O
HO
O I
O O I O HO O
HO

H
F. Other Oxidants
3. Al(OiPr)3, acetone: Oppenauer Oxidation
• reactivity
OH O
Al(OiPr)3
MeO acetone MeO Boger J. Org. Chem.
Me Me 1984, 49, 4045.

- 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

H OiPr OiPr O
OH Al(OiPr)3 O Al OiPr - HOiPr O Al
OiPr OiPr

OiPr OiPr
O Al OiPr H+ transfer O Al OiPr O
H O O

H
- use of acetone solvent drives reaction to the right
F. Other Oxidants
4. Sodium Chlorite (NaClO2): Pinnick Oxidation
• reactivity
CHO CO2H
NaClO2 NaClO2
tBuOH, H2O tBuOH, H2O
OH OH

CHO CO2H

- useful method for oxidation of sensitive CHO  CO2H, esp. α,β-unsaturated CHO
- use hampered by formation of chlorine dioxide
- suppressed by addition of chlorine scavenger (alkene)

5. Sodium Hypochlorite (NaOCl): Stevens Oxidation

• reactivity

OH O
NaOCl
AcOH
OH 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 TEMPO, NaOCl, NaBr Boc

N N
O OH EtOAc:toluene:H2O (1:1:0.15) O 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 N
OH O
RCH2OH + B
N
RCHO O O
BH
H R
H
Oxidation of Ketones

O O O
O

O
OH
Ketone  Enone
1. IBX ! !
• reactivity

O H O H
IBX (2 equiv)
TIPS TIPS
tol/DMSO
H H
87%

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

2. Saegusa Oxidation! !
• reactivity

OTMS O
Pd(OAc)2
MeCN, rt
Danishefsky J. Am. Chem. Soc.
O O 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 O
LDA; SePh H2O2
PhSeBr

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

Ketones  Esters/Lactones
1. Baeyer Villager Oxidation ! !

• reactivity

O
O
O mCPBA O Me mCPBA O
O H 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
mCPBA OR
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

OO
O O
O Mo O
OH
LDA; (Me2N)3P O N O
MoOPh
MoOPh

- MoOPh = MoO5•pry•HMPA
- attack of enolate at peroxyl oxygen atom leads to O-O bond cleavage
Alpha Hydroxylation
3. Davis Oxaziridine ! !
• preparation
Ph O Ph
N mCPBA or
N
PhSO2 oxone
PhSO2

- N-sulfonyloxaziridines prepared by oxidation of corresponding sulfonimine

- chiral reagents are known

• reactivity
OTBS OTBS
HO
KHMDS;
Davis oxaziridine
O O O O
H H
68% OTMS
OTMS

O 1. NaHMDS O
Me Me
Ph 2. Ph
Cl OH
Cl
O S N
O O
61%, 95% ee

- nucleophilic attack of enolate on electrophilic oxaziridine oxygen

- potassium enolates tend to work best