Acidic properties.

The greater mobility of the hydrogen atom of the hydroxyl group of phenols compared to alcohols also determines their greater acidity. Evidence of the greater acidity of phenols compared to alcohols is that phenol and its derivatives react with aqueous solutions of alkalis, forming salts called phenoxides. Phenoxides are relatively stable and, unlike alcoholates, can exist in aqueous alkaline solutions. However, when a current of carbon dioxide is passed through such a solution, phenoxides are converted into free phenols. This reaction proves that phenol is a weaker acid than carbonic acid.

1. Phenols can interact:

a) with alkali metals:

b) with alkalis:

Salts of phenols (phenolates) are easily decomposed by mineral acids, even carbonic acid:

Nucleophilic substitution reactions.

Due to +M-by the effect of the hydroxyl group, phenols are weaker nucleophiles than alcohols.

Interaction with halogen derivatives. Given the weak nucleophilic properties, in nucleophilic substitution reactions it is usually not phenols themselves that are used, but their salts - alkali metal phenoxides. When phenoxides react with alkyl and aryl halides, they form ethers phenols.

1. Alkylation (formation of ethers):

2. Acili

When phenols are exposed to acid chlorides or carboxylic acid anhydrides, esters are formed. Unlike alcohols, phenols do not form esters when exposed to carboxylic acids.

Interaction with FeCl 3 (qualitative reaction to phenol)

Reactions of hydrocarbon radicals.

It was previously noted that the hydroxyl group in phenols exhibits a +M effect and behaves as an electron donor with respect to the benzene ring. It is a type I orientation agent and directs the attack of electrophilic reagents into ortho-And pair- position of the benzene ring. Due to the electron-donating effect of the hydroxyl group, phenols undergo electrophilic substitution reactions more easily than benzene.

Reactions occurring on the benzene ring.

The influence of atoms is mutual. The hydroxyl group affects the benzene ring. Hydrogen atoms become mobile in the ortho- and para-position and are replaced by other atoms and radicals:

a) halogenation (reaction with bromine water):
This reaction is used for the qualitative detection and quantification of phenols.

b) nitration:

c) sulfination:

According to IUPAC rules, the sulfonic group is older than the hydroxyl group, so sulfonation products are called sulfonic acids.

D) oxidation of phenols.

Phenols are easily oxidized under the influence of atmospheric oxygen:

No. 30. Phenol, resorcinol, pyrocatechol, hydroquinone, use in medicine.

a) C 6 H 5 - OH (phenol). - Colorless crystalline substance with a pungent characteristic odor. During storage, it is oxidized by atmospheric oxygen, acquiring a pink color. Melts at 42.3ºС, boils at 182ºС, partially soluble in water (6g per 100g of water). It has strong antiseptic properties and is poisonous. When applied to the skin, it burns, forming blisters and ulcers. A 3% solution of phenol in water is called carbolic acid and is used as a disinfectant. It is used for the synthesis of dyes, plastics, and medicines.

b) Hydroquinone - found in bearberry, easily oxidized, poe This is why they are used in photography as developers.

c) Pyrocatechol- a crystalline substance that darkens during storage, used as a developer in photography, in the synthesis of dyes, plastics, medicines.

d) Resorcinol- a crystalline substance that darkens in air and is used as an antiseptic in the production of dyes and plastics.

No. 31. Oxo compounds. Electronic structure of the oxo group. Nomenclature of aldehydes and ketones. Methods for obtaining aldehydes.

Functional analysis of organic medicinal substances

The overwhelming majority of medicinal substances used in medical practice are compounds of organic nature. Unlike the analysis of inorganic substances, which uses the properties of the ions that form them, the basis of the analysis of organic medicinal substances is the properties of functional groups.

Functional groups- these are individual atoms or groups of atoms associated with a hydrocarbon radical, which, due to their characteristic properties, can be used for the purposes of identification and quantification of medicinal substances.

The presence of several functional groups influences the effects of some general reactions and the properties of the products formed as a result of their occurrence.

Classification of functional groups

1. Oxygen-containing functional groups:

OH - hydroxyl (alcoholic or phenolic);

C=O; -C=O - carbonyl (ketone or aldehyde);

COOH - carboxyl;

C-O- - ester group;

CH-(CH 2) n -C=O – lactone group.

