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 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)

Cr(VI) General Mechanism

Cr(IV)
O
OH2 proton O H
O H Cr
O Cr O
–H2O transfer HO OH
Cr Cr
O O R
O O O HO R HO
H
O R

• 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

• Harsh, acidic conditions limit use of this method

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 Pyridinium Chlorochromate (PCC)
Cl
must avoid
water Cr O
O N
O H
OH O OH O

R H R H R R1 R R1

• 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 OH O
PDC PDC
R H DCM R H DMF 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
OH O

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 O

2. Et3N

• Mild (especially with wide choice of reagents)

• Overoxidation never a problem
• 1,2-Diols are not cleaved (see below)

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis

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 Mechanism
O O Cl
O O S
Cl S Cl
S S Cl O
O O R O
Cl H

common intermediate to all

activated DMSO oxidations
O S
O
S
H R O R
H R
H base: 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
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

From Nicolaou's synthesis of amphoteronolide B

OH 1. (COCl)2, DMSO; then Et3N
BnO BnO CO2Me
O 2. Ph3P=CH2CO2Me 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 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

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis

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 • 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 LiAlH4 would
react with NaBH4 reduce both
O O OH O
still reducing agent
OR OR but alkoxide reduces
reactivity

H 3B H R R
O H OEt OH EtOBH3
O R1 R1
H Et

• 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 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

• Advantage of DIBAL is that reduction of esters can be stopped at alcohol or aldehyde

stable at low
temperature
AlR2
OH O O H O
2 x DIBAL 1 x DIBAL
R H R OR1 -78 ˚C R H R H
R1O

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis

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 From Corey's synthesis of the prostaglandins
O OH
OH
O O H
H H
1 x DIBAL CHO
-78 ˚C H
H H
RO R
RO R RO 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 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.

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 OMe O OMe OH O OH
MeOH R-MgBr H2O
H MeO R H R
OMe MeO OMe R R

aldehyde would be acetal inert

regenerate aldehyde
attacked by Grignard
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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
O O O

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
+

– H2O imine enamine

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

• 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

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis

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