OXIDATION AND REDUCTION

Cl
R

R"

R'

R"

O
R

R'
R

OH
R

R"'

R'

R'
R

R'

O
R

R'

OH

R"

R"
R

R'
Nuc

OR"

N
R'

Introduction
Fundamental backbone of organic chemistry is the ability to alter oxidation states
Hydroxyl and carbonyl moiety provide an invaluable means for transforming molecules so
the ability to introduce and remove them very important

Course Outline
Oxidations
alcohol to carbonyl
alkene epoxidation and dihydroxylation
CH oxidation
miscellaneous
Reductions
carbonyl group
hydrogenation
electron transfer

This is not an all inclusive lecture course

To list every reagent would be boring, so I have tried to be selective with the criteria being
those that are more common, useful or interesting, but this is just my opinion
As this is a new course, if you feel I have missed out any important examples (or too much
detail on others) please tell me: g.rowlands@sussex.ac.uk

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

ALCOHOL OXIDATION
Alcohols can readily be oxidised to the carbonyl moiety
This is an incredibly important reaction - you should realise that the carbonyl group is one of
the cornerstones of CC bond formation (organometallics, neutral nucleophiles, aldol, Julia,
Peterson & Wittig reactions)
R1 = H
OH

O
R1

O
R1

OH

Primary (R1 = H) alcohols normally more reactive than seconary alcohols on steric grounds
Need to be able to control oxidation of primary alcohols so only obtain aldehyde or acid
Large number of reagents all have their advantages and disadvantages
Look at some of the more common...
General Fragmentation Mechanism
EH

E
[O]

HO

E
[O]

H
O

[R]
R
R

This fragmentation mechanism is common to most oxidations regardless of the nature of the
reagent
Chromium (VI) Oxidants
General Mechanism

Cr(VI)
OH2
O

Cr O
O

Cr

proton
transfer

H2O

O HO

Cr(IV)
O

O
HO

Cr

Cr

HO
O

OH

R
R

"Overoxidation" formation of carboxylic acids

Invariably achieved in the prescence of H2O and proceeds via the hydrate
O
O
R

OH

H2O
R

Cr

H
OH

Cr OH
O

H
OH

OH

Jones Oxidation
H2SO 4, CrO3, acetone
OH
R

O
H

OH
OH

O
R1

R1

Harsh, acidic conditions limit use of this method

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Pyridinium Chlorochromate (PCC)

Cl

must avoid
water

OH
R

Cr O
O

N
H

O
H

OH
H

O
R1

R1

Less acidic than Jones reagent (although still acidic)

Pyridinium Dichromate (PDC)
O

Cr O

Cr O

N
H

Even milder than PCC and has useful selectivity

O
R

PDC
DCM

OH
R

PDC
DMF

O
R

OH

Other Oxidants
Manganese Dioxide
MnO2
Mild reagent
Very selective only oxidises allylic, benzylic or propargylic alcohols
HO

HO

MnO2

only oxidises
activated alcohol

OH

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

ALCOHOL OXIDATION
Activated DMSO
Reagent:
DMSO, activator (X) and base
Transformation:
COH C=O (primary or secondary alcohols)
General Mechanism
H

X
S

HO

S
H

base

intermediate common to all

activated DMSO reactions

18O labelling has determined mechanism

alternative activation of hydroxyl followed by
displacement not occurring

+
R

Common Side-Reactions
Pummerer Reaction

Displacement Reactions
The cationic intermediate formed is an excellent leaving group
Intramolecular
OH

CH2 OH
CH2 OH

DMSO /
(COCl)2 93%

O
O

Intermolecular
CH2 OH

CH2 Cl

OBn

DMSO /
(COCl)2 95%

OBn

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Enolisation
Generation of a carbonyl compound in the presence of an amine base is asking for trouble
-chiral centre can be racemised
Overcome by: keeping temperature low, remove base with cold acid buffer, use Pyr.SO3
system
Eliminations
Problem due to mild acidity of earlier steps
or if suitable leaving group present when base added

HO
OH

1. DMSO /
(COCl)2
2. Et3N
72%

OMe
O

OMe

OMe
O

1. DMSO /
(COCl)2
2. Et3N

OP
TBSO

OH
SO2 Ph

+
OP

OP

TBSO

TBSO

67 %

O
SO2 Ph

28%

Activators
Pfitzner-Moffatt (DMSO / DCC then base)
N

The original
Pros: mild conditions, normally rt
Cons: DCC urea by-product hard to remove
frequently generates Pummerer side-product
mildly acidic conditions lead to eliminations
OH

O
O

OH

DMSO / DCC
TFA / Pyr
88 %

O
O

Swern (DMSO / (COCl)2)

Cl

active intermediate
of Swern reaction

Most popular, as mild and easy

Pros: low temperature reduces enolisation
very little Pummerer reaction
Cons: Chlorination
Parikh-Doering (DMSO / PyrSO3)
Pros: very mild conditions, very little enolisation
very little Pummerer Reaction
O
TBSO