NH 2 - primary amino group, aliphatic or aromatic;

NO 2 - aromatic nitro group;

NH- - secondary amino group;

N- - tertiary nitrogen atom;

C-NH- - amide group;

CH-(CH 2) n -C=O – lactam group;

С-NH-C- - imide group;

SO 2 -NH- - sulfamide group;

CH = N- - azomethine group;

3. Other functional groups:

Aromatic (phenyl) radical;

- pyridine ring;

R―Gal - covalently bonded halogen (Cl, Br, I, F);

R―S― - covalently bound sulfur.

Alcohol hydroxyl:Alk- HE

Alcohol hydroxyl is a hydroxyl bonded to an aliphatic hydrocarbon radical. It contains alcohols, carboxylic acids and their salts, terpenes, phenylalkylamine derivatives, steroid compounds, aromatic antibiotics and some other medicinal substances.

Identification

1. Esterification reaction with acids or their anhydrides in the presence of water-removing agents. Based on the property of alcohols to form esters. In the case of low molecular weight compounds, esters are detected by smell, and in the analysis of high molecular weight substances - by melting point.

C 2 H 5 OH + CH 3 COOH + H 2 SO 4 k. → CH 3 -C = O + H 2 O

alcohol ethyl ethyl acetate (fruity scent)

2. Oxidation reaction. It is based on the property of alcohols to oxidize to aldehydes, which are detected by smell. Various oxidizing agents are used as reagents: potassium permanganate, potassium dichromate, potassium hexacyanoferrate (III), etc. Potassium permanganate has the greatest analytical value, which, when reduced, changes the oxidation state from

7 to +2 and becomes discolored, i.e. makes the reaction more effective.

C 2 H 5 OH + [O] → CH 3 -C=O + H 2 O

alcohol ethyl acetaldehyde (smell of apples)

Oxidation may be accompanied by side chemical reactions. For example, in the case of ephedrine - hydramine decomposition, in the case of lactic acid - decarboxylation.

3. Complexation reaction, based on the property of polyhydric alcohols to form complex compounds with copper (II) sulfate in an alkaline environment.

CuSO 4 + 2 NaOH → Cu(OH) 2 + Na 2 SO 4

blue glycerin complex

Aminospirates (ephedrine, mezatone, etc.) give a similar color reaction. The alcohol hydroxyl and the secondary amino group take part in complex formation. The resulting colored complexes have the structure:

In the case of ephedrine, the resulting complex, when extracted into ether, colors it violet-red, while the aqueous layer retains the blue color.

quantitation

1. Acetylation method: alkalimetry, neutralization option, indirect titration method. Based on the property of alcohols to form insoluble esters. Acetylation is carried out with an excess of acetic anhydride when heated in the presence of pyridine. During the titration process, an equivalent amount of acetic acid is released, which is titrated with sodium hydroxide with the indicator phenolphthalein.

CH 2 -OH CH 2 -O-COCH 3

CH -OH + 3 (CH 3 CO) 2 O → CH -O-COCH 3 + 3 CH 3 COOH

CH 2 -OH CH 2 -O-COCH 3

At the same time, the acid formed during the hydrolysis of excess acetic anhydride taken for acetylation will also be titrated, so a control experiment is necessary.

(CH 3 CO) 2 O + H 2 O → 2 CH 3 COOH

CH 3 COOH + NaOH → CH 3 COONa + H 2 O E=M/3

2. Bichromatometry. The method is based on the oxidation of alcohols with excess potassium bichromate in an acidic environment. In this case, ethyl alcohol is oxidized to acetic acid, glycerin - to carbon dioxide and water. Oxidation occurs over time and therefore the back titration method is used.

3 C 2 H 5 OH + 2 K 2 Cr 2 O 7 + 16 HNO 3 → 3 CH 3 COOH + 4 Cr(NO 3) 3 + 4 KNO 3 + 11 H 2 O

Excess potassium dichromate is determined iodometrically with the indicator - starch:

K 2 Cr 2 O 7 + 6 KJ + 14 HNO 3 → 3 J 2 + 2 Cr(NO 3) 3 + 8 KNO 3 + 7 H 2 O

J 2 + 2 Na 2 S 2 O 3 → 2 NaJ + Na 2 S 4 O 6 E=M/4

3. Cuprimetry. The method is based on the property of alcohols to form stable complex compounds with copper sulfate in an alkaline environment. Direct titration. Titrant – copper sulfate. The indicator is murexide. The method is used in intrapharmacy quality control of dosage forms with chloramphenicol.

