Antipyretics for children are prescribed by a pediatrician. But there are emergency situations for fever when the child needs to be given medicine immediately. Then the parents take responsibility and use antipyretic drugs. What is allowed to give to infants? How can you bring down the temperature in older children? What medicines are the safest?
Introduction
Majority medicines used in medical practice are organic compounds. The authenticity of such substances is confirmed by reactions to functional groups.
A functional group is a reactive atom, a group of atoms, or a reactive center in an organic compound molecule.
The general principle of functional analysis is the application of characteristic reactions for the groups to be determined. The reaction should not only be as specific as possible, but also fast enough, and should involve a reactant or reaction product that can be easily determined.
Alcohol hydroxyl identification
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.
Esters formation reaction
Alcohols form esters with organic acids or acid anhydrides in the presence of dehydrating agents (for example, concentrated sulfuric acid). Esters derived 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 gently heat; a characteristic smell of ethyl acetate (fresh apples) is detected.
The oxidation reaction of alcohols to aldehydes
The resulting aldehydes are detected by smell. Potassium hexacyano - (Sh) - ferrate, potassium permanganate, potassium dichromate, etc. are used as oxidizing agents.
Methodology. 2 drops of ethanol, 1 drop of 10% sulfuric acid solution and 2 drops of 10% potassium dichromate solution are placed in 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 acetic aldehyde is felt, reminiscent of the smell of Antonov apples). Add 1 drop of the resulting solution to the second test tube with 3 drops of fuchsine sulfuric acid. Appears pink-violet coloration.
The reaction of the formation of complex compounds
Polyhydric alcohols form blue complex compounds with copper sulfate in an alkaline medium (with Fehling's reagent).
Methodology. 5 drops of sodium hydroxide and copper (II) sulfate solutions are added to 0.5 ml of glycerin, an intense blue coloration.
Phenolic hydroxyl identification
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, their relative position, pH of the medium, temperature, complex compounds of various composition and color are formed.
Methodology. To 0.01 g of the drug dissolved in 1 ml of water (for phenol, resorcinol) add 2 drops of a solution of iron (III) chloride - a characteristic staining is observed (Table 1.).
Table 1. Staining of complexes of preparations with iron (III) chloride
|
A drug |
Solvent |
Coloring of the complex |
|
purple |
||
|
Resorcinol |
blue purple |
|
|
Adrenaline hydrochloride |
Emerald green, changing from the addition of one drop of ammonia solution to cherry red and then to orange red. |
|
|
Morphine hydrochloride |
Blue, disappearing from the addition of dilute acetic or hydrochloric acids |
|
|
Paracetamol |
blue purple |
|
|
Pyridoxine hydrochloride |
Red that disappears with the addition of dilute hydrochloric acid and does not disappear with dilute acetic acid. |
|
|
Salicylic acid and sodium salicylate |
blue purple, not disappearing from the addition of a few drops of dilute hydrochloric or acetic acid. |
|
|
Phenyl salicylate |
purple, disappearing from the addition of dilute hydrochloric or acetic acids and turning into blood red by adding 1-2 drops of ammonia solution. |
Ammonia solution can be used to distinguish phenol from resorcinol. The color of the complex of resorcinol with iron after the addition of the reagent changes to brownish yellow.
As a result of interaction with aldehydes, oligomers and are formed, the structure of which depends on:
- the functionality of the used phenol,
- type of aldehyde
- 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 resolami.
In phenols, hydrogens are reactive, which are in ortho- And pair- positions to the hydroxyl group. Therefore, from monohydric phenols trifunctional are phenol, and , and from diatomic resorcinol:
Bifunctional 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.
At and furfural with trifunctional phenols, both 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.) do not form thermosetting oligomers due to reduced reactivity and steric hindrance.
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, resole 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 bases are added to them, they pass into an infusible and insoluble state.
