chemistry

1. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
1
OXIDATION AND REDUCTION
R R'
R R'
OH
R R'
O
R OR"
O
R O
O
R'
R R'
OH
Nuc
R R'
Cl
R R'
R" R"'
R
R"
O
R R'
N
R"
R
R"
O
E
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

2. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
2
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 R1
OH
R R1
O
R OH
O
R1
= H
• 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...
Chromium (VI) Oxidants
General Mechanism
RHO
H
O Cr O
O
OH2
RO
Cr
O H
HO
O
H
O
Cr
O O
O
Cr
HO OH
O R
–H2O
proton
transfer
Cr(VI) Cr(IV)
• This fragmentation mechanism is common to most oxidations regardless of the nature of the
reagent
"Overoxidation" formation of carboxylic acids
• Invariably achieved in the prescence of H2O and proceeds via the hydrate
R H
O OH
OH
R
H
O
Cr
O O
O
OH
R
H
Cr
O
O
OH
R OH
OH2O
Jones Oxidation
H2SO4, CrO3, acetone
R H
OH
R OH
O
R R1
OH
R R1
O
• Harsh, acidic conditions limit use of this method
E
[O]
H
HO R
H
O R
[O]
E
O R
[R]
EH
General Fragmentation Mechanism

3. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
3
Pyridinium Chlorochromate (PCC)
Cl
Cr
O
O
O
N
H
R H
OH
R H
O
R R1
OH
R R1
O
must avoid
water
• Less acidic than Jones reagent (although still acidic)
Pyridinium Dichromate (PDC)
O Cr
O
O
O Cr
O
O
O
N
H 2
• Even milder than PCC and has useful selectivity
R H
O
PDC
DMF
PDC
DCM R H
OH
R OH
O
Other Oxidants
Manganese Dioxide
MnO2
• Mild reagent
• Very selective – only oxidises allylic, benzylic or propargylic alcohols
HO
OH
HO
O
MnO2
only oxidises
activated alcohol

4. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
4
ALCOHOL OXIDATION
Activated DMSO
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 O
S
Hbase
R O
S
R H
O
S +
H H
H H
• intermediate common to all
activated DMSO reactions
• 18
O labelling has determined mechanism
• alternative activation of hydroxyl followed by
displacement not occurring
Common Side-Reactions
Pummerer Reaction
R O
S
R O + S R O S
Displacement Reactions
• The cationic intermediate formed is an excellent leaving group
Intramolecular
H
CH2OH
CH2OH
DMSO /
(COCl)2 93%
H
OH
O
S
H
O
Intermolecular
CH2OH
OBn
DMSO /
(COCl)2 95%
CH2Cl
OBn

5. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
5
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
OO
TBSO
OMe
OP
SO2Ph
OH
1. DMSO /
(COCl)2
2. Et3N
OO
TBSO
OMe
OP
OO
TBSO
OMe
OP
SO2Ph
O
+
O
67 % 28%
OH
HO
1. DMSO /
(COCl)2
2. Et3N
72%
O
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
O
O
OH
OH
DMSO / DCC
TFA / Pyr
88 %
O
O
O
Swern (DMSO / (COCl)2)
• Most popular, as mild and easy
Pros: low temperature reduces enolisation
very little Pummerer reaction
Cons: Chlorination
S
Cl
Parikh-Doering (DMSO / Pyr–SO3)
Pros: very mild conditions, very little enolisation
very little Pummerer Reaction
TBSO O
O
TBSO
Ph
CH2OH
TBSO O
O
TBSO
Ph
CHO
DMSO / Pyr–SO3
Et3N 94%
• active intermediate
of Swern reaction

6. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
6
Activated DMSO Oxidations in Synthesis
O
O
OTIPS
HO
1. DMSO /
(COCl)2
2. Et3N
92 %
O
O
OTIPS
O
• 1,2-diols are not cleaved
HO
HO
1. DMSO /
(CF3CO)2O
2. Et3N
90 %
O
O
• sequential reactions possible due to the high yields and purity of products
especially useful when aldehyde readily forms hydrate
Me3Si OH
Me3Si O
H
Me3Si
CO2Et
1. DMSO /
(COCl)2
2. Et3N
Ph3P=CMeCO2Et
54% overall
• tertiary alcohols often do not need to be protected
OMe
OMe
OMe OH
OH
H
OH
1. DMSO /
(COCl)2
2. Et3N
81%
OMe
OMe
OMe O
O
H
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 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
N
Me
H
MeO
O
O
OH
OH
DMSO /
(CF3CO)2O
N
Me
H
MeO
O
O
O
O
S
S
N
Me
H
MeO
O
O
OCOCF3
O
S
N
MeH
MeO
O
OH
O
O
Et3N
OCOCF3
(±)-tazettine
61 %
• the activity of allylic and
benzylic alcohols means they
undergo rapid displacement
and hence a form of protection

7. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
7
• lactol or lactone formation can be surpressed
• most oxidising agents oxidise primary alcohols faster
than secondary and this can lead to problems
OH OH [O] OH O
O
OH
O
O
[O]
• activated DMSO does not have this problem as aldehyde only formed on addition of base
OH OH
DMSO /
(COCl)2
O O
S S O OEt3N
• 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
OTES
O
OTES
1. DMSO /
(COCl)2
2. Et3N
62 %
O
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

8. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
8
Dess-Martin Periodinane (DMP)
(1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one)
Reagent:
Transformation:
C–OH → C=O (primary or secondary alcohols)
O
I
O
OAcAcO
OAc
General mechanism
O
I
O
OAc
AcO
OAc R
OH
H
H
O
I
O
O
O
H
OAcO
R
H
O
I
O
OAc
R H
O
2 x AcOH
• ligand exchange
• could be intra or
intermolecular
• 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
O
H
H
DEIPSO
TBSO
H
O
O
O
O
O
OTES
OTES
TESO
O O
OTES
H
MeO
Si
tBu
tBuH
93 %
Preparation
I
CO2H
+ KBrO3
0.73 M H2SO4
65˚C
O
I
O
OH
O
O
I
O
OAcAcO
OAc
AcOH
• mild and extremely reactive oxidant
• Insoluble in most organic solvents
and impact sensitive

9. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
9
Use in Synthesis
Selectivity
• first step is ligand exchange so an inherent steric selectivity exists
• primary alcohols oxidised faster than secondary
HO
O
O
OTBS
TBSO OTBS
HO
OTBSOMe
O
O
O
OTBS
TBSO OTBS
HO
OTBSOMe
DMP, pyr,
DCM,
88%
• Allylic and benzylic alcohols react ≥~5 faster than saturated alcohols
OO
H
HO
OH
DMP, pyr,
DCM, rt 2hrs
>75%
OO
H
HO
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

10. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
10
O
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
Ru
OO
O
R
OH
H
H
R
O
H
H
Ru
O
O
HO O
R H
O O
Ru
O
O
H
OH2
O
Ru
O
O
N O
O
N O
ORu
O
O
O O
Ru
OO
O
O
N
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
OH
O OO
O
OPMB
TPAP / NMO,
DCM, 4Åms
96%
O
O
O OO
O
OPMB
H2O

11. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
11
OH
• selectivity for primary hydroxyl group allows lactone preparation
O
OH
OH
TPAP / NMO,
DCM / MeCN,
4Åms 91%
O
OH
O
O
O O
TPAP
• secondary alcohols oxidise far slower but they do oxidise
N
O
TMS
TPAP / NMO,
DCM, 4Åms,
73%
N
O
TMS
OH O
Swern Oxidation = 0%
PCC = 0%
• depending on sterics can get selectivity for least hindered hydroxyl group
O
O
HO
O
OH
H
O
O
OH
O
O
HO
O
O
H
O
O
OH
TPAP / NMO,
DCM, 4Åms
61%
O
O
O
AcO
MeO2C H
OH
O OH
CO2Me
O
O
OH
O
• lactols can be oxidised selectively (again sterics)
TPAP / NMO,
MeCN, 4Åms
75% OH
O
O
O
AcO
MeO2C H
OH
O OH
CO2Me
O
O
O
O
• TPAP oxidises sulfur but not other heteroatoms
SMe
O
O
TPAP / NMO,
MeCN, 4Åms
80%
SO2Me
O
O
• again we see how
mild TPAP is

12. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
12
• Sequential reactions – due to ease of w/u and anhydrous conditions, TPAP is well suited
to sequential reactions
OH
CO2Me
O
CO2Me CO2Me
CO2tBu
TPAP / NMO,
DCM, 4Åms
Ph3P=CMeCO2tBu
72% overall
• Disadvantages: TPAP can cleave 1,2-diols like other metal oxidants
O
O
HO
OH
O
O
TPAP,
NaOCl
93%
O
O
O
• Disadvantages: can cause retro-aldol reaction
TPAP /
NMO,
DCM,
4Åms
O
O
H
OOH
O
O
H
OO
O O
• 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

13. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
13
Modified Chromium (VI) Oxidants
Pyridinium Chlorochromate PCC
Reagent:
Transformation:
C–OH → C=O (primary or secondary alcohols)
NH
ClCrO3
General Mechanism
O
R
H
H
H O
Cr
O
O
Cl
O
R
H
H
Cr
O
OHO
R H
O
HO
Cr
OH
O
≡ CrO2 + H2O
Use in Synthesis
• Must be dry, water hampers reaction and can result in the formation of acids (over-oxidation)
OH
OH
H
PCC, 4Åms,
DCM 93%
O
OH
H
• Disadvantages: reagent is acidic

14. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
14
Pyridinium Dichromate PDC
Reagent:
Transformation:
C–OH → C=O (primary or secondary alcohols)
NH
Cr2O7
2–
Use in Synthesis
• Neutral variant of PCC
• Addition of SiO2 to reaction aids work up and addition of pyridinium trifluroracetate increases rate
• DCM normal solvent
• DMF gives carboxylic acids
O
OH PDC, DCM
92%
O
O
OH
PDC, DMF
83% CO2Me
Oxidation to the Acid
R
O
H R
O
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:
R
O
H R
OH
H
NaClO2,
NaH2PO4
ClO2
R H
HO
O
ClO
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

15. Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
15
Ru
NTs
Ru
N
PhPh
R
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)
Un R
OH
+
Un R
OH
+
O
N
H
Ru
Ts
N
Ph
Ph
+
Un R
O
+
Un R
OH
+
OH
Yield = 43-51 %
e.e. = > 90 %
Un = unsaturated group
• note you can not get better than 50% with kinetic resolution
Un
R
O
H
H
O
H
N
H
NTs
Ph
Ph
H
Un
R
NTs
Ru
N
PhPh
HO
Un
R
NTs
Ru
N
PhPh
HO
H
H
H
H
Ru
O
H
N
H
NTs
Ph
Ph
H
O
O
Un R
OH
Mechanism
• More appealing is the desymmetrisation of meso-diols
• Theoretical maximum yield is 100 %
OH
OH
H
H
70 %
96 % e.e.
OH
O
H
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