Pharmaceutical Process Chemistry

1. Oxidation (Unit Process-1)
Pharmaceutical Process
Chemistry
Aikan Gupta (Pharmaceutical Chemistry)
Nitin Goel (Pharmacognosy)
G.H.G. Khalsa College of Pharmacy,
Gurusar Sudhar

2. Oxidation
 Oxidation may be defined as the chemical process in which a substance gains
oxygen or loses electrons and hydrogen. When one of the reactants is oxygen, then
oxidation is the gain of oxygen.
For example:
Fe2O3 + 3CO → 2Fe + 3CO2
 Oxidation is any chemical reaction that involves the moving of electrons.
Specifically, it means the substance that gives away electrons is oxidized.
Normally, this is a reaction between oxygen and a substance such as iron.
For example:
4Fe + 3O2 → 2Fe2O3
xH2O→Fe2O3.x H2O
Or

3. Types of Oxidative
Reactions
In the organic chemical industry, oxidation constitutes one of the most powerful tools
used in the synthesis of chemical compounds. The oxidation processes are many,
varied and are manifested in a variety of net effects. The principal types of oxidative
reactions may be set forth as further.

4. Dehydrogenation is illustrated in the transformation of a primary
alcohol to an aldehyde:
or a secondary alcohol to a ketone:
1. Dehydrogenation

5. Peroxidation occurs readily under certain conditions. Thus, some reactions occur
directly with air when catalysed by ultraviolet irradiation:
Isopropyl benzene Isopropyl benzene peroxide
Others require the interaction of an inorganic peroxide:
2. Peroxidation
Air
UV

6. An atom of oxygen may be introduced into a molecule, as is illustrated
by the oxidation of an aldehyde to an acid:
or of a hydrocarbon to an alcohol:
3. Introduction of oxygen atom

7. 4. A combination of dehydrogenation and
introduction of oxygen
A combination of dehydrogenation and introduction of oxygen may occur, as in
the preparation of aldehydes from hydrocarbons:
or the preparation of benzoic acid from benzyl alcohol:

8. As in the case when two molecules of benzene form diphenyl or two
molecules of toluene form stilbene or when methylanthraquinone is
converted to anthracene yellow :
5. Dehydrogenation may also be accompanied by
molecular condensation

9. Dehydrogenation, oxygen introduction, and destruction of carbon linkages may all
occur in the same process of oxidation, e.g., in the oxidation of naphthalene to
phthalic anhydride:
5. Dehydrogenation, oxygen introduction, and
destruction of carbon linkages
6. Oxidation may be accomplished indirectly through the use of intermediate
reactions:

10. Olefins may be oxidized under mild conditions to hydroxy derivatives and may be
converted to aldehydes and carboxylic acids of lower molecular weight when stronger
oxidizers are employed. Thus, oleic acid can be converted to dihydroxystearic acid with
alkaline potassium permanganate:
When sodium dichromate in acid solution is employed, fission as well as oxidation occur
and pelargonic and azelaic acids are produced:
7. Olefins Oxidation

11.  Azobenzene
 p-Amino-Phenol
 Nitrobenzene under moderate conditions.
9. Amino compounds may be oxidized to:

12. Sulfur compounds may be oxidized by acid permanganate, as in the preparation of sulfonals,
trionals, and tetranals from (CH3)2C(S.C2H5)2 in which the sulfide sulfur is oxidized to
sulfonic groups.
It should be noted that the mercaptans behave differently toward oxidizing agents from the
alcohols, in that the action of strong oxidizing agents increases the valence of the sulfur atom
instead of removing hydrogen, as in the case of the alcohols. Thus: oxidation
10 . Sulfur compounds Oxidation

13. Liquid phase oxidation
with
oxidizing agents

14. Results obtained by conducting the reaction under conditions best suited for the particular agent are
shown in the accompanying tabulation
Oxidizing agent Product
Manganese dioxide in sulfuric acid Quinone
Potassium dichromate in dilute sulfuric acid at 0-10⁰C, for 24 hr. Quinone
Potassium permanganate:
Arid -Aniline black
Alkaline -Azobenzcne plus ammonia
Neutral -Azohcmcnc plus
nitrobenzene
Alkaline hypochlorite -Nitrobcnzene
Hypochlorous acid -p-Aminophenol
The oxidation of aniline furnishes an example for comparison of a number of oxidizing agents.

15. The aldehyde group normally behaves like that of acetaldehyde toward oxidation, but in the
presence of certain agents, the ring structure is destroyed and polybasic acids are formed.
For example:
Oxidizing agent Product
Sodium chlorate in neutral solution with V₂0, catalyst Fumaric acid
Sodium chlorate in dilute acid with OsO₄, catalyst Me80tartaric acid
Caros' acid, HO·O·SO₃H, a strong oxidizing agent Succinic acid
Hydrogen peroxide in prescnce of ferrous salts 5-Hydroxyfurfural
Bromine water at 100°C Mucobromic acid
Potassium permanganate (diluted solution) Pyromucic acid
Another substance exhibiting a variety of action toward oxidation agents is furfural:

16. The action of oxidizing agents on organic compounds depends not only upon the
nature of the agent or the compound but also upon following factors:
 Concentration
 Temperature
 Hydrogen-ion concentration
 Method of mixing
Factor effecting action of oxidizing agents:
Consequently, any comparison of the variety of effects obtainable by varying the
oxidizing agent or organic compound cannot be pursued too far.