Thermosetting (resol) oligomers are formed in the following cases:
- in the polycondensation of an excess of trifunctional phenol with formaldehyde in the presence of basic catalysts (in an alkaline medium, 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 feature of the interaction of phenols with formaldehyde is the use of formaldehyde mainly in the form of aqueous solutions. Such a solution has a complex composition due to the following:
CH 2 O + H 2 O<=>NOSN 2 OH
BUT (CH 2 O) n H + NOCH 2 OH<=>BUT (CH 2 O) n + 1 H + H 2 0
BUT (CH 2 O) n H + CH 3 OH<=>CH 3 O (CH 2 O) n H + H 2 0
involved in the reaction with phenol. most reactive free formaldehyde, whose concentration in solution is low. As formaldehyde is consumed, shift of balance to the left. In this case, the rate of formaldehyde formation is higher than the rate of its consumption for the reaction with phenol. Therefore, in the process of interaction of phenol with formaldehyde of the stage dehydration of methylene glycol, 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 amounts, then due to higher reactivity proportion of para-isomer becomes 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 less 2,2'-dihydroxydiphenylmethane:
In the products of the reaction to initial stage condensations are also found 1,3-benzodioxane and hemiacetal derivatives hydroxymethylphenols. At the same time, polycondensation products are almost absent. di- And trihydroxymethylphenols And . The latter are formed by the interaction of hydroxymethyl derivatives of phenol with each other: 
The low concentration of these compounds in the reaction mass is explained by their low stability. Dihydroxydibenzyl ethers decompose with the release of formaldehyde: 
In addition, it is 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:
| Reaction | Equilibrium constant | |
| at 25 °C | at 100 °C | |
| Formation of hydroxymethylphenols | 8 10 3 | 10 2 |
| Formation of dihydroxydiphenylmethanes | 10 9 | 3 10 6 |
| Formation of dihydroxydibenzyl ethers | 8 10 -2 | 9 10 -3 |
| Destruction of the dimethylene ether bond | 2 10 6 | 5 10 6 |
As can be seen from the values of the equilibrium constants, the formation of a methylene bridge between the phenyl rings 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 formaldehyde is used in the form of aqueous solutions, the formation of dihydroxydibenzyl ethers is practically impossible.
When using ortho-substituted phenol derivatives, the corresponding orthochisomers are additionally stabilized due to the formation of an intramolecular hydrogen bond: 
At the subsequent stages of the chemical process, the interaction occurs monohydroxymethyl phenol derivatives with dihydroxydiphenylmethanes. Addition and condensation reactions occurring in acidic environment, have the first order for each of the reagents, in 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.
The rate of addition and condensation reactions over unsubstituted ortho- provisions novolac oligomer little depends on , i.e. all free ortho- positions have equal reactivity.
An increase in the conversion of monomers leads to separation of the reaction mass into two layers: aqueous and oligomeric, after which the reaction continues in a heterogeneous system. The interaction at the phase boundary is practically unimportant due to the relatively slow flow of the considered reactions.
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 nuclei. The reactivity of these positions depends on the nature of the catalyst, pH environment and temperature.
Under the usual conditions for the production of novolacs (catalyst - acid, pH=0-2, 37% foralin solution, temperature about 100 °C) unsubstituted pair- positions of phenolic units and pair- hydroxymethyl groups are much more active than the corresponding ortho- regulations and ortho- hydroxymethyl groups. This difference is especially significant in the case of a condensation reaction, as can be seen from the data below:
| Reactions | rate constant,
k 10 5 s -1 |
activation energy,
kJ/mol |
| Phenol -> o-hydroxymethylphenol | 1,5 | 93,5 |
| Phenol -> P-hydroxymethylphenol | 1,8 | 79,6 |
| o-Hydroxymethylphenol ->
2,2'-dihydroxydiphenylmethane |
5,9 | 96,0 |
| p-Hydroxymethylphenol ->
2,4'-dihydroxydiphenylmethane |
35,6 | 79,3 |
| o-Hydroxymethylphenol ->
2,4'-dihydroxydiphenylmethane |
14,8 | 78,0 |
| p-Hydroxymethylphenol ->
4,4'-dihydroxydiphenylmethane |
83,9 | 72,5 |
Reaction rate according to ortho- positions increases with increasing pH and temperature. The isomeric composition of the polycondensation products in 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.
Acid polycondensation
In acid catalysis, the reaction proceeds according to the following mechanism. First happens
Further emerged 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 terms, the process of obtaining novolac can be represented by the following scheme: Reducing the excess of phenol in the initial mixture is accompanied an increase in the molecular weight of the resulting novolac, and at a ratio close to equimolar, it is possible to obtain a polymer of a spatial structure.
The 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 novolak ( paraforms, α-polyoxymethylene, β-polyoxymethylene) or hexamethylenetetramine. In the latter case, apparently, the curing process involved 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, they do not turn into an infusible and insoluble state. However, if such oligomers are heated above 180 °С, they are capable of passing, albeit slowly, into an infusible and insoluble state.
