LECTURE № 7

LECTURE LECTURE № № 77

Aromatic compounds as drugs Aromatic compounds as drugs ((p-p-Aminophenol derivatives, Aminophenol derivatives,

quinones, phenols). Acids of aromatic quinones, phenols). Acids of aromatic series, their salts, esters and amides series, their salts, esters and amides

as drug substancesas drug substances

associate prof. Mosula L. M.associate prof. Mosula L. M.

The PlanThe Plan

1. 1. Derivatives ofDerivatives of p-p-aminophenol as aminophenol as drug.drug.

2. 2. QuinonesQuinones, which are used in , which are used in medicine.medicine.

3. 3. Phenols as drugs.Phenols as drugs. 4.4. Aromatic acids and their salts Aromatic acids and their salts, ,

which are used in medicine.which are used in medicine. 5. 5. Esters of aromatic acidsEsters of aromatic acids as drugs. as drugs. 6. 6. AAmides mides of of aromatic acids and aromatic acids and

their derivativestheir derivatives , which are used in , which are used in medicine.medicine.

p-p-Aminophenol derivativesAminophenol derivatives The hydroxilated (The hydroxilated (o, m, po, m, p), better known as the aminophenols, are ), better known as the aminophenols, are

quite interesting from the standpoint of being considerably less toxic quite interesting from the standpoint of being considerably less toxic than aniline. The para-compounds (C-3) is of particular interast from than aniline. The para-compounds (C-3) is of particular interast from two standpoint: namely it is the metabolic product of aniline, and it is two standpoint: namely it is the metabolic product of aniline, and it is the least toxic of the three possible aminophenols. It also possesses the least toxic of the three possible aminophenols. It also possesses a strong antipyretic and analgesic action. However, it is too toxic to a strong antipyretic and analgesic action. However, it is too toxic to serve as a drug, and for this reason, there were numerous serve as a drug, and for this reason, there were numerous modifications attempted.modifications attempted.

One of the first was acetylation of the amine group to provide N-One of the first was acetylation of the amine group to provide N-acetyl-p-aminophenol (acetaminophenol), a producr that retained a acetyl-p-aminophenol (acetaminophenol), a producr that retained a good measure of the desired activities. Another approach to the good measure of the desired activities. Another approach to the detoxication of p-aminophenol was the atherification of the phenolic detoxication of p-aminophenol was the atherification of the phenolic group. The best known of these are anisidine(C-9) and phenetidine group. The best known of these are anisidine(C-9) and phenetidine (C-10), which are the methyl and ethyl ethers, respectively. (C-10), which are the methyl and ethyl ethers, respectively. However, it becomes apparent that a free amino group in these However, it becomes apparent that a free amino group in these compounds, although promoting a strong antipyretic action, was also compounds, although promoting a strong antipyretic action, was also conducive to methemoglobin formation. The only exception to the conducive to methemoglobin formation. The only exception to the preceding was for compounds in which a carboxyl group or sulfonic preceding was for compounds in which a carboxyl group or sulfonic acid group had been substituted on the benzene nucleus. In these acid group had been substituted on the benzene nucleus. In these compounds, however, the antipyretic activity also had disappeared. compounds, however, the antipyretic activity also had disappeared. The foregoing consideration led to the preparation of the alkyl ethers The foregoing consideration led to the preparation of the alkyl ethers of N-acetyl-p-aminophenol of which the ethyl ether was the best and of N-acetyl-p-aminophenol of which the ethyl ether was the best and is known as phenacetin (C-11). The methyl and propyl homologues is known as phenacetin (C-11). The methyl and propyl homologues were undesirable from the standpoint of causing emesis, salivation, were undesirable from the standpoint of causing emesis, salivation, diuresis and other reactions. Alkylation of the nitrogen with a methyl diuresis and other reactions. Alkylation of the nitrogen with a methyl group has a potentiating effect on the analgesic action, but, group has a potentiating effect on the analgesic action, but, unfortunately, has a highly irritant action on mucous membranes.unfortunately, has a highly irritant action on mucous membranes.

ParacetamolParacetamol

General NoticesGeneral Notices ParacetamolumParacetamolum

СН3СОNHC6H4OH СН3СОNHC6H4OH C8H9NO2C8H9NO2

М m. = 151,2 g/mol М m. = 151,2 g/mol

The chemical nameThe chemical name: : NN - - (4-hydroxiphenyl) (4-hydroxiphenyl)

p-acetaminophenolp-acetaminophenol.. Content Content 99.0 per cent to 101.0 per 99.0 per cent to 101.0 per

cent (dried substance). cent (dried substance).

OH NH C

O

CH3

ObtainingObtaining1. Nitrosation of phenol with the next 1. Nitrosation of phenol with the next reduction and aceetylationreduction and aceetylation::

H

OH

Na-O-N=O

H2SO4

N

OH

O

NH3

H2S

NH2

OH

(CH3CO)2O

- CH3COOH

HN

OH

C

O

CH3

CHARACTERSCHARACTERS Appearance Appearance White, crystalline powder. White, crystalline powder. Solubility Solubility Sparingly soluble in water, freely soluble in alcohol, very slightly Sparingly soluble in water, freely soluble in alcohol, very slightly

soluble in methylene chloride. soluble in methylene chloride. IDENTIFICATIONIDENTIFICATION First identificationFirst identification  A, C.A, C. Second identificationSecond identification  A, B, D, E.A, B, D, E.   

A. Melting pointA. Melting point (2.2.14)(2.2.14): : 168 °C to 172 °C. 168 °C to 172 °C.   B. UV-spectroscopy.B. UV-spectroscopy. Dissolve 0.1 g in Dissolve 0.1 g in methanol Rmethanol R and and

dilute to 100.0 ml with the same solvent. To 1.0 ml of the dilute to 100.0 ml with the same solvent. To 1.0 ml of the solution add 0.5 ml of a 10.3 g/l solution of solution add 0.5 ml of a 10.3 g/l solution of hydrochloric acid Rhydrochloric acid R and dilute to 100.0 ml with and dilute to 100.0 ml with methanol Rmethanol R. Protect the solution . Protect the solution from bright light and immediately measure the absorbance from bright light and immediately measure the absorbance (2.2.25)(2.2.25) at the absorption maximum at 249 nm. The at the absorption maximum at 249 nm. The specific specific absorbance at the maximum is 860 to 980. absorbance at the maximum is 860 to 980.

  C.C. Infrared absorption spectrophotometryInfrared absorption spectrophotometry (2.2.24)(2.2.24). . PreparationPreparation  Discs. Discs. ComparisonComparison  paracetamol CRSparacetamol CRS. .

D.D. Indophenol test after acid hydrolysisIndophenol test after acid hydrolysis (for a (for a primary aromatic amino group)primary aromatic amino group)..To 0.1 g add 1 ml of To 0.1 g add 1 ml of hydrochloric acid Rhydrochloric acid R, heat to boiling for 3 min, add 1 ml , heat to boiling for 3 min, add 1 ml of of water Rwater R and cool in an ice bath. No precipitate is and cool in an ice bath. No precipitate is formed. Add 0.05 ml of a 4.9 g/l solution of formed. Add 0.05 ml of a 4.9 g/l solution of potassium potassium dichromate Rdichromate R. A . A violet colour develops which does not violet colour develops which does not change to redchange to red (difference from Phenacetinum)(difference from Phenacetinum). .

