Synthesis of Aldehydes and

Ketones

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Aldehydes can be prepared
by reduction.
• This would be desirable to do:
O O
[H]
R C Cl R C H

[H] represents any general reduction

• The problem is, how to stop the reduction at

the aldehyde state, without reducing all the
way to a primary alcohol?
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 Rosenmund Reduction
O O
Pd/BaSO4
R C Cl + H2 R C H
sulfur
quinoline

The catalyst is selectively poisoned.

The reaction generally goes in very good yield.
Quinoline is:

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 Example

O H2 O
Pd
CH3 CH2 C Cl CH3 CH2 C H
sulfur
boiling quinoline

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Another, similar, method
uses a new reagent:
CH3

CH3 C CH3

CH3 O

CH3 C O Al H

CH3 O
Lithium Tri-tert-butoxy-
aluminum Hydride
CH3 C CH3

CH3

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•The tert-butyl groups provide steric
hindrance.

•This diminishes the ability of the reagent

to act as a hydride donor (as compared
with LiAlH4).

•Also, there is only one reducing

hydrogen per molecule of this reagent.

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 Example

O O

C Cl C H
LiAlH[O-tert-Butyl]3

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 Reduction of Esters
to Aldehydes

An ester is reduced by lithium aluminum

hydride to yield two different alcohols:

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 O
LiAlH4 H2O
CH C O CH3
ether H+
CH3

acyl part alkyl part

CH CH2 OH + CH3 OH

CH3

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• The lithium aluminum hydride reduces the
acyl part of the ester to a primary alcohol.

• The alkyl part of the ester simply drops off

as a second alcohol -- it is not reduced in
this reaction.

• You would generally do this reaction to

prepare the primary alcohol deriving from
the acyl portion of the ester.

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• Lithium aluminum hydride is such a
powerful reducing agent that it reduces
the ester through two 2-electron
reduction stages, all the way to the
alcohol

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• Chemists have wondered if it might be
possible to modify the structure of the
aluminum hydride reducing agent so as to
reduce an ester through one 2-electron
reduction step, but no further.

• You have already seen a similar modification

in the example of lithium tri-tert-
butoxyaluminum hydride.

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Among the most useful modified aluminum
hydride reducing agents is Diisobutylaluminum
Hydride, also known as DIBALH.

CH3 H CH3

CH3 CH CH2 Al CH2 CH CH3

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• Reductions are typically carried out in
toluene or hexane solution at -78 °C (dry
ice-acetone bath).

• The reduction is followed by hydrolysis

with aqueous acid to decompose the
aluminum salts and liberate the aldehyde.

• After hydrolysis, the reaction is allowed to

warm to room temperature.

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 Reduction of Esters to
Aldehydes

O O
DIBALH H2O
R C R C
toluene HCl
O R' H
-78°C

+ R' OH

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 In more detail...
O O Al(i-Bu)2
DIBALH
R C O R' R C O R'
toluene
-78°C H

H2O
H+

R C H + R' OH
CH3

+ 2 CH3 CH CH3 + Al(OH)3

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Reduction of esters with DIBALH has
become a valuable method for the
synthesis of aldehydes.

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 Example
O
DIBALH H 2O
CH3 (CH2)10 C O CH2 CH3
toluene HCl
Ethyl dodecanoate -78°C

CH3 (CH2)10 C H + HO CH2 CH3

Dodecanal
(88% yield)

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If the temperature of the reaction is
not maintained at dry ice
temperatures, the ester will be
reduced all the way to the alcohol.

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 O
AlR2
R C O R' O

R C O R'
H
H
Al
R R

This will not lose an alkoxy

group at low temperatures --
thus, no leaving group!

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Loss of the alkoxy group does not happen
until after the hydride reagent has been
destroyed with acid, so a second
reduction step cannot happen.

Thus, temperature control is critical for the

selective reduction of an ester to an
aldehyde.

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 Hydrolysis Step
O O H
H+
R C O R' R C O R'

H H

O O

R C + O R' R C O R'

H H H H

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Nitriles can also be reduced to
aldehydes, using DIBALH

DIBALH H2O
C N
toluene HCl
-78°C

Benzaldehyde
(90% yield)

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Ketone Synthesis Using
Organometallic Reagents
• We want to do:

O O
R MgX
R C Cl R C R
ether

• Too bad it doesn’t work! No ketone is

obtained.

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 Instead, we get alcohol:

O O OH
R MgX R MgX
R C Cl R C R R C R
ether ether
R
(after hydrolysis)

The Grignard reagent reacted twice.

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• The problem is that the
organomagnesium reagent is too
reactive -- we need something milder.

• So, we use an organocadmium reagent,

instead:

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 Ketone Synthesis using
Organocadmium Reagents

2 R MgX + CdCl2 R Cd R + 2 MgXCl

O O

2 R C Cl + R Cd R 2 R C R + Cd Cl2

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 Example

CdCl2
CH3 CH2 MgBr CH3 CH2 Cd CH2 CH3

O O

C Cl C CH2 CH3
(CH3CH2)2Cd

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 Alternative:
O O

C Cl C CH2 CH3
CH3 CH2 MgBr

FeCl3
-78°C

Apparently, both Grignard addition steps are too slow

at low temperature.
But, the ferric chloride catalyzes the first addition,
making it proceed fast enough to be useful.
Ferric chloride does not catalyze the second addition,
so it remains very slow and is not observed!
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Lithium dialkylcuprates can also be
used to prepare ketones from acid
chlorides.

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 Ketone Synthesis using
Lithium Dialkylcuprates

O O
0°
R C Cl + R2CuLi R C R + R Cu
ether

+ LiCl

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 Example
O

CH3 (CH2)4 C Cl + (CH3)2CuLi

0°C
ether

CH3 (CH2)4 C CH3

81% yield
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 Synthesis Problem

O O

H3C C OH H3C C CH3

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Another Synthesis Problem

OH

CH CH3

C CH2

+ Br

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 Are We Having Fun Yet?

CH3
CH OH CH3
CH3 C CH CH2 CH3
CH3
+ CH3 CH2 CH2 OH

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 Let’s Make Some
Drugs!
OH HO
C CH
CH3 CH3

O O
Norethisterone

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