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WWU -- ChemistryWWU -- Chemistry
OXIDATIVE PREPARATION OF ALDEHYDES AND KETONES
WWU -- ChemistryWWU -- Chemistry
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).
WWU -- ChemistryWWU -- Chemistry
OxidationsOxidations
NOTE: A dehydrogenationis also a form of oxidation!
O
CR H
O
CR H
O
CR R'
O
CR OH
O
CR OH
R CH2 OH
R CH OH
R'
WWU -- ChemistryWWU -- Chemistry
Oxidation of Primary Oxidation of Primary AlcoholsAlcohols
R CH2 OH R C H
O
R C OH
O
[O] [O]
[O] represent an oxidation
The aldehyde can be oxidized in a second step
WWU -- ChemistryWWU -- Chemistry
Oxidation of Secondary Oxidation of Secondary AlcoholsAlcohols
R C R
OH
H
[O]R C R
O
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Oxidation of Tertiary Oxidation of Tertiary AlcoholsAlcohols
R C R
OH
R
[O]NO REACTION
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Oxidation of Primary Oxidation of Primary Alcohols with KMnOAlcohols with KMnO44
You can’t pull the aldehyde out of this reaction, so the only product is the carboxylic acid.
R CH2 OH C H
O
R
R C OH
O
KMnO4 KMnO4
heat heat
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Specifically...Specifically...
R CH2 OH + KMnO4
H2O
heatR C O
O
K
+ KOH + MnO2
(brownprecipitate)
R C O
O
+ H3O+ R C OH
O
+ H2O
WWU -- ChemistryWWU -- Chemistry
•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 Primary alcohols are oxidized by atmospheric oxygen to by atmospheric oxygen to aldehydes and carboxylic aldehydes and carboxylic
acids.acids.
CH3 CH2 OHO2
CH3 C H
O
O2CH3 C OH
O
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 Oxidation of Primary Alcohols to AldehydesAlcohols 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 Dehydrogenation over CopperCopper
R CH2 OHCopper metal
200 - 300 °CR C H
O
+ H2
•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 Oxidation of Primary Alcohols with KAlcohols with K22CrCr22OO77
•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.
R CH2 OH R C H
O
R C OH
OK2Cr2O7
H2SO4
K2Cr2O7
H2SO4
+ Cr3+
WWU -- ChemistryWWU -- Chemistry
• The acidic conditions keep the chromium in the Cr2O7
2- 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 Dichromate Oxidation of EthanolEthanol
3 CH3 CH2 OH + 2 Cr2O72- + 16 H+
3 CH3 C OH
O
+ 4 Cr3+ + 11 H2O
Orange solution
Green precipitate
WWU -- ChemistryWWU -- Chemistry
Secondary alcohols are Secondary alcohols are oxidized to ketonesoxidized to ketones
R CH R
OHCr2O7
2-
H2SO4
R C R
O
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!
WWU -- ChemistryWWU -- Chemistry
““Mechanism” of OxidationMechanism” of Oxidation
R C R
OH
H
+ CrO3
C
O Cr OH
O
O
H
RR
C
O Cr OH
O
O
H
RR
O
H H
slowO
CR R
H
OH H
CrO3Hseveral
stepsCr3+
WWU -- ChemistryWWU -- Chemistry
•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 Which would react faster?faster?
OH
C
H
RR or
OH
C
D
RR
There is a primary isotope effect -- C-H bond-breaking occurs during the rate-
determining 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 Oxidation of Secondary AlcoholsAlcohols
Jones OxidationJones Oxidation
R CH R
OH
R C R
OK2Cr2O7
H2SO4
+ Cr3+
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ExampleExampleCH3
CHCH3 CH3
OH
K2Cr2O7
H2SO4
CH3
CHCH3 CH3
O
(-)-Menthol (-)-Menthone
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… … but what if you want to but what if you want to make an aldehyde?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.
WWU -- ChemistryWWU -- Chemistry
… … but what if you want to but what if you want to make an aldehyde? (Part make an aldehyde? (Part
Two)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 Oxidation with Chromic Oxide and PyridineOxide and Pyridine
Sarett OxidationSarett Oxidation
R CH R
OH
R C R
O
N
CrO3.
CH2Cl2
WWU -- ChemistryWWU -- Chemistry
The oxidizing reagent is a type of complex between the chromic oxide and the pyridine.
R CH2 OHN
CrO3
CH2Cl2
R C H
O
WWU -- ChemistryWWU -- Chemistry
Preparation of an Preparation of an AldehydeAldehyde
CH CH CH2 OH CH CH C H
OCrO3 pyr
CH2Cl2
Cinnamyl alcohol 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 Oxidation with Pyridinium Pyridinium
ChlorochromateChlorochromate
““PCC” OxidationPCC” Oxidation
R CH R
OH
R C R
O
N
CrO3Cl
CH2Cl2
.
WWU -- ChemistryWWU -- Chemistry
The reagent is prepared by dissolving CrO3 in hydrochloric acid and then adding pyridine. The reagent precipitates as a solid, with the formula:
N
H
CrO3ClCrO3Cl pyr.
WWU -- ChemistryWWU -- Chemistry
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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ExampleExample
CH3 (CH2)18 CH2 OH PCC
CH2Cl2CH3 (CH2)18 C H
O
92% yield
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Example #2Example #2
OHCCH3
CH3
CH3
PCC
CH2Cl2OCCH3
CH3
CH3
97% yield
Getting better!
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Example #3Example #3
CH OH PCC
CH2Cl2C O
100% yield
WOW!!!
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Notice how the other functional Notice how the other functional groups survive without being groups survive without being
changedchanged..
HO CH2 CH2 C CH CH C O CH3
CH3
CH3
O
PCC
CH2Cl2
H C CH2 C CH CH C O CH3
CH3
CH3
OO
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 TestThe Tollens Test
silver mirror
This test is specific for aldehydes -- ketones will not react with silver ion.
RC
O
O
C
O
R H NH4
+2 Ag(NH3)2OH 2 Ag
+ H2O + NH3
+ +
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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
C
OHH
HOH
OHH
OHH
CH2 OH
OH
C O
CH2
CH2
OH
HOH
OHH
OHH
OH
Glucose Fructose
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O
HOH
H
HO
H
H
HO
CH2
H
OH
OH
D-(+)-D-(+)-GlucopyranoseGlucopyranose
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.
WWU -- ChemistryWWU -- Chemistry
D-(-)-FructofuranoseD-(-)-Fructofuranose
This is a hemiacetal
O
HOH
H
H
OH
CH2OH
OHOH
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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….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: hydroxyketones also give a positive test!
•Fructose is an -hydroxyketone (go back and check out its structure).
WWU -- ChemistryWWU -- Chemistry
Maltose: A DisaccharideMaltose: A Disaccharide
Position (a) is still a hemiacetal
Maltose is a reducing sugar
Position (b) is now an acetal
O
CH2OH
H
OH
H OH
H
OH
H O
CH2OH
H
OH
H OH
H
H
OHO
bc
a
WWU -- ChemistryWWU -- Chemistry
Sucrose: A DisaccharideSucrose: A Disaccharide
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!
O
CH2OH
H
H
OH
H
OH
OH
H
H O
CH2OH
OH
H
H
OH
CH2OH
H
O
ab
WWU -- ChemistryWWU -- Chemistry
What about a What about a monosaccharide-ether (a monosaccharide-ether (a
glycoside)?glycoside)?
O
HOH
H
HO
H
H
HO
CH2
H
O
OH
CH3
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 How do hydride transfer (oxidation-reduction) (oxidation-reduction)
reactions take place in reactions take place in biological systems?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 Nicotinamide Adenine DinucleotideDinucleotide
NN
NN
NH2
O
H
OH
H
OH
H
H
CH2 O P O
O
O
P O
O
O
CH2O
H
OH
H
OH
H
H
N
HH
C NH2
O
_ _
“NADH”
WWU -- ChemistryWWU -- Chemistry
•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.
WWU -- ChemistryWWU -- Chemistry
Reduction of Reduction of Acetaldehyde in Acetaldehyde in
FermentationFermentation
N
C NH2
OH H
R
N
C NH2
O
R
H
CH3 C H
O
CH3 C H
OH
H
H+
+
NADH NAD+
WWU -- ChemistryWWU -- Chemistry
Reduction of Pyruvic Acid Reduction of Pyruvic Acid in Muscle Tissuein Muscle Tissue
N
C NH2
OH H
R
N
C NH2
O
R
H
CH3 C
O
C OH
O
C OH
O
CH3 C
OH
H
H+
+
NADH NAD+
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A biological oxidation would take place as the reverse of the reactions shown.
WWU -- ChemistryWWU -- Chemistry
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