E. It gives the reaction of acetyl E. It gives the reaction of acetyl (2.3.1)(2.3.1). Heat over a naked . Heat over a naked flame. flame.

About 15 mg test substances place in a test tube in length About 15 mg test substances place in a test tube in length about 180 mm and external diameter 18 mm and add 0,15 ml about 180 mm and external diameter 18 mm and add 0,15 ml of phosphoric acid R. of phosphoric acid R. Close test tube by means of stopper, Close test tube by means of stopper, through which 10 mm which contains through which 10 mm which contains water Rwater R are passed a are passed a small test tube the in length about 100 mm and in external small test tube the in length about 100 mm and in external diameter and carries out a refrigerator role. On an external diameter and carries out a refrigerator role. On an external surface of a smaller test tube place 1 drop surface of a smaller test tube place 1 drop of lanthanum of lanthanum nitrate solution R. nitrate solution R. If substance rather easily hydrolyzes, the If substance rather easily hydrolyzes, the device place on 5 mines at a water heater, then take out a device place on 5 mines at a water heater, then take out a smaller test tube. For substances, which it is difficult smaller test tube. For substances, which it is difficult hydrolyzes, a mix slowly heat up on an open flame to boiling. hydrolyzes, a mix slowly heat up on an open flame to boiling. A drop remove, mix on a porcelain plate about 0,05 ml A drop remove, mix on a porcelain plate about 0,05 ml of 0,01 of 0,01 MM. . iodine solution. iodine solution. On drop edge put 0,05 ml On drop edge put 0,05 ml of ammonia of ammonia diluted solution R2diluted solution R2; through 1–2 mines in a junction of two ; through 1–2 mines in a junction of two drops there is drops there is a dark blue colouringa dark blue colouring which amplifies and which amplifies and remains during a short time interval.remains during a short time interval.

La (NO3) 3 + 2CH3COOK + NH4OH = LaOH (CH3COO) 2 + La (NO3) 3 + 2CH3COOK + NH4OH = LaOH (CH3COO) 2 + NH4NO3 + 2 KNO3NH4NO3 + 2 KNO3

LaOH (CH3COO) 2 + I2 = LaOH (CH3COO) 2 LaOH (CH3COO) 2 + I2 = LaOH (CH3COO) 2 I2I2 Dark blue colouringDark blue colouring

Other reactions of identificationOther reactions of identification1. SPU. Formation azo dye (identification of a primary 1. SPU. Formation azo dye (identification of a primary aromatic amino group after acid hydrolysis)aromatic amino group after acid hydrolysis). The . The examinee a solution acidifyexaminee a solution acidify HClHCl diluted R diluted R, add , add 0,2 0,2 mlml of solution of solution sodium nitrite R sodium nitrite R NaNO2 a and NaNO2 a and through through 1–2 mines1–2 mines add add 1 ml1 ml of a solution of a solution --naphtholnaphthol; there is an intensive ; there is an intensive orangeorange or or red red colouringcolouring and, as a rule, and, as a rule, the precipitate of the the precipitate of the same coloursame colour is formed. is formed.

NHCOCH3

OH

+H2O

HCl

- CH3COOH

NH2

OH

H-O-N=O

(NaNO2 + HCl)

N

OH

N+

Cl

HO

H

NaOH

ONa

N N

NaO

orange or red

2. 2. Formation azo dye from diazonium saltsFormation azo dye from diazonium salts (identification phenolic hydroxyl).(identification phenolic hydroxyl). At interaction with diazonium At interaction with diazonium saltssalts occurs azocoupling in occurs azocoupling in o-positiono-position from OH-group to from OH-group to formation formation azo dye of red colourazo dye of red colour::

OH

H

NHCOCH3

+

R

N N

Cl2NaOH

- HCl

NHCOCH3

ONa

N N R

+ NaCl + 2H2O

azo dye of red colour

3. Interaction with solution of iron (III) chloride3. Interaction with solution of iron (III) chloride (presence phenolic hydroxyl)(presence phenolic hydroxyl).. 0,1 g a drug shake up about 0,1 g a drug shake up about 10 ml 10 ml of waterof water and add some drops of a solution FeCl3; there and add some drops of a solution FeCl3; there is is a blue-violeta blue-violet colouring colouring::

СН3СОNHC6H4OH + FeCl3 = СН3СОNHC6H4OFeCl2 + СН3СОNHC6H4OH + FeCl3 = СН3СОNHC6H4OFeCl2 + HClHCl

blue-violetblue-violet 4. Acid hydrolysis with the next 4. Acid hydrolysis with the next identification of acetic identification of acetic

acid.acid. 0,1 g drug cautiously boil about 0,1 g drug cautiously boil about 2 ml2 ml of sulphatic acidof sulphatic acid diluted diluted H2SO4 during H2SO4 during 2 mines2 mines; there is ; there is a smell acetic acid a smell acetic acid CН3CООН: CН3CООН:

СН3СОNHC6H4OH + НОН = H2NC6H4OН + СН3СООH СН3СОNHC6H4OH + НОН = H2NC6H4OН + СН3СООH TESTS Related substances Liquid chromatography (2.2.29). Prepare the solutions immediately before use.Heavy metals (2.4.8) Maximum 20 ppm. Loss on drying (2.2.32) Maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 100-105 °C. Sulphated ash (2.4.14) Maximum 0.1 per cent, determined on 1.0 g.

ASSAYASSAY Ceriumetry, direct titrationCeriumetry, direct titration Dissolve 0.300 g in a mixture of 10 ml of Dissolve 0.300 g in a mixture of 10 ml of water Rwater R and 30 ml of and 30 ml of dilute sulphuric acid Rdilute sulphuric acid R. Boil under a reflux condenser for 1 h, . Boil under a reflux condenser for 1 h, cool and dilute to 100.0 ml with cool and dilute to 100.0 ml with water Rwater R. To 20.0 ml of the . To 20.0 ml of the solution add 40 ml of solution add 40 ml of water Rwater R, 40 g of ice, 15 ml of , 40 g of ice, 15 ml of dilute dilute hydrochloric acid Rhydrochloric acid R and 0.1 ml of and 0.1 ml of ferroin Rferroin R. Titrate with . Titrate with 0.1 M 0.1 M cerium sulphatecerium sulphate until a greenish-yellow colour is obtained. until a greenish-yellow colour is obtained.

Carry out a blank titration.Carry out a blank titration.

OH

HN

O

NC

O

CH3

+ 2 Ce(SO4)2

CCH3

O

+4

+ Ce2(SO4)2 + H2SO4

+3

Еm (C8H9NO2) = M. m./2 1 ml of 0.1 M cerium sulphate is equivalent to 7.56 mg of C8H9NO2.

