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Functional Group Interconversions Alcohols & The Carbonyl Group
Functional Group Interconversions Alcohols & The Carbonyl Group
Functional Group Interconversions Alcohols & The Carbonyl Group
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... fragmentation common
to most oxidations (as
Chromium (VI) Oxidants you shall see)
• 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
O H2O OH Cr O
O O Cr OH
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
R H R H R R1 R R1
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
• 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
HO OH NaIO4 O O
R R1 R R1
O O
I proton transfer
O O
O OH O
O O O
O I proton transfer I
O OH O O
R R1 R R1
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 Lithium Aluminium Hydride (LiAlH4 or LAH)
carbonyl
H3Al Li H3Al Al
Li O
H3Al O O O
H R R H R
R δ+ R
1
group 3 so H
R1
H
R1 R1
Lewis acid 4
number of repetitions
depends on sterics of the
carbonyl
• Each addition is slower
• Alkoxide electron-withdrawing group so reduces reactivity of hydride
H 3B H R R
O H OEt OH EtOBH3
O R1 R1
H Et
NaBH4 vs LiAlH4
NaBH4
O O O O O
R H
> R R1
> R OR1
> R NR1 2
> 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 intramolecular
activates hydride R delivery
R AlR2
O Al O H OH
O H
Al R1
R R1 R H R
H R R1 R1
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 O O O O
R H R R1 R OR1 R NR1 2 R OH
LiAlH4
✓ ✓ ✓ ✓ ✗ /✓
NaBH4
✓ ✓ ✗ ✗ ✗
BH3
✗ /✓ ✗ /✓ ✗ /✓ ✓ ✓
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.
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
H2O, H
• Reversibility of reaction useful as it means acetals can used as carbonyl protecting group
O O OMe O OMe OH O OH
MeOH R-MgBr H2O
H MeO R H R
OMe MeO OMe R R
R OMe H R OMe
Mechanism
H OH H
O H OH
O
O O
H Me Me
O Me
protonation increases polarisation of
hemiacetal
H
carbonyl considerably
provides another resonance form
OMe H Me OH2
MeO OMe O
O
Me O
Me
acetal O Me
H water a good leaving
group (stable, a lot of it
Nitrogen Nucleophiles about)
O R R H
RNH2 N N
+
Mechanism
proton transfer
O HNRR' O NHRR' H2O NRR'
loss of proton to
neutralise charge
R R' R R'
N N
base
H
enamine iminium