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Non aqueous titrations

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Non aqueous titrations

  1. 1. Non Aqueous Titrations Deokate U. A. Copyright © by U. A. Deokate, all rights reserved.
  2. 2. Points to be covered • Types of solvents, • End point detection, • Application in assay of Sodium acetate, • Sodium benzoate, • Norfloxacin tablet 9/9/2018 2 Deokate U.A.
  3. 3. Introduction • Nonaqueous titration is the titration of substances dissolved in solvents other than water. • It is the most common titrimetric procedure used in pharmacopoeial assays and serves a double purpose: ▫ it is suitable for the titration of very weak acids and very weak bases, and ▫ it provides a solvent in which organic compounds are soluble. • The most commonly used procedure is the titration of organic bases with perchloric acid in anhydrous acetic acid. • These assays sometimes take some perfecting in terms of being able to judge the endpoint precisely. 9/9/2018 3 Deokate U.A.
  4. 4. Need of Non aqueous titrations Oftentimes we need to perform an acid-base titration in non- aqueous solvent due to: ▫ The analyte is too weak acid or a base to be titrated in H2O ▫ Reactants or products are insoluble in H2O ▫ Reactants or products react with H2O ▫ Titration in H2O doesn’t allow a sharp end point but in a nonaqueous solvent with a stronger base than OH- it is possible to get an sharp end point 9/9/2018 4 Deokate U.A.
  5. 5. Definitions of acids and bases • Bronsted Lowry; a general definition applicable to both aqueous and non aqueous systems ▫ Acids: proton donors ▫ Bases: proton acceptors • Lewis theory: Acids: electron pair acceptors Bases: electron pair donors • Strong acids in water HCl + H2O -----------> H3O+ + Cl- (acid) (base) (conjugate (conjugate acid) base) 9/9/2018 5 Deokate U.A.
  6. 6. weak acids in water HCOOH + H2O --------> H3O+ + HCOO (acid) (base) (conjugate (conjugate acid) base) weak acids in non aqueous solvents HCOOH + CH3NH2 -------> CH3NH4 + + HCOO (acid) (base) (conjugate (conjugate acid) base) It follows from these definitions that an acid may be either: * an electrically neutral molecule, e.g. HCl, or * a positively charged cation, e.g. C6H5NH3+, or * a negatively charged anion, e.g. HSO4-. A base may be either: * an electricially neutral molecule, e.g. C6H5NH2, or an anion, e.g. Cl-. Substances which are potentially acidic can function as acids only in the presence of a base to which they can donate a proton. Conversely basic properties do not become apparent unless an acid also is present 9/9/2018 6 Deokate U.A.
  7. 7. • The apparent strength of an acid or base is determined by the extent of its reaction with a solvent. • In aqueous solution all strong acids appear equally strong because they react with the solvent to undergo almost complete conversion to hydronium ion (H3O+) and the acid anion. • In a weakly protophilic solvent such as acetic acid, the extent of formation of the acetonium ion (CH3COOH2+) due to the addition of a proton provides a more sensitive differentiation of the strength of acids and shows that the order of decreasing strength for acids is perchloric, hydrobromic, sulfuric, hydrochloric, and nitric. • Acetic acid reacts incompletely with water to form hydronium ion and is, therefore, a weak acid. • In contrast, it dissolves in a base such as ethylenediamine, and reacts so completely with the solvent that it behaves as a strong acid. • This so-called levelling effect 9/9/2018 7 Deokate U.A.
  8. 8. Leveling effect or solvent leveling • Leveling effect or solvent: leveling refers to the effect of solvent on the properties of acids and bases. • The strength of a strong acid is limited ("leveled") by the basicity of the solvent. Similarly the strength of a strong base is leveled by the acidity of the solvent. • When a strong acid is dissolved in water, it reacts with it to form hydronium ion (H3O+).[2] An example of this would be the following reaction, where "HA" is the strong acid: • HA + H2O → A− + H3O+ • Any acid that is stronger than H3O+ reacts with H2O to form H3O+. Therefore, no acid stronger than H3O+ exists in H2O. • Similarly, when ammonia is the solvent, the strongest acid is ammonium (NH4+), thus HCl and a super acid exert the same acidifying effect. • The same argument applies to bases. In water, OH− is the strongest base. Thus, even though sodium amide (NaNH2) is an exceptional base (pKa of NH3 ~ 33), in water it is only as good as sodium hydroxide. • On the other hand, NaNH2 is a far more basic reagent in ammonia than is NaOH. 9/9/2018 8 Deokate U.A.