STORAGESTORAGE Protected from light. Protected from light. Action and use Action and use Analgesic and antipyretic. Analgesic and antipyretic. Preparations Preparations Co-codamol Tablets Co-codamol Tablets Effervescent Co-codamol Tablets Effervescent Co-codamol Tablets Co-dydramol Tablets Co-dydramol Tablets Co-proxamol Tablets Co-proxamol Tablets Paediatric Paracetamol Oral Solution Paediatric Paracetamol Oral Solution Paracetamol Oral Suspension Paracetamol Oral Suspension Paracetamol Suppositories Paracetamol Suppositories Paracetamol Tablets Paracetamol Tablets Dispersible Paracetamol Tablets Dispersible Paracetamol Tablets Soluble Paracetamol TabletsSoluble Paracetamol Tablets

Quinone derivativesQuinone derivatives

Vitamin KVitamin K The term vitamin K was applied to the vitamin The term vitamin K was applied to the vitamin

isolated from alfalfa, and a similar principle isolated from alfalfa, and a similar principle from fishmeal was named vitamin K2. Vitamin from fishmeal was named vitamin K2. Vitamin K2 refers to a series of compounds called the K2 refers to a series of compounds called the menaquinones. These have a longer side chain menaquinones. These have a longer side chain with more unsaturation. Many other closely with more unsaturation. Many other closely related compounds possess vitamin K activity. related compounds possess vitamin K activity. The synthetic compounds menadione and The synthetic compounds menadione and menadiol are referred to as vitamin K3 and K4.menadiol are referred to as vitamin K3 and K4.

Vitamin K is a naphthoquinone derivativeVitamin K is a naphthoquinone derivative containing diterpenoid units biosynthesized by containing diterpenoid units biosynthesized by the intermediate, geraylpyrophosphate.the intermediate, geraylpyrophosphate.

Numerous compounds have been tested for their Numerous compounds have been tested for their antihemorrhagic activity, and significant biologic activity is antihemorrhagic activity, and significant biologic activity is manifested in compounds with the following structure when:manifested in compounds with the following structure when:

R

R'

R"

R"'

A B

1. ring A is aromatic or hydroaromatic2. ring A is not substituted3. ring B is aromatic or hydroaromatic4. R equals OH, CO, OR, OAc (the R in OR equals methyl or ethyl)5. R’ equals methyl6. R” equals H, sulfonic acid or an alkyl group containing ten or more carbon

atoms. A double bond in the β, γ-position of this alkyl group enhances potency, whereas, if the double bound is further removed, it exerts no effect. Isoprenoid groups are more effective than straight chains.

7. R”’ equals H, OH, NH2, CO, OR, Ac (the R in OR equals methyl or ethyl).It is interesting that, if ring A is benzenoid, the introduction of sulfur in place of

–CH=CH- in this ring in 2-methylnaphthoquinone permits the retention of some antihemorrhagic activity.

Products:Products: MenadioneMenadione (2-methyl-1,4-naphthoquinone; menaphthone; (2-methyl-1,4-naphthoquinone; menaphthone;

thyloquinone).thyloquinone). On a mole-for-mole basis, menadione is equal to vitamin K1 in On a mole-for-mole basis, menadione is equal to vitamin K1 in

activity and can be used as a complete substitute for this activity and can be used as a complete substitute for this vitamin. It is effective orally, intravenously and vitamin. It is effective orally, intravenously and intramuscularly.intramuscularly.

Menadione Sodium BisulfiteMenadione Sodium Bisulfite (2-methyl-1,4-naphthoquinone (2-methyl-1,4-naphthoquinone sodium bisulfite; Hykinone, sodium bisulfite; Hykinone, VikasolVikasol) is prepared by adding a ) is prepared by adding a solution of sodium bisulfite to menadione.solution of sodium bisulfite to menadione.

CH3

O

O

CH3

O

O

SO3NaNaHSO3

Menadione sodium bisulfite occurs as a white, crystalline, odorless powder. One gram of it dissolves in about 2 ml of water, and it is slightly soluble in alcohol. It decomposes in the presence of alkali to liberate the free quinone.

Menadione Sodium DiphosphateMenadione Sodium Diphosphate (tetrasodium (tetrasodium 2-methyl-1,4-naphthalenediol bis(dihydrogen 2-methyl-1,4-naphthalenediol bis(dihydrogen phosphate); Synkayvite; Kappadione) is a white phosphate); Synkayvite; Kappadione) is a white hygroscopic powder, very soluble in water, giving hygroscopic powder, very soluble in water, giving solutions that have a pH of 7 to 9.solutions that have a pH of 7 to 9.

CH3

OPO3Na2

OPO3Na2

It is available in ampules for use subcutaneusly, intramuscularly, intravenously and in tablets for oral administration.

IdentificationIdentification A. Menadione Sodium Bisulfite and Menadione Sodium Diphosphate A. Menadione Sodium Bisulfite and Menadione Sodium Diphosphate

yield the reaction characteristic of sodium salts and burn with yellow yield the reaction characteristic of sodium salts and burn with yellow flame.flame.

B. Menadione Sodium Bisulfite reacts with concentrated sulphuric B. Menadione Sodium Bisulfite reacts with concentrated sulphuric acid to form sulphur(IV) oxide.acid to form sulphur(IV) oxide.

CH3

O

O

SO3Na H2SO4 Na2SO4 SO2 H2O2 + 2

CH3

O

O

+ + +2

C. Destruction of Menadione Sodium Bisulfite in base medium to sodium sulphite and 2-methyl-1,4- naphthoquinone. 2-Methyl-1,4- naphthoquinone may be identified by its melting point (104-107*C).

CH3

O

O

SO3Na + H2O+NaOH Na2SO3+

CH3

O

O

This reaction may be used for assay of vitamin K. For this reason reduce obtained 2-methyl-1,4- naphthoquinone to 1,4-dioxi-2-methylnaphtaline and titrate with 0.2N Ce(SO4)3 using a o-phenantroline as an indicator.

Derivatives of phenolsDerivatives of phenols

Phenols are Phenols are the derivatives of the derivatives of aromatic hydrocarbons containing in aromatic hydrocarbons containing in a molecule one or several a molecule one or several hydroxygroupshydroxygroups, which are directly , which are directly connected with an aromatic connected with an aromatic ringring. .

PhenolphthaleinPhenolphthalein (Ph Eur monograph 1584)(Ph Eur monograph 1584)

C20H14O4C20H14O4     318.3 318.3    77-09-877-09-8 Action and use Action and use Laxative. Laxative. DEFINITIONDEFINITION Phenolphthalein contains not less than 98.0 per cent and Phenolphthalein contains not less than 98.0 per cent and

not more than the equivalent of 101.0 per cent of 3,3-bis(4-not more than the equivalent of 101.0 per cent of 3,3-bis(4-hydroxyphenyl)isobenzofuran-1(3hydroxyphenyl)isobenzofuran-1(3HH)-one, calculated with )-one, calculated with reference to the dried substance.reference to the dried substance.