Phenolic hydroxyl: Ar- HE

It is a hydroxyl bound to an aromatic radical. It contains medicinal substances of the group of phenols, phenolic acids and their derivatives, phenanthrene isoquinoline derivatives, synestrol, adrenaline, etc.

Identification

1. Complexation reaction phenolic hydroxyl with iron (III) ions. It is based on the properties of phenolic hydroxyl to form soluble complex compounds, often colored blue (phenol) or violet (resorcinol, salicylic acid), less often red (PAS sodium) and green (quinosol).

The composition of the complexes, and, consequently, their color is determined by the amount of phenolic hydroxyls: blue (phenol) or violet (resorcinol), the influence of other functional groups (salicylic acid, sodium PAS, quinosol), and the reaction of the medium (resorcinol).

salicylic acid

2. Bromination reaction aromatic ring. Based on electrophilic substitution of hydrogen in O- And P- positions on bromine to form an insoluble white bromine derivative. With an excess of bromine water, an oxidation and halogenation product (tetrabromocyclohexadien-2,5-one) is formed in the form of a yellow precipitate.

Due to the presence of hydroxyl groups and the electronic structure of the benzene ring, phenols have the properties of weak acids.

The most important are oxidation reactions. The tendency to easily give up an electron, inherent in the structure of the benzene ring, undergoes certain changes with the introduction of one or more hydroxyl groups into the ring. The ability to reversibly oxidize to quinone, through the intermediate stage of formation of a semiquinone radical (see above), is not characteristic of all phenolic compounds. When hydroxyl groups are located nearby (ortho position), o-quinones are easily formed; opposite (para position) are n-quinones. But 1,3-dihydroxybenzenes (mega position) are practically not oxidized by this mechanism, because with this arrangement of hydroxyls, the restructuring of the electronic structure and bonding system of the aromatic ring into a quinone one is impossible.

Only phenols with a certain arrangement of hydroxyl groups can be easily and reversibly oxidized into semiquinone and quinone, donating electrons and hydrogen nuclei and thereby acting as reducing agents and antioxidants. Due to the special ease of recoil, this reaction can occur spontaneously with or without oxygen. Moreover, the products of reversible oxidation - semiquinone and quinone - act as reaction self-accelerators, autocatalysts. The process is reversible up to the quinone stage. But if oxidation continues, it leads to the connection of individual phenolic molecules with each other - to oxidative condensation with the formation of polymer products.

If other easily oxidized substances are contained along with o- or n-phenol, the phenolic compound gradually consumes its electrons and protons, turning into quinone, but protecting the neighboring substance from oxidation. And only after the phenol resources are exhausted does the oxidation of the substance that was previously possible to be preserved, for example fat, begin. Even a small admixture of phenol (0.01-0.02%) can protect a perishable product from oxidation for a long time. This is why phenols are called antioxidant substances. This ability is very widely used in medicine, in the food industry, in cosmetics, and in the production of a number of medicines, vitamins, etc.

It is well known that most polycyclics are toxic to the body. Their oxidation, hydroxylation, including the formation of phenols, is the main way to neutralize these compounds. As more and more hydroxyls are introduced into the ring, the toxicity of the substance decreases. This process ends with the rupture of the ring and the combustion of the hydrocarbon into water. with a meta-arrangement of hydroxyl groups are not capable of reversible oxidation - dehydrogenation; therefore, for them the main path of transformation lies through direct hydroxylation of the ring with its rupture.

Under the influence of multipurpose oxidases, most aromatic substances that enter the human body, when oxidized, lose their toxic properties. Sometimes, however, the opposite happens: in the process of oxidation of some aromatic hydrocarbons, compounds are formed that are more toxic and, in particular, carcinogenic, causing malignant degeneration of cells.

