Chapter 14. Analysis of furane, benzopyrane, pyrazole, imidazole and indol derivatives

5-nitrofurane derivatives

NITROFURAL

Nitrofuralum

Appearance: yellow or brownish-yellow crystalline powder.

Solubility: very slightly soluble in water, slightly soluble in ethanol (96%).

ACID-BASE PROPERTIES

The acidic properties of nitrofural are caused by the mobile hydrogen atom of the amide group in the semicarbazide residue; when dissolved in 10% sodium hydroxide solution, it results in an orange-red color. In this case, deprotonation of the NH-acid center causes a redistribution of the electron density, which, in turn, leads to the ionization of the substance and the formation of a new conjugated system of double bonds. These two factors cause the deepening of the color:

The acidic nature makes complexation reactions with heavy metal ions (Cu²⁺, Co²⁺, Ag⁺) possible. These reactions are nonspecific.

HYDROLYTIC SPLITTING

As a semicarbazone, nitrofural undergoes hydrolysis when heated in both acidic and alkaline media to form the corresponding products:

QUANTITATION

UV spectroscopy.

APPLICATION IN MEDICINE

Antibacterial agent.

STORAGE

Protected from light.

NITROFURANTOIN

Nitrofurantoinum

A yellow crystalline powder or yellow crystals, very slightly soluble in water and in ethanol (96%), soluble in dimethylformamide.

ACID-BASE PROPERTIES

Nitrofurantoin exhibits acidic properties due to keto-enol and lactim-lactam tautomerism in the hydantoin fragment:

QUANTITATION

UV spectroscopy.

APPLICATION IN MEDICINE

Antibacterial agent.

STORAGE

Store protected from light, at a temperature below 25 °C.

BENZOPYRAN DERIVATIVES

RUTOSIDE TRIHYDRATE

Rutosidum trihydricum

Appearance: yellow or greenish-yellow, crystalline powder.

Solubility: practically insoluble in water, soluble in methanol, sparingly soluble in ethanol (96%), practically insoluble in methylene chloride. It dissolves in solutions of alkali hydroxides.

In terms of chemical structure, rutin is a glycoside. The sugar part (disaccharide rutinose) includes D-glucose and L-rhamnose. Aglycone quercetin is a flavonoid containing a chroman nucleus.

ACID-BASE PROPERTIES

The presence of phenolic hydroxyls gives the compound acidic properties and, consequently, the ability to dissolve in dilute alkalis with a deepening of the color to yellow-orange.

AZO DYE FORMATION

As a phenol, rutin is able to enter into an azo coupling reaction with the formation of an azo dye. This requires obtaining diazonium salt and adding it to an alkaline solution of rutin. A dark red color appears.

REACTIONS TO THE SUGAR COMPONENT

As a glycoside, rutin reacts positively to the sugar component with Fehling’s reagent. For this, rutin is preliminarily subjected to acid hydrolysis by heating, as a result of which the glycosidic bond is destroyed and sugars with reducing properties are released. Then, boiling with Fehling’s reagent results in a red precipitate of copper(I) oxide.

FORMATION OF PYRYLIUM SALTS (CYANIDIN TEST)

The specific reaction that helps determine the authenticity of rutin is the cyanidin test. It is based on the formation of colored pyrylium salts upon reduction of the flavonoid fragment with hydrogen. To do this, an alcoholic solution of rutoside is mixed with concentrated hydrochloric acid and zinc powder. The resulting red coloration is inherent in cyanine chloride, i.e., benzopyrylium or benzopyroxonium salts:

QUANTITATION

Acid-base titration in a non-aqueous medium (medium: DMF; titrant: tetrabutylammonium chloride, CTT: potentiometric).

1 mL of 0.1 M tetrabutylammonium hydroxide is equivalent to 30.53 mg of C27H30O16.

APPLICATION IN MEDICINE

Vitamin PP.

STORAGE

Protected from light.

PYRAZOLE DERIVATIVES

Pyrazole is a five-membered aromatic heterocycle with two nitrogen heteroatoms in positions 1 and 2. In medicine, derivatives of pyrazoline (a partially hydrogenated system) are used, the oxidized form of which is called pyrazolone-5:

PHENAZONE

Phenazonum

Appearance: white or almost white, crystalline powder or colorless crystals.

Solubility: very soluble in water, in ethanol (96%) and in methylene chloride.

Phenazone is soluble in water, wherein it forms an internal salt (zwitterion) or a betaine structure which is easily solvated with water:

ACID-BASE PROPERTIES

The weakly expressed basic center is a nitrogen heteroatom in position 2. The nitrogen atom in position 1 practically does not exhibit basic properties due to the influence of the oxygen atom of the carbonyl group and the phenyl radical. Thus, phenazone is a weak one-acid base. Its aqueous solution is neutral (pH=6.0-7.5).

As nitrogen-containing organic bases, medicinal substances of the pyrazolone group form precipitates of complex salts when they react with general alkaloid reagents. The reaction with Lugol’s reagent (iodine solution in potassium iodide) is notable. First, phenazone and iodine solution form the colorless iodopyrine, therefore, iodine discoloration occurs when the first drops of the reagent are added. Then (with an excess of the reagent) there appears a brown precipitate of the complex salt periodide.

S_E REACTION

Due to the formation of the betaine structure and its aromatic character, antipyrine enters into S_E reactions at position 4. Nitroso and nitro derivatives are electrophiles, as well as halogens; therefore, unlike analgin, antipyrine is not oxidized by solutions of iodine and sodium nitrite in an acidic medium, but forms substitution products: