Oxidative preparation of
aldehydes and ketones
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REMEMBER:
•Go back to Special Topics Box at the beginning
of Chapter 14.
•Conversion of an alcohol to an aldehyde or
ketone represents an oxidation (removal of H
atoms).
•Conversion of an aldehyde to a carboxylic acid
is also an oxidation (addition of an O atom).
•Oxidation can involve the addition of oxygen
atoms or it can involve the removal of hydrogen
atoms (dehydrogenation).
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Oxidations
R
CH2 OH
O
O
C
C
R
H
O
O
C
C
R
H
R
R
OH
OH
NOTE: A dehydrogenation
is also a form of oxidation!
O
R
CH
OH
C
R'
R
R'
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Oxidation of Primary
Alcohols
O
O
[O]
R
CH2 OH
[O]
R
C
H
R
C
OH
The aldehyde can be oxidized in
a second step
[O] represent an oxidation
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Oxidation of Secondary
Alcohols
OH
O
[O]
R
C
R
R
C
R
H
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Oxidation of Tertiary
Alcohols
OH
[O]
R
C
R
NO REACTION
R
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Oxidation of Primary
Alcohols with KMnO4
O
O
R
CH2 OH
KMnO4
heat
R
C
H
KMnO4
heat
R
C
OH
You can’t pull the aldehyde out of this reaction,
so the only product is the carboxylic acid.
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Specifically...
O
R
CH2 OH
H2O
+ KMnO4
R
C
O
K
heat
+ KOH + MnO2
(brown
precipitate)
O
O
R
C
O
+ H3O+
R
C
OH
+ H2O
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•The aldehyde is formed as an intermediate, but it
is unstable under the reaction conditions and
cannot be isolated.
•There is a color change that accompanies the
reaction -- the purple solution (KMnO4) changes
to a brown mud (MnO2)
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Primary alcohols are oxidized by
atmospheric oxygen to aldehydes
and carboxylic acids.
O
CH3 CH2 OH
O2
CH3 C
O
H
O2
CH3 C
OH
This reaction is very slow.
It is catalyzed by enzymes (Acetobacter)
This is how wine turns to vinegar!!!
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Oxidation of Primary
Alcohols to Aldehydes
• Requires less vigorous oxidation conditions.
• We can try to remove the aldehyde from the
reaction medium as quickly as it is formed
– Generally, the aldehyde has a lower boiling
point than either the corresponding alcohol or
carboxylic acid
• We can also try to find a milder oxidizing agent.
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Dehydrogenation over
Copper
O
Copper metal
R
CH2 OH
R
C
H
+ H2
200 - 300 °C
•This reaction is generally done by passing the vapors of the
alcohol through a tube furnace in a stream of inert carrier gas.
•This is not a practical laboratory method -- it is better suited to
industrial processes.
•The reaction stops at the aldehyde stage -- no more removal of
hydrogen can take place.
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Oxidation of Primary
Alcohols with K2Cr2O7
O
O
K2Cr2O7
R
CH2 OH
H2SO4
K2Cr2O7
R
C
H
H2SO4
R
C
+
OH
Cr 3+
•This reaction can also be done using CrO3 (chromic oxide) in
sulfuric acid.
•The aldehyde is distilled away from the reaction vessel as
quickly as it is formed. If the aldehyde is not removed, it will
suffer a second oxidation, and the product will be the
carboxylic acid.
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• The acidic conditions keep the chromium in
the Cr2O72- state.
• Potassium dichromate is not as powerful an
oxidizing agent as is potassium
permanganate
• Sodium dichromate can be substituted for
potassium dichromate -- it makes no
difference.
• There is a color change during the reaction.
The orange color of the dichromate changes
to the green of Cr3+ ion.
• This is not the world’s greatest way to prepare
an aldehyde!
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Dichromate Oxidation of
Ethanol
3 CH3 CH2 OH
+ 2 Cr2O72- + 16 H+
Orange
solution
O
3 CH3 C
OH
+ 4 Cr3+ + 11 H2O
Green
precipitate
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Secondary alcohols are
oxidized to ketones
OH
Cr2O7
R
CH
O
2-
R
R
C
R
H2SO4
Here, it doesn’t really matter whether you use potassium
permanganate, potassium dichromate, nitric acid, sodium
hypochlorite (Bleach), or other oxidizing agents.
