OXIDATION AND REDUCTION

O R" R"'
Cl O
R"
R R'
R R' R O
R R'
E

OH O O
R R'
R R' R R' R OR"

OH R"
O N
R"
R R R'
Nuc R 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
• C–H 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

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 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 C–C bond formation (organometallics, neutral nucleophiles, aldol, Julia,
Peterson & Wittig reactions)

R1 = H

OH O O

R R1 R R1 R 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

H EH
E
E H
[O] [R]
HO R [O]
O R
O R

• This fragmentation mechanism is common to most oxidations regardless of the nature of the
reagent
Chromium (VI) Oxidants
Cr(VI) General Mechanism
Cr(IV)
O
OH2 proton O H
O H Cr
O Cr O
–H2O transfer HO OH
Cr Cr
O O R
O O O HO R HO
H
O R

"Overoxidation" formation of carboxylic acids

• Invariably achieved in the prescence of H2O and proceeds via the hydrate

O
O
OH Cr
O H2O O O Cr OH O
O O
H
R H R R OH
OH H
R
OH

Jones Oxidation
H2SO 4, CrO3, acetone
OH O OH O

R H R OH R R1 R 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

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 Pyridinium Chlorochromate (PCC)
Cl
must avoid
water Cr O
O N
O H
OH O OH O

R H R H R R1 R R1

• Less acidic than Jones reagent (although still acidic)

Pyridinium Dichromate (PDC)

O O
O Cr O Cr O
O O N
H 2
• Even milder than PCC and has useful selectivity
O OH O
PDC PDC
R H
DCM R H DMF 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 O

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

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

H H
X
S
S O + X S O + HO R R O

base H

• intermediate common to all

activated DMSO reactions
• 18O labelling has determined mechanism
• alternative activation of hydroxyl followed by
displacement not occurring
O H H
S + S
R H R O

Common Side-Reactions
Pummerer Reaction

S
R O R O + S R O S

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

CH2 OH OH O
CH2 OH
DMSO / S
O
(COCl)2 93%
H H
H

Intermolecular
CH2 OH CH2 Cl

DMSO /
(COCl)2 95%
OBn OBn

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

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 Enolisation
• Generation of a carbonyl compound in the presence of an amine base is asking for trouble
• α-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
1. DMSO /
(COCl)2
2. Et3N
HO
72%
OH O
OMe OMe OMe

O O O O O O
1. DMSO /
+
(COCl)2
OP 2. Et3N OP OP
OH O
TBSO SO2 Ph TBSO O TBSO SO2 Ph
67 % 28%
Activators
Pfitzner-Moffatt (DMSO / DCC then base)
N C 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 DMSO / DCC O
TFA / Pyr
O OH
88 % O

Swern (DMSO / (COCl)2)

Cl
• active intermediate
of Swern reaction S

• Most popular, as mild and easy

Pros: low temperature reduces enolisation
very little Pummerer reaction
Cons: Chlorination

Parikh-Doering (DMSO / Pyr–SO3)

Pros: very mild conditions, very little enolisation
very little Pummerer Reaction
O Ph O Ph
DMSO / Pyr–SO3
TBSO O TBSO O
Et3N 94%
TBSO CH2 OH TBSO CHO
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
5
 Activated DMSO Oxidations in Synthesis

O
1. DMSO / O
HO (COCl)2 O
O O
2. Et3N
92 %
OTIPS OTIPS
• 1,2-diols are not cleaved

HO
1. DMSO / O
(CF3CO)2O
2. Et3N
HO O
90 %
• sequential reactions possible due to the high yields and purity of products
especially useful when aldehyde readily forms hydrate
Me3 Si O
Me3 Si OH
1. DMSO / Ph3P=CMeCO 2Et
Me3 Si
(COCl)2 54% overall CO2Et
H
2. Et3N
• tertiary alcohols often do not need to be protected
OMe OMe
H H
OH 1. DMSO / O
(COCl)2
2. Et3N
OH 81% OH
OMe OMe OH OMe OMe O

• 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 0˚C but secondary at -78˚C
• 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 O
O O S O
OCOCF3
OH O OCOCF3
DMSO /
OH O O
(CF3CO)2O S S

MeO N MeO N MeO N

Me Me Me
H H H

Et3N
O
• the activity of allylic and
benzylic alcohols means they O
undergo rapid displacement O
(±)-tazettine
and hence a form of protection
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
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 • lactol or lactone formation can be surpressed
• most oxidising agents oxidise primary alcohols faster
than secondary and this can lead to problems

OH O
OH OH [O] [O]
OH O
O O

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

OH OH S S Et3N O O
DMSO /
O O
(COCl)2

• 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 O

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

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 Dess-Martin Periodinane (DMP)
(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one)
Reagent:
AcO OAc
I OAc
O

O
Transformation:
C–OH → C=O (primary or secondary alcohols)

