Non Aqueous Titrations

A Comprehensive Note from Pharm-Analysis

1. NON AQUEOUS TITRATION

2. L1F16PHMD0097 Muhammad Awais L1F16PHMD0102 Fiza Areeb L1F16PHMD0121 Wajdan Rasheed L1F16PHMD0126 Ahmad Hasan Faizi L1F16PHMD0129 Noor F atima Presentation by Group 8, Section-B

3. Non aqueous titration is the titration in which titration of “ weak acidic or weak basic substance ” is carried out using “ non- aqueous substance” to get end point. Introduction

4. Weak Acid A weak acid is an acid that is ‘ partially dissociated’ into its ions in an aqueous solution or water. In contrast, a strong acid fully dissociates into its ions in water, e.g. Hydrofluoric acid (HF) Weak Base A weak base is a base that is ‘ partially dissociated’ in an aqueous solution, e.g . NH 4 OH.

5. Many substances like therapeutic agents are mostly, not only poorly soluble, but also weakly reactive in water. This disadvantage is overcome by Non aqueous solvents. Non-aqueous titration is a titration of substance which doesn’t dissolve in an aqueous solvent and a ‘Non- aqueous solvent’ is required for it.

6. Water behaves as both a weak acid and a weak base; thus, in an aqueous environment, it can compete effectively with very weak acids and bases with regard to proton donation and acceptance. Principle

7. The effect is that, the change in the titration curves for very weak acids and very weak bases is small, because they approach the pH limits in water of 14 and respectively, thus making end-point detection more difficult . A general rule is that bases with pKa < 7 or acids with pKa > 7 cannot be determined accurately in aqueous solution. Various organic solvents may be used to replace water since they compete less effectively with the analyte for proton donation or acceptance. Principle (Cont’d)

8. Substances which are either too weakly basic or too weakly acidic to give sharp endpoints in aqueous solution can often be titrated in non-aqueous solvents . The reactions which occur during many non-aqueous titrations can be explained by means of the concepts of the “ Bronsted - Lowry Theory ”. According to this theory, “ An acid is a proton donor and a base is proton acceptor .”

9. For example, Acetic acid in water is weakly acidic where as acetic acid in ammonia is strongly acidic, thus the acidic or basic characters of a compound depend on the uses of appropriate solvent. Principle (cont’d):

10. non-aqueous solvents Solvent which are used in non aqueous titration are called non aqueous solvent. They are following types :- Aprotic Solvent Protogenic Solvent Protophillic Solvent Amphiprotic Solvent THEORY

11. Aprotic solvents are most important solvent in this titration. These solvents are chemically inert and they work as a catalyst. These solvents increase the rate of speed in reaction and also decrease the rate of speed in reaction during the chemical process or reaction (it depends on condition ). The most important examples of aprotic solvent are; Chloroform, Benzene, Carbon tetra Chloride, Dioxan , Ethyl acetate &Toluene Aprotic solvents ( inert / neutral)

12. Protogenic solvents are acidic in nature and they can donate the proton, and enhance the strength of weak bases. Examples of Protogenic solvents are; HCL, H 2 SO 4. Protogenic solvents

13. Protophillic solvents are basic in nature, which possess a high affinity for proton. Example are; Liquid ammonia , amines and ketone. Protophillic solvents

14. Amphiprotic solvents are those solvents, which work as a both mean Protogenic or Protophillic . It means Amphiprotic solvents are acidic and basic in nature. And they accept the proton and donate the proton. For example; Alcohols and weak organic acids. Amphiprotic solvents:

15. Solvent Selection In non-aqueous titration, the solvent selection is mainly based upon the following parameters: Solubility of the sample Nature of the sample Should produce sharp end point Should have the high dielectric constant Should be of low toxicity Should be easily purified Should be in expensive

16. The procedure is same as general titration techniques (e.g. Acid-Base Titration, Redox Titration, etc .) Solvents for NAT Acetic acid is used for titration of weak bases and Nitrogen containing compounds. Acetonitrile/with AcOH : Metal Ethanoates . Alcohols: Soaps and salts of organic acids. Dimethylformamide : Benzoic acid and Amides. PROCEDURE

17. Titrants for NAT Perchloric acid in acetic acid (for Amines, Amine salts, Amino acid, salts of acids). Potassium methoxide in toluene- methanol. Quaternary Ammonium Hydroxide in Acetonitrile-Pyridine (for Acids, enols , imides & sulfonamides).