A similar picture is observed for 250-280 °С and for novolacs obtained by polycondensation 1 mole of phenol with 0.8 mole of 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 medium
In the interaction of phenol with formaldehyde in an alkaline medium, as in the case of acid catalysis, first formed O- And p-hydroxymethylphenols, then 2,4- And 2,6-dihydroxymethylphenols and finally trihydroxymethylphenols. In polycondensation, they are predominantly involved pair- hydroxymethyl groups and unsubstituted pair- positions of phenolic nuclei.
Of the hydroxymethyl derivatives, the most reactive is 2,6-dihydrocoimeylphenol, which reacts rapidly with formaldehyde to form trihydroxymethylphenol. The hydroxymethylphenols formed in an alkaline medium (in contrast to an acidic one) are very stable. Therefore, at a reaction temperature not higher than 60 °C hydroxymethylphenols remain practically the only reaction products.
With an increase in temperature, hydroxymethyl derivatives begin to interact both with each other and with phenol. The main product at homocondensation of p-hydroxymethylphenol is 5-hydroxymethyl-2,4'-dihydroxydiphenylmethane:
In this case, by analogy with acid catalysis, the formation of 4,4'-dihydroxydiphenylmethane. However, since this compound was also found in the absence of phenol, the reaction apparently proceeds through the intermediate formation of an unstable dihydroxydibenzyl ether:
It should be noted that in an alkaline environment, in general, stable compounds with a dimethylene ether bond
-CH 2 OCH 2 -
are not formed in appreciable quantities. Ratio papa- And ortho- substituted hydroxymethylphenols depends on with decreasing pH share pair- substituted products decreases (at pH=13 it is 0.38, with pH=8.7 it is equal to 1.1).
Depending on the used alkaline catalyst in the series of cations, this ratio increases in the following sequence:
mg
At pH≤9 addition reactions are of the first order in terms of phenol and formaldehyde, their rate is directly proportional to the concentration HE --ions. For catalysis NaOH at 57 °C and pH≈8.3 the following values of the rate constants and activation energy were obtained:
| Reactions | Rate constant, k 10 5 , l mol/s | Activation energy, kJ/mol |
| Phenol -> o-hydroxymethylphenol | 1,45 | 68,55 |
| Phenol -> P-hydroxymethylphenol | 0,78 | 65,20 |
| o-Hydroxymethylphenol ->
2,6'-dihydroxymethylphenol |
1,35 | 67,71 |
| o-Hydroxymethylphenol ->
2,4'-dihydroxymethylphenol |
1,02 | 60,61 |
| P-Hydroxymethylphenol ->
2,4'-dihydroxymethylphenol |
1,35 | 77,23 |
| p-Hydroxymethylphenol ->
4,4'-dihydroxymethylphenol |
83,9 | 72,5 |
| 2,6-Dihydroxymethylphenol ->
2,4,6-trihydroxymethylphenol |
2,13 | 58,40 |
| 2,4-Dihydroxymethylphenol ->
2,4,6-trihydroxymethylphenol |
0,84 | 60,19 |
Thus, the interaction of hydroxymethyl derivatives with each other occurs faster than their reactions with phenol.
The mechanism of interaction of phenol with formaldehyde under conditions of basic catalysis includes the formation pseudoacid anions with high nucleophilicity: 
Localization of a negative charge in ortho- And pair- positions of the pseudoacid makes them highly reactive towards electrophilic agents, in particular formaldehyde: 
negative charge in phenolate ion is displaced towards the ring due to the inductive influence and the conjugation effect. At the same time, the electron density in ortho- And pair- positions increases to a greater extent than on the oxygen of the hydroxymethyl group, since charge transfer through π bonds more efficient than δ bonds. That's why ortho- And pair- core positions are more nucleophilic than the hydroxymethyl group.
The consequence of this is the attack of the electrophilic agent along the ring, which is accompanied by the formation methylene bond(not dimethylene ether). The reaction rate is maximum at pH=pK a reagents and is minimal at pH=4-6. With these values pH resole oligomers are the most stable.