Ph
O

TBSO

DMSO / PyrSO3
Et3N 94%

CH2 OH

TBSO

Ph
O

TBSO

CHO

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Activated DMSO Oxidations in Synthesis

1. DMSO /
(COCl)2
2. Et3N
92 %

HO

O
O

OTIPS

OTIPS

1,2-diols are not cleaved

1. DMSO /
(CF3CO)2O
2. Et3N
90 %

HO

HO

sequential reactions possible due to the high yields and purity of products
especially useful when aldehyde readily forms hydrate
Me3 Si

Me3 Si

1. DMSO /
(COCl)2
2. Et3N

OH

Ph3P=CMeCO 2Et
54% overall

Me3 Si

CO2Et

tertiary alcohols often do not need to be protected

OMe

OMe
OH

OH
OH

OMe OMe

1. DMSO /
(COCl)2
2. Et3N
81%
OMe OMe O

OH

selective oxidations primary alcohols oxidised much faster

but use of iPr2S and NCS as activator (proceeds via same intermediate
as Swern) oxidises primary alcohols at 0C but secondary at -78C
do not understand this reaction AND it was only a communication
84CC762 that has never been followed up
oxidation in the presence of allylic or benzylic alcohols
O

O
S

O
OH
OH

MeO

N
Me

DMSO /
(CF3CO)2O

MeO

N
Me

OCOCF3

OCOCF3
O

MeO

N
Me

Et3N
O

the activity of allylic and

benzylic alcohols means they
undergo rapid displacement
and hence a form of protection

O
O

()-tazettine
61 %

OH
MeO

N
H Me

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

 lactol or lactone formation can be surpressed

most oxidising agents oxidise primary alcohols faster
than secondary and this can lead to problems
OH
OH

OH

[O]

OH

[O]

activated DMSO does not have this problem as aldehyde only formed on addition of base
OH

OH

DMSO /
(COCl)2

Et3N

selective oxidation of primary silyl ethers

Mildly acidic nature and the nucleophilic chloride ion generated allows selective
deprotection and concomitant oxidation of primary TES & TMS ethers
O

1. DMSO /
(COCl)2
2. Et3N
62 %

O
OTES
OTES

O
O
OTES

Limitations
activated DMSO systems will not oxidise propargylic alcohols

OH

OH

What have we learnt?

Activated DMSO reactions are generally mild
Offer many advantages of metallic reagents
Drawbacks include a number of possible side-reactions
Will not oxidise propargylic alcohols

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Dess-Martin Periodinane (DMP)

(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one)
Reagent:
OAc
I OAc

AcO

O
O

Transformation:
COH C=O (primary or secondary alcohols)
General mechanism

ligand exchange
OH

OAc
AcO
I OAc

R
H

OAc

could be intra or
intermolecular

AcO O

O
O

O
H

2 x AcOH
since introduction in 1983 become one of the most popular oxidants
mild reagent operating at nearly neutral conditions (buffer with NaHCO3 if worried about AcOH)
many very sensitive molecules can be oxidised

O
H

DEIPSO

OTES

O
O
O
H
TESO

H
TBSO

O
tBu
tBu
O
MeO
O
O
Si

93 %
OTES

OTES

Preparation
O
I

+ KBrO3
CO2H

0.73 M H2SO4
65C

AcO

OH
O

AcOH

OAc
I OAc
O
O

mild and extremely reactive oxidant

Insoluble in most organic solvents
and impact sensitive
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Use in Synthesis
Selectivity
first step is ligand exchange so an inherent steric selectivity exists
primary alcohols oxidised faster than secondary
OTBS
HO
O
HO

DMP, pyr,
DCM,
88%

O
TBSO

OTBS OMe

OTBS

OTBS
HO
O

O
O
TBSO

OTBS OMe

OTBS

Allylic and benzylic alcohols react ~5 faster than saturated alcohols

O

DMP, pyr,
DCM, rt 2hrs
>75%

HO

HO

OH

Advantages:
no over oxidation is ever observed
no enolisation
no oxidation of heteroatoms (eg N or S)
Disadvantages:
Behaves like periodate and cleaves 1,2-diols. BUT not always, no consistancy

What have we learnt?

DMP is a mild reagent
selective oxidations are possible
1,2-diols behave unpredictably

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

Tetrapropylammonium Perruthenate
TPAP
Reagent:
Pr4N+RuO4 Stoichiometric or catalytic with NMO
Transformation:
COH C=O (primary or secondary alcohols)
COH CO2H (if H2O present)
General mechanism
not entirely clear
it is thought that TPAP is a 3e oxidant but each step is a 2e
process and that radicals / S.E.T. is not involved
due to steric selectivity it is thought that TPAP is a bulky
reagent & oxidation occurs primarily through the intermediacy
of a ruthenate ester
OH
R