Along with inactivating oxidative free radicals, phenolic compounds exert antioxidant effects through another biochemical mechanism. Many phenolic compounds form fairly strong, brightly colored and stable complexes with metal ions. For example, the ferric ion forms a green complex with three molecules of pyrocatechol. Lead salts form yellow or orange complexes with flavonoids. Metal ions catalyze the free oxidation of organic compounds when molecular oxygen is available. The presence of iron, copper, cobalt, manganese, molybdenum, and aluminum ions in body fluids and tissues, in food products, and medications is one of the reasons for their accelerated oxidation. Phenols, combining complexing ability with relative harmlessness and low toxicity, thereby weaken or turn off the catalytic effect of free heavy metal ions.

Even more important, similar complexing activity of phenols is also observed in relation to those metal ions that are included in the active centers of most redox enzymes or play the role of cofactors or activators. Therefore, phenolic compounds act as inhibitors of many oxidative enzymes, in particular enzymes of microorganisms involved in food spoilage.

The existence of two effective mechanisms of antioxidant activity makes phenols particularly strong antioxidants. But when using them as food antioxidants and preservatives, as well as in light perfumery, toxicity, solubility in water or fat, taste, etc. must be taken into account.

If one or two massive, voluminous groups of the (CH3)3C type are introduced next to the phenolic hydroxyl, the hydroxyl becomes protected from oxygen and other chemically active substances. Such “sterically hindered” phenols (butyloxyanisole, butyloxytoluene) are very stable and convenient for use in the food industry and medicine.

The preservative effect of smoke smoke largely depends on the presence of simple phenols in it - hydroquinone, pyrocatechin, 3- and 4-methylpyrocatechol, and especially pyrogallol. Many flavonoids, such as quercetin, etc., also have pronounced antioxidant activity. The French pharmacist Deschamps was the first to use an organic antioxidant additive for food preservation in 1843. He used benzoic acid to extend the shelf life of lard. Hydroquinone, pyrocatechol, pyrogallol, guaiacol, naphthol and other phenolic compounds began to be used as antioxidants in 1932-1935. Esters of gallic acid and “sterically hindered” phenols - even later.

But the principle of delaying the oxidation of fats and lipids with the help of phenolic antioxidants, recently mastered by mankind, has been used in nature for a long time and widely. Essentially all fats, both plant and animal, naturally contain antioxidants. These are primarily tocopherols - vitamin E preparations, carotenoids (provitamins A), naphthoquinones, ubiquinones, etc. Refining oils and fats, their excessive purification, which is often carried out by food industry workers, actually leads to the fact that pork lard, vegetable fats and Moreover, such substances are deprived of natural protection and are unstable during storage. Therefore, they need the addition of artificial, synthetic antioxidants. Each such drug, before being used as a food preservative, undergoes very strict testing for safety and effectiveness.

The lack of natural antioxidants, which are an essential component of biological membranes, is the cause (or, in any case, one of the causes) of early vascular sclerosis and aging - this is what many scientists believe today. Long-term addition of antioxidants to food helps to prolong the life of animals in experiments on rats. It is possible that soon effective and harmless antioxidants will be selected for people that can delay old age and disease and prolong a person’s active life. And plant phenolic compounds (or their synthetic analogues) may be the most suitable means for this.

Introduction

Most drugs used in medical practice are organic compounds. The identity of such substances is confirmed by reactions to functional groups.

A functional group is a reactive atom, group of atoms, or reaction center in a molecule of an organic compound.

The general principle of functional analysis is the use of characteristic reactions for the groups to be determined. The reaction must not only be as specific as possible, but also sufficiently rapid, and it must involve a reactant or product of the reaction that is easily identifiable.

Identification of alcohol hydroxyl

Alcohols - These are derivatives of hydrocarbons, in the molecules of which one or more hydrogen atoms are replaced by hydroxyl groups. In general, an alcohol molecule can be represented as ROH.

Ester formation reaction

Alcohols form esters with organic acids or acid anhydrides in the presence of water-removing agents (for example, concentrated sulfuric acid). Esters obtained from low molecular weight alcohols have a characteristic odor, and esters based on high molecular weight alcohols are crystalline substances with a clear melting point.

Methodology. To 1 ml of ethanol add 5 drops of glacial acetic acid, 0.5 ml of concentrated sulfuric acid and carefully heat; a characteristic odor of ethyl acetate (fresh apples) is detected.

Oxidation reaction of alcohols to aldehydes

The resulting aldehydes are detected by smell. Potassium hexacyano-(III)-ferrate, potassium permanganate, potassium dichromate, etc. are used as oxidizing agents.