Has some specific reaction of phenol with formaldehyde when used as a catalyst ammonia. Ammonia readily reacts quantitatively with formaldehyde to form hexamethylenetetramine:
Therefore, along with the interaction of phenol with formaldehyde, the reaction of phenol with hexamethylenetetraamine can occur. Naturally, the probability of this reaction depends on the ratio CH 2 O: NH 3. The smaller it is, the more likely the second reaction will occur, the consequence of which is the presence in the reaction products, along with hydroxymethylphenols, 2-hydroxybenzylamine, 2,2'-dihydroxydibenzylamine, as well as the derivative benzocoazine buildings: 
The use of metal salts, oxides or hydroxides as catalysts in some cases leads to a significant increase in the proportion of oligomers containing ortho- substituted phenolic cores. Ortho-orienting influence Zn, Cd, Mg, Ca, Sr, Ba, Mn, Co, Ni, Fe, Pb. The ortho-orienting effect of these catalysts is especially noticeable at pH = 4-7, when the catalytic effect of ions H+ And HE - minimum. Therefore, salts of weak carboxylic acids are most often used as catalysts, for example, acetates.
Education hydroxymethylphenols during catalysis by metal hydroxides can be represented as follows: 
In this way, both novolaks and resols can be obtained. Ortho-isomers are predominantly formed in the case of a non-catalytic reaction, for which a mechanism has been proposed, according to which the reaction proceeds through H-complex phenol-formaldehyde:
Resols are a mixture of linear and branched products of the general formula:
H-[-C 6 H 2 (OH) (CH 2 OH)CH 2] m -[-C 6 H 3 (OH)CH 2 -] n -OH
Where n=2.5, m =4-10.
The molecular weight of resols (from 400 to 800-1000) is lower than novolac oligomers, since polycondensation is carried out very quickly to prevent gelation. When heated, the resols gradually harden, that is, they turn into polymers of a spatial structure.
In the process of curing resole oligomers, three stages are distinguished:
- IN stages A also called resole, the oligomer is similar in its physical properties to the novolak oligomer, since, like novolak, it melts and dissolves in alkalis, alcohol and acetone. But unlike novolac, resol is an unstable product that, when heated, becomes infusible and insoluble.
- IN stages IN a polymer called resitol, only partially soluble in alcohol and acetone, does not melt, but still retains the ability to soften (turn into a highly elastic, rubber-like state when heated) and swell in solvents.
- IN stages WITH- the final stage of curing - a polymer called resit, is an infusible and insoluble product that does not soften when heated and does not swell in solvents.
In the resit stage, the polymer has a high disparity and a very complex spatial structure:
This formula shows only the content of certain groups and groupings, but does not reflect their quantitative ratio. It is currently believed that phenol-formaldehyde polymers are quite rarely cross-linked (a small number of nodes in a three-dimensional network). The degree of completion of the response to last stage curing is small. Typically, up to 25% of the functional groups that form bonds in a three-dimensional network are consumed.
Bibliography:
Kuznetsov EV, Prokhorova IP Album of technological schemes for the production of polymers and plastics based on them. Ed. 2nd. M., Chemistry, 1975. 74 p.
Knop A., Sheib V. Phenolic resins and materials based on them. M., Chemistry, 1983. 279 p.
Bachman A., Muller K. Phenoplasts. M., Chemistry, 1978. 288 p.
Nikolaev A.F. Technology of plastics, L., Chemistry, 1977. 366 p.
Monatomic phenols (arenols). Nomenclature. Isomerism. Ways to get. Physical Properties and building. Chemical properties: acidity, formation of phenolates, ethers and esters; nucleophilic substitution of the hydroxyl group; reactions with electrophilic reagents (halogenation, nitration, nitrosation, azo coupling, sulfonation, acylation and alkylation); interaction with formaldehyde, phenol-formaldehyde resins; oxidation and hydrogenation reactions.
Dihydric phenols (arendiols): pyrocatechin, resorcinol, hydroquinone. Methods of obtaining, properties and application.
Trihydric phenols (arentriols): pyrogallol, hydroxyhydroquinone, phloroglucinol. Methods of obtaining, properties and application.
Hydroxyl derivatives of arenes
Phenols are derivatives of aromatic hydrocarbons in which one or more hydroxyl groups are directly bonded to the benzene ring.
Depending on the number of hydroxyl groups in the core, one-, two- and three-atomic phenols are distinguished.
Trivial names are often used to name phenols (phenol, cresols, pyrocatechol, resorcinol, hydroquinone, pyrogallol, hydroxyhydroquinone, phloroglucinol).
