R R'
R
Cl
R'
R
O
E
R"
R
O
O
R'
R" R"'
R R'
R
OH
R'
O
R R'
O
R OR"
O
R"
OH R"
N
R R R'
Nuc R R'
• 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
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
1

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)
R
1
= H
OH O O
R R
1
R R
1
R OH
• Primary (R
1
= 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
E
[O]
HO
H
R
E
[O]
O
H
R
EH
[R]
O R
• This fragmentation mechanism is common to most oxidations regardless of the nature of the reagent
Cr(VI)
Chromium (VI) Oxidants
General Mechanism
OH
2
O Cr O
O
H
–H
2
O
O
O
Cr
O HO
H
R proton transfer
O
O
HO
Cr
O
H
R
Cr(IV)
HO
O
Cr
OH
O R
R
O
H
"Overoxidation" formation of carboxylic acids
• Invariably achieved in the prescence of H
2
O and proceeds via the hydrate
H
2
O
OH
R
OH
H
OH
O
O
Cr
O
R
O
O
Cr
O
OH
H
OH
Jones Oxidation
H
2
SO
4
, CrO
3
, acetone
O OH O
R
O
OH
R H R OH R R
1
• Harsh, acidic conditions limit use of this method
R R
1
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
2

R must avoid water
R
OH
Pyridinium Chlorochromate (PCC)
O
Cl
Cr
O
O
N
H
O OH
H R H R R
1
• Less acidic than Jones reagent (although still acidic)
R
O
R
1
O
H
Pyridinium Dichromate (PDC)
O O
O Cr O Cr O
O O
N
H
2
• Even milder than PCC and has useful selectivity
OH
PDC
DCM
R H
PDC
DMF
R
O
OH
Other Oxidants
Manganese Dioxide
MnO
2
• Mild reagent
• Very selective – only oxidises allylic, benzylic or propargylic alcohols
HO HO
MnO
2 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
3

Reagent:
DMSO, activator (X) and base
Transformation:
C–OH
→
C=O (primary or secondary alcohols)
General Mechanism
S O
+ X
S O
X
+
HO R
R
H H
O
S base
H
•
18
O labelling has determined mechanism
• intermediate common to all activated DMSO reactions
• alternative activation of hydroxyl followed by displacement not occurring
O
S
+
R H
Common Side-Reactions
Pummerer Reaction
R O
S
R O
+
S
R
H H
O
S
R O S
Displacement Reactions
• The cationic intermediate formed is an excellent leaving group
Intramolecular
H
CH
2
OH
CH
2
OH
DMSO /
(COCl)
2
93%
OH
H
Intermolecular
CH
2
OH
OBn
DMSO /
(COCl)
2
95%
O
S
CH
2
Cl
OBn
H
O
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
4

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.SO
3 system
Eliminations
• Problem due to mild acidity of earlier steps
• or if suitable leaving group present when base added
OMe
HO
OH
1. DMSO /
(COCl)
2
2. Et
3
N
72%
OMe
O
OMe
O
TBSO
O
SO
2
Ph
OH
OP
O O
1. DMSO /
(COCl)
2
2. Et
3
N
OP
TBSO
O
67 %
Pfitzner-Moffatt (DMSO / DCC then base)
+
O
TBSO
O
SO
2
Ph
O
28%
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
O
OH
DMSO / DCC
TFA / Pyr
88 %
O
O
• active intermediate of Swern reaction
Swern (DMSO / (COCl)
2
)
Cl
S
• Most popular, as mild and easy
Pros: low temperature reduces enolisation
very little Pummerer reaction
Cons: Chlorination
Parikh-Doering (DMSO / Pyr–SO
3
)
Pros: very mild conditions, very little enolisation
very little Pummerer Reaction
O Ph O Ph
TBSO O
DMSO / Pyr–SO
3
Et
3
N 94%
TBSO O
TBSO CH
2
OH
TBSO CHO
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
5
OP