Actually, it does matter, but here we are presenting the simple
introduction!
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“Mechanism” of Oxidation
O
OH
R
C
O
R
+ CrO3
Cr
OH
O
R
H
C
R
H
O
O
Cr
several
OH
CrO3H
O
O
Cr3+
steps
slow
R
C
R
C
R
H
R
H
O
H
H
O
H
H
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•The important point about the
mechanism is that the loss of the alcohol
C-H occurs during the rate-determining
step.
•What is not well understood is what
happens to the chromium after the
formation of the ketone. There is some
sort of cascading down through a series
of oxidation states, but no one is sure
exactly how this happens.
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Which would react faster?
OH
OH
R
C
H
R
or
R
C
R
D
There is a primary isotope effect -- C-H
bond-breaking occurs during the ratedetermining step!
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Tertiary alcohols are not oxidized
Under acidic conditions, the only
available reaction is dehydration.
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Let’s re-examine methods for
oxidizing primary alcohols to
aldehydes and secondary
alcohols to ketones (and let’s try
some modern reactions!)
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Oxidation of Secondary
Alcohols
OH
O
K2Cr2O7
R
CH
R
R
C
H2SO4
+
Cr
R
3+
Jones Oxidation
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Example
CH3
CH3
K2Cr2O7
H2SO4
O
OH
CH
CH
CH3
CH3
(-)-Menthol
CH3
CH3
(-)-Menthone
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… but what if you want to
make an aldehyde?
•The problem is how to stop the oxidation at the
aldehyde stage.
•We need mild oxidizing conditions -- strong
enough to do one 2-electron oxidation, but not
strong enough to do the second 2-electron
oxidation.
•We can use the Jones oxidation (potassium
dichromate and sulfuric acid) and try to distill the
aldehyde out of the reaction vessel before it gets
oxidized a second time.
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… but what if you want to
make an aldehyde? (Part
Two)
•Or, we can tinker with the oxidizing agent, to
attenuate its properties -- i.e., we can try to “dial in”
the power of the oxidizing agent to just the right level.
•Which brings us to...
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Oxidation with Chromic
Oxide and Pyridine
OH
R
CH
CrO3 .
O
N
R
R
C
R
CH2Cl2
Sarett Oxidation
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The oxidizing reagent is a type of complex
between the chromic oxide and the pyridine.
CrO3
O
N
R
CH2 OH
R
C
H
CH2Cl2
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Preparation of an Aldehyde
O
CrO3 pyr
CH
CH
CH2 OH
Cinnamyl alcohol
CH
CH
C
H
CH2Cl2
Cinnamaldehyde
Note that the reaction does not affect other functional groups.
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Another useful reagent for oxidizing alcohols
to aldehydes or ketones -- in good yield (!) -is pyridinium chlorochromate (PCC).
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Oxidation with Pyridinium
Chlorochromate
OH
R
CH
O
CrO3Cl .
N
R
R
C
R
CH2Cl2
“PCC” Oxidation
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The reagent is prepared by dissolving CrO3 in
hydrochloric acid and then adding pyridine.
The reagent precipitates as a solid, with the
formula:
.
CrO3Cl pyr
CrO3Cl
N
H
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The reagent is used in nearly stoichiometric ratios
to perform oxidations under mild conditions.
Because the reagent is mildly acidic, however, it
may not be suitable for use with acid-sensitive
compounds.
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Example
O
PCC
CH3 (CH2)18 CH2 OH
CH2Cl2
CH3 (CH2)18 C
H
92% yield
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Example #2
CH3
CH3
PCC
CH3 C
CH3
OH
CH2Cl2
CH3 C
O
CH3
97% yield
Getting better!
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Example #3
PCC
CH
OH
C
O
CH2Cl2
100% yield
WOW!!!
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Notice how the other functional groups
survive without being changed.
