LECTURE № 1

THEME: The most important THEME: The most important derivatives of the derivatives of the fivemember fivemember heterocyclic compounds with one heterocyclic compounds with one heteroatom. Fivemember heteroatom. Fivemember heterocyclic compounds with two heterocyclic compounds with two heteroatomsheteroatoms

LECTURE № 1

associate. prof. Ye. B. Dmukhalska, assistant. I.I. Medvid

Outline:Outline:1. The important derivatives of pyrrole, furan and thiophene.2. Physical and chemical properties of indole.3. The important derivatives of indole (indoxyl , indigo, isatin,

tryptophan, serotonin, β- indolyl acetic acid)

4. Fivemember heterocyclic compounds with two heteroatoms 5. Structure, classification, nomenclature, izomery, methods of

getting and chemical properties of imidazole. Histamine. Histidine. Benzimidazole.

6. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyrazole. Analhine.

7. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of oxazole. Isoxazole.

8. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of thiazole. Thiamine. Isothiazole.

1. The i1. The importantmportant derivativesderivatives of pyrrole, furan and of pyrrole, furan and thiophene.thiophene.

2-Pyrrolidone (2-Pyrrolidinone,2-Pyrol) 2-Pyrrolidone (2-Pyrrolidinone,2-Pyrol) is an organic compound consisting is an organic compound consisting

of a five-of a five- membered lactam. It is a colorless membered lactam. It is a colorless liquid liquid which is used in industrial settings which is used in industrial settings as a high-boiling non-corrosive polar solvent for a wide as a high-boiling non-corrosive polar solvent for a wide variety of applications. It is miscible with a wide variety variety of applications. It is miscible with a wide variety of other solvents including water, ethanol, diethyl ether, of other solvents including water, ethanol, diethyl ether, chloroform, benzene, ethyl acetate and carbon disulfide.chloroform, benzene, ethyl acetate and carbon disulfide.

NHO

DDerivativeserivatives of pyrrole of pyrrole

NH NHCOOH COOH

OH

proline oxyproline

PolyvinylpyrrolidonePolyvinylpyrrolidone ( (PVPPVP) is a ) is a water-soluble polymer made from water-soluble polymer made from the monomer the monomer NN-vinylpyrrolidone-vinylpyrrolidone. . PVP is soluble in water and PVP is soluble in water and

other polar solvents. In water it has the useful other polar solvents. In water it has the useful property of Newtonian viscosity.property of Newtonian viscosity.

The function of hemoglobin in an organism is to transport oxygen; 1 g of hemoglobin absorbs 1.35 ml of oxygen at STP, corresponding to exactly one molecule of О2 per iron.

Vitamin Vitamin BB1212 (cyanocobalamin) (cyanocobalamin), , is an especially common vitamer is an especially common vitamer of the vitamin Bof the vitamin B1212 family. family. Cyanocobalamin is usually Cyanocobalamin is usually prescribed for the following prescribed for the following reasons: after surgical removal of reasons: after surgical removal of part, or all of the stomach or part, or all of the stomach or intestine to ensure there are intestine to ensure there are adequate levels of vitamin Badequate levels of vitamin B1212 in in the bloodstream; to treat the bloodstream; to treat

pernicious pernicious anemia; vitamin Banemia; vitamin B1212 deficiency due deficiency due to low intake from to low intake from food; food; thyrotoxicosis, thyrotoxicosis, hemorrhage, hemorrhage, malignancy, liver or malignancy, liver or kidney kidney disease. disease. Cyanocobamide is also Cyanocobamide is also used used to perform the Schilling test to to perform the Schilling test to check your check your ability to absorb vitamin Bability to absorb vitamin B1212

DDerivativeserivatives of furan of furan

FurfuralFurfural is an industrial chemical compound derived from a variety of is an industrial chemical compound derived from a variety of agricultural byproducts, including corncobs, oat and wheat bran, and agricultural byproducts, including corncobs, oat and wheat bran, and sawdust. sawdust. IIt is a colorless oily liquid with the odor of almonds, but upon t is a colorless oily liquid with the odor of almonds, but upon exposure to air it quickly becomes yellow.exposure to air it quickly becomes yellow. Furfural's physical Furfural's physical propertiesproperties are summarized in the table at right. Furfural dissolves are summarized in the table at right. Furfural dissolves readily in most polar organic solvents, but is only slightly soluble in readily in most polar organic solvents, but is only slightly soluble in

either water or alkanes.either water or alkanes.

The method of extraction :The method of extraction :

OH

C H

OC

C

C

C

OH OH

HOH

H

H

H

H

CH

O

O

(C5H8O4)n nC5H10O5

nH2O

t0

t0

+ 3H2O

polypentozes pentoza

furfural

C

H

O

O

N HCO

N HCO

furfural

2

NaOH

C

O

O

ONa

+CH2OHO

furfurilic alcoholsodium salt of furoic acid

KCN

CHO C O

OH O

furoin

2 NH3+

- 3H2O CHO

hydrofurfuramide

Chemically, furfural participates in the same kinds of reactions as other aldehydes and other aromatic compounds. The aromatic stability of furfural is not as great as in benzene, and furfural participates in hydrogenation and other addition reactions more readily than many other aromatics.