Substituted phenols are referred to as phenol derivatives or as hydroxy derivatives of the corresponding aromatic hydrocarbon.
Monatomic phenols (arenols) ArOH
ortho-cresol meta-cresol para-cresol
2-methylphenol 3-methylphenol 4-methylphenol
2-hydroxytoluene 3-hydroxytoluene 4-hydroxytoluene
In the aromatic series, there are also compounds with a hydroxyl group in the side chain - the so-called aromatic alcohols.
The properties of the hydroxyl group in aromatic alcohols do not differ from the properties of aliphatic alcohols.
Dihydric phenols (arendiols)
pyrocatechin resorcinol hydroquinone
1,2-dihydroxybenzene 1,3-dihydroxybenzene 1,4-dihydroxybenzene
Trihydric phenols (arentriols)
pyrogallol hydroxyhydroquinone phloroglucinol
1,2,3-trihydroxybenzene 1,2,4-trihydroxybenzene 1,3,5-trihydroxybenzene
Monatomic phenols
How to get
The natural source of phenol and its homologues is coal, during the dry distillation of which coal tar is formed. During the distillation of the resin, a "carbolic oil" fraction (t 0 160-230 0 C) containing phenol and cresols is obtained.
1. Fusion of salts of aromatic sulfonic acids with alkalis
The reaction underlies the industrial methods for obtaining phenols.
The reaction consists in heating benzenesulfonic acid with solid alkali (NaOH, KOH) at a temperature of 250-300 0 C:
The reaction proceeds by the mechanism of nucleophilic substitution S N 2 aroma(attachment-cleavage).
The presence of electron-withdrawing substituents in the ortho and para positions relative to the substitution site facilitates the nucleophilic substitution reaction.
2. Hydrolysis of aryl halides
Aryl halides that do not contain activating electron-withdrawing substituents react under very harsh conditions.
So, chlorobenzene is hydrolyzed with the formation of phenol by the action of concentrated alkali at a temperature of 350-400 0 C and high pressure 30 MPa, or in the presence of catalysts - copper salts and high temperature:
The reaction proceeds according to the mechanism of nucleophilic substitution (cleavage-addition) (arine or kine-mechanism).
The presence of electron-withdrawing substituents in the ortho and para positions with respect to the halogen greatly facilitates the hydrolysis reaction.
So, para-nitrochlorobenzene is able to replace chlorine with hydroxyl by conventional heating with an alkali solution at atmospheric pressure:
para-nitrochlorobenzene para-nitrophenol
The reaction proceeds according to the mechanism S N 2
aroma(attachment-cleavage).
3. Obtaining phenol from cumene (cumene method)
Synthesis based on cumene is of industrial importance and is valuable in that it makes it possible to simultaneously obtain two technically important products (phenol and acetone) from cheap raw materials (oil, oil cracking gases).
Cumene (isopropylbenzene), when oxidized with atmospheric oxygen, turns into hydroperoxide, which, under the action of an aqueous acid solution, decomposes to form phenol and acetone: 
hydroperoxide phenol acetone
4. Hydroxylation of arenes
For the direct introduction of a hydroxyl group into the benzene ring, hydrogen peroxide is used in the presence of catalysts (iron (II) or copper (II) salts):
5. Oxidative decarboxylation of carboxylic acids
Phenols are obtained from aromatic acids by passing water vapor and air into the reactor at a temperature of 200-300 0 C in the presence of copper (P) salts:
6. Obtaining from diazonium salts
When heating arenediazonium salts in aqueous solutions, nitrogen is released to obtain phenols: 
Physical properties of phenols
The simplest phenols under normal conditions are low-melting, colorless crystalline substances with a characteristic odor.
Phenols are sparingly soluble in water, but highly soluble in organic solvents. When stored in air, they darken due to oxidation processes.
They are toxic substances that cause skin burns.
Electronic structure of phenol
The structure and distribution of electron density in a phenol molecule can be represented by the following scheme:
The hydroxyl group is a substituent of the 1st kind, i.e. electron donor substituent.
This is due to the fact that one of the lone electron pairs of the hydroxyl oxygen atom enters into p, π-conjugation with the π-system of the benzene nucleus, exhibiting the +M effect.
On the other hand, the hydroxyl group, due to the greater electronegativity of oxygen, exhibits the –I effect.