PhenolPhenol (Ph Eur monograph 0631)(Ph Eur monograph 0631)

C6H6OC6H6O     M.m. 4.1 M.m. 4.1    108-95-2108-95-2

ObtainingObtaining From coal pitchFrom coal pitch At processing of coal pitch receive various products At processing of coal pitch receive various products

(oils), including phenol. With that end in view process (oils), including phenol. With that end in view process alkalialkali; ; phenolate phenolate СС66НН55ООNa which we will well dissolve Na which we will well dissolve in water is formed and easily separates from insoluble in water is formed and easily separates from insoluble impurity in water and other components of coal pitch:impurity in water and other components of coal pitch:

СС66НН55ОНОН + Na + NaОНОН = = СС66НН55ООNa + Na + НН22ОО The received solution of phenolate process The received solution of phenolate process carbonic carbonic

gasgas СОСО2 or the diluted mineral acid, for example, HCl. 2 or the diluted mineral acid, for example, HCl. Thus receive Thus receive phenolphenol which is partially dissolved in which is partially dissolved in water:water:

СС66НН55ООNa + Na + НН22ОО + + СОСО2 = 2 = СС66НН55ОНОН + Na + NaНСОНСО3 3 СС66НН55ООNa + HCl = Na + HCl = СС66НН55ОНОН + NaCl + NaCl The received product overtake and collect fraction The received product overtake and collect fraction

which boils at which boils at 180–200 180–200 C.C.

2. A synthetic method2. A synthetic method from benzol.from benzol. a) Sulphonatoin of benzola) Sulphonatoin of benzol by means of by means of sulphatic acidsulphatic acid

НН2SO4 with formation benzolsulphoacid:2SO4 with formation benzolsulphoacid:H

+ HOSO3H

SO3H

+ H2O

b) eutralization of a product by means of Са (OH) 2 with formation calcium salts of benzolsulphoacid:

SO3H

Ca(OH)2Ca 2H2O

2 +2

+

SO3

Surplus Ca(OH)2 eliminate by means of sulphatic acid:Са (OH) 2 + Н2SO4 = СаSO4 + 2Н2О

c) Afterc) After filtering a filtrate filtering a filtrate process of solution sodium process of solution sodium carbonatecarbonate Na2CO3; it is formed sodium salt of Na2CO3; it is formed sodium salt of benzolsulphoacid:benzolsulphoacid:

Ca Na2CO3 Ca2CO3

SO3Na

2

+ + 2

SO3

d) The received solution evaporate and alloy with alkali NaOH; sodium phenolate is formed:

SO3Na

+ 2NaOHt

ONa

+ Na2SO3 + H2O

e) At processing of phenolate by sulphatic acid Н2SO4 obtain phenol:

ONa

2 + H2SO4Na2SO4 +

OH

The obtained product overtake and collect fraction which boils at 178–182 C.

2. Synthesis from benzene chloride2. Synthesis from benzene chloride:: СС66НН55ССl + l + ННOH OH СС66НН55ООH + HClH + HCl

3.Synthesis from benzolsulphoacid3.Synthesis from benzolsulphoacid:: СС66НН5SO3H + 2NaOH 5SO3H + 2NaOH СС66НН55ООNa + NaHSO3 + H2ONa + NaHSO3 + H2O СС66НН55ООNa + HCl Na + HCl СС66НН55ООH + NaClH + NaCl DEFINITIONDEFINITION Phenol contains not less than 99.0 per cent and not Phenol contains not less than 99.0 per cent and not

more than the equivalent of 100.5 per cent of C6H6O. more than the equivalent of 100.5 per cent of C6H6O. CHARACTERSCHARACTERS Colourless or faintly pink or faintly yellowish crystals Colourless or faintly pink or faintly yellowish crystals

or crystalline masses, deliquescent, soluble in water, or crystalline masses, deliquescent, soluble in water, very soluble in alcohol, in glycerol and in methylene very soluble in alcohol, in glycerol and in methylene chloride. chloride.

IDENTIFICATIONIDENTIFICATION   A.A. Oxidation of phenol Oxidation of phenol by means ofby means of sodium sodium

hypochlorite (NAClO) solutionhypochlorite (NAClO) solution in the presence in the presence of concentrated ammoniaof concentrated ammonia (indophenol test)(indophenol test).. Dissolve 0.5 g in 2 ml of Dissolve 0.5 g in 2 ml of concentrated ammonia Rconcentrated ammonia R. The . The substance dissolves completely. Dilute to about 100 ml with substance dissolves completely. Dilute to about 100 ml with water Rwater R. To 2 ml of the dilute solution add 0.05 ml of . To 2 ml of the dilute solution add 0.05 ml of strong strong sodium hypochlorite solution Rsodium hypochlorite solution R. A . A blue colourblue colour develops and develops and becomes progressively more intense.becomes progressively more intense.

OH

O

NaClO

O

O

N H

H

H

-H2O

O

NH

-H2

OHO

N OH

blue colour

B.B. Reaction with a neutral iron (III) chlorideReaction with a neutral iron (III) chloride solutionsolution (reaction for phenolic hydroxyl).(reaction for phenolic hydroxyl). To 1 ml of To 1 ml of solution S (see Tests) add 10 ml of solution S (see Tests) add 10 ml of water Rwater R and 0.1 ml of and 0.1 ml of iron iron (III) chloride(III) chloride (ferric chloride) solution R1(ferric chloride) solution R1. A violet colour is . A violet colour is produced which disappears on addition of 5 ml of produced which disappears on addition of 5 ml of 2-propanol 2-propanol RR. .

6C6H5OH + FeCl3 Fe

O-C6H5

O C6H5

H

..

O-C6H5

O-C6H5

H

..O-C6H5

H5C6-O

H

+ 3HCl

..

This reaction it is possible to distinguish a solution of phenol from a solution of salicylic acid (phenolic acid); in this case colouring remains at presence of acetic acid.

  C.C. Reaction with bromine water (Br2)Reaction with bromine water (Br2)

(reaction for benzene ring).(reaction for benzene ring). To 1 ml of solution S add 10 To 1 ml of solution S add 10 ml of ml of water Rwater R and 1 ml of and 1 ml of bromine water Rbromine water R. . A pale-yellow A pale-yellow precipitateprecipitate is formed. is formed.

2,4,6-tribromphenol2,4,6-tribromphenol pale-yellow precipitatepale-yellow precipitate D. SPU. IR-spectroscopyD. SPU. IR-spectroscopy.. The IR-spectrum of The IR-spectrum of

absorption of substance solution in absorption of substance solution in ССССl4 for should l4 for should correspond correspond to reference spectrum SPU of phenolto reference spectrum SPU of phenol..

