Chapter 15. Pyridine derivatives

General reactions of pyridine cycle

1. Pyrolysis

Heating crystals of pyridine derivatives with sodium carbonate leads to pyridine formation, which can be identified by specific smell.

2. Colored reaction with citric acid and acetic anhydride

Heating a substance with crystalline citric acid and acetic anhydride produces cherry-red color.

3. Polymethine dye formation through glutaconaldehyde:

Nicotinic acid derivatives

Nicotinic acid

Acidum nicotinicum

Pyridine-3-carbonic acid

Description: white crystalline powder; slightly soluble in cold water, soluble in hot water, solutions of acids and bases.

Nicotinamide

Nicotinamidum

Amide of nicotinic acid

Description: white crystalline powder; freely soluble in water.

Nicotine diethylamide

Description: oily yellow liquid.

Identification:

• melting temperature, UV and IR spectroscopy;
• all pyridine cycle reactions;
• proof of acidic properties of nicotinic acid:

a) dissolution in alkali, carbonates and hydrocarbonates of alkali metals;

b) reactions with heavy metal salts:

• proof of amide bond in nicotinamide:

a) hydrolysis (specific reaction):

b) hydroxamic test (non-specific reaction).

Assay

1. Nicotinic acid ― alkalimetry.
2. Nicotinamide.

А. Non-aqueous titration of pyridine nitrogen.

B. Kjeldahl method.

Substance is heated with concentrated sulfuric acid, producing ammonia sulfate, which is decomposed using alkali, forming ammonia, which escapes reaction mixture and is absorbed by boric acid:

B(OH)₃ + H₂O = HB(OH)₄;

NH₃ + HB(OH)₄ = (NH)₄B(OH)₄.

Forming ammonia tetrahydroxyborate is titrated with 0.1 M solution of hydrochloric acid:

(NH)₄B(OH)₄ + HCl = NH₄Cl + H₃BO₃ + H₂0.

3. For amides

Instead of mineralization with sulfuric acid, substance is heated with NaOH, forming ammonia is treated as described above.

4. For both substances ― UV-spectrophotometry, HPLC.

Isonicotinic acid derivatives

Isoniazid. Isoniazidum

Hydrazide of isonicotinic acid:

Description: White crystalline powder; freely soluble in water.

Ftivazide. Phthivazidum.

ftivazide = isoniazide + vanilline = hydrazone:

Description: Light-yellow or yellow fine crystalline powder with faint vanillin smell; very slightly soluble in water, freely soluble in acids and alkalis with intensifying color, soluble in alcohol.

Differentiation

Identification:

1. melting temperature, UV and IR spectroscopy;
2. all pyridine cycle reactions.

ISONIAZID

Proof of acidic properties in neutral solutions and reducing properties at high temperatures:

FTIVAZIDE

1. Ampholytic ― soluble in acids and alkalis with intensifying color.
2. Acid hydrolysis of azomethine group.
3. All phenol hydroxyl reactions:
   • acidic properties (solving in NaOH, reaction with FeCl₃);
   • three dye formation reactions (azo dye, aurin, indophenol).

Assay

Isoniazid

1. Acid-base titration in glacial acetic acid with addition of acetic anhydride. Titrant ― perchloric acid.

2. Iodometry in alkaline medium, back titration.

Excess of standard iodine solution is titrated with sodium thiosulfate:

I₂+ 2Na₂S₂O₃=2NaI+Na₂S₄O₆.

Ftivazide

Acid-base titration in non-aqueous medium. Titrant - HClO₄.

Both substances ― UV-spectrophotometry, HPLC.

Pyridinemethanol derivatives

Pyridoxine

Pyridoxine hydrochloride

Pyridoxini hydrochloridum

Description: White fine crystalline powder; freely soluble in water, practically insoluble in alcohol. Vitamin B₆.

Chemical structure:

1. pyridine derivative;
2. salt;
3. phenol hydroxyl;
4. two aliphatic hydroxyls.

Identification:

1. melting temperature, UV- and IR-spectroscopy;
2. tests:
   • pyridine cycle reactions;
   • proof of salt (solubility in water, acidic pH, base can be precipitated with ammonia);
   • proof of basic properties: reactions with general alkaloid reagents;
3. chloride ion reaction: with silver nitrate;
4. all phenol hydroxyl reactions (see Ftivazide).

Specific case ― formation of indophenol dye with 2,5-dichlorquinonchlorimide (blue color):

Assay

Acid-base titration in non-aquatic medium, solvent ― glacial acetic acid with addition of mercury acetate or acetic anhydride for binding of chloride-ion; titrant ― HClO₄.