However, the +M effect in phenols is much stronger than the oppositely directed –I effect (+M > -I).
The result of the pairing effect is:
1) increase in polarity O-N connections, leading to an increase in the acidic properties of phenols compared to alcohols;
2) due to conjugation, the C-OH bond in phenols becomes shorter and stronger in comparison with alcohols, since it is partially double in nature. Therefore, the substitution reactions of the OH group are difficult;
3) an increase in the electron density on carbon atoms in the ortho- and para-positions of the benzene nucleus facilitates the reactions of electrophilic substitution of hydrogen atoms in these positions.
Chemical properties of phenols
The chemical properties of phenols are determined by the presence of a hydroxyl group and a benzene ring in the molecule.
1. Reactions on the hydroxyl group
1. Acid properties
Phenols are weak OH acids, but much stronger than alkanols. Acidity constant RK A phenol is 10.
The higher acidity of phenol is due to two factors:
1) the greater polarity of the O-H bond in phenols, as a result of which the hydrogen atom of the hydroxyl group acquires greater mobility and can be split off in the form of a proton to form phenolate ion;
2) The phenolate ion is mesomerically stabilized due to the conjugation of the lone pair of oxygen with the benzene ring, i.e. the negative charge on the oxygen atom of the phenolate ion is significantly delocalized:
None of these boundary structures in isolation describes the real state of the molecule, but their use makes it possible to explain many reactions.
Electron-withdrawing substituents increase the acidic properties of phenol.
Pulling the electron density from the benzene nucleus to themselves, they contribute to the strengthening of the p, π-conjugation (+ M-effect), thereby increasing the polarization of the O-H bond and increasing the mobility of the hydrogen atom of the hydroxyl group.
For example:
phenol 2-nitrophenol 2,4-dinitrophenol picric acid
pKa 9.98 7.23 4.03 0.20
Electron donor substituents reduce the acidity of phenols.
1. Substitution of phenolic hydroxyl by halogen
The hydroxyl group in phenols is replaced with great difficulty by a halogen.
When phenol interacts with phosphorus pentachloride PCl 5, triphenyl phosphate is the main product, and chlorobenzene is formed only in small quantities:
Triphenyl Phosphate Chlorobenzene
The presence of electron-withdrawing substituents in the ortho and para positions with respect to the hydroxyl greatly facilitates the reactions of nucleophilic substitution of the OH group.
So, picric acid under the same conditions easily turns into 2,4,6-trinitrochlorobenzene (picryl chloride): 
picric acid picryl chloride
2. Interaction with ammonia
When interacting with ammonia elevated temperature and pressure in the presence of an aluminum chloride catalyst, the OH group is replaced by an NH 2 group with the formation of aniline:
phenol aniline
3. Recovery of phenol
When phenol is reduced with lithium aluminum hydride, benzene is formed:
3. Reactions involving the benzene ring
1. Reactions of electrophilic substitution in the benzene ring
The hydroxyl group is a substituent of the 1st kind, therefore, electrophilic substitution reactions in the benzene ring proceed much more easily with phenols than with benzene, and the substituents are directed to the ortho and para positions.
1) Halogenation reactions
Phenol easily reacts with bromine water at room temperature to form a white precipitate of 2,4,6-tribromophenol:
2,4,6-tribromophenol
This reaction is qualitative for phenols.
Chlorination of phenol occurs easily:
2) Nitration reactions
Phenol is easily nitrated with dilute nitric acid at a temperature of 0 0 C with the formation of a mixture of ortho- and para-isomers with a predominance of the ortho-isomer: 
ortho- and para-nitrophenols
Isomeric nitrophenols are easily separated due to the fact that only the ortho isomer is volatile with water vapor.
The high volatility of ortho-nitrophenols is explained by the formation of an intramolecular hydrogen bond, while the para-isomer forms intermolecular hydrogen bonds: 
When using concentrated nitric acid, 2,4,6-trinitrophenol (picric acid) is formed:
picric acid
3) Sulfonation reactions
Phenol is easily sulfonated at room temperature with concentrated sulfuric acid to form an ortho-isomer, which at temperatures above 100 0 C rearranges into a para-isomer:
4) Alkylation reactions
Phenols readily enter into alkylation reactions.