17. Example related to liquid phase oxidation
with oxidizing agents

18. Oxidizing Agents used:
- Dichromate ( but result in formation of acids)
- Permanganate
- Nitrobenzene
1. Isoeugenol to Vanillin
This is an example of an oxidation of a side chain to an aldehydic group in which it is convenient to
protect one substituent against oxidation. . Eugenol obtained from oil of cloves is heated with an alkali
such as sodium hydroxide to convert it to Isoeugenol, the hydroxyl group is protected by acetylation,
and the substance is oxidized and then saponified to vanillin.

19. Technically process in Vanillin synthesis
Eugenol from oil of cloves is dissolved
in dilute sodium hydroxide solution
Then heated to 160°C under
pressure in an autoclave.
This converts the Eugenol to Isoeugenol
and forms the sodium salt.
For oxidation, 1 mole of nitrobenzene is added
for each mole of Eugenol originally transferred to the autoclave.

20. Vanillin may be recovered from the alkaline
solution by precipitation with hydrochloric acid.
The yield approximates 80 per cent.
After the reaction is completed, pressure on the autoclave is released, and the
gaseous by-products are permitted to blow off.
Nitrobenzene
is added slowly as the oxidation proceeds

21. 2. Isoborneol to Camphor.
(1) Distillation of turpentine to obtain pinene
(2) Saturation with HCI gas to obtain bornyl chloride
(3) Hydrolyzing this to obtain camphene
(4) Esterifying camphene to isobornyl acetate
(5) Saponification to Isoborneol
(6) Oxidation to camphor.
Nitric acid has been widely used in the production of synthetic camphor from turpentine. The commonly
accepted general practice for this manufacture (the one adapted by Gubelmann ) involves the following steps:

22. 3. Oxidation of Toluene
 The use of manganese dioxide for the oxidation of toluene to benzaldehyde and benzoic acid was
formerly extensive.
 With manganese dioxide, the principal product is benzaldehyde. For benzaldehyde production, the
reaction is usually carried to the point where about 50 parts of benzaldehyde and 250 parts of toluene
are recovered from a batch operation starting with 300 parts of toluene. In order to prevent extensive
oxidation to benzoic acid, oxidation is not carried further than this

23. For high yields of benzoic acid, a stronger oxidizing agent such as
chromic acid or potassium permanganate is required.
300 kg of toluene and 700 kg of 65 per cent
sulfuric acid are mixed with intense stirring
then 90 kg of finely powdered manganese dioxide is added
while the temperature is held at 40°C.
Benzaldehyde is recovered by steam distillation
and constitutes a chlorine-free product.
Benzoic acid forms as a by-product.

24. 4. Aniline to Quinone
Sodium or potassium dichromate may be used to oxidize aniline to quinone, but a
low temperature and slow addition of the oxidizing agent must be employed.

25. • A mixture of 25 parts of aniline, 200 parts of water-white sulfuric
acid, and 600 parts of water, contained in a wooden or corrosion-
resistant vat, is cooled by ice or refrigeration.
• A solution of 25 parts of sodium dichromate in 100 parts of water is
then slowly added to with agitation and stirring is continued for 12 hr.
• A solution of 50 parts of sodium dichromate in 200 parts of water is
then added, and stirring is continued until the reaction is complete.
• During the whole operation, the temperature is maintained below
about 5°C through the addition of ice or by refrigeration.
• Quinone is recovered by skimming from the surface of the solution
and is purified by steam distillation.
Method

26. The oxidation of olefins and olefin derivatives with dilute aqueous potassium
permanganate may be used for the formation of dihydroxy compounds.
For example :
 With 2 per cent permanganate solution, cinnamic acid yields phenyl-glyceric acid through the
formation of a glycol derivative.
 Dilute permanganate oxidizes ethylenic bonds of fatty acids to dihydroxy groups, thus oleic acid to
dihydroxy stearic acid
 Hydrogen peroxide in the presence of catalysts of the oxides of Ru, V, Cr, or Mo also oxidizes organic
unsaturated compounds to glycols.
 More drastic oxidation of the ethylenic bonds of oleic, linoleic, and similar unsaturated fatty acids
causes the action to go beyond the formation of oxygenated groups and to result in rupture of the bond
as well as in oxidation. Such agents as the dichromates, permanganates, and nitric acid may be used to
obtain the effect. Thus, oleic acid, dihydroxystearic, and sterolic acids yield azelaic and pelargonic
acids, products that may be further oxidized if the reaction is forced.
5. Ethylenic Bonds to Dihydroxy Groups

27. Refrences
 https://simple.wikipedia.org/wiki/Oxidation
 P. H. Groggins, “Unit Processes In Organic Synthesis Fifth Edition”, Chemical Engineer
Technical Advisor, Food Machinery And Chemical Corporation, 5th Edition, Page No. 486-
506