OH

+ 3Br2

OH

Br Br

Br

+ 3H2O

Not Not pharmacopoeialpharmacopoeial reactions reactions Formation azo dye with diazonium salts.Formation azo dye with diazonium salts. The The

alkaline solution of phenol with diazonium salts forms azo alkaline solution of phenol with diazonium salts forms azo dyes dyes durk reddurk red or or orange-red colourorange-red colour. Azocoupling proceeds, . Azocoupling proceeds, basically, in basically, in para-positionpara-position to OH-group ( to OH-group (substitute of substitute of ІІ sortssorts) and if this position is occupied replacement occurs in ) and if this position is occupied replacement occurs in ortho-positionortho-position::

OH

NaOH

-H2O

ONa

H

+N N

SO3H

Cl-HCl

ONa

N N SO3H

+

dark red or orange-red colour

RReaction with eaction with nitricnitric acid acid At interaction with HNO3 (depending on its concentration At interaction with HNO3 (depending on its concentration

and quantity) can be formed and quantity) can be formed mononitro-derivatives mononitro-derivatives (orto - (orto - or para-) or or para-) or 2,4,6-trinitrophenol 2,4,6-trinitrophenol (yellow dye – (yellow dye – picric acidpicric acid):):

a) a) with 20 % solution HNO3: with 20 % solution HNO3:

OH

H

H

+ 2HONO2

OH

NO2

+

OH

NO2

+ 2H2O

o-nitrophenol p-nitrophenolb) with HNO3 concentrated:

OH

+ 3HONO2

O2N

OH

NO2

NO2

+ 3H2O

2,4,6-trinitrophenol (yellow dye – picric acid)

3. Reaction with the Marki reagent3. Reaction with the Marki reagent ( (solutionsolution of of formaldehydeformaldehyde НСНОНСНО in in conc. sulphatic acidconc. sulphatic acid H2SO4 H2SO4); it ); it is formed is formed aurin dyeaurin dye of red colourof red colour..

aurin dye of red colouraurin dye of red colour

OH H +

C HH

O + H OHH2SO4

-H2O

HO C

H

H

OHO

-H2O

HO CH O

ASSAYASSAY BromatometryBromatometry, , backback titration, with titration, with

iodometric finishingiodometric finishing Dissolve 2.000 g in Dissolve 2.000 g in water Rwater R and dilute to 1000.0 ml with the same solvent. Transfer and dilute to 1000.0 ml with the same solvent. Transfer

25.0 ml of the solution to a ground-glass-stoppered flask and add 50.0 ml of 25.0 ml of the solution to a ground-glass-stoppered flask and add 50.0 ml of 0.0167 M 0.0167 M bromide-bromatebromide-bromate and 5 ml of and 5 ml of hydrochloric acid Rhydrochloric acid R, close the flask, allow to stand with , close the flask, allow to stand with occasional swirling for 30 min and then allow to stand for a further 15 min. Add 5 ml occasional swirling for 30 min and then allow to stand for a further 15 min. Add 5 ml of a 200 g/l solution of of a 200 g/l solution of potassium iodide Rpotassium iodide R, shake and titrate with , shake and titrate with 0.1 M sodium 0.1 M sodium thiosulphatethiosulphate until a faint yellow colour remains. Add 0.5 ml of until a faint yellow colour remains. Add 0.5 ml of starch solution Rstarch solution R and 10 and 10 ml of ml of chloroform Rchloroform R and continue the titration with vigorous shaking. and continue the titration with vigorous shaking.

Carry out a blank titrationCarry out a blank titration. . ChemismChemism it is possible to present by means of such equations: it is possible to present by means of such equations: KBrO3 + 5KBr + 6HCl = 3Br2 + 6KCl + 3H2OKBrO3 + 5KBr + 6HCl = 3Br2 + 6KCl + 3H2O Allocated bromine Br2 reacts with phenol Allocated bromine Br2 reacts with phenol СС66НН55ОНОН with formation with formation

of a white precipitate 2,4,6-tribromphenol:of a white precipitate 2,4,6-tribromphenol:OH

+ 3Br2

OH

Br Br

Br

+ 3H2O

Not reacted bromine Not reacted bromine Br2 Br2 reacts with reacts with KI KI with formation with formation of iodine of iodine I2I2::

Br2 + 2KI = Br2 + 2KI = I2I2 + 2KBr + 2KBr The allocated The allocated iodineiodine titrate bytitrate by standard standard solution solution

Na2S2O3Na2S2O3 in the presence of the indicator in the presence of the indicator of starchof starch and and solvent solvent of chloroformof chloroform before disappearance before disappearance of dark of dark blueblue colouring (add starch towards the end of colouring (add starch towards the end of titration):titration):

I2 + 2Na2S2O3 = 2NaI + Na2S4O6I2 + 2Na2S2O3 = 2NaI + Na2S4O6 I2 + 2I2 + 2ее 2I– 2I– 2S2O32– – 22S2O32– – 2ее S4O62– S4O62–

ЕЕm m (C6Н6О) = М m./6; (C6Н6О) = М m./6; kk (KBrO3) = 6 (KBrO3) = 6

1 ml of 0.0167 M bromide-bromate is equivalent to 1.569 mg of C6H6O.

STORAGESTORAGE Store in an airtight container , protected from light. Store in an airtight container , protected from light. Action and use Action and use Antiseptic; antimicrobial preservative; antipruritic. Antiseptic; antimicrobial preservative; antipruritic. Preparations Preparations Aqueous Phenol Injection Aqueous Phenol Injection Oily Phenol Injection Oily Phenol Injection Phenol Phenol Ph Eur Ph Eur and Glycerol Injectionand Glycerol Injection

Aromatic acids and their Aromatic acids and their derivativesderivatives

Aromatic acids and their saltsAromatic acids and their salts Aromatic acidsAromatic acids – derivatives of aromatic – derivatives of aromatic

hydrocarbons in which molecules in an aromatic ring hydrocarbons in which molecules in an aromatic ring one or several atoms of the Hydrogene are one or several atoms of the Hydrogene are substituted on substituted on carboxyl group – carboxyl group – СООНСООН. .

PropertiesProperties. Aromatic acids – crystal substances, . Aromatic acids – crystal substances, usually a little soluble in water and well soluble in usually a little soluble in water and well soluble in organic solvents (spirit, benzene, chloroform). organic solvents (spirit, benzene, chloroform). Constants of their acidity a little more than at fat Constants of their acidity a little more than at fat acids. In particular, benzoic acid acids. In particular, benzoic acid СС66НН55СООНСООН is a little is a little stronger acid in comparison with stronger acid in comparison with СНСН33СООНСООН, that , that speaks effect of linking of group –speaks effect of linking of group –СООНСООН with with СС66НН5-5-ring. Possess the general chemical properties, ring. Possess the general chemical properties, characteristic for carbopxylic acids: form salts, characteristic for carbopxylic acids: form salts, anhydrides, halogenanhydride, esters, amides, etc.anhydrides, halogenanhydride, esters, amides, etc.