Methodology. Place 2 drops of ethanol, 1 drop of 10% sulfuric acid solution and 2 drops of 10% potassium dichromate solution into the first test tube. The resulting solution has orange color. Heat it over a flame until the solution begins to acquire bluish-green color(at the same time, a characteristic smell of acetaldehyde is felt, reminiscent of the smell of Antonov apples). Add 1 drop of the resulting solution to a second test tube with 3 drops of fuchsinsulfurous acid. Appears pink-violet color.

Reaction of formation of complex compounds

Polyhydric alcohols form blue complex compounds with copper sulfate in an alkaline medium (with Fehling's reagent).

Methodology. To 0.5 ml of glycerin add 5 drops of solutions of sodium hydroxide and copper (II) sulfate, intense blue coloring.

Identification of phenolic hydroxyl

Reaction with iron (111) chloride

A characteristic qualitative reaction to phenols is the reaction with iron (III) chloride. Depending on the amount of phenolic hydroxyls, the presence of other functional groups in the phenol molecule, their relative position, the pH of the environment, and temperature, complex compounds of various compositions and colors are formed.

Methodology. To 0.01 g of the drug dissolved in 1 ml of water (for phenol, resorcinol), add 2 drops of iron (III) chloride solution - characteristic coloring is observed (Table 1).

Table 1. Staining of preparation complexes with iron (III) chloride

A drug	Solvent	Coloring of the complex
		Purple
Resorcinol		Blue-violet
Adrenaline hydrochloride		Emerald green, turning from adding one drop of ammonia solution to cherry red, and then orange-red.
Morphine hydrochloride		Blue, disappearing with the addition of diluted acetic or hydrochloric acids
Paracetamol		Blue-violet
Pyridoxine hydrochloride		Red, disappearing with the addition of dilute hydrochloric acid and not disappearing with dilute acetic acid.
Salicylic acid and sodium salicylate		Blue-violet, does not disappear with the addition of a few drops of diluted hydrochloric or acetic acid.
Phenyl salicylate		purple, disappearing from the addition of diluted hydrochloric or acetic acids and turning into blood red by adding 1-2 drops of ammonia solution.

Using an ammonia solution, you can distinguish phenol from resorcinol. The color of the resorcinol complex with iron after adding the reagent changes to brownish yellow.

Phenolic hydroxyl is a hydroxyl associated with an aromatic ring.

1. Acid-base properties are due to the presence of a mobile hydrogen atom in phenolic hydroxyl. The electron pair of the hydroxyl is shifted towards the aromatic ring, therefore the acidic properties are stronger than those of alcohols. So pKa of carbonic acid = 6.35, and pKa of phenol = 9.89.

Phenols dissolve in aqueous solutions of alkalis to form phenolates (phenoxides):

However, the acidic nature of phenols is expressed so insignificantly that even such a weak acid as carbonic acid displaces phenols from their salts:

Therefore, phenols, dissolving in alkalis, cannot dissolve in carbonates, because the carbonic acid released in this case immediately decomposes the phenolate:

This property of phenols distinguishes them from carboxylic acids.

As the temperature increases, the reaction proceeds in the forward direction. Alkali metal phenolates, as salts of strong bases and weak acids, are partially hydrolyzed in aqueous solutions, therefore solutions of phenolates have an alkaline reaction.

2. Esterification reaction (similar to alcohol hydroxyl).

The formation of ethers is the reaction of phenolates and alkyl halides (or alkyl sulfates).

C 6 H 5 ONa+JCH 3 ®C 6 H 5 OCH 3 +NaJ

Esters are formed by the reaction of sodium phenolates with anhydrides (or acid chlorides).

3. Redox properties.

Phenols exhibit strong reducing properties and are very easily oxidized even by weak oxidizing agents, resulting in the formation of colored compounds with a quinoid structure.

[O] – CaOCl 2, H 2 O 2, Cl 2, Br 2

An example of an oxidation reaction is the formation of an indophenol dye: the resulting quinone, upon interaction with NH 3, is converted into a quinone imine, which reacts with unreacted phenol. In the presence of ammonia, indophenol is formed, colored blue.

quinoneimine indophenol

n- benzoquinoneimine

A type of indophenol reaction is the Lieberman nitroso reaction, which is characteristic of those phenols in which no substituents at ortho and para positions.