  9. 9. Solvents used in non aqueous titration • Solvent which are used in non aqueous titration are called non aqueous solvent. • They are following types:- 1. Aprotic Solvent 2. Protogenic Solvent 3. Protophillic Solvent 4. Amphiprotic Solvent 9/9/2018 9 Deokate U.A.
  10. 10. Aprotic solvents • Aprotic solvents are neutral, chemically inert substances such as benzene and chloroform. They have a low dielectric constant, do not react with either acids or bases and therefore do not favor ionization. • The fact that picric acid gives a colorless solution in benzene which becomes yellow on adding aniline shows that picric acid is not dissociated in benzene solution and also that in the presence of the base aniline it functions as an acid, the development of yellow color being due to formation of the picrate ion. • Carbon tetrachloride and toluene come in this group; they possess low dielectric constants, do not cause ionization in solutes and do not undergo reactions with acids and bases. • Aprotic solvents are frequently used to dilute reaction mixture 9/9/2018 10 Deokate U.A.
  11. 11. Protogenic solvents • Protogenic solvents are acidic substances, e.g. sulfuric acid. They exert a leveling effect on bases. • Anhydrous acids such as hydrogen fluoride and sulphuric acid fall in this category, because of their strength and ability to donate protons, they enhance the strength of weak bases. • Ex:- sulphuric acid , formic acid, propanoic acid ,acetic anhydride etc. • They have high dielectric constant and ionised because of their strength and ability to donate protons. 9/9/2018 11 Deokate U.A.
  12. 12. Protophilic Solvents : • Protophilic solvents are the substances that possess a high affinity for protons. The over all reaction can be represented as: ▫ HB+S ↔ SH+ + B- • The equilibrium in this reversible reaction will be generally influenced by the nature of the acid and the solvent. • Weak acids are normally used in the presence of strongly protophilic solvents as their acidic strengths are then enhanced and then become comparable to these of strong acids; this is known as the levelling effect. 9/9/2018 12 Deokate U.A.
  13. 13. Amphiprotic solvents • Amphiprotic solvents have both protophilic and protogenic properties. Examples are acetic acid and the alcohols. They are dissociated to a slight extent. The dissociation of acetic acid, which is frequently used as a solvent for titration of basic substances, is shown in the equation below: • CH3COOH ⇌ H+ + CH3COO− • Here the acetic acid is functioning as an acid. If a very strong acid such as perchloric acid is dissolved in acetic acid, the latter can function as a base and combine with protons donated by the perchloric acid to form protonated acetic acid, an onium ion: • HClO4 ⇌ H+ + ClO4− • CH3COOH + H+ ⇌ CH3COOH2+ (onium ion) • Since the CH3COOH2+ ion readily donates its proton to a base, a solution of perchloric acid in glacial acetic acid functions as a strongly acidic solution. 9/9/2018 13 Deokate U.A.
  14. 14. Glacial acetic acid • It is a solvent for base in particular • The water content should be less than 1% • Acetic anhydiride is added • When a weak base, such as pyridine, is dissolved in acetic acid, the acetic acid exerts its levelling effect and enhances the basic properties of the pyridine. It is possible, therefore, to titrate a solution of a weak base in acetic acid with perchloric acid in acetic acid, and obtain a sharp endpoint when attempts to carry out the titration in aqueous solution are unsuccessful. 9/9/2018 14 Deokate U.A.
  15. 15. Other solvent • Formic acid: is only used for the titratin of weakest base eg caffeine or urea • Trifluoroacetic acid: suitable as solvent for weakest base where acetic anhydride cannot be used because of acetylation. But it is expensive solvent. • Amphipotic basic solvent: eg Ethylendiamine, Butylamine, Benzylamine • Aprotic basic solvent: Pyridine, Dimethylformamide, Dimethylsulphoxide, 9/9/2018 15 Deokate U.A.
  16. 16. DETECTION OF END POINT • Visual indicator are found to the most suitable for the detection of end point in non-aqueous titration. The important indicator used for non-aqueous titration are follow: • 1. Crystal voilet:- It is used as 0.5% solution in glacial acetic acid, it gives voilet colour in basic medium and yellowish green in acidic medium. It is most widely use for the titration of pyridine with prechloride acid. • 2. Oracet Blue B Indicator:- It is prepared o.5% glacial acetic acid. It gives blue colour in basic medium while pink colour in acidic medium. • 3. Quinaldine Red Indicator:- It is used 0.1% solution in methenol/ethenol. Methenol is more stable. It gives yellow colour in basic medium while almost colourless in acidic medium. a 9/9/2018 16 Deokate U.A.
