Download OXIDATION AND REDUCTION

OXIDATION AND REDUCTION
O
Cl
R
R"
R
R'
R"
O
R
O
R'
R
E
OH
R
R"'
R'
O
O
R'
R
R'
O
R
R
R'
OH
R
R"
R"
R
R'
Nuc
R
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
• 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: [email protected]
Gareth Rowlands ([email protected]) 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)
R1 = H
OH
O
R1
R
O
R1
R
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
EH
H
E
[O]
HO
E
[O]
R
H
O
[R]
R
R
O
• 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
O
H
Cr
proton
transfer
H
O
–H2O
O HO
Cr(IV)
O
O
HO
R
Cr
O
H
Cr
HO
O
OH
R
R
O
"Overoxidation" formation of carboxylic acids
• Invariably achieved in the prescence of H2O and proceeds via the hydrate
O
O
R
OH
H2O
R
H
O
O
Cr
O
H
OH
R
O
Cr OH
O
O
R
H
OH
OH
Jones Oxidation
H2SO 4, CrO3, acetone
OH
R
O
H
R
OH
OH
R
O
R1
R
R1
• Harsh, acidic conditions limit use of this method
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
2
Pyridinium Chlorochromate (PCC)
Cl
must avoid
water
O
OH
R
Cr O
O
N
H
O
H
R
OH
H
O
R1
R
R1
R
• 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
R
PDC
DCM
H
OH
R
H
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
O
OH
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
3
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
O
+
X
S
+
O
HO
R
R
O
S
H
base
• intermediate common to all
activated DMSO reactions
• 18O labelling has determined mechanism
• alternative activation of hydroxyl followed by
displacement not occurring
O
S
H
H
+
R
H
R
O
O
S
S
Common Side-Reactions
Pummerer Reaction
R
O
S
R
+
O
R
S
Displacement Reactions
• The cationic intermediate formed is an excellent leaving group
Intramolecular
OH
CH2 OH
CH2 OH
DMSO /
(COCl)2 93%
H
O
O
S
H
H
Intermolecular
CH2 OH
CH2 Cl
OBn
DMSO /
(COCl)2 95%
OBn
Gareth Rowlands ([email protected]) 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.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
O
O
OMe
O
O
1. DMSO /
(COCl)2
2. Et3N
OP
TBSO
O
OH
SO2 Ph
O
+
OP
OP
O
TBSO
TBSO
67 %
O
SO2 Ph
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
O
OH
DMSO / DCC
TFA / Pyr
88 %
O
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
TBSO
Ph
O
TBSO
O
DMSO / Pyr–SO3
Et3N 94%
CH2 OH
TBSO
Ph
O
TBSO
CHO
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
5
Activated DMSO Oxidations in Synthesis
1. DMSO /
(COCl)2
2. Et3N
92 %
O
HO
O
O
O
O
OTIPS
OTIPS
• 1,2-diols are not cleaved
1. DMSO /
(CF3CO)2O
2. Et3N
90 %
HO
HO
O
O
• 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
O
Ph3P=CMeCO 2Et
54% overall
H
Me3 Si
CO2Et
• tertiary alcohols often do not need to be protected
OMe
H
OMe
OH
OH
OH
OMe OMe
H
1. DMSO /
(COCl)2
2. Et3N
81%
OMe OMe O
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 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
S
O
OH
OH
MeO
H
N
Me
O
DMSO /
(CF3CO)2O
O
MeO
N
Me
H
O
OCOCF3
OCOCF3
O
S
S
MeO
H
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 ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
6
• 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
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
O
Et3N
S
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
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 ([email protected]) 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-(1H)-one)
Reagent:
OAc
I OAc
AcO
O
O
Transformation:
C–OH → C=O (primary or secondary alcohols)
General mechanism
• ligand exchange
OH
OAc
AcO
I OAc