CH3
HO
CH2 CH2 C
O
CH
CH
C
O
CH3
CH3
PCC
CH2Cl2
O
H
C
CH3
CH2 C
O
CH
CH
C
O
CH3
CH3
83% yield
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CHANGE OF GEARS:
•Aldehydes can be oxidized to
carboxylic acids.
•This oxidation can take place under
very mild oxidizing conditions.
•Aldehydes can be oxidized with such
weak oxidizing agents as metal cations,
especially:
Ag+
Cu2+
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The Tollens Test
O
O
C
R
H
+ 2 Ag(NH3)2OH
C
R
+
O
NH4
+
2 Ag
+ H2O + NH3
silver mirror
This test is specific for aldehydes -- ketones will
not react with silver ion.
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The Tollens test is important in
carbohydrate chemistry, for proof of
structure.
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These monosaccharides cyclize to form
hemiacetals
H
O
C
H
HO
CH2 OH
OH
H
C
HO
O
H
H
OH
H
OH
H
OH
H
OH
CH2 OH
Glucose
CH2 OH
Fructose
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b-D-(+)-Glucopyranose
OH
H
CH2
H
O
HO
HO
OH
H
H
OHH
Notice that this is a
hemiacetal
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•The hemiacetal form is in equilibrium with
the open-chain free aldehyde form
(remember mutarotation?).
•While in the free aldehyde form, glucose
can reduce silver ion (give a silver mirror -a positive Tollens test).
•Because it can reduce silver ion, glucose
is considered a reducing sugar.
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b-D-(-)-Fructofuranose
OH
O
H
This is a hemiacetal
H
OH
OH
OH
CH2OH
H
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•Being a hemiacetal, the cyclic form of
fructose is in rapid equilibrium with the
open-chain, free ketone form.
•Therefore, fructose is also capable of
reducing silver ion, and is thus classified a
reducing sugar!
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Yeah, but….
•I thought you said that only aldehydes
were capable of giving a positive Tollens
test, and fructose is a ketone!
•There is an exception: a-hydroxyketones
also give a positive test!
•Fructose is an a-hydroxyketone (go back
and check out its structure).
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Maltose: A Disaccharide
CH2OH
H
O
OH H
b
H
H
O
c OH H
H
a
OH
O
OH
H
CH2OH
OH
Position (b) is now an
acetal
H
OH
Position (a) is still a hemiacetal
Maltose is a reducing sugar
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Sucrose: A Disaccharide
CH2OH
CH2OH
O
H
H
OH
OH
H
a
H
H
O
H
b
H
OH
O
OH
CH2OH
OH
H
Both positions (a) and (b) are now acetals. Neither is in
equilibrium with the open-chain free carbonyl form.
Sucrose is a non-reducing sugar!
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What about a monosaccharideether (a glycoside)?
OH
H
CH2
H
O
HO
HO
O CH3
H
OHH
H
This is an acetal -- it is not in equilibrium with a free
aldehyde form
This is a non-reducing sugar
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How do hydride transfer
(oxidation-reduction)
reactions take place in
biological systems?
• We can’t use lithium aluminum hydride or
pyridinium chlorochromate inside a living
cell!
• Any reagent has to be water-soluble,
capable of being transported across cell
membranes, and able to act in concert
with an enzyme.
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Nicotinamide Adenine
Dinucleotide
NH2
N
H
H
C
N
O
N
N
CH2 O
O
H
P
O
O_
H
P
O
OH
CH2
O_
H
H
H
OH
NH2
O
N
H
O
“NADH”
O
H
H
OH
OH
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•The reactive portion is the hydrogen
attached to Carbon #4 of the pyridine ring
(see previous slide)
•NADH acts as a reducing agent by
transfering a hydride from the C-4 position.
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Reduction of Acetaldehyde
in Fermentation
OH
O
CH3 C
+
H
H
CH3 C
H
H
H
H
H
O
C
O
C
NH2
NH2
+
N
N
R
R
NADH
+
NAD
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Reduction of Pyruvic Acid
in Muscle Tissue
O
CH3 C
OH
O
C
OH
H
O
+
CH3 C
C
OH
H
H
H
H
O
C
O
C
NH2
NH2
+
N
N
R
R
NADH
+
NAD
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A biological oxidation would take place as
the reverse of the reactions shown.
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