Phenolic hydroxyl. I

Phenolic hydroxyl is a hydroxyl bound to an aromatic radical. It contains drugs from the phenol group (phenol, resorcinol); phenolic acids and their derivatives (salicylic acid, phenyl salicylate, salicylamide, oxafenamide); phenanthrene isoquinoline derivatives (morphine hydrochloride, apomorphine); sinestrol, adrenaline, etc.

Chemical properties compounds containing phenolic hydroxyl are due to the interaction of an electron pair with the π-electrons of the aromatic ring. This interaction leads to a shift in electron density from the OH group to the ring, disruption of the uniform distribution of electrons in it, and the creation of an excess negative charge in the ortho ( O)- and pair ( P)-positions. The hydrogen atom of the hydroxy group ionizes and gives phenols weak acidic properties (pKa of phenol = 10.0; pKa of resorcinol = 9.44). Therefore, unlike alcohols, they form salts with alkalis (at pH 12-13), soluble complex compounds with iron (III) chloride (in neutral, slightly alkaline and acidic solutions).

Phenols exhibit strong reducing properties and are very easily oxidized even by weak oxidizing agents. They form colored compounds with a quinoid structure.

The reactions of electrophilic substitution of hydrogens in O- And P-positions of the aromatic ring – halogenation (bromination), condensation with aldehydes, nitration, combination with diazonium salts.

Based on the properties of the phenolic hydroxyl and the aromatic ring activated by it, the following reactions are used in drug analysis:

1 – complex formation;

2 – halogenation (bromination);

3 – azo combinations;

4 – oxidation;

5 – formation of indophenol dye;

6 – condensation with aldehydes.

Identification

2.1. Complexation reaction with iron ions (III)

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, adrenaline).

The composition of the complexes, and, consequently, their color is determined by the amount of phenolic hydroxyls, the influence of other functional groups, and the reaction of the environment.

If there is an excess of phenol:

Presumable composition of the final product in the reaction with phenol:

2.2. Aromatic ring bromination reaction

Based on electrophilic substitution of hydrogen in O- And P- positions on bromine with the formation of an insoluble bromine derivative (white precipitate).

Basic rules for bromination:

Bromine replaces hydrogen in O- And P- positions relative to phenolic hydroxyl (the most reactive is P- position):

If available in O- or P- positions of the aromatic ring of substituents, fewer bromine atoms react;

If in O- or P- positions there is a carboxyl group, then in the presence of excess bromine, decarboxylation occurs and the formation of a tribromo derivative:

If the deputy is in m- position, then it does not interfere with the formation of the tribromo derivative:

If a compound contains two phenolic hydroxyls in m- position, then as a result of their coordinated orientation a tribromo derivative is formed:

If two hydroxyl groups are located in O- or P- positions to each other, they act inconsistently: bromination does not occur quantitatively:

If, in addition to phenolic hydroxyls, the compound contains an amide or ester group (salicylamide, phenyl salicylate), preliminary hydrolysis is necessary for their quantitative assessment by bromatometry.

2.3. Azo coupling reaction

The combination also goes to O- And P- provisions, in this case, as well as with bromination, it is preferable P- position. Diazo reagent is diazonium salt (diazotized sulfanilic acid). The environment is alkaline. The reaction product is an azo dye.

2.4. Oxidation reaction

Phenols can be oxidized to various compounds, but most often to O- or P-quinones (cyclic diketones), colored pink or, less commonly, yellow.

2.5. Reaction of formation of indophenol dye

It is based on the oxidation of phenols to quinones, which, when condensed with ammonia or an amino derivative and an excess of phenol, form an indophenol dye, colored violet.

A variation of this reaction is the Lieberman nitro reaction; it is characteristic of phenols that do not have substituents in O- And P- provisions.

When exposed to sodium nitrite in an acidic environment, it forms P-nitrosophenol, isomerizing to P- quinoidoxime, which, reacting with excess phenol in an acidic environment, forms indophenol:

2.6. Formation of nitroso compounds

When interacting with dilute nitric acid, phenols can be nitrated at room temperature, forming O- And P- nitro derivatives. The resulting nitro derivative contains P- position of the mobile hydrogen atom of the hydroxyl group, a tautomeric aci form with a quinoid structure is formed; it is usually colored yellow. The addition of alkali enhances the color due to the formation of a well-dissociated salt:

2.7. Condensation reaction with aldehydes or acid anhydrides

With formaldehyde in the presence of concentrated sulfuric acid to form an auric (arylmethane) dye colored red.

The reaction is pharmacopoeial for salicylic acid. Concentrated sulfuric acid at the first stage of the reaction it plays the role of a water-removing agent, at the second it is an oxidizing agent.

