FUNCTIONAL GROUP INTERCONVERSIONS
ALCOHOLS & THE CARBONYL GROUP
INTRODUCTION
• So far we have discussed methods for the formation of the carbon skeleton
• In a large number of these reactions we found that either the starting material or the product
contained an alcohol or a carbonyl group
• Due to the importance of these two groups we will take a very brief look at them both
ALCOHOL OXIDATION
• Alcohols can readily be oxidised to the carbonyl moiety
• This is an incredibly important reaction as we have seen 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...
fragmentation common
Cr(VI)
OH2
O
Cr O
O
to most oxidations (as
you shall see)
Chromium (VI) Oxidants
General Mechanism
H
O
–H2O
O
H
Cr
proton
transfer
O HO
Cr(IV)
O
O
HO
R
Cr
O
H
Cr
HO
O
OH
R
R
O
• 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
O
O
R
OH
H2O
R
H
O
O
Cr
O
H
OH
R
O
Cr OH
O
O
R
H
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
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OH
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
OH
PDC
DCM
H
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
Activated Dimethylsulfoxide (DMSO) Oxidations
DMSO, activator & base
• Possibly the most widely used group of oxidants
• Huge number of variants depending on the nature of the activator or the base
• The most common is the Swern Oxidation
activator
DMSO
OH
1. Me2S(O), (COCl)2, DCM
2. Et3N
O
• Mild (especially with wide choice of reagents)
• Overoxidation never a problem
• 1,2-Diols are not cleaved (see below)
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Mechanism
O
O
O
S
S
Cl
Cl
S
O
common intermediate to all
activated DMSO oxidations
Cl
O
O
R
O
Cl
S
O
H
S
Cl
R
H
O
H
O
S
R
base:
H
O
R
H
• Please note the similarity between this mechanism and the Cr(VI) mechanism
Cleavage of 1,2-Diols
• Many metal based oxidising agents will cleave 1,2-diols
• This can be synthetically useful reaction
• When it is desired NaIO4 or Pb(OAc)4 normally used
O
HO
OH
R
R1
O
O
R1
R
O
proton transfer
I
O
NaIO4
O
O OH
O
O I
O
OH
R
O
proton transfer
O
R1
R
From Nicolaou's synthesis of amphoteronolide B
OH
1. (COCl)2, DMSO; then Et3N
BnO
2. Ph3P=CH2CO2Me
O
BnO
O
I
O
O
R1
CO2Me
O
CARBONYL REDUCTION
• Alcohols prevalent throughout pharmacologically interesting molecules
• A versatile method of introducing them is via carbonyl reduction
• Again not going into great detail just give you an overview of some of the more common
lithium activates
carbonyl
H3Al
H
O
R
Li
1
δ+ R
Lithium Aluminium Hydride (LiAlH4 or LAH)
H3Al
group 3 so
Lewis acid
O
H
Li
H3Al
R
H
R1
Al
O
O
R
R1
H
number of repetitions
depends on sterics of the
carbonyl
• Each addition is slower
• Alkoxide electron-withdrawing group so reduces reactivity of hydride
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R
R1
4
• Reduces most carbonyl functionality
• Little or no selectivity
• By altering the substituents on aluminium the reactivity can be tuned
• Bulky and electron withdrawing groups (alkoxides) reduce activity and make reagent more
selective
Sodium Borohydride (NaBH4)
• Considerably milder than LiAlH4
• Selectively reduces aldehydes and ketones in the presence of esters
only ketone will
react with NaBH4
O
LiAlH4 would
reduce both
OH
O
O
H 3B
H
R
Et
R1
R
O
H
O
still reducing agent
but alkoxide reduces
reactivity
OR
OR
H OEt
EtOBH3
OH
R1
• Not saying this is concerted (all occuring at once)
