Organic pharmaceutical chemistry III

4th stage 2nd course

CANNIZARO
REACTION
Pharmacist : Amal saleh

Cannizaro reaction
The Cannizzaro reaction is a reaction of organic compounds
having an aldehydic group (-CHO).
It was propounded by Stanislao Cannizzaro in 1853 and hence was
named after him.

It is a chemical reaction that involves the base- induced

disproportionation of an aldehyde lacking a hydrogen atom in alpha
position to yield a carboxylic acid and a primary alcohol from two
molecules of an aldehyde
 benzylaldehyde

Trimethyl acetaldehyde

Theoretical aspect
In the presence of concentrated alkali, aldehydes containing no
hydrogen undergo self oxidation and reduction (Redox) reaction to
yield a mixture of an alcohol ( carbinol * ) and a salt of carboxylic
acid.

In general, a mixture of aldehydes undergoes a Cannizzaro reaction

to yield all possible products . If one of the aldehydes is
formaldehyde, the reaction yields almost exclusively salt of formic
acid and the alcohol corresponding to the other aldehyde. Such a
reaction is called a Crossed Cannizzaro Reaction.
 Mechanism of Cannizzaro Reaction:
Three proposed mechanisms:

Step I:
Nucleophilic addition of an OH - ion to the 1st aldehyde molecule
gives a tetrahedral intermediate I .

Step II:
Hydride shift: The tetrahedral intermediate I , expels a hydride ion*
as a leaving group** and is thereby oxidized. A second aldehyde
molecule accepts the hydride ion in another nucleophilic addition
step and is thereby reduced. Alkoxide anion
Carboxylate anion
Second mechanism:
Step I:
Nucleophilic addition of OH -ion to an aldehyde molecule to give
a carbonyl hydroxide anion (intermediate I) as in the 1st
mechanism.
Step II:
A hydride ion from one carbonyl hydroxide anion (I) is added
to another carbonyl hydroxide anion ( I ).
In the last step the alkoxide anion receives a proton from
the carboxylic acid.
The acid can be recovered by acidifying the mixture.
Third mechanism:
Step I:
Nucleophilic addition to give intermediate I as in the 1st mechanism.
Step II:
Deprotonation of intermediate I to give a dianion intermediate II.

Step III:
The unstable intermediate II releases a hydride anion which attacks another
molecule of aldehyde. In this process the dianion intermediate converts to a
carboxylate anion and the aldehyde to an alkoxide anion . The alkoxide
anion then picks up a proton from water to provide the alcohol final
product, while the caboxylate anion is converted to the carboxylic acid
product after acid work-up
 is more basic than water, so it can pick up a
proton from water.
is less basic than water, thus it can not pick
up a proton from water and require an acid work up to protonate.

Benzaldehyde, C7H6O , (C6H5CHO): Molar mass = 106.12 g mol 1

It s a colorless or yellowish liquid.
It has a characteristic pleasant almond-like odor.

Benzoic acid, C7H6O2 , (C6H5COOH):

Molar mass = 122.12 g mol Melting point = 121 123 oC.
It is a colorless plate or needle like crystals with a faint, pleasant odor.
Sparingly soluble in water but soluble in hot or boiled water.
Reacts with sodium bicarbonate to give CO2 gas.
Benzoic acid and it's salts are used as food preservatives.
Also used externally in the form of lotions, ointments ( e.g. Whitfield
ointment), mouth washes, etc.
Benzyl alcohol ,C7H8O , (C6H5CH2OH):
Molar mass =108.14 g mol, Boiling point = 204 207

It is a colorless oily liquid with a mild pleasant aromatic odor,

immiscible with water and completely miscible with alcohols and
organic solvents as diethyl ether. It's a useful solvent due to its
polarity, low toxicity and low vapor pressure ( volatile with steam ).
It has some local anesthetic properties so it is useful as an
antipruretic and it is included in some dental remedies & injectibles.
Used in pharmaceutical preparations for local application up to 10%
in ointments as antipruretic and antiseptic.

Benzyl alcohol can be prepared by hydrolysis of benzylchloride

with NaOH .

Benzoic acid can be prepared by the oxidation of toluene.

However, both benzoic acid and benzyl alcohol can be prepared in
the laboratory by ,
by the action of concentrated NaOH or KOH on benzaldehyde.

Procedure:
 Experiment No. I:
Name of experiment : Cannizzaro reaction.
Aim of experiment: Synthesis of Benzoic
acid & Benzyl alcohol

1-Dissolve 7.2 g of KOH in about 7 ml of H2O contained in

a beaker.
2- Cool the solution to about 20ºC in an ice-water bath.
3- Pour the solution into a 125 ml reagent bottle.
4- Add 7.5 ml of pure benzaldehyde, cork the bottle and
shake vigorously until it has been converted into a thick
emulsion.
5- Allow the mixture to stand overnight (until the next lab.).
 Experiment No.II:
Name of experiment : Cannizzaro reaction.
Aim of experiment : Isolation of Benzoic
acid & Benzyl alcohol

1- Add 30 ml of H2O to completely dissolve the Potassium

Benzoate.
2- Pour the liquid into a separatory funnel.
3- Rinse the bottle with 10 ml of ether & add this ether to the
solution in the separatory funnel.
4- Shake well & separate the lower aq. layer from upper ethereal
layer.
5- Extract the aq. layer with 10 ml ether. ( two times).
A- Isolation of Benzyl alcohol:
1- Combine the ethereal extracts.
2- Distil the ether on a water bath until 10 15 ml of liquid remains.
3- Cool the remaining liquid & transfer it to a separatory funnel.
4- Shake the ether layer with 3 ml of saturated Sodium bisulfite
solution, NaHSO3 *, & separate the oily liquid from the aqueous
NaHSO3 solution, ( two times ).

* To remove any unreacted Benzaldehyde which may be present.

5- Wash the oily liquid with 5 ml of 10 % Na2CO3

Na2CO3 + 2 NaHSO3 excess CO2 + H2O + 2 Na2SO3
To ensure complete removal of unreacted NaHSO3 .
6- Wash with 5 ml H2O .
7- Dry the oily liquid over anhydrous Magnesium sulfate, Mg2SO4 .
8- Filter the solution into a small distilling flask & distil off the
ether on a water bath.
9- Attach a short air cooled condenser& distil the Benzyl alcohol,
by heating the flask directly with a luminous flame kept in motion.
10- Collect the material boiling at 204 207 oC .
B- Isolation of Benzoic acid:
1- Pour the alkaline aqueous layer with stirring into a mixture o f
20 ml conc. HCl + 20 ml H2O + 20g of crushed ice.
2- Filter the ppt. ( Benzoic acid ) at the pump.
3- Wash the ppt. with little cold H2O .
4- Drain & recrystallize from boiling H2O .
( colorless crystals of Benzoic acid, m.p.121ºC )
Thank
you!
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