HO

O
Ru
O
O

H
H

O
R

O
Ru
O

O
Ru

H2O

O
Ru
O

OH2
H

H
O

O
Ru O

O
N

O
Ru
O
O

Use in Synthesis
Introduced in 1987
its mildness and practically have made it popular (coupled to its none explosive nature)
should be used dry with 4ms or get over-oxidation and cleavage of alkenes
mechanism changes in presence of H2O
advantages:
good functional group tolerance
no epimerisation of -chiral centres or double bond isomerisation
no competative -elimination
OPMB
O

OPMB

TPAP / NMO,
DCM, 4ms
96%

OH

O
O

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

10

 selectivity for primary hydroxyl group allows lactone preparation

OH

TPAP / NMO,
DCM / MeCN,
4ms 91%

OH

TPAP
OH

secondary alcohols oxidise far slower but they do oxidise

TPAP / NMO,
DCM, 4ms,
73%

N
OH
O

N
O
O

Swern Oxidation = 0%
PCC
= 0%

TMS

TMS

depending on sterics can get selectivity for least hindered hydroxyl group
HO

HO
O

TPAP / NMO,
DCM, 4ms
61%

O
OH

O
OH

O
OH

lactols can be oxidised selectively (again sterics)

O

CO2Me
OHO

O O

O O
O

AcO
MeO 2C

CO2Me
OHO

OH

O
OH

OH

TPAP / NMO,
MeCN, 4ms
75%
AcO
MeO 2C

O
OH

OH
O

TPAP oxidises sulfur but not other heteroatoms

again we see how

mild TPAP is

SMe

SO2 Me

TPAP / NMO,
MeCN, 4ms
80%

O
O

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

11

 Sequential reactions due to ease of w/u and anhydrous conditions, TPAP is well suited
to sequential reactions
CO2Me

CO2Me

TPAP / NMO,
DCM, 4ms

OH

CO2Me

Ph3P=CMeCO2tBu
O

CO2tBu

72% overall

Disadvantages: TPAP can cleave 1,2-diols like other metal oxidants

O
O
HO
OH
O

TPAP,
NaOCl
93%

Disadvantages: can cause retro-aldol reaction

OH

O
H

TPAP /
NMO,
DCM,
4ms

O
O

O
H

retro-aldol results in
cleavage of -hydroxyketones

What have we learnt?

TPAP is a mild oxidant
Its bulk allows selective reactions
It can be used in catalytic quantities

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

12

Modified Chromium (VI) Oxidants

Pyridinium Chlorochromate PCC

Reagent:
ClCrO3
NH

Transformation:
COH C=O (primary or secondary alcohols)

General Mechanism

O
O

O
H
H

O
Cr
Cl
O

O
R

OH

Cr

O
R

O
H

HO

Cr

CrO2 + H 2O
OH

Use in Synthesis
Must be dry, water hampers reaction and can result in the formation of acids (over-oxidation)

OH

OH

PCC, 4ms,
DCM 93%
OH

Disadvantages: reagent is acidic

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

13

Pyridinium Dichromate PDC

Reagent:

NH

Cr2O7

Transformation:
COH C=O (primary or secondary alcohols)
Use in Synthesis
Neutral variant of PCC
Addition of SiO 2 to reaction aids work up and addition of pyridinium trifluroracetate increases rate
DCM normal solvent
DMF gives carboxylic acids
OH

PDC, DCM
92%

PDC, DMF
83%

OH

CO2Me

Oxidation to the Acid

O
R

O
H

OH

Many variants involving chromium or manganate which proceed via the hydrated aldehyde
But invariably require strongly acidic conditions so not useful in organic synthesis
You can find them yourselves in March or Smith
A mild alternative is:
NaClO2,
NaH2PO4

O
R

OH

HO

ClO2
R

Cl

O
HOCl

O
H

OH

HOCl is very unpleasnt so alkene added as a scavenger

What have we learnt?

Chromium reagents can be used to oxidise to either aldehyde or carboxylic acid
They are toxic

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

14

Kinetic Resolution by Selective Oxidation

Noyori has developed a method for resolving racemic alcohols via selective oxidation
Uses hydrogen transfer (analgous to Oppenauer oxidation or Meerwein-Ponndorf-Verley
reduction)
OH

OH

+
Un

Un

Ph

OH

Un

Un = unsaturated group
Yield = 43-51 %
e.e. = > 90 %

OH

+
Un

Ts
N
Ru
N
H

Ph

note you can not get better than 50% with kinetic resolution
Mechanism
Un

Un
O

H
H

Ru
N

NTs

Ru

Un
NTs

N
H

Ph

Ph

O
R
Ph

H Ru
H N
NTs
H
Ph

Ph

Ph

OH
O
Un

Ru

H Ru

NTs

NTs

Ph

Ph

Ph

Ph

More appealing is the desymmetrisation of meso-diols

Theoretical maximum yield is 100 %
OH

OH

70 %
96 % e.e.
OH

H
O

What have we learnt?

Stereoselective oxidations are now possible
Hydrogen transfer allows preparation of enantiopure compounds from racemates
As both reductant and oxidant are organic this type of reaction will be appearing again
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002

15