• Altering substituents on boron changes behaviour
• Add electron donating groups (alkyl) and increase the reactivity
NaBH4 vs LiAlH4
NaBH4
O
R
H
>
O
R1
R
O
>
R
OR1
>
O
>
NR1 2
R
O
R
OH
LiAlH4
Diisobutylaluminium hydride (DIBAL)
• A good, strong reducing agent
• Different mechanism to the two previous metal-hydrides
• Aluminium centre is a Lewis acid and needs to coordinate to a Lewis base to activate hydride
• DIBAL = electrophilic reducing agent (e– rich carbonyls)
• NaBH 4 & LiAlH 4 = nucleophilic reducing agent (e– poor carbonyls)
coordination
activates hydride
O
R
R1
O
Al
R
Al
intramolecular
delivery
R
O
R
R1
R1
OH
H
H
R
H
AlR2
R1
R
H
• Advantage of DIBAL is that reduction of esters can be stopped at alcohol or aldehyde
stable at low
temperature
OH
R
O
2 x DIBAL
H
R
OR1
1 x DIBAL
-78 ˚C
O
R
R1O
AlR2
O
H
H
R
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H
From Corey's synthesis of the prostaglandins
O
H
OH
O
H
RO
H
1 x DIBAL
-78 ˚C
O
H
OH
CHO
H
H
R
RO
RO
R
R
Borane (BH3)
• Like DIBAL, borane is an electrophilic reducing agent (e– rich carbonyls first)
• As a result reactivity is complete reverse of LiAlH 4 & NaBH4
O
R
LiAlH4
NaBH4
BH3
O
H
✓
✓
✗ /✓
R1
R
O
O
R
✓
✓
✗ /✓
OR1
R
✓
✗
✗ /✓
O
NR1 2
R
OH
✗ /✓
✗
✓
✓
✗
✓
Oxidation and Reduction
• The importance of these two operations is highlighted by the vast number of methods for
excuting both. You need to be aware that there are many examples reagents and catalysts that
can perform both diastereo and enantioselective reductions. There are also a number of
reagents that can perform selective oxidations via either kinetic resolution or
desymmetrisations.
FUNCTIONAL GROUP INTERCONVERSION: ACETAL FORMATION
• Last transformation for todays lecture combines alcohol and aldehyde / ketone
• You should have already met this...
Oxygen nucleophilies
• Add to carbonyls BUT they are also good leaving groups so reaction reversible
• Normally use large excess of nucleophile to drive reaction to completion
• Can stop at half way stage to form hemiacetals
O
MeOH, H
MeO
OMe
H2O, H
• Reversibility of reaction useful as it means acetals can used as carbonyl protecting group
O
O
MeOH
H
OMe
aldehyde would be
attacked by Grignard
OMe O
MeO
OMe OH
R-MgBr
MeO
OMe
acetal inert
R
R
H2O
H
O
OH
R
R
regenerate aldehyde
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• It should be noted that if your compound is a diol it too can be protected as an acetal
O
OH
OH
O
R
O
OMe
H
O
R
OMe
Mechanism
H
O
O
O
Me
H
O
Me
O
OH2
O
O
acetal
O
water a good leaving
group (stable, a lot of it
about)
Nitrogen Nucleophiles
R
– H2O
R
N
Me
Me
H
RNH2
Me
hemiacetal
Me
O
OH
Me
protonation increases polarisation of
carbonyl considerably
provides another resonance form
OMe H
O
OMe
H
OH
H
H
MeO
O
+
imine
N
H
enamine
Mechanism
proton transfer
O
HNRR'
O
NHRR'
H2O
NRR'
loss of proton to
neutralise charge
R
N
R'
R
base
enamine
N
R'
H
iminium
• Primary amines generally give imines
• Secondary amines generally give neutral enamines via the charged iminum species
• You have seen the use of enamines as enolate equivalents already
What have we learnt?
• A number of selective reagents for both oxidation and reduction
• Acetal formation is reversible
• As a result acetals make good protecting groups
• O, N and S nucelophiles can be used to form acetals
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