With phthalic anhydride (fusion and subsequent dissolution of the melt in alkali) is recommended by the pharmacopoeia for the identification of phenol and resorcinol.

quantitation

2.8. Bromatometry

The method is based on the electrophilic substitution of hydrogen atoms of the aromatic ring with bromine, isolated in the reaction of potassium bromate with potassium bromide in an acidic environment.

K BrO 3 + 5KBr + 6 HCl → 3Br 2 + 6KCl + 3H 2 O

Direct and reverse titration methods are used. Directly - titrate with potassium bromate in the presence of potassium bromide with a methyl orange or methyl red indicator from pink to discolored. At the equivalence point, an excess drop of potassium bromate releases bromine, which oxidizes the indicator and the solution becomes colorless. During back titration, excess potassium bromate is introduced, potassium bromide is added, an acidic environment is created, the time required for bromination is maintained, and then the excess bromine is determined iodometrically (starch as an indicator).

Br 2 + 2KI → I 2 + 2KBr

I 2 + 2Na 2 S 2 O 3 → Na 2 S 4 O 6 + 2NaI

By direct titration, thymol is determined by GF, and phenol, resorcinol, salicylic acid, synestrol and other drugs are determined by reverse titration.

M.E. = ¼ M.m. (thymol)

M.E. = 1/6 M.m. (phenol, resorcinol, salicylic acid)

M.E. = 1/8 M.m. (sinestrol)

2.9. Iodometry

Based on the electrophilic substitution of hydrogen atoms of the aromatic ring with iodine.

To bind hydroiodic acid, which shifts the equilibrium in the opposite direction, sodium acetate or sodium bicarbonate is added.

HI + NaHCO 3 → NaI + H 2 O + CO 2

HI + CH 3 COONa → NaI + CH 3 COOH

Direct and reverse titration methods are used. In the latter, excess iodine is titrated with sodium thiosulfate.

I 2 + 2NaS 2 O 3 → 2NaI + Na 2 S 4 O 6

M.E. = 1/6 M.m. (phenol)

2.10. Iodine chlorometry

The method is based on the electrophilic substitution of hydrogen atoms of the aromatic ring with iodine, which is part of iodine monochloride.

A back titration method is used - the excess of iodine monochloride is determined iodometrically.

ICl + KI → I 2 + KCl

I 2 + 2Na 2 S 2 O 6 → 2NaI + Na 2 S 4 O 6

M.E. = 1/6 M.m. (phenol)

2.11. Acetylation method

Used according to GF X for quantitative assessment of sinestrol.

M.E. = ½ M.m.

2.12. Alkalimetric method of neutralization in the protophilic solvent dimethylformamide (DMF).

The drug groups of phenols exhibit very weak acidic properties; their determination by the alkalimetric method of neutralization in aqueous or mixed media is impossible, therefore titration is used in a medium of non-aqueous solvents, in particular DMF. The method is based on the salt formation of a determined weak acid (phenol) with a titrant (sodium methylate) in a protophilic solvent that enhances acidic properties.

Total:

2.13. Photocolorimetry (FEC) and spectrophotometry (SPM)

It is based on the property of colored solutions to absorb non-monochromatic (FEC) or monochromatic (SPM) light in the visible region of the spectrum.

Obtaining colored solutions;

Measurement of optical density (D), which characterizes the absorption of electromagnetic radiation by a solution containing the analyte;

Carrying out calculations based on the basic law of light absorption using a calibration graph, specific absorption coefficient, and standard sample solution.

When determining drugs containing phenolic hydroxyl by these methods, colored compounds are obtained based on complexation reactions with iron (III) ions, azo coupling with diazonium salts and the formation of indophenol dye.

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.

General principle functional analysis is the application characteristic reactions for 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 view an alcohol molecule can be represented as ROH.

Ester formation reaction

Alcohols form with organic acids or acid anhydrides in the presence of water-removing agents (for example, concentrated sulfuric acid) esters. 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

Characteristic qualitative reaction for phenols is a 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

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.

As a result of interaction with aldehydes, oligomers and are formed, the structure of which depends on:

• functionality of the phenol used,
• aldehyde type,
• molar ratio of reagents,
• pH of the reaction medium.

In this case, either linear (or weakly branched) products are formed, which are called novolaks, or highly branched thermosetting oligomers called resolutions.
In phenols, the hydrogens present in the ortho- And pair- positions to the hydroxyl group. Therefore from monohydric phenols are trifunctional phenol, and , and from diatomic ones - resorcinol:
Bifunctional phenols include phenols with a substituent in ortho- or pair- position- O- And p-cresols 2,3- , 2,5- And 3,4- xylenols:
2,6- And 2,4-xylenols - monofunctional.
When and furfural with trifunctional phenols, both oligomers and oligomers can be obtained. Bifunctional phenols form only thermoplastic oligomers.
Of the aldehydes, only formaldehyde and furfural are capable of forming thermosetting oligomers upon polycondensation with trifunctional phenols. Other aldehydes (acetic, butyric, etc.) due to reduced chemical activity and steric hindrances do not form thermoreactive oligomers.