R
O
H
R
H
OAc
• could be intra or
intermolecular
H
I
O
O
AcO O
H
I
O
O
O
O
R
O
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
H
DEIPSO
OTES
O
O
O
H
TESO
H
TBSO
O
tBu
tBu
O
MeO
O
O
Si
O
93 %
OTES
OTES
H
Preparation
O
I
+ KBrO3
CO2H
I
0.73 M H2SO4
65˚C
AcO
OH
O
O
AcOH
OAc
I OAc
O
O
• mild and extremely reactive oxidant
• Insoluble in most organic solvents
and impact sensitive
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
8
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
O
O
O
H
H
DMP, pyr,
DCM, rt 2hrs
>75%
HO
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 ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
9
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
OH
R
O
HO
O
O
Ru
O
O
H
H
O
R
O
Ru
O
O
O
Ru
O
O
O
O
H
H2O
R
H
O
Ru
O
OH2
H
H
O
N
O
O
O
Ru O
O
N
O
Ru
O
O
O
N
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
O
O
O
OPMB
TPAP / NMO,
DCM, 4Åms
96%
O
O
OH
O
O
O
O
O
O
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
10
• selectivity for primary hydroxyl group allows lactone preparation
OH
O
TPAP / NMO,
DCM / MeCN,
4Åms 91%
OH
O
TPAP
OH
O
O
O
O
• secondary alcohols oxidise far slower but they do oxidise
TPAP / NMO,
DCM, 4Åms,
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
O
HO
O
O
H
TPAP / NMO,
DCM, 4Åms
61%
O
OH
O
O
H
O
OH
O
O
O
OH
O
• lactols can be oxidised selectively (again sterics)
O
O
CO2Me
OHO
O O
O O
O
AcO
MeO 2C
H
CO2Me
OHO
OH
O
OH
OH
TPAP / NMO,
MeCN, 4Åms
75%
AcO
MeO 2C
O
O
H
O
OH
OH
O
• TPAP oxidises sulfur but not other heteroatoms
• again we see how
mild TPAP is
SMe
O
SO2 Me
TPAP / NMO,
MeCN, 4Åms
80%
O
O
O
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
11
O
• Sequential reactions – due to ease of w/u and anhydrous conditions, TPAP is well suited
to sequential reactions
CO2Me
CO2Me
TPAP / NMO,
DCM, 4Åms
OH
CO2Me
Ph3P=CMeCO2tBu
O
CO2tBu
72% overall
• Disadvantages: TPAP can cleave 1,2-diols like other metal oxidants
O
O
HO
OH
O
O
O
TPAP,
NaOCl
93%
O
O
• Disadvantages: can cause retro-aldol reaction
OH
O
O
H
O
O
TPAP /
NMO,
DCM,
4Åms
O
O
O
O
O
H
• 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 ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
12
Modified Chromium (VI) Oxidants
Pyridinium Chlorochromate PCC
Reagent:
ClCrO3
NH
Transformation:
C–OH → C=O (primary or secondary alcohols)
General Mechanism
H
R
O
O
O
H
H
O
Cr
Cl
O
O
R
OH
Cr
O
O
R
H
O
H
HO
Cr
≡ CrO2 + H 2O
OH
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%
OH
H
O
H
• Disadvantages: reagent is acidic
Gareth Rowlands ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
13
Pyridinium Dichromate PDC
Reagent:
NH
Cr2O7
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%
OH
CO2Me
Oxidation to the Acid
O
R
O
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,
NaH2PO4
O
R
H
OH
HO
ClO2
R
H
R
O
Cl
O
HOCl
O
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 ([email protected]) 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
+
R
Un
O
+
R
Ph
OH
+
R
Un
R
Un = unsaturated group
Yield = 43-51 %
e.e. = > 90 %
OH
+
Un
Ts
N
Ru
N
H
Ph
O
R
• note you can not get better than 50% with kinetic resolution
Mechanism
Un
Un
O
R
H
H
R
Ru
N
O
NTs
H
Ru
H
Un
NTs
N
H
Ph
Ph
O
R
Ph
H Ru
H N
NTs
H
Ph
Ph
Ph
O
OH
O
Un
O
H
Ru
H
H Ru
NTs
N
R
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.
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 ([email protected]) Ar402, http://www.sussex.ac.uk/Users/kafj6, Reduction and Oxidation 2002
15