Pharmacological action and medical Pharmacological action and medical application. Introduction carboxyl group – application. Introduction carboxyl group – СООНСООН in a molecule of aromatic hydrocarbon in a molecule of aromatic hydrocarbon lowers toxicitylowers toxicity of conpound and of conpound and simultaneously causes occurrence simultaneously causes occurrence of of cauterisingcauterising, , irritatingirritating action on tisue. Apply action on tisue. Apply aromatic acids as aromatic acids as antisepticantiseptic, and their salts – , and their salts – as carriers specific anions. The best solubility as carriers specific anions. The best solubility of salts in water reduces irritating action. of salts in water reduces irritating action.

Benzioc acid in an organism easily react with Benzioc acid in an organism easily react with amino acid amino acid glycolglycol with formation with formation hyppuric hyppuric acid,acid, which quantity testifies to a functional which quantity testifies to a functional condition of a liver. condition of a liver.

In medical practice apply benzoic and In medical practice apply benzoic and salicylic acids, and also their salts: sodium salicylic acids, and also their salts: sodium benzoate and sodium salicylate.benzoate and sodium salicylate.

Benzoic AcidBenzoic Acid General NoticesGeneral Notices (Ph Eur monograph 0066)(Ph Eur monograph 0066)

C7H6O2C7H6O2    M.mM.m.=122.1.=122.1    65-95-0 65-95-0 DEFINITIONDEFINITION Benzoic acid contains not less than Benzoic acid contains not less than 99.099.0 per cent and not per cent and not

more than the equivalent of more than the equivalent of 100.5100.5 per cent of per cent of benzenecarboxylic acid. benzenecarboxylic acid.

Benzoic acid and its esters occur naturally in gum benzoin Benzoic acid and its esters occur naturally in gum benzoin and in Peru and tolu balsams. It is found as a white crystalline and in Peru and tolu balsams. It is found as a white crystalline solid that slowly sublimes at room temperature and is steam solid that slowly sublimes at room temperature and is steam distillable. It is slightly soluble in water, but more soluble in distillable. It is slightly soluble in water, but more soluble in alcohol and other polar organic solvents. alcohol and other polar organic solvents.

ObtainingObtaining Now benzoic acid obtain several synthetic methods.Now benzoic acid obtain several synthetic methods. 1. Toluene oxidation1. Toluene oxidation in the in the sulphatic-acid mediumsulphatic-acid medium by by

means of MnO2 or K2Cr2O7:means of MnO2 or K2Cr2O7: С6Н5СН3 + 3MnO2 + 3H2SO4 = С6Н5СООН + 3MnSO4 + С6Н5СН3 + 3MnO2 + 3H2SO4 = С6Н5СООН + 3MnSO4 +

4Н2О4Н2О С7Н8 + 2Н2О – 6е С7Н8 + 2Н2О – 6е С7Н6О2 + 6Н+ С7Н6О2 + 6Н+ MnO2 + 4Н+ + 2е MnO2 + 4Н+ + 2е Mn2+ + 2Н2О Mn2+ + 2Н2О С6Н5СН3 + 3MnO2 + 6H+ С6Н5СН3 + 3MnO2 + 6H+ С6Н5СООН + 3Mn2+ + С6Н5СООН + 3Mn2+ +

4Н2О4Н2О2. 2. 2. Chlorination of toluene with the further hydrolysis 2. Chlorination of toluene with the further hydrolysis

benzenetrichloridebenzenetrichloride::CH3

+3Cl2-3HCl

CCl3

+3HOH-3HCl

C

OH

OH

OH

COH

O

-H2O

CHARACTERSCHARACTERS A white, crystalline powder or colourless crystals, odourless A white, crystalline powder or colourless crystals, odourless

or with a very slight characteristic odour, slightly soluble in or with a very slight characteristic odour, slightly soluble in water, soluble in boiling water, freely soluble in alcohol and water, soluble in boiling water, freely soluble in alcohol and in fatty oils. in fatty oils.

IDENTIFICATIONIDENTIFICATION   A. Melting pointA. Melting point (2.2.14): (2.2.14): 121 °C to 124 °C121 °C to 124 °C. .   B.B. Solution S (see Tests) gives Solution S (see Tests) gives reaction (a) of reaction (a) of

benzoatesbenzoates (2.3.1). (2.3.1). a) Reaction with iron (a) Reaction with iron (ІІІІІІ) chloride) chloride To To 1 ml1 ml of the solution specified in separate article, add of the solution specified in separate article, add 0,5 0,5

mlml solution of iron ( solution of iron (ІІІІІІ) chloride R1; the light-yellow ) chloride R1; the light-yellow precipitate, soluble in ether R is formed. precipitate, soluble in ether R is formed.

C6H5COOH + NaOH = C6H5COONa + H2OC6H5COOH + NaOH = C6H5COONa + H2O 6C6H5COONa + 2FeCl3 + 10H2O = 6C6H5COONa + 2FeCl3 + 10H2O =

(C6H5COO)3Fe(C6H5COO)3FeFe(OH)3Fe(OH)37H2O7H2O + 3C6H5COOH + 6NaCl + 3C6H5COOH + 6NaCl light-yellow light-yellow

SPU. Preparation sublimationSPU. Preparation sublimation Some crystals of the crushed drug moisten Some crystals of the crushed drug moisten with sulphatic acid with sulphatic acid

RR, cautiously heat up a test tube bottom; on test tube walls , cautiously heat up a test tube bottom; on test tube walls white touch white touch C6H5COOH is formed.C6H5COOH is formed.

Not pharmacopoeial reaction. Reaction with solution Not pharmacopoeial reaction. Reaction with solution AgNO3 AgNO3

C6H5COOH + AgNO3 = C6H5COOH + AgNO3 = C6H5COOAgC6H5COOAg + HNO3 + HNO3 whitewhite TESTSTESTS Solution S Solution S Dissolve 5.0 g in Dissolve 5.0 g in alcohol Ralcohol R and dilute to 100 ml with the same and dilute to 100 ml with the same

solvent. solvent. Appearance of solution Appearance of solution Solution S is clear Solution S is clear (2.2.1)(2.2.1) and colourless and colourless (2.2.2, Method II)(2.2.2, Method II). . Carbonisable substancesCarbonisable substances

Oxidisable substances Oxidisable substances Dissolve 0.2 g in 10 ml of boiling Dissolve 0.2 g in 10 ml of boiling water Rwater R. Cool, shake and filter. To . Cool, shake and filter. To

the filtrate add 1 ml of the filtrate add 1 ml of dilute sulphuric acid Rdilute sulphuric acid R and 0.2 ml of and 0.2 ml of 0.02 M 0.02 M potassium permanganatepotassium permanganate. After 5 min, the solution is still coloured . After 5 min, the solution is still coloured pink. pink.

Halogenated compounds and halides.Halogenated compounds and halides.

Heavy metals Heavy metals (2.4.8)(2.4.8) 12 ml of solution S complies with limit test B for heavy metals 12 ml of solution S complies with limit test B for heavy metals

(10 ppm). Prepare the standard using a mixture of 5 ml of (10 ppm). Prepare the standard using a mixture of 5 ml of lead standard solution (1 ppm Pb) Rlead standard solution (1 ppm Pb) R and 5 ml of and 5 ml of alcohol Ralcohol R. .