Thermoplastic (novolac) oligomers are formed in the following cases:

• with an excess of phenol (ratio phenol: formaldehyde 1: 0.78-0.86) in the presence of acid catalysts; in the absence of excess phenol, resol oligomers are formed;
• with a large excess of formaldehyde (ratio phenol: formaldehyde 1: 2-2.5) in the presence of strong acids as a catalyst; the oligomers obtained in this case do not harden when heated, but when a small amount of base is added to them, they become infusible and insoluble.

Thermosetting (resol) oligomers are formed in the following cases:

• during the polycondensation of an excess of trifunctional phenol with formaldehyde in the presence of basic catalysts (in an alkaline environment, thermosetting oligomers are obtained even with a very large excess of phenol, which in this case remains dissolved in the reaction product);
• with a slight excess of formaldehyde in the presence of both basic and acid catalysts.
  A peculiarity of the interaction of phenols with formaldehyde is the use of formaldehyde mainly in the form of aqueous solutions. This solution has a complex composition due to the following:

CH 2 O + H 2 O<=>NOSN 2 OH
HO(CH 2 O) n H + HOCH 2 OH<=>HO(CH 2 O) n+1 H + H 2 0
HO(CH 2 O) n H + CH 3 OH<=>CH 3 O (CH 2 O) n H + H 2 0

Participates in the reaction with phenol the most reactive free formaldehyde, the concentration of which in solution is low. As formaldehyde is consumed, balance shift to the left. In this case, the rate of formation of formaldehyde is higher than the rate of its consumption in the reaction with phenol. Therefore, in the process of interaction of phenol with formaldehyde stage methylene glycol dehydrations, depolymerization of oligooxymethylene glycols And decomposition of hemiacetals are not limiting.
The kinetics and mechanism of the formation of phenol-formaldehyde oligomers are determined by the type of catalyst used. In the presence of acids, the reaction proceeds as follows:
Initially, these compounds are formed in approximately equal quantities, then due to higher reactivity para-isomer fraction gets smaller. Total content monohydroxymethylphenols in the reaction medium initially increases, reaching 6-8% , and then begins to decrease, since the rate of addition reactions is almost an order of magnitude lower than the rate of condensation reactions.
As condensation proceeds, 4.4′- And 2,4′-dihydroxydiphenylmethanes and then in smaller quantities 2,2′-dihydroxydiphenylmethane:
The reaction products at the initial stage of condensation also contained 1,3-benzodioxane and hemiacetal derivatives hydroxymethylphenols. At the same time, there are almost no polycondensations in the products di- And trihydroxymethylphenols And . The latter are formed by the interaction of hydroxymethyl phenol derivatives with each other:
The low concentration of these compounds in the reaction mass is explained by their low stability. Dihydroxydibenzyl ethers decompose to release formaldehyde:

It is also possible phenolysis of dihydroxydibenzyl ethers (K=2·10 10 at 25 °C), which results in the formation of a mixture of products containing o-hydroxymethylphenol, 2.2′- And 2,4′-dihydroxydiphenylmethanes, and three- And quad core with methylene bonds. Below are data on the equilibrium constants of these reactions:

As can be seen from the values ​​of the equilibrium constants, the formation of a methylene bridge between phenyl nuclei is thermodynamically much more favorable than the formation of a bridge -CH 2 OCH 2 -(the corresponding equilibrium constants differ by 8-9 orders of magnitude). Under normal conditions for the synthesis of phenol-formaldehyde oligomers, when using formaldehyde in the form of aqueous solutions, the formation of dihydroxydibenzyl ethers is practically impossible.

When using ortho-substituted phenol derivatives, the corresponding ortho isomers are further stabilized due to the formation of intramolecular hydrogen bonds:
At subsequent stages chemical process interaction occurs monohydroxymethyl phenol derivatives with dihydroxydiphenylmethanes. Addition and condensation reactions occurring in an acidic medium are of first order for each of the reactants, and the rate constants are directly proportional to the activity of hydrogen. Activation energies of addition reactions 78.6-134.0 kJ/mol, condensation reactions of phenol with o-hydroxymethylphenol 77.5-95.8 kJ/mol And n-hydroxymethylphenol 57.4-79.2 kJ/mol.

Rate of addition and condensation reactions on unsubstituted ortho- provisions novolac oligomer depends little on , i.e. all are free ortho- positions have equal reactivity.

An increase in monomer conversion leads to dividing the reaction mass into two layers: aqueous and oligomeric, after which the reaction continues in a heterogeneous system. Interaction at the interface is practically unimportant due to the relatively slow occurrence of the reactions under consideration.