Haloalkanes, alkanols and alkenes are used as alkylating agents in the presence of protic acids (H 2 SO 4, H 3 PO 4) or Lewis acids (AlCl 3 , BF 3): 
5) Acylation reactions
Acylation of phenols easily occurs under the action of halogen anhydrides or anhydrides of carboxylic acids in the presence of Lewis acids: 
6) Nitrosation reactions
Nitrosophenols are obtained by direct nitrosation of phenols:
para-cresol ortho-nitroso-para-cresol
7) Azo coupling reactions
The combination with phenols leads to slightly alkaline environment, since the phenolate ion is much more active than phenol itself:
8) Condensation reactions
Phenols are such active components in electrophilic substitution reactions that they interact with very weak electrophiles - aldehydes and ketones in the presence of acids and bases.
Condensation with formaldehyde
Formaldehyde is most readily involved in condensation reactions.
If the condensation reaction of phenol with formaldehyde is carried out under mild conditions, then ortho- and para-hydroxymethylphenols can be isolated: Individual representatives
Phenol- crystalline substance with so pl. 43°C, has a characteristic pungent odor, causes burns on the skin. This is one of the first antiseptics used in medicine. It is used in large quantities to obtain plastics (condensation with formaldehyde), medicines(salicylic acid and its derivatives), dyes, explosives (picric acid).
Phenol methyl ester - anisole- It is used to obtain fragrant substances and dyes.
Phenol ethyl ester - phenetol.
Cresols (methylphenols) used in the production of plastics, dyes, disinfectants.
Among the numerous color reactions to phenol hydroxyl, the test with ferric chloride is the most widely used in the pharmacopoeial analysis. The coloration resulting from the reaction is usually blue or violet and depends on the substituents. S. Weibel points to the empirically established “following regularities, which, however, are not valid in all cases”:
1) substituted phenols having two hydroxyl groups in the ortho position give a green color;
2) the presence of a carboxyl group in the ortho position to the hydroxyl leads to the appearance of a purple color instead of blue,
3) if the carboxyl group is in the para position with respect to the hydroxyl, the color becomes yellow or red, the intensity of the color in the first case increases, and in the latter it decreases, p-hydroxycarboxylic acids can also form yellow or reddish precipitates with ferric chloride,
4) meta-substituted phenols usually give a weak color reaction or do not stain at all, however, m-dioxibenzene (resorcinol) stains in an intense purple color.
Dilute 1 ml of a 0.1% aqueous solution of adrenaline with 4 ml of water, add 1 drop of ferric chloride solution: a green color immediately appears, turning into cherry red when 0.5 ml of diluted ammonia is added. (A solution of adrenaline hydrochloride, GPC.)
Phenols with free ortho or para positions decolorize bromine water and form substitution products, which usually precipitate and can be characterized by melting point after recrystallization.
So, tribromophenol, obtained by bromination of phenol, after recrystallization from alcohol and drying at 80 ° melts at 92-95 °.
The same phenols combine with diazotized primary aromatic amines in all cases where the substitutions are not in the meta position to the amino group or to another hydroxy group.
The reaction is described above in the primary aromatic amino group test.
Many free para phenols condense with 4-chloroim,in-2,6-dichloroquinone to form colored indophenols. The indophenol reaction can be performed both in solution and on filter paper.
Place 1 ml of a 0.01% solution in two tubes, designated A and B, respectively, and add 2 ml of a 20% sodium acetate solution to each tube. Add 1 ml of water to test tube A, add 1 ml of 4% boric acid solution to test tube B and mix. Both test tubes are cooled to 20°C and 1 ml of a 0.5% solution of 4-chlorimin-2,6-dichloroquinone in alcohol is quickly added to each test tube: a blue color appears in test tube A, which quickly disappears and turns red after a few minutes , there is no blue color in tube B. (Pyridoxine hydrochloride. International Pharmacopoeia, USP XVII.)
The specificity of the method common to phenols is achieved in the case of pyridoxine due to the reaction of two molecules of pyridoxine with one molecule of boric acid, as a result of which a compound is formed that does not react with chloroquinone.
Complex of pyridoxine with boric acid
The latter allows for a control determination that distinguishes pyridoxine from other phenolic compounds and from pyridoxamine and pyridoxal, which do not have an oxymethylene group in position 4. The same reaction was used in the X edition of the State Pharmacopoeia to test for the absence of pyridoxine methyl ester.
Phenols are converted into acetyl derivatives by heating a substance dissolved in pyridine with acetic anhydride.