  17. 17. Other Indicator used • Methyl Red: Used as a 0.2% w/v solution in dioxane with a yellow to red colour change. • Naphthol Benzein: When employed as a 0.2% w/v solution in ethanoic acid gives a yellow to green colour change. It gives sharp end points in nitro methane containing ethanoic anhydride for titration of weak bases against perchloric acid. • Thymol Blue: Used extensively as an indicator for titrations of substances acting as acids in dimethyl formamide solution. A 0.2% w/v solution in methanol gives a sharp colour change from yellow to blue at the end point. 9/9/2018 17 Deokate U.A.
  18. 18. Visual indicators Indicator Color change Color change Color change basic neutral acidic Crystal violet (0.5 per cent in glacial acetic acid) violet blue-green yellowish -green α-Naphtholbenzein (0.2 per cent in glacial acetic acid) blue or blue- green orange dark- green Oracet Blue B (0.5 per cent in glacial acetic acid) blue purple pink Quinaldine Red (0.1 per cent in methanol) magenta almost colorless 9/9/2018 18 Deokate U.A.
  19. 19. Titrants used in non-aqueous titrimetry • Acidic titrants: ▫ Perchloric acid ▫ p- Toluenesulfonic acid, ▫ 2,4-Dinitrobenzenesulfonic acid • Basic titrants ▫ Tetrabutylammonium hydroxide ▫ Sodium acetate ▫ Potassium methoxide ▫ Sodium aminoethoxide 9/9/2018 19 Deokate U.A.
  20. 20. ASSAY BY NON-AQUEOUS TITRATIONS • Acidimetry in Non-aqueous Titrations • It can be further sub-divided into two heads, namely : 1. Titration of primary, secondary and tertiary amines, and 2. Titration of halogen acid salts of bases. • Alkalimetry in Non-aqueous Titrations— titration of acidic substances 9/9/2018 20 Deokate U.A.
  21. 21. Preparation of 0.1N solution of HClO4 and its standardization • Dissolve 8.5 ml of 72% HClO4 in about 900 ml glacial acetic acid with constant stirring, add about 30 ml acetic anhydride and make up the volume (1000 ml) with glacial acetic acid and keep the mixture for 24 hour. • Acetic anhydride absorbed all the water from HClO4 and glacial acetic acid and renders the solution virtually anhydrous. HClO4 must be well diluted with glacial acetic acid before adding acetic anhydride because reaction between HClO4 and acetic anhydride is explosive. • Standardize the above prepared 0.1N HClO4 with A.R. Grade Potassium acid Phthalate. • Solution in HClO4 in dioxane may be the 2nd titrant 9/9/2018 21 Deokate U.A.
  22. 22. Precautions • Perchloric acid is usually available as a 70 to 72% mixture with water .It usually undergoes a spontaneous explosive decomposition and, therefore, it is available always in the form of a solution. • Conversion of acetic anhydride to acetic acid requires 40-45 minutes for its completion. • It being an exothermic reaction, the solution must be allowed to cool to room temperature before adding glacial acetic acid to volume, • Avoid adding an excess of acetic anhydride especially when primary and secondary amines are to be assayed, because these may be converted rapidly to their corresponding acetylated non-basic products : • R—NH2 + (CH3CO)2O → R.NH.(CH3CO) + CH3COOH Primary amine Acetylated product • Perchloric acid is not only a powerful oxidising agent but also a strong acid. Hence, it must be handled very carefully. 9/9/2018 22 Deokate U.A.
  23. 23. Application of non aqueous titrations 9/9/2018 23 Deokate U.A.
  24. 24. Acidimetry 9/9/2018 24 Deokate U.A.
  25. 25. Alkali Metry • Many weakly acidic pharmaceutical substances may be titrated effectively by making use of a suitable non-aqueous solvent with a sharp end-point. • 0.1 N Potassium Methoxide in Toluene-Methanol • 0.1 N Sodium Methoxide or 0.1 N Lithium Methoxide 9/9/2018 25 Deokate U.A.
  26. 26. ADVANTAGES OF NON AQUEOUS TITRATIONS 1. Organic acids and bases that are insoluble in water are soluble in non-aqueous solvent. 2. Organic acid, which is of comparable strength to water, can be titrated easily in non-aqueous solvent. Bases also follow the same rules. 3. A non-aqueous solvent may help two are more acids in mixture. The individual acid can give separate end point in different solvent. 4. By the proper choice of the solvents or indicator, the biological ingredients of a substance whether acidic or basic can be selectively titrated. 5. Non aqueous titrations are simple and accurate, examples of non aqueous titration are: Ephedrine preparations, codeine phosphate in APC, tetracycline, teramycin, Antihistamines and various piperazine preparations. 9/9/2018 26 Deokate U.A.

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