The presence of three reactive groups in phenol creates the prerequisites for isomerism of phenol-formaldehyde oligomers. Their isomeric composition is determined by the ratio of reaction rates according to O- And P– provisions phenolic kernels. The reactivity of these positions depends on the nature of the catalyst, pH environment and temperature.

Under conditions usual for the production of novolacs (catalyst - acid, pH=0-2, 37% solution of foralin, temperature about 100 °C) unsubstituted pair- positions of phenolic units and pair- hydroxymethyl groups are significantly more active than the corresponding ortho- provisions and ortho- hydroxymethyl groups. This difference is especially significant in the case of condensation reactions, as can be seen from the data below:

Speed ​​of reactions according to ortho- positions increases with increasing pH and temperature. The isomeric composition of polycondensation products in an aqueous solution depends little on the nature of the acid. In the case of polycondensation in organic solvents (ethyl alcohol, toluene, tetrachloroethane), the proportion ortho- substitution decreases in the series of acids:acetic > oxalic > benzenesulfonic acid > hydrochloric.
Conventional novolacs contain 50-60% ortho-, pair- methylene bonds, 10-25% ortho-, ortho- and 25-30% pair-, pair- methylene bonds.
In the process of obtaining phenolic oligomers, linear And branched products. However, the degree of branching is low, since the proportion of trisubstituted phenolic units is 10-15% . The low degree of branching is explained by the fact that the initial mixture of isomers contains an excess of phenol.

Polycondensation in an acidic environment

In acid catalysis, the reaction proceeds according to the following mechanism. First happens
Further arose carbonium ion attacks phenol, forming:
In an acidic environment, hydroxymethylphenols form relatively stable and long-lived carbonium ions, which react as electrophilic agents with phenol or its hydroxymethyl derivatives:
In general, the process of producing novolac can be represented by the following diagram: A decrease in the excess of phenol in the initial mixture is accompanied by an increase in the molecular weight of the resulting novolac, and at a ratio close to equimolar, a polymer with a spatial structure can be obtained.
In novolacs obtained from trifunctional phenol or a mixture of phenols containing at least one trifunctional phenol, there are still active hydrogens in ortho- And pair - positions to phenolic hydroxyls. Therefore, when treating them with formaldehyde, replacing the acid catalyst with a basic one, it is possible to obtain resol directly, an infusible and insoluble polymer resit .

Resit is also obtained by the action of formaldehyde polymers on novolac ( paraforms, α-polyoxymethylene, β-polyoxymethylene) or hexamethylenetetramine. In the latter case, apparently, the curing process involves di- And trimethylamines, formed during the decomposition of hexamethylenetetramine, and the released ammonia plays the role of a catalyst.

Novolacs obtained from bifunctional phenols (O- And P- cresols), when treated with formaldehyde, do not become infusible and insoluble. However, if such oligomers are heated above 180 °C, they are capable of passing, albeit slowly, into an infusible and insoluble state.

A similar picture is observed when 250-280 °C and for novolacs obtained by polycondensation 1 mol phenol with 0.8 mol formaldehyde, which can be explained by the activation of hydrogen atoms in meta- position to phenolic hydroxyls or the interaction of the latter with the formation of ether bonds.

Polycondensation in an alkaline environment

When phenol reacts with formaldehyde in an alkaline environment, as in the case of acid catalysis, first O- And p-hydroxymethylphenols, then 2,4- And 2,6-dihydroxymethylphenols and finally trihydroxymethylphenols. In polycondensation, they mainly participate pair- hydroxymethyl groups and unsubstituted pair- positions of phenolic nuclei.

Of the hydroxymethyl derivatives, the most reactive is 2,6-dihydrocoimeylphenol, which quickly reacts with formaldehyde to form trihydroxymethylphenol. Hydroxymethylphenols formed in an alkaline environment (as opposed to an acidic environment) are very stable. Therefore, at the reaction temperature no higher 60 °C hydroxymethylphenols remain practically the only reaction products.

With increasing temperature, hydroxymethyl derivatives begin to interact both with each other and with phenol. The main product for homocondensation of p-hydroxymethylphenol is 5-hydroxymethyl-2,4′-dihydroxydiphenylmethane:
In this case, by analogy with acid catalysis, the formation also occurs 4,4′-dihydroxydiphenylmethane. However, since this compound was also found in the absence of phenol, the reaction apparently proceeds through the formation of an unstable intermediate dihydroxydibenzyl ether:

It should be noted that in an alkaline environment, generally stable compounds with a dimethylene ether bond

-CH 2 OCH 2 -

are not formed in noticeable quantities. Ratio couple- And ortho- substituted hydroxymethylphenols depends on with a decrease pH share pair- of substituted products decreases (with pH=13 it is 0.38, with pH=8.7 it is equal to 1.1).
Depending on the alkaline catalyst used in the series of cations, this ratio increases in the following sequence:
Mg