Sulphated ash Sulphated ash (2.4.14)(2.4.14) Not more than 0.1 per cent, determined on 1.0 g.Not more than 0.1 per cent, determined on 1.0 g.

ASSAYASSAY Alkalimetry in alcohol solution, direct titrationAlkalimetry in alcohol solution, direct titration Dissolve 0.200 g in 20 ml of Dissolve 0.200 g in 20 ml of alcohol Ralcohol R and titrate with and titrate with 0.1 M sodium hydroxide0.1 M sodium hydroxide, ,

using 0.1 ml of using 0.1 ml of phenol red solution Rphenol red solution R as indicator, until the colour changes from as indicator, until the colour changes from yellow to violet-red.yellow to violet-red.

C6H5COOH + NaOH = C6H5COONa + C6H5COOH + NaOH = C6H5COONa +

H2OH2O ЕЕmm (C6H5COOH) = М m.(C6H5COOH) = М m. 1 ml of 1 ml of 0.1 M sodium hydroxide0.1 M sodium hydroxide is equivalent to 12.21 mg of C7H6O2. is equivalent to 12.21 mg of C7H6O2. StorageStorage In dense In dense corkedcorked container container,, protecting from action of a moisture and light. protecting from action of a moisture and light.

Action and use Action and use Antimicrobial preservative. Antimicrobial preservative. Benzoic acid is employed externally as an antiseptic in lotions, ointment and Benzoic acid is employed externally as an antiseptic in lotions, ointment and

mouthwashes. It is more effective as a preservative in foods and pharmaceutic mouthwashes. It is more effective as a preservative in foods and pharmaceutic products at low pH. When used as a preservative in emulsions, its effectiveness products at low pH. When used as a preservative in emulsions, its effectiveness depends upon both pH and distribution into the two phases.depends upon both pH and distribution into the two phases.

Preparations Preparations Compound Benzoic Acid Ointment Compound Benzoic Acid Ointment Benzoic Acid SolutionBenzoic Acid Solution

Sodium benzoateSodium benzoate Ph EurPh Eur General Notice General Notice (Ph Eur monograph 0123)(Ph Eur monograph 0123) C7H5NaO2C7H5NaO2     M.m.M.m.=144.1=144.1    532-32-1532-32-1

DEFINITIONDEFINITION Sodium benzoate contains not less than 99.0 per Sodium benzoate contains not less than 99.0 per

cent and not more than the equivalent of 100.5 cent and not more than the equivalent of 100.5 per cent of sodium benzenecarboxylate, per cent of sodium benzenecarboxylate, calculated with reference to the dried substance. calculated with reference to the dried substance.

COONa

ObtainingObtaining Dissolution of benzoic acid in a hot Dissolution of benzoic acid in a hot

solution of sodium carbonate solution of sodium carbonate Na2CO3.Na2CO3. 22СС6H5COOH + Na2CO3 = 26H5COOH + Na2CO3 = 2СС6H5COONa6H5COONa + +

H2O + CO2H2O + CO2 The received solution condenses before the The received solution condenses before the

crystallisation, the allocated crystals filter crystallisation, the allocated crystals filter and dry up.and dry up.

CHARACTERSCHARACTERS A white, crystalline or granular powder or A white, crystalline or granular powder or

flakes, slightly hygroscopic, freely soluble in flakes, slightly hygroscopic, freely soluble in water, sparingly soluble in alcohol (90 per water, sparingly soluble in alcohol (90 per centcent V/V V/V). ).

IDENTIFICATIONIDENTIFICATION   A. It gives reactions A. It gives reactions (b)(b) and and (c)(c) of of

benzoatesbenzoates (2.3.1)(2.3.1). . b) Sublimation of benzoic acid.b) Sublimation of benzoic acid. Some crystals of the Some crystals of the

crushed drug moisten crushed drug moisten with sulphatic acid Rwith sulphatic acid R, cautiously , cautiously heat up a test tube bottom; on test tube walls heat up a test tube bottom; on test tube walls white white touch touch C6H5COOH is formed.C6H5COOH is formed.

2C6H5COONa + H2SO4 = 2C6H5COOH + 2C6H5COONa + H2SO4 = 2C6H5COOH + Na2SO4Na2SO4

c) Definition of melting pointc) Definition of melting point (must be 121 °C to 124 (must be 121 °C to 124 °C) of benzoic acid, after interaction drug with chloride °C) of benzoic acid, after interaction drug with chloride acid.acid.

To drug solution add HClTo drug solution add HCl R R; the precipitate which after ; the precipitate which after recrystallization from warm recrystallization from warm water Rwater R and drying in and drying in vacuum has melting point (121 °C to 124 °C) is formed.vacuum has melting point (121 °C to 124 °C) is formed.

C6H5COONa + HCl = C6H5COOHC6H5COONa + HCl = C6H5COOH + NaCl + NaCl

ASSAYASSAY Acidimetry,non-agueous titrationAcidimetry,non-agueous titration Dissolve 0.250 g in 20 ml of Dissolve 0.250 g in 20 ml of anhydrous acetic acid anhydrous acetic acid

RR, heating to 50 °C if necessary. Cool. Using 0.05 ml of , heating to 50 °C if necessary. Cool. Using 0.05 ml of naphtholbenzein solution Rnaphtholbenzein solution R as indicator, titrate with as indicator, titrate with 0.1 0.1 M perchloric acidM perchloric acid until a green colour is obtained. until a green colour is obtained. C6H5COONa + HClO4 = NaClO4 + C6H5COOHC6H5COONa + HClO4 = NaClO4 + C6H5COOH

ЕЕm(C6H5COONa) = М. m.m(C6H5COONa) = М. m. StorageStorage

In In the the dense dense corkedcorked container container,, protecting from action of protecting from action of a moisture and light.a moisture and light.

Action and use Action and use Expectorant.Expectorant. It is used as a preservative in acidic liquid preparations It is used as a preservative in acidic liquid preparations

in which benzoic acid is released.in which benzoic acid is released. PreparationsPreparations Powder, mixture.Powder, mixture.

Esters of aromatic Esters of aromatic carboxylic acidscarboxylic acids

Methyl SalicylateMethyl Salicylate General NoticesGeneral Notices (Ph Eur monograph 0230)(Ph Eur monograph 0230) C8H8O3C8H8O3     M.m. = M.m. = 152.1 152.1     Chemical name:Chemical name: methyl salicylate, methyl 2-hydroxybenzoate, methyl salicylate, methyl 2-hydroxybenzoate,

methyl ester of 2-oxybenzoic acid, methyl ester of salicylic acid. methyl ester of 2-oxybenzoic acid, methyl ester of salicylic acid. DEFINITIONDEFINITION Methyl salicylate contains not less than 99.0 per centMethyl salicylate contains not less than 99.0 per cent m/m m/m and not and not

more than the equivalent of 100.5 per centmore than the equivalent of 100.5 per cent m/m m/m of of methyl 2-methyl 2-hydroxybenzoatehydroxybenzoate. .