CH

O

OC

OH

O

O

+ 2[Ag(NH3)2]OH + 2Ag +4NH3 + H2O

CH

O

OC N

O

H

H2N-NHNH

Phenylhydrazone furfural

+ + H2O

SynthesisSynthesis of furacilin of furacilin

C

H

O

O

C CH3

C CH3

C

H

O

O

c. HNO3

(CH3CO)20 O2N CHO

O

O

O

O

HOH, H+

O2N

H2N NH NH2

O2N CHO N

C

O

NH C NH2

O

furfural

5-nitrofurfuraldiacetate 5-nitrofurfural

semicarbazone of 5-nitrofurfural,

furacilin

DDerivativeserivatives of thiophene of thiophene

BiotinBiotin (vitamin H) (vitamin H) is a is a water-water- soluble B-complex vitamin soluble B-complex vitamin

which is composed of an which is composed of an ureido ureido tetrahydroimidizalone) tetrahydroimidizalone)

ring ring used with a used with a tetrahydrothiophene ring. A valeric acid substituent is tetrahydrothiophene ring. A valeric acid substituent is attached to one of the carbon atoms of the attached to one of the carbon atoms of the tetrahydrothiophene ring. Biotin supplements are often tetrahydrothiophene ring. Biotin supplements are often recommended as a natural product to counteract the recommended as a natural product to counteract the problem of hair loss in both children and adults. The problem of hair loss in both children and adults. The signs and symptoms of biotin deficiency include hair loss signs and symptoms of biotin deficiency include hair loss which progresses in severity to include loss of eye lashes which progresses in severity to include loss of eye lashes and eye brows in severely deficient subjects. Some and eye brows in severely deficient subjects. Some shampoos are available that contain biotin, but it is shampoos are available that contain biotin, but it is doubtful whether they would have any useful effect, as doubtful whether they would have any useful effect, as biotin is not absorbed well through the skin. biotin is not absorbed well through the skin.

Extraction of indole:Extraction of indole:

1. Cyclization of N-1. Cyclization of N-formyl-o-toluidineformyl-o-toluidineCH3

NH C

O

H

NaNH2

N

H

N-formyl-o-toluidine

indoleindole

2. Fischer indole synthesis2. Fischer indole synthesis

One of the oldest and most reliable methods for synthesizing substituted indoles is the Fischer indole synthesis developed in 1883 by Emil Fischer. Although the synthesis of indole itself is problematic using the Fischer indole synthesis, it is often used to generate indoles substituted in the 2- and/or 3-positions.

N

H

C5H5N SO3

NH

SO3H

SO2Cl2

NH

Cl

C6H5COONO2

NH

NO2

NH

N=N-C6H5

12

34

5

67[C6H5NCl-

+

indole

3-chlorindole

3-nitroindoleindole-3-sulfoacid

3-benzolazoindole

Oxidation of indoleDue to the electron-rich nature of indole, it is easily oxidized. Simple oxidants such as N-bromosuccinimide will selectively oxidize indole 1 to oxindole (4 and 5).

3.The i3.The importantmportant derivativesderivatives of indole. of indole.a) indoxyla) indoxyl

N

C

H

N

C

O

H

OH

keto form enol form

N

C

O

H

NH2

ClCH2COONa

NHCH2

CONaO

NaNH2

180-200

aniline sodium salt ofN-phenylaminoacetic acid indoxyl

Indoxyl is isomeric with oxindol and is obtained as an oily liquid. Indoxyl is obtained from indican, which is a glycoside. The hydrolysis of indican yields β-D-glucose and indoxyl.Indigo dye is a product of the reaction of indoxyl by a mild oxidizing agent such as atmospheric oxygen.

C

C

N

N

C

C

O

O

H

H

N

C

O

H

O

indigoindoxyl

b) Indigo is a powder, insoluble in water, with a melting point higher than 300C. It absorbs light in the yellow region of the spectrum (maximum at 602 nm), which gives it its intense blue colour. The indigo molecule is relatively small with molecular weight of 262.27 atomic units of mass. In the molecular models illustrated on this page carbon is shown in grey, oxygen in bright red, nitrogen in blue, bromine in deep red and hydrogen in white.

