Non-Aqueous Acid-Base Titration Non-aqueous acid-base titration is the titrimetric method in which the neutralization reaction between acid and base is conducted in purely non-aqueous medium. Reasons for performing non-aqueous acid-base titration Non-aqueous titration was introduced to eliminate 3 basic problems related to aqueous acid-base titration. 1. Interaction of water with the titrant: Water behaves as both weak acid and weak base. If the drug is very weakly acidic (weaker acid than water) or very weakly basic (weaker base than water), then water will compete with the drug for the titrant. H 2O + B OH- + BH+ H2O + H+ competes with competes with ROH + B acid RO- + BH+ H3O+ RNH2 + H+ RNH3+ Base Hence, the end-point may not be detected (the inflection in the titration curve is small) or may give wrong result. Reasons for performing non-aqueous acid-base titration 2. Poor solubility of the drug in water: Most of the weak acids and weak bases are non-polar and organic. Thus they tend to be less soluble or insoluble in water. So aqueous titration becomes impossible. 3. Water sensitivity: There are many drugs which are sensitive to water and therefore should be assayed via non-aqueous titration (e.g. ) Acidity and basicity An acid can only donate its proton in presence of a base. So an acid can show its acidity only in the presence of a base and vice versa. Now when a weak base is added to water then, only a fraction of the base accepts proton. This is because the base has weak proton accepting capacity and water has weak donating capacity. So, the base shows weak basicity in water. Now, suppose the base is dissolved in acetic acid (a weak acid). The solvent has greater tendency to donate proton than water. So the base can more easily accept proton. Thus the basicity of the base is higher in acetic acid. Acidity and basicity Thus a sharper end point can be achieved when acetic acid is used as solvent rather than water. Generally, bases with pKa<7 and acids with pKa>7 can’t be accurately titrated in aqueous media and non-aqueous titration becomes necessary. Solvents used in non-aqueous titration According to the acid-base character, non-aqueous solvents are categorized into four groups – Protophillic solvents: 1. They are basic in nature – possess high affinity for protons. 2. When weak acid is added to a strongly protophillic solvent, the weak acid act as a strong acid. Thus they are used for titration of weak acids so that they would act as strong acids. e.g. ethers (and dioxane), ketones (e.g. acetone), amines (including liquid ammonia), pyridine, acetic anhydride etc. Solvents used in non-aqueous titration Protogenic solvents: 1. They are acidic in nature 2. Donate protons. 3. When a weak base is added to a strongly protogenic solvent, the weak base act as strong base. Thus they are utilized for the titration of weak bases. All acids can act as protogenic solvent. e.g. sulfuric acid, hydrochloric acid. Solvents used in non-aqueous titration Amphiprotic solvents: 1. They can donate or accept proton. 2. They are both acidic and basic in nature. 3. They are all capable of slight dissociation. 4. They can produce levelling effect (enhance acidity or basicity) on both weak acids and weak bases. e.g. acetic acid, alcohols and water itself. Solvents used in non-aqueous titration Aprotic solvents: 1. They neither donate nor accept proton. 2. They are neutral, chemically inert substances. 3. They have low dielectric constant. 4. They do not participate in the neutralization reaction, rather act as carriers. Thus they are useful to study reactions free from solvent effects. 5. They are non-dissociating. e.g. benzene, chloroform, hydrocarbons. Acidimetry Acidimetry is the determination of acidic substance by titrating with a standard base solution (this definition was taken from Pharmaceutical chemistry – Leslie G. Chatten vol. 1 and also sources from internet, other books define acidimetry as the determination of basic substances with a standard acid solution). Exemplary, determination of aspirin with sodium hydroxide, determination of phenytoin with sodium methoxide etc. Principle of Acidimetry Solvents: Commonly used solvents are – 1. Strong protophillic (basic) solvents: e.g. Ethylenediamine, n-butylamine etc. These are suitable for very weak acids. 2. Weak protophillic (basic) solvents: e.g. Dimethylformamide (DMF), pyridine etc. These are suitable for medium strength acidic substance. 3. Relatively neutral solvents: Suitable for strongly acidic compounds. Examples – acetone, acetonitrile, ,methylethyl ketone. All solvents commonly used are non-acidic. Basic solvents e.g. n-butylamine can be used for enhancing the acidic character. But since those solvents exert a leveling effect on acids, these solvents are not suitable for titration of mixtures. Principle of Acidimetry Titrants: Methoxides of alkali metals e.g. Na-methoxide, Li-methoxide, K-methoxide etc. are most widely used as titrants in non-aqueous acidimetry. Among them Na- oMe is probably most used. Potassium methoxide is not used anymore due to the formation of gelatinous reaction product (sodium methoxide can also form gels). Other than that, terbutyl ammonium hydroxide, KOH in methanol etc. are also used. Apparatus: Three-necked flask. This flask contains an inlet and a outlet for nitrogen atmosphere and on opening for the burette tip.