18. Detection of End Point 1. Visual indicators are formed to the most suitable for the detection of end point in NAT. The important indicators used for NAT are as follow; CRYSTAL VOILET : It is used as 0.5 % solution in glacial acetic acid. It gives violet color in basic medium and yellowish green in acidic medium. It is most widely used for the titration of pyridine with perchloric acid . QUINALDINE RED INDICATOR : It is used 0.1 % solution in methanol/ethanol. Methanol is more stable, it gives yellow color in basic medium and colorless in acidic medium.

19. SOME IMPORTANT I N D I C A T O R S

20. Assay by Non-aqueous Titration Acidimetry in non aq. Titration Alkalimetry in non aq. Titration Acidmetry in non-aq. titrations: “ The term  Acidimetry  refers to that part of volumetric analysis whereby an acid solution at known concentration , along with a specific indicator , is used to titrate a base solution and thus work out its concentration ” is further divided into two types: Titration of primary, secondary or tertiary amines. Titration of halogen acid salts of bases .

21. Alkalimetry in non aq. Titrations “The term  Alkalimetry refers to that part of volumetric analysis whereby a base solution at known concentration , along with a specific indicator , is used to titrate an acidic solution and thus work out its concentration” Many weakly acidic substances may be titrated effectively by making use of suitable non-aqueous solvent with a sharp end point i.e., 0.1N Potassium Methoxide in Toluene Methanol 0.1N Sodium Methoxide or 0.1 N Lithium Methoxide

22. FACTORS AFFECTING THE NON-AQUEOUS TITRATIONS Acid-base characteristics of the non-aqueous solvents affect the end-point in the non-aqueous titration . In the titration of weak base or acids, the addition of highly acidic or basic solvents increases the acidity or basicity and that increases the consumption of the titrant . Protolysis of the substance leads to the increase in the end point . The low dielectric constant solvents are commonly employed in the non-aqueous titrations which produce the accurate end points.

23. Precautions for the non-aqueous titrations Moisture must be avoided for non-aqueous titrations. Carbon dioxide must be avoided for non-aqueous procedures.

24. Advantages Organic acids and bases that are insoluble in water are soluble in non- aqueous solvent. A non-aqueous solvent may help two are more acids in mixture. The individual acid can give separate end point in different solvent. Enlargement of solubility range: Many substances that are not soluble in water can be easily titrated in water-free media (e.g. fats and oils). Enlargement of application range: weak bases and acids can be easily titrated.

25. Substance compositions that cannot be separately determined in aqueous media can often be titrated in non-aqueous media . Non-aqueous solvents are useful for the titration of very weak acids or bases that cannot be titrated in water. Non aqueous titrations are simple and accurate.

26. Solvents are expensive. Volatile solvents can pollute environment. Indicator must be prepared in non-aqueous medium. Temperature corrections are necessary for the non-aqueous solvents . Non-aqueous solvents are not stable compared to aqueous solvents. DisAdvantages

27. Applications Percentage of purity is determined by the assays i.e., Sulphonylamides . Used in the determination of hydrophobic compounds like Amantadine HCL Barbiturates alkaloids. Used in the determination of diuretics . Used to quantify mixtures of primary , secondary & tertiary amines. F or many other organic amino compounds and salts of organic acids. Used in the Analysis of Certain Pharmaceutical Preparations Like steroids, anti-tubercular drugs, adrenergic drugs etc.

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