Oxidation (Unit Process-1) Pharmaceutical Process Chemistry Aikan Gupta (Pharmaceutical Chemistry) Nitin Goel (Pharmacognosy) G.H.G. Khalsa College of Pharmacy, Gurusar SudharOxidation Q 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: Fe,0, + 3CO — 2Fe + 3C0, / Or O Oxidation is any chemical reaction that involves the moving of electrons. pecifically, it means the substance that gives away electrons is oxidized. Normally, this is a reaction between oxygen and a substance such as iron. ‘or example: 4Fe + 30, > 2Fe,0, °—+Fe,03.x H,0Types of Oxidative Reactions In thie organic chemical industry, oxidation constitutes one of the most powerful tools sd 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 “actions may be set forth as further.1. Dehydrogenation | Dehydrogenation is illustrated in the transformation of a primary alcohol to an aldehyde: C3H;OH + 1/20, ——* CH,CHO + H,0 or a/secondary alcohol to a ketone: CHjCHOHCH, + 1/20, ——> CH,COCH, +H,02. Peroxidation | Peroxidation occurs readily under certain conditions. Thus, some reactions occur directly with air when catalysed by ultraviolet irra Isopropyl benzene —“*— _ Isopropyl benzene peroxide uv Others‘require the interaction of an inorganic peroxide: Hy 2 a pea + NaO; —= Cp-é-0-0-€-€) + 2NaCl Benzoyl Chloride Benzoyl Peroxide3. Introduction of oxygen atom | An atom of oxygen may be introduced into a molecule, as is illustrated by the oxidation of an aldehyde to an acid: CH;CHO + 1/20,——* CH,;COOH ydrocarbon to an alcohol: (CgHs)3CHy + 1/2 05 (CoHs);COH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: CH, +O CH,0 + H30 r the preparation of benzoic acid from benzyl alcohol: CcHgCH,OH +0,— C,H,COOH + H,0§. Dehydrogenation may also be accompanied by molecular condensation 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 2C gH, + 1/20, CeHs-CoH; + H20 2C4HsCH; + 0, CHsCH=CHC Hs + 2H,05. Dehydrogenation, oxygen introduction, and destruction of carbon linkages Dehydrogenation, oxygen intreduction, and destruction of carbon linkages may all occur in the same process of oxidation, e.g., inthe oxidation of naphthalene to phthalic anhydride: C\oHy + 4.50, CgHyO3 + 2H,0 + 2C0, 6. Oxidation may be accomplished indirectly through the use of intermediate reactions: - CgHsCH}—* _CgH,CCl, —> CyHsCOOH Naout CcHg ——™ CoHsS03H ——> CgHsOH CH,OH+CO CH,COOH7. Olefins Oxidation 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 dihydroxystearie acid with alkaline potassium permanganate: KMn0, CH4(CH3);CH=CH(CH3),;COOH — CH;(CH2);CHOH-CHOH(CH;);-COOH CH;-(CH,);-COOH N CHy(CH,);CH=CH(CH,),;COOH ie So, COOH-(CH3);-COOH9. Amino compounds may be oxidized to: | * Azobenzene = p-Amino-Phenol = Nitrobenzene under moderate conditions.10. Sulfur compounds Oxidation ‘Sulfur compounds may be oxidized by acid permanganate, as in the preparation of sulfonals, trionals, and tetranals from (CH,),C(S.C,H,), in which the sulfide sulfur is oxidized to sulfonic groups. It should be noted that the mercaptans behave differently toward oxidizing agents from the aleohols, in that the action of strong oxidizing agents increases the valence of the sulfur atom instead oPfemovinig hydrogen, as in the case of the aléohols. Thuis: oxidation dati CHiCH,OH “= CH,CHO + H50 Ethyl Alcohol Acetaldehyde CH;CH,SH ——* CH,CH,SO,0H Ethy! Mereaptan Ethanestilfonic Acidf / Liquid phase oxidation with oxidizing agentsJ shown in the accompanying tabulation Oxidizing agent cid at O-10°C, for 24 hie, “Alkaline hypochlorite Hypachlorous acid The oxidation of aniline furnishes an example for comparison of a number of oxidizing agents. Results obtained by conducting the reaction under conditions best suited for the particular agent are Product Quinone Quinone -Aniline black -Azobenzene plus ammonia -Azohemene plus -Nitrobenzene -p-AminophenolAnother substance exhibiting a Variety of action toward oxidation agents is furfural: hw Ht \ “3 eH0 behaves like that of acetaldehyde toward oxidation, but in the ids are formed. The aldehyde group norm: presence of certain agents, the ring structure is destroyed and poly tas For example: Oxidizing agent Product Sodium chlorate in neutral solution with Vz0, catalyst Fumaris acid Sodium chlorate in dilute acid with Os, eatalyst MexOtartaric acid Catos' acid, HO-O-SO3H, a strong oxidizing