CHARACTERSCHARACTERS A colourless or slightly yellow liquid, very slightly soluble in water, miscible A colourless or slightly yellow liquid, very slightly soluble in water, miscible

with alcohol and with fatty and essential oils. with alcohol and with fatty and essential oils. IDENTIFICATIONIDENTIFICATIONA. Heat 0.25 ml with 2 ml of A. Heat 0.25 ml with 2 ml of dilute sodium hydroxide solution Rdilute sodium hydroxide solution R on a water-bath for on a water-bath for

5 min. Add 3 ml of 5 min. Add 3 ml of dilute sulphuric acid Rdilute sulphuric acid R. A crystalline precipitate is formed. . A crystalline precipitate is formed. Filter. The precipitate, washed with Filter. The precipitate, washed with water Rwater R and dried at 100 °C to 105 °C, melts and dried at 100 °C to 105 °C, melts (2.2.14)(2.2.14) at 156 °C to 161 °C. at 156 °C to 161 °C.

HOC6H4COOCH3 + 2NaOH = NaOC6H4COONa + CH3OH + H2OHOC6H4COOCH3 + 2NaOH = NaOC6H4COONa + CH3OH + H2O NaOC6H4COONa + 2HCl = HOC6H4COOHNaOC6H4COONa + 2HCl = HOC6H4COOH + 2NaCl + 2NaCl

It is possible to confirm formation of salicylic acid with reaction with It is possible to confirm formation of salicylic acid with reaction with the Marki the Marki reagentreagent; it is formed ; it is formed aurin dye of red colouraurin dye of red colour . .

B.B. To 10 ml of a saturated solution add 0.05 ml of To 10 ml of a saturated solution add 0.05 ml of iron (III) chlorideiron (III) chloride ( (ferric ferric chloride) solution R1chloride) solution R1. . A violet colour develops. A violet colour develops.

СН3ОСОС6Н4ОН + FeCl3 = СН3ОСОС6Н4ОFeCl2 + HClСН3ОСОС6Н4ОН + FeCl3 = СН3ОСОС6Н4ОFeCl2 + HCl violet colourviolet colour

HO

HOOC

H CH H

O

HO

HOOC

C

H

H

OH

COOH

OH

COOH

H

[O]

HO

HOOC

CH

O

COOH

H2SO4

+ +

.

ASSAYASSAY Acidimetry after alkaline hydrolysis, back Acidimetry after alkaline hydrolysis, back

titrationtitration HOC6H4COOCH3 + HOC6H4COOCH3 + 22NaOH = NaOC6H4COONa + CH3OH + H2ONaOH = NaOC6H4COONa + CH3OH + H2O

excessexcess NaOC6H4COONa + HCl = HOC6H4COONa + 2NaClNaOC6H4COONa + HCl = HOC6H4COONa + 2NaCl

TT 22NaOH + NaOH + 22HCl = 2NaCl + 2H2OHCl = 2NaCl + 2H2O

restrest Еm(C8H8O3) = М. м./2Еm(C8H8O3) = М. м./2

STORAGESTORAGE

Store protected from light. Store protected from light.

Action and useAction and use Counter-irritant. Counter-irritant. Preparations Preparations Methyl Salicylate Liniment Methyl Salicylate Liniment Methyl Salicylate Ointment Methyl Salicylate Ointment

AAmides mides of of aromatic acids and aromatic acids and their derivativestheir derivatives as drugs as drugs

SalicylamideSalicylamide Salicylamidum Salicylamidum AlgamonAlgamon SalamideSalamide Salіamide Salіamide НОС6Н4СОNH2НОС6Н4СОNH2 М m. = М m. =

137,14 g/mol137,14 g/mol Not lessNot less than 99,0 % than 99,0 % The chemical name: The chemical name: salicylamide, o-hydroxybenzamide, amide salicylamide, o-hydroxybenzamide, amide

of salicylic acid.of salicylic acid. A white crystaline powder without a smell. At heating it is A white crystaline powder without a smell. At heating it is

sublimated. Melting point sublimated. Melting point 140–142 140–142 CC.. Very slightly soluble in water, soluble in 95 % ethanol, ether, Very slightly soluble in water, soluble in 95 % ethanol, ether,

slightly soluble in chloroform.slightly soluble in chloroform.

CNH2

OH

O

IdentificationIdentification 1. Interaction with iron (III) 1. Interaction with iron (III)

chloridechloride FeCl3 FeCl3 solution solution ((presence phenolic presence phenolic hydroxylhydroxyl);); red-violetred-violet colour is colour is formedformed::

2. Reaction with bromic 2. Reaction with bromic water water ((for benzene ringfor benzene ring).). A A substance dissolve in alcohol, dilute substance dissolve in alcohol, dilute with water and add 1 ml of bromic with water and add 1 ml of bromic water Br2; water Br2; the the white precipitatewhite precipitate dibromderivatives is formed:dibromderivatives is formed:

3. Alkaline hydrolysis with 3. Alkaline hydrolysis with ammonia allocation ammonia allocation (for (for amide group).amide group). At boiling of At boiling of substance with 30 % NaOH is felt substance with 30 % NaOH is felt a a specific smellspecific smell of ammonia of ammonia NH3NH3 which can be identified by means of which can be identified by means of blue discoloration wet litmus paperblue discoloration wet litmus paper::

C

OH

O

NH2 + FeCl3

C

OFeCl2

O

NH2 + HCl

C

OH

O

NH2C

OH

O

NH2+ 2Br2

Br

Br

C

OH

O

NH2+

H O Na t0 C

OH

O

ONa + NH3

AssayAssay Modified Keldal methodModified Keldal method, establishing the maintenance , establishing the maintenance

of ammonia, which is formed at alkaline hydrolysis.of ammonia, which is formed at alkaline hydrolysis. a) Hydrolysis of substance by alkali NaOH:a) Hydrolysis of substance by alkali NaOH:

НОС6Н4СОNH2 + NaOH = НОС6Н4СООNa + NH3НОС6Н4СОNH2 + NaOH = НОС6Н4СООNa + NH3 b) The allocated ammonia distil off in the container b) The allocated ammonia distil off in the container

(receiver) with hydrochloric acid: (receiver) with hydrochloric acid: NH3 + HCl = NH4ClNH3 + HCl = NH4Cl

c) Ammonium chloride titrate with standard solution of c) Ammonium chloride titrate with standard solution of sodium hydroxide:sodium hydroxide:

NH4Cl + NaOH = NH4OH + NaClNH4Cl + NaOH = NH4OH + NaCl In parallel spend In parallel spend control experiencecontrol experience..

ЕmЕm (НОС6Н4СОNH2) = M.m.(НОС6Н4СОNH2) = M.m. StorageStorage.. In good corked container, in the place In good corked container, in the place

protected from light.protected from light. Action and useAction and use.. Anaesthetic, antipyretic and Anaesthetic, antipyretic and

antirheumaticantirheumatic.. PreparationsPreparations:: powder and tablets ( powder and tablets (0,250,25 g g and and 0,5 g).0,5 g).

Thanks for attention!