• ligand exchange General mechanism

• could be intra or OAc
H intermolecular I
OH H
OAc R O O
AcO
I OAc R H
H AcO O
O I O O O
O
O R H
O
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

H
O OTES
O
H
DEIPSO O
H O
O
H tBu
TBSO TESO Si
O tBu
MeO
O O O
93 % OTES
OTES
H

Preparation

O AcO OAc
OH
I I
AcOH I OAc
0.73 M H2SO4
+ KBrO3 O O
65˚C
CO2H
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

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 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,
O DCM,
TBSO OTBS OMe OTBS 88%
OTBS
HO
O
O
O
TBSO OTBS OMe OTBS

• Allylic and benzylic alcohols react ≥~5 faster than saturated alcohols

O O O O
H H
DMP, pyr,
DCM, rt 2hrs
HO >75% HO
OH O

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

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 Tetrapropylammonium Perruthenate
TPAP
Reagent:

Pr4N+RuO4– Stoichiometric or catalytic with NMO

Transformation:

C–OH → C=O (primary or secondary alcohols)

C–OH → 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

O
OH HO O
O O Ru O O O
O O OH2
Ru Ru
R H
O O R H O H
H H H2O
R
H

O
O O O O O O N
Ru N O Ru O Ru
O N O
O O 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 4Åms or get over-oxidation and cleavage of alkenes
• mechanism changes in presence of H2O

advantages:
• good functional group tolerance
• no epimerisation of α-chiral centres or double bond isomerisation
• no competative β-elimination

OPMB OPMB
TPAP / NMO,
O O O DCM, 4Åms O O O
O O
96%
OH O
O O

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

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 • selectivity for primary hydroxyl group allows lactone preparation

OH O

O O
TPAP / NMO, TPAP
DCM / MeCN,
OH 4Åms 91% OH
O
O O

• secondary alcohols oxidise far slower but they do oxidise

TPAP / NMO,
N DCM, 4Åms, N
OH O
73%
O O
TMS Swern Oxidation = 0% TMS
PCC = 0%

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

HO O HO O
O O
H H

O TPAP / NMO, O
OH DCM, 4Åms OH
O O
61%

O O

OH O

• lactols can be oxidised selectively (again sterics)

O O
CO2Me CO2Me
OHO OHO
O O O O
TPAP / NMO,
O OH O O
O MeCN, 4Åms O
OH OH
AcO OH
75% AcO OH
MeO 2C H MeO 2C H
O O

• again we see how • TPAP oxidises sulfur but not other heteroatoms
mild TPAP is
SMe SO2 Me

TPAP / NMO,
MeCN, 4Åms
O O
80%
O O

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

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 • Sequential reactions – due to ease of w/u and anhydrous conditions, TPAP is well suited
to sequential reactions
CO2Me CO2Me CO2Me
Ph3P=CMeCO2tBu
TPAP / NMO,
CO2tBu
OH DCM, 4Åms O 72% overall

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

O

O
O O
HO TPAP,
NaOCl O
OH
O 93%

O
• Disadvantages: can cause retro-aldol reaction

OH O O O
TPAP / O O
O NMO, O
O O
DCM,
H H
4Åms

• retro-aldol results in
cleavage of β-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

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 Modified Chromium (VI) Oxidants
Pyridinium Chlorochromate PCC

Reagent:

ClCrO3
NH

Transformation:
C–OH → C=O (primary or secondary alcohols)

General Mechanism

O OH
H O
O O Cr O O
Cr O O
Cr ≡ CrO2 + H 2O
H Cl R H HO OH
R O H
H R
H

Use in Synthesis

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

OH OH
PCC, 4Åms,
DCM 93%
H H
OH O

• Disadvantages: reagent is acidic

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

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 Pyridinium Dichromate PDC
Reagent:

2–
Cr2O7
NH

Transformation:
C–OH → 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 O
O O
92%

PDC, DMF
83% CO2Me
OH

Oxidation to the Acid

O O

R H R 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,
O NaH2PO4 OH O Cl O
ClO2 HO HOCl
O
R H R H R H R 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

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 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)

Ph Ts R
OH OH O N
+ + + Ru
Un R Un R N
Ph H

O OH OH Un = unsaturated group
+ + Yield = 43-51 %
Un R Un R e.e. = > 90 %

• note you can not get better than 50% with kinetic resolution
Mechanism
Un
Un
O
R H Ru Un H Ru
R H
Ru H NTs
O N O H N NTs
N NTs
H R H
H
Ph
Ph Ph Ph Ph
Ph O

OH
O

Un R

Ru H Ru
H
H NTs
O N O H N NTs

H H
Ph Ph Ph
Ph

• More appealing is the desymmetrisation of meso-diols

• Theoretical maximum yield is 100 %
OH OH
H H

70 %
96 % e.e.
H H
OH 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

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