Sulfonation of indigoSulfonation of indigo

C

C

N

N

C

C

O

O

H

H

C

C

N

N

C

C

O

O

H

H

HO3S

SO3H

+2HOSO3H

blue indigo

5,5-disulfoindigo (indigocarmine)

Reduction of indigo and cubic dyeingReduction of indigo and cubic dyeing

C

C

N

N

C

C

O

O

H

H

C

C

N

N

C

C

OH

OH

H

H

Blue indigo

SnCl2+4NaOH Na2SnO2+2NaCl+2H2O

2SnO22-+2OH- 2SnO3

2-+2[H]

White indigo (leicobasic)

2[H]

[O]

Change the colour is, until in a solution is Change the colour is, until in a solution is present glucose, which in alkaline medium present glucose, which in alkaline medium can reduce indigocarmine.can reduce indigocarmine.

c) isatinIsatin is commercially available. It may be prepared from cyclicizing the condensation product of chloral hydrate, aniline and hydroxylamine in sulfuric acid. This reaction is called the Sandmeyer isonitrosoacetanilide Isatin Synthesis and discovered by Traugott Sandmeyer in 1919.

N

C

N

C

O

H

O

O

C ONa

O

H2

NaOH

HCl

isatinsodium salt ofisatinic acid

N

C

N

C

O

H

lactam form

O OH

O

lactim form

N

C

O

H

O

isatin

N

C

H

N

C

H

C6H5NHNH2NH2OH

-H20-H20

O

N OH

oxim isatin

O

N NH C6H5

phenylhydrazon isatin

SerotoninSerotonin

Serotonin is a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system (CNS) and enterochromaffin cells in the gastrointestinal tract of animals including humans. Serotonin is also found in many mushrooms and plants, including fruits and vegetables.

N

СH 2

H

СH 2 NH 2

OH

Serotonin [5-hydroxy-3-( -aminoethyl) іndole]

Fivemember heterocyclic compounds with two

heteroatoms Azoles are five-membered ring aromatic heterocycles containing two nitrogens, one nitrogen and one oxygen, or one nitrogen and one sulfur. They may be considered as aza analogs of furan, pyrrole, and thiophene, in the same way that pyridine is an aza analog of benze.

From a molecular orbital standpoint, the azoles are similar to the simpler aromatic heterocycles. For example, in imidazole, each carboneand nitrogen may be considered to be spa hybridized. One nitrogen makes two sp²-sp² σ bonds to carbone and one sp²-s σ bonds to hydrogen. The other nitrogen has its lone pair in the third spa orbital. The π molecular orbital system is made up from the рz orbitals from each ring atom. Six electrons (one from each carbon and from one nitrogen, two from the other

nitrogen) complete the aromatic shell.

5. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of imidazole. Histamine. Histidine.Benzimidazole.

Imidazole

IUPAC name 1,3-diazole

Other namesImidazole

1,3-diazacyclopenta-2,4-diene

Molecular formula C3H4N2

Molar mass 68.08 g/mol

Appearance white or pale yellow solid

Density 1.23 g/cm3, solid

Melting point 89-91 °C (362-364 K)

Boiling point 256 °C (529 K)

Solubility in water miscible

Imidazole is a organic compound with the formula C3H4N2. This aromatic heterocyclic is classified as an alkaloid. Imidazole refers to the parent compound whereas imidazoles are a class of heterocycles with similar ring structure but varying substituents.

Discovery Imidazole was first synthesized by Heinrich Debus in 1858, but various

imidazole derivatives had been discovered as early as the 1840s. His synthesis, as shown below, used glyoxal and formaldehyde in ammonia to form imidazole. This synthesis, while producing relatively low yields, is still used for creating C-substituted imidazoles.

In one microwave modification the reactants are benzil, formaldehyde and ammonia in glacial acetic acid forming 2,4,5-triphenylimidazole (Lophine).

Structure and properties Structure and properties

Imidazole is a 5-membered planar ring, which is soluble Imidazole is a 5-membered planar ring, which is soluble in water and other polar solvents. It exists in two in water and other polar solvents. It exists in two equivalent tautomeric forms because the hydrogen atom equivalent tautomeric forms because the hydrogen atom can be located on either of the two nitrogen atoms. The can be located on either of the two nitrogen atoms. The compound is classified as aromatic due to the presence of compound is classified as aromatic due to the presence of a sextet of a sextet of ππ-electrons, consisting of a pair of electrons -electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of from the protonated nitrogen atom and one from each of the remaining four atoms of the ring.the remaining four atoms of the ring.

Some resonance structures of imidazole are shown below:Some resonance structures of imidazole are shown below:

Formation of one bondFormation of one bond

The (1,5) or (3,4) bond can be formed by the reaction of an immediate The (1,5) or (3,4) bond can be formed by the reaction of an immediate and an and an αα-aminoaldehyde or -aminoaldehyde or αα-aminoacetal, resulting in the cyclization of -aminoacetal, resulting in the cyclization of an amidine to imidazole. The example below applies to imidazole when an amidine to imidazole. The example below applies to imidazole when R=RR=R11=Hydrogen.=Hydrogen.

Formation of two bondsFormation of two bonds

The (1,2) and (2,3) bonds can be formed by treating a 1,2-diaminoalkane, The (1,2) and (2,3) bonds can be formed by treating a 1,2-diaminoalkane, at high temperatures, with an alcohol, aldehyde, or carboxylic acid. A at high temperatures, with an alcohol, aldehyde, or carboxylic acