OXIDATIVE PREPARATION OF ALDEHYDES AND KETONES

WWU -- 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 -- Chemistry

Oxidations
O R CH2 OH R O C R H R O C OH C H R O C OH

NOTE: A dehydrogenation is also a form of oxidation!

O R CH R' OH C R R'
WWU -- Chemistry

Oxidation of Primary Alcohols

O [O] R CH 2 OH R C H [O] R C OH O

The aldehyde can be oxidized in a second step

[O] represent an oxidation

WWU -- Chemistry

Oxidation of Secondary Alcohols

OH [O] R C H R R C R O

WWU -- Chemistry

Oxidation of Tertiary Alcohols

OH [O] R C R R NO REACTION

WWU -- Chemistry

Oxidation of Primary Alcohols with KMnO4

O R CH2 OH KMnO4 heat R C H KMnO4 heat R O C OH

You cant pull the aldehyde out of this reaction, so the only product is the carboxylic acid.

WWU -- Chemistry

Specifically...
O R CH2 OH H2O + KMnO4 heat + KOH + MnO2 (brown precipitate) O R C O + H3O+ R O C OH + H2O R C O K

WWU -- 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)

WWU -- Chemistry

Primary alcohols are oxidized by atmospheric oxygen to aldehydes and carboxylic acids.
O CH3 CH2 OH O2 CH3 C H O2 CH3 C OH O

This reaction is very slow. It is catalyzed by enzymes (Acetobacter)

This is how wine turns to vinegar!!!

WWU -- Chemistry

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.
WWU -- Chemistry

Dehydrogenation over Copper

O Copper R CH2 OH et l R 200 - 300 C C H + 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.
WWU -- Chemistry

Oxidation of Primary Alcohols with K2Cr2O7

O K2Cr2O7 R CH2 OH H2SO4 R C H K2Cr2O7 H2SO4 R + C OH O

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.
WWU -- Chemistry

 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 worlds greatest way to prepare an aldehyde!
WWU -- Chemistry

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
WWU -- Chemistry

Secondary alcohols are oxidized to ketones

OH R CH R H2SO4
Here, it doesnt 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 -- Chemistry

2Cr2O7

O R C R

Mechanism of Oxidation
O OH R C H R + CrO3 R C H O O Cr O slow R C H O H H H R R H O H C R OH CrO3H O several steps Cr3+ O Cr O R OH

WWU -- 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.
WWU -- Chemistry

Which would react faster?

OH R C H R or R OH C D R

There is a primary isotope effect -- C-H bond-breaking occurs during the ratedetermining step!
WWU -- Chemistry

Tertiary alcohols are not oxidized

Under acidic conditions, the only available reaction is dehydration.

WWU -- Chemistry

Lets re-examine methods for oxidizing primary alcohols to aldehydes and secondary alcohols to ketones (and lets try some modern reactions!)

WWU -- Chemistry

Oxidation of Secondary Alcohols

OH K2Cr2O7 R CH R H2SO4 R + C Cr 3+ R O

Jones Oxidation
WWU -- Chemistry

Example
CH3 CH3

K2Cr2O7 H2SO4 OH CH CH3 (-)CH3 t ol CH3 (-)t o

WWU -- Chemistry

O CH CH3

 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.
WWU -- Chemistry

 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...

WWU -- Chemistry

Oxidation with Chromic Oxide and Pyridine

OH R CH R CH2Cl2 CrO3 .
N

O R C R

Sarett Oxidation
WWU -- Chemistry

The oxidizing reagent is a type of complex between the chromic oxide and the pyridine.

CrO3 N R CH2 OH R CH2Cl2

O C H

WWU -- Chemistry

Preparation of an Aldehyde
O CrO3 pyr CH CH CH2 OH CH CH2Cl2 Cinnamaldehyde CH C H

Cinnamyl alcohol

Note that the reaction does not affect other functional groups.

WWU -- Chemistry

Another useful reagent for oxidizing alcohols to aldehydes or ketones -- in good yield (!) -is pyridinium chlorochromate (PCC).

WWU -- Chemistry

Oxidation with Pyridinium Chlorochromate

OH R CH R CH2Cl2 CrO3Cl .
N

O R C R

PCC Oxidation
WWU -- Chemistry

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 N H

CrO3Cl

WWU -- 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.

WWU -- Chemistry

Example

O CC CH3 (CH2)
8

CH 2 OH

CH2Cl2

CH3 (CH 2)

92% yiel

WWU -- Chemistry

Example #2

CH3 PCC CH3 C CH3 OH CH2Cl2

CH3 CH3 C CH3 97% yield O

Getting better!

WWU -- Chemistry

Example #3

PCC CH OH CH2Cl2 C O

100% yield

WOW!!!
WWU -- Chemistry

Notice how the other functional groups survive without being changed.
CH3 HO CH2 CH2 C CH3 CC CH2Cl2 O H C CH3 CH2 C CH3 83% yiel CH CH O C O CH3 CH CH O C O CH3

WWU -- Chemistry

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+
WWU -- Chemistry

The Tollens Test

O C R H + 2 Ag(NH3)2OH R O C O NH4
+

2 Ag

+ H2O + NH3

silver mirror

This test is specific for aldehydes -- ketones will not react with silver ion.
WWU -- Chemistry

The Tollens test is important in carbohydrate chemistry, for proof of structure.

WWU -- Chemistry

These monosaccharides cyclize to form hemiacetals

H C H HO H H OH H OH OH CH2 OH Glucose HO H H O CH2 OH C O H OH OH CH2 OH ructose
WWU -- Chemistry

FD-(+)-Glucopyranose (+)OH H CH
2

O OH

HO HO H H OHH

Notice that this is a hemiacetal

WWU -- Chemistry

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 -- Chemistry

FD-(-)-Fructofuranose
OH H
This is a hemiacetal

OH OH CH2OH H

H OH

WWU -- Chemistry

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!

WWU -- Chemistry

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: Ehydroxyketones also give a positive test! Fructose is an E-hydroxyketone (go back and check out its structure).
WWU -- Chemistry

Maltose: A Disaccharide
CH2OH H O OH H OH H OH b H H CH2OH O a OH H OH H c OH H O

Position (b) is now an acetal

Position (a) is still a hemiacetal Maltose is a reducing sugar

WWU -- Chemistry

Sucrose: A Disaccharide
CH2OH H H OH OH H O a H OH H b O OH H H CH2OH O OH CH2OH 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!
WWU -- Chemistry

What about a monosaccharidemonosaccharideether (a glycoside)?

OH H CH 2 H

O O CH 3

HO HO H OH H

H This is an acetal -- it is not in equilibrium with a free aldehyde form

This is a non-reducing sugar
WWU -- Chemistry

How do hydride transfer (oxidation(oxidation-reduction) reactions take place in biological systems?

We cant 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.
WWU -- Chemistry

Nicotinamide Adenine Dinucleotide

NH2 N N O N O H H OH H H OH CH2 O P O_ O P O_ H O CH2 H O H H OH OH O N H H O C NH2

NADH

WWU -- 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 -- Chemistry

Reduction of Acetaldehyde in Fermentation

O CH3 C H + H OH CH3 C H H H O C NH2 H O C NH2 H

+
N R NADH N R + NAD

WWU -- Chemistry

Reduction of Pyruvic Acid in Muscle Tissue

O CH3 C O C OH H + CH3 C H H H O C NH2 H O C NH2 C OH OH O

+
N R NADH N R + NAD

WWU -- Chemistry

A biological oxidation would take place as the reverse of the reactions shown.

WWU -- Chemistry

WWU -- Chemistry