Me
3
Si
HO
O
O
1. DMSO /
(COCl)
2
2. Et
3
N
92 %
O
O
O
OTIPS OTIPS
• 1,2-diols are not cleaved
HO
HO
1. DMSO /
(CF
3
CO)
2
O
2. Et
3
N
90 %
O
O
• sequential reactions possible due to the high yields and purity of products especially useful when aldehyde readily forms hydrate
Me
3
Si O
OH
1. DMSO /
(COCl)
2
2. Et
3
N
H
Ph
3
P=CMeCO
54% overall
2
Et
Me
3
Si
• tertiary alcohols often do not need to be protected
OMe OMe
H H
OMe OMe OH
OH
OH
1. DMSO /
(COCl)
2
2. Et
3
N
81%
OMe OMe O
OH
O
CO
2
Et
O
O
• selective oxidations – primary alcohols oxidised much faster
• but use of i Pr
2
S 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
S
O
O
OCOCF
3
OH
OH
DMSO /
(CF
3
CO)
2
O
O
S
O
O
S
OCOCF
3
MeO
H
N
Me
MeO
H
N
Me
MeO
O
H
N
Me
Et
3
N
• the activity of allylic and benzylic alcohols means they undergo rapid displacement and hence a form of protection
(±)-tazettine
61 %
O
O
OH
MeO
N
Me
H
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
6

OH OH
• 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 O
O
[O]
O
O
• activated DMSO does not have this problem as aldehyde only formed on addition of base
OH OH
DMSO /
(COCl)
2
O
S
O
S Et
3
N O O
• 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
O
OTES
1. DMSO /
(COCl)
2
2. Et
3
N
62 %
O
O
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
7

Dess-Martin Periodinane (DMP)
(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1 H )-one)
Reagent:
AcO
OAc
I
OAc
O
• ligand exchange
O
Transformation:
C–OH
→
C=O (primary or secondary alcohols)
General mechanism
• could be intra or intermolecular
AcO
I
OAc
OAc
O
R
OH
H
H
R
H
H
O
AcO
O
I
O
O
O
O
I
OAc
O
R
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 NaHCO
3
if worried about AcOH)
• many very sensitive molecules can be oxidised
I
CO
2
H
+
TBSO
DEIPSO
93 %
H
H
O
O
O
H
O
O
H
TESO
OTES
OTES
O
O
O
Si t Bu
MeO
O t Bu
OTES
H
Preparation
KBrO
3
0.73 M H
65˚C
2
SO
4
O
I
O
OH
AcOH
O
• mild and extremely reactive oxidant
• Insoluble in most organic solvents and impact sensitive
AcO
I
OAc
OAc
O
O
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
8

HO
TBSO
Selectivity
• first step is ligand exchange so an inherent steric selectivity exists
• primary alcohols oxidised faster than secondary
OTBS
HO
O
OTBS OMe
O
OTBS
DMP, pyr,
DCM,
88%
HO
O
O
O
TBSO OTBS OMe OTBS
OTBS
• Allylic and benzylic alcohols react
≥
~5 faster than saturated alcohols
O O
H
O O
H
HO
DMP, pyr,
DCM, rt 2hrs
>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
9

Reagent:
Pr
4
N
+
RuO
4
–
Stoichiometric or catalytic with NMO
Transformation:
C–OH
→
C=O (primary or secondary alcohols)
C–OH
→
CO
2
H (if H
2
O 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
R
OH
H
H
O
O
O
Ru
O
R
HO
O
O
O
Ru
O
H
H H
2
O
R
O
H
O O
Ru
O H
OH
2
O O
Ru
O
O
N O
O
O
Ru O
O N O
O
O
O
Ru
O
N
• 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 H
2
O
O advantages:
• good functional group tolerance
• no epimerisation of
α
-chiral centres or double bond isomerisation
• no competative
β
-elimination
O O
OPMB
O
O
OH
TPAP / NMO,
DCM, 4Åms
96%
O O
OPMB
O
O
O
O O
Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
10

