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)
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
R HO
H O Cr O
O OH2
R O 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
R OHH
O Cr
O O
O R OHH
Cr O
OOH
R OH O H2O
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
fragmentation common to most oxidations (as
you shall see)
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
NH 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
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
OH 1. Me2S(O), (COCl)2, DCM O
2. Et3N
DMSO activator
• Mild (especially with wide choice of reagents)
• Overoxidation never a problem
• 1,2-Diols are not cleaved (see below)
S O
S O
Cl Cl
O
O
S
O Cl
O O
S Cl
R O
H
S
O R
H S
O
H R
H
H R
O
Cl
base:
Mechanism
common intermediate to all activated DMSO oxidations
• 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
R
HO OH
R1
NaIO4
R O
R1 O
O I
O O O
R
O OH
R1 I O
O OHO
O I O
R R1 O
O O
proton transfer
proton transfer
BnO OH
O
1. (COCl)2, DMSO; then Et3N
2. Ph3P=CH2CO2Me BnO O CO2Me
From Nicolaou's synthesis of amphoteronolide B
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 Aluminium Hydride (LiAlH4 or LAH)
O R R1 H H3Al lithium activates
carbonyl
O R R1 H Al
4 number of repetitions
depends on sterics of the carbonyl
• Each addition is slower
R R1 O H3Al
H
Li O
R R1 H
Li H3Al
δ+ group 3 so Lewis acid
• 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
OR
O O
OR OH O only ketone will
react with NaBH4 LiAlH4 would reduce both
R R1
O H OEt H O
Et
H3B H R
R1
OH EtOBH3
• Not saying this is concerted (all occuring at once)
• Altering substituents on boron changes behaviour
• Add electron donating groups (alkyl) and increase the reactivity
still reducing agent but alkoxide reduces
reactivity
R H
O
R R1 O
R OR1 O
R NR12 O
R OH
> > > >
ONaBH4
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)
• NaBH4 & LiAlH4 = nucleophilic reducing agent (e– poor carbonyls)
R R1 O
Al
H R R1
O Al H R R
O H R R1
AlR2
R R1 H OH
coordination activates hydride
intramolecular delivery
• Advantage of DIBAL is that reduction of esters can be stopped at alcohol or aldehyde
R OR1 O
R H
OH 2 x DIBAL O
H RR1O
AlR2
R H
1 x DIBAL O
-78 ˚C
H stable at low
temperature
NaBH4 vs LiAlH4
H O
H R RO
O
1 x DIBAL -78 ˚C
H O
H R RO
OH OH
H
H R RO
CHO
From Corey's synthesis of the prostaglandins
Borane (BH3)
• Like DIBAL, borane is an electrophilic reducing agent (e– rich carbonyls first)
• As a result reactivity is complete reverse of LiAlH4 & NaBH4
R H
O
R R1 O
R OR1 O
R NR12 O
R OH O
✓ ✓ ✗ ✗ ✗
✗ / ✓
NaBH4 LiAlH4
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.
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
• Reversibility of reaction useful as it means acetals can used as carbonyl protecting group
O O
OMe
OMe O OMe MeO
OMe OH
MeO R
R
O OH R R
MeOH H
H2O, H
H2O H R-MgBr
Mechanism
O O H
O Me H
H OH
O H Me
OH
O Me
H
OH2
O Me O
Me
O Me H
OMe
MeO OMe
O H Me
hemiacetal
acetal
protonation increases polarisation of carbonyl considerably provides another resonance form
water a good leaving group (stable, a lot of it
about)
• It should be noted that if your compound is a diol it too can be protected as an acetal
R OMe
OH OH O
O
H R OMe
O O O
Nitrogen Nucleophiles
O R N
N
R H
+
imine enamine
RNH2
– H2O
Mechanism
O O NHRR' H2O NRR'
N R R'
base H N
R R'
iminium enamine
HNRR'
• 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
proton transfer
loss of proton to neutralise charge
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