When exposed to sodium nitrite in an acidic environment, it forms n-nitrosophenol, isomerizing to monooxime n-benzoquinone, which then reacts with excess phenol in an acidic environment to give indophenol.

A color is observed that changes when an alkali solution is added:

phenol – dark green, turning into cherry red;

thymol – blue-green, turning purple;

resorcinol – violet-black, turning into violet;

hexestrol (sinestrol) – red-violet, turning into cherry.

4. Complexation reaction with iron ions.

Depending on the amount of phenolic hydroxyls, the presence of other functional groups in the molecule, their relative position, the pH of the environment, and temperature, complex compounds of various compositions and colors are formed (with the exception of thymol).

Complexes are colored:

phenol – blue color;

resorcinol – blue-violet color;

salicylic acid – blue-violet or red-violet color;

osalmid (oxaphenamide) – red-violet color;

sodium para-aminosalicylate – red-violet color;

quinosol – bluish-green color.

The reaction is pharmacopoeial for most phenolic compounds.

5. Reactions of electrophilic substitution - SE of a hydrogen atom in the aromatic ring (bromination, condensation with aldehydes, combination with diazonium salts, nitration, nitrosation, iodination, etc.). The ability of phenols to enter into electrophilic substitution reactions is explained by the interaction of the lone electron pair of the oxygen atom with the π-electrons of the benzene ring. The electron density shifts towards the aromatic ring. The greatest excess of electron density is observed at carbon atoms in O- And n- positions relative to the phenolic hydroxyl (type I orientant).

5.1. Halogenation reaction (bromination and iodination).

5.1.1. When interacting with bromine water, white or yellow precipitates of bromine derivatives are formed.

When there is an excess of bromine, oxidation occurs:

The bromination reaction of phenols depends on the nature and position of the substituents.

Iodization occurs similarly, for example:

5.1.2. If there are substituents in O- And n- positions of the aromatic ring, unsubstituted hydrogen atoms of the aromatic ring react.

5.1.3. If in O- And n- positions in relation to the phenolic hydroxyl there is a carboxyl group, then under the action of excess bromine decarboxylation occurs:

5.1.4. If a compound contains two phenolic hydroxyls in m- position, then under the action of bromine tribromo derivatives are formed (consistent orientation):

5.1.5. If two hydroxyl groups are located relative to each other in O- or n- positions, then the bromination reaction does not occur (inconsistent orientation)

5.2. Condensation reactions

5.2.1. With aldehydes.

An example of the condensation of phenols with aldehydes is the reaction with Marquis reagent. When phenols are heated with a solution of formaldehyde in the presence of concentrated H 2 SO 4, colorless condensation products are formed, the oxidation of which produces intensely colored compounds of a quinoid structure. Sulfuric acid plays the role of a dehydrating, condensing and oxidizing agent in this reaction.

5.2.2. The reaction of phenols with chloroform (CHCl 3) to form aurine dyes.

When phenols are heated with CHCl 3 in an alkaline environment, aurines– triphenylmethane dyes:

Aurines are colored:

phenol – yellow color;

thymol – yellow color turning to purple;

resorcinol – red-violet color.

5.2.3. With acid anhydrides.

A. The reaction of fluorescein formation (condensation of resorcinol with phthalic anhydride).

B. Reaction of formation of phenolphthalein (condensation of phenol with phthalic anhydride).

With a large excess of alkali, a trisubstituted sodium salt is formed.

The condensation of thymol with phthalic anhydride proceeds similarly to the reaction of the formation of phenolphthalein; thymolphthalein is formed, which has a blue color in an alkaline medium.

5.3. Nitration reaction

Phenols react with dilute nitric acid (HNO 3) and form ortho- and para-nitro derivatives. The addition of sodium hydroxide solution enhances the color due to the formation of a well-dissociated salt.

5.4. The reaction of azo coupling of phenols with diazonium salt in an alkaline medium.

When phenols react with diazonium salt at pH 9-10, azo dyes are formed, colored yellow-orange or red. The azo coupling reaction occurs in the ortho and para positions relative to the phenolic hydroxyl. Diazotized sulfanilic acid is usually used as a diazo reagent.