agent Suiceinic aciel Hydrogen peroxide in presence of ferrous salis S-Hydroxy furfural Bromine water at 100°C Mucobromie acid Potassium perimanganate (diluted solution) Pyromucie acidFactor effecting action of oxidizing agents: | 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 * Hydrogén-ion concentration Method of mixing sequently, any comparison of the variety of effects obtainable by varying the oxidizing agent or organic compound cannot be pursued too far.Example related to liquid phase oxidation with oxidiz ing agents1. Isoeugenol to Vanillin ‘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 Isocugenol, the hydroxyl group is protected by acetylation, and the substance is oxidized and then saponified to vanillin, on on oc OCH, lochs oH Eugenet fwoougeno! Varin ‘idizing Agents used: - Dichromate ( but result in formation of acids) - Permanganate - NitrobenzeneTechnically process in Vanillin synthesis Eugenol from oil of cloves is dissolved in dilute sodium hydroxide solution I Then heated to 160°C under pressure in an autoclave, l This converts the Eugenol to soeugenol and forms the sodium salt. | For oxidation, 1 mole of nitrobenzene is added for each mole of Eugenol originally transferred to the autoclave.| Nitrobenzene is added slowly as the oxidation proceeds ! After the reaction is completed, pressure on the autoclave is released, and the gaseous by-products are permitted to blow off. | ‘Vanillin may be recovered from the alkaline solution by precipitation with hydrochloric acid. | ‘The yield approximates 80 per cent.2. Isoborneol 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: o-oo Pinche Bomiyl chloride’ Camiphene Fabornyl aectane Isobornyl —— Camphor Distillation of turpentine to obtain pinene ‘Saturation with HCI gas to obtain borny| chloride Hydrolyzing this to obtain camphene Esteri fying camphene to isobornyl acetate Saponification to Isabormeo! Oxidation to camphor.3. Oxidation of Toluene = The use of manganese dioxide for the oxidation of toluene to benzaldehyde and benzdic 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 CH3 CHO 6-6 Toluene Benzaldehyde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 COOH sulfuric acid are mixed with intense stirring Chromic acid then 90 kg of finely powdered manganese di is added ee while the temperature is held at 40°C. Benzaldehyde Benzaldehyde is recovered by steam distillation and constitutes a chlorine-free product. Benzoie acid forms as a by-product.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. NH, 9 ° Aniline QuinoneMethod 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 iv [00 parts of water is then slowly added to with agitation and stirring is continued for 12 hr Aolution of 50 parts of sodium dichromate ir 200 parts of water is en added, and stirring is continued until the reaction is complete. During the whole operation, the temperature is maintained below about 5°C threugh the addition of ice or by refrigeration. Quinone is recovered by skimming from the surface of the solution and is purified by steam distillation.5. Ethylenic Bonds to Dihydroxy Groups |The oxidation of olefins and olefin derivatives with dilute aqueous potassium | permanganate may be used for the formation of dihydroxy compounds. Forexample = © With 2 per cent permanganate solution, cinnamic acid yields phenyl-glyceri¢ acid. through the formation of a glycol derivative. * Dilute pefmanganate o: dihydngxy stearic acid acid to i2es ethylenic bonds of fatty acids to dihydroxy groups, thus 0 Hygfogen peroxide in the presence of catalysts of the ox ‘ungaturated compounds to glycols. of Ru, ¥, Cr, or Mo also oxidizes organic lore drastic oxidation of the ethylenic bonds of oleic, linoleic, and similar unsaturated fatty acids fauses the action to go beyond the formation of oxygenated groups and to result in rupture of the bond is Well as [Link]. Such agents as the dichromates, permanganates, and nitric acid may be used to biain the effect. Thus, oleic acid, dihydroxystearic, and sterolic acids. yield azelaic and pelurgonic cds, products that may be further oxidized if the reuction is forced.Refrences = https//[Link]/wiki/Oxiciation = PH. Gro, “Unit Processes In Organi Technical Advisor, Food Mac 506 ‘nthesis Fifth Edition”, Chemical Engineer ition, Page No. 486-