0.2 g is boiled for 5 minutes with 1 ml of acetic anhydride and 2 ml of pyridine in a flask for acetylation. After cooling, 10 drops of water are added and after the formation of crystals another 50 ml of water, the flask is left to stand with constant shaking for 1 hour. Filter through a glass filter, rinsing the flask and filter with 50 ml of water. Dry the filter at 105°. The melting point of the resulting diacetate is 121-124°. (Diethylstilbestrol, Scandinavian Pharmacopoeia.)
In the same way, dicoumarin, fluorescein and phenolphthalein are determined, the melting points of acetyl derivatives of which are 262-271°, 202-207° and 147-150°, respectively.
As with aromatic amines, phenol benzoates are crystalline solids with a characteristic melting point.
0.03 g of the powdered preparation is dissolved in a flask with a ground stopper with a capacity of 50 ml in 12 ml of 5% potassium hydroxide solution, cooled to a temperature not exceeding 10 ° and 3-4 drops of benzoyl chloride are added. The solution is shaken vigorously, the precipitate is filtered off on a small glass filter No. 3 or No. 4, washed with 1-2 ml of water, transferred to a 25 ml flask equipped with an air cooler, 2 ml of methyl alcohol are added and heated in a water bath with stirring until complete dissolution , and then
chilled in ice. The precipitate formed is filtered off and dried for 30 minutes in an oven at 100-105°. The melting temperature of the resulting ethinylestradiol benzoate is 199-202°. (Ethinylesgradiol, GPC.)
Phenols in a neutral medium in aqueous or alcoholic solutions form salts with iron (III) chloride, colored blue-violet (monatomic), blue (diatomic: resorcinol), green (pyrocatechin) or red (phloroglucinol). This is due to the formation of cations C 6 H 5 OFe 2+, C 6 H 5 OFe +, etc.
Methodology: to 1 ml of an aqueous or alcoholic solution of the test substance ( phenol - 0.1:10, resorcinol - 0.1:10, sodium salicylate - 0.01:10, pyridoxine hydrochloride - 0.01:10) add 1 to 5 drops of iron (III) chloride solution. Characteristic coloration is observed.
7.2. Oxidation reactions (indophenol test)
A). Reaction with chloramine.
When phenols interact with chloramine and ammonia, indophenol is formed, colored in various colors: blue-green (phenol), brownish-yellow (resorcinol), red-brown (PAS-sodium), etc.
Methodology:
0.05 g of test substance ( phenol, resorcinol, PAS-sodium) is dissolved in 0.5 ml of chloramine solution, 0.5 ml of ammonia solution is added. The mixture is heated in a boiling water bath. Staining is observed.
b). Lieberman's nitrosoreaction. The colored product (red, green, red-brown) is formed by phenols, which have no substituents in the ortho and para positions.
Methodology:
A grain of matter ( phenol, resorcinol, thymol, salicylic acid) is placed in a porcelain cup and moistened with 2-3 drops of a 1% solution of sodium nitrite in concentrated sulfuric acid. Coloring is observed, which changes with the addition of sodium hydroxide solution.
7.3. Condensation reactions with aldehydes.
Phenols in the presence of concentrated sulfuric acid condense with aldehydes to form a colorless substance. Then concentrated sulfuric acid dehydrates the condensation product with the formation of a substance with a quinoid structure. A red color appears.
Methodology: Several grains of matter ( phenol, resorcinol, salicylic acid, chinosol etc.) are placed in a porcelain cup and moistened with 2-3 drops of Mark's reagent (or a solution of another aldehyde in sulfuric acid). When standing, a red color is observed.
Some heterocyclic drugs containing phenol hydroxyl give a red-violet or blue-violet color (oxidation products).
7.4. Combination with diazonium salts
Phenols in an alkaline and ammonia environment interact with diazonium salts to form an azo dye (red color):
azo dye (red dye)
Methodology: A). Preparation of the diazo reagent: 0.1 g of sulfanilic acid is dissolved in 10 ml of water. The solution is acidified with hydrochloric acid and heated for 3 minutes. To the cooled solution is added 2 ml of 0.1 M sodium nitrite solution.
b). K 0.05 g medicinal substance (resorcinol, phenol, sodium salicylate, sodium PAS, chinosol), dissolved in 5 ml of water, add 2 ml of ammonia solution and 1 ml of diazo reagent. A red color is formed.