O
OH
• selectivity for primary hydroxyl group allows lactone preparation
O
OH
TPAP / NMO,
DCM / MeCN,
4Åms 91%
OH
TPAP
O
O
• secondary alcohols oxidise far slower but they do oxidise
O
O
O
N
OH
TMS
• depending on sterics can get selectivity for least hindered hydroxyl group
HO O HO O
O O
H
OH
O
O
TPAP / NMO,
DCM, 4Åms
61%
OH
O
O
O O
OH O
O
AcO
MeO
2
C
O
O
H
O
CO
2
Me
OH
O
• lactols can be oxidised selectively (again sterics)
O
O
O
CO
2
Me
OH
O
OH
O
O
OH
OH
TPAP / NMO,
MeCN, 4Åms
75%
AcO
MeO
2
C
H
O
OH
O
O
OH
• again we see how mild TPAP is
• TPAP oxidises sulfur but not other heteroatoms
SMe SO
2
Me
H
O
O
O
TPAP / NMO,
DCM, 4Åms,
73%
Swern Oxidation = 0%
PCC = 0%
O
N
O
TMS
TPAP / NMO,
MeCN, 4Åms
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
CO
2
Me CO
2
Me CO
2
Me
OH
TPAP / NMO,
DCM, 4Åms
O
Ph
3
P=CMeCO
2 t Bu
72% overall
CO
2 t Bu
O
• Disadvantages: TPAP can cleave 1,2-diols like other metal oxidants
O
OH O
O
H
O
HO
OH
O
TPAP,
NaOCl
93%
O O
O
O
O
• Disadvantages: can cause retro-aldol reaction
O
TPAP /
NMO,
DCM,
4Åms
O
O
H
• retro-aldol results in cleavage of
β
-hydroxyketones
O O
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

Reagent:
NH
ClCrO
3
Transformation:
C–OH
→
C=O (primary or secondary alcohols)
H
O
R
H
H
O
Cr
O
O
Cl
General Mechanism
R
O
O
Cr
OH
O
H
H
R
O
H
O
HO
Cr
OH
≡
CrO
2
+ H
2
O
Use in Synthesis
• Must be dry, water hampers reaction and can result in the formation of acids (over-oxidation)
OH
OH
H
OH
PCC, 4Åms,
DCM 93%
O
H
• 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
Cr
2
O
7
2–
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
O
PDC, DCM
92%
O
O
PDC, DMF
83%
CO
2
Me
OH
O O
R
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:
O
H
NaClO
NaH
2
2
,
PO
4
R
OH
H
ClO
2
HO
R
O
H
Cl
O
R
O
OH
HOCl
• 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

• Noyori has developed a method for resolving racemic alcohols via selective oxidation
• Uses hydrogen transfer (analgous to Oppenauer oxidation or Meerwein-Ponndorf-Verley reduction )
Un
OH
R
+
Un
OH
R
+
O
+
Ph
Ph
N
H
Ts
N
Ru
R
Un
O
+
OH
+
OH
Un = unsaturated group
Yield = 43-51 % e.e. = > 90 %
R Un R
• note you can not get better than 50% with kinetic resolution
Mechanism
Un
R
O
H
H
N
Ru
NTs
Ph Ph
R
O
Un
H
H
N
Ru
NTs
H
Ph
Ph O
Un
R
O H
H
N
Ru
H
Ph
NTs
Ph
OH
O
Un R
O
H
H
N
Ru
NTs
H
Ph
Ph
O H
H
H
N
Ru
Ph
NTs
Ph
• More appealing is the desymmetrisation of meso -diols
• Theoretical maximum yield is 100 %
OH
H
OH
H
70 %
96 % e.e.
OH
H
O
H
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