Chapter 11. Derivatives of phenols, quinones, aromatic acids, phenolic acids, aromatic amino acids

Medicinal substances of the phenol group

Phenols are aromatic compounds in which one or more hydrogen atoms are replaced by hydroxyl groups.

Phenol

(Phenolum)

Antiseptic, preservative

Thymolol

(Thymol. Thymolum)

2-isopropyl-5-methylphenol

Anthelmintic

General chemical structure

1. Aromatic ring.

2. Phenolic hydroxyl.

Description

All preparations are colorless crystals with a characteristic odor.

Phenol is soluble in water.

Timol is freely soluble in ethanol.

IR-spectrum,UV-spectrum.

Identification

1. Acidic properties.

2. Oxidation reactions.

3. Substitution reactions.

4. Condensation and oxidation reactions.

1. Acidic properties

Phenols exhibit acidic properties due to the mobility of the hydrogen proton of the hydroxyl group. Phenols dissolve well in aqueous alkaline solutions to form phenolates, but they do not react with hydrocarbonates of alkali metals.

Characteristic qualitative reaction on phenols is formation of colorful complexes of [Fe(OR)₆]^3- with trivalent iron salts.

2. Oxidation reactions

Phenols are easily oxidized even by air oxygen, so the storage of phenols may produce tints (pink, yellow, brown).

The oxidation reaction of phenols-indophenol assay is used in the analysis.

3. Substitution reactions

(a) Halogenation

The formation of tribromophenol as a precipitate is used to confirm the authenticity of phenol:

(b) Nitration

Phenols are nitrated with nitric acid at room temperature to form a mixture of o- and p-nitrophenol:

(c) Coupling reactions of phenols with a diazonium salt

Phenols easily enter into a substitution reaction with diazonium salts in a slightly alkaline medium (in sodium acetate medium), a yellow to brown precipitate falls out.

Obtaining the diazonium salt. Because of its instability, the reagent is prepared immediately before use. The formation of diazonium salt occurs in an acidic environment in the interaction of compounds with a primary aromatic group (e.g., streptocide) with sodium nitrite.

4. Oxidation and condensation reactions

During condensation of phenols with aldehydes followed by oxidation of the condensation product the formation of colorants occurs:

Assay

Bromatometric method

(a) TIMOL (direct method)

Titrant - potassium bromate.

Methyl orange with methyl red indicator.

A titrated solution of potassium bromate in an acidic medium reacts with potassium bromide.

KBrO₃ + 5KBr + 3H₂SO₄ ⇒ 3Br₂ + 3K₂SO₄ + 3H₂O

Bromine is consumed for halogenation of phenol:

(b) PHENOL (reverse method).

Titrant: potassium bromate, sodium thiosulfate.

Starch is the indicator.

Excess of titrated potassium bromate solution reacts with potassium bromide in an acidic medium:

KBrO₃ + 5KBr + 6НCl ⇒ 3Br₂ + 6K Cl+ 3H₂O

The bromine released as a result of the reaction is used for halogenation of phenol:

Excess bromine reacts with potassium iodide:

Br₂ + 2KI ⇒ I₂ + 2KBr

The released iodine is titrated with sodium thiosulfate. Starch is an indicator:

I₂ + 2Na₂S₂O₃ ⇒ 2NaI +Na₂S₄O₆

P-aminophenol derivatives

The n-aminophenol group includes the drug paracetamol.

Paracetamol

(Paracetamolum)

N-(4 hydroxyphenyl) acetamide

An antipyretic and analgesic

Chemical structure

1) phenolic hydroxyl;

2) amide bond.

Description

White crystalline powder; sparingly soluble in water; melting point 168-172°, IR spectrum, UV spectrum.

Identification

1. Acidic properties.

2. Oxidation reactions.

3. Substitution reactions.

1. Acidic properties

Reaction on phenolic hydroxyl: with alkalis and with salts of heavy metals the formation of salts ―phenolates:

2. Oxidation reaction

When boiled with hydrochloric acid diluted paracetamol undergoes hydrolytic cleavage to form acetic acid and p-aminophenol.

Afterwards, p-aminophenol is oxidized with potassium dichromate and condensed with unreacted p-aminophenol to give the violet color indamine colorant (similar to indophenol in its characteristics):

3. Substitution reaction

Formation of the azo dye

The azo dye is due to the phenolic hydroxyl. The drug is dissolved in alkali, sodium acetate and 1-2 drops of freshly prepared diazonium salt are added. A red precipitate appears.

Assay

Nitrite titration method

Titrant: sodium nitrite.

Indicator: starch-iodide paper.

The drug substance is first acid hydrolyzed by heating under reflux for 1 hour:

Then titrated with sodium nitrite using starch-iodide paper as an indicator:

At the point of equivalence sodium nitrite reacts with potassium iodide, the iodine released stains the starch blue:

2NaNO₂ + 2KI + 4HCl → I₂ + 2NO + 2KCl + 2NaCl + 2H₂O.

It is necessary:

1. slowly titration;
2. temperature less than 10-20 °C;
3. addition of KBr.

Quinone derivatives

The synthetic drug Vikasolum, a water-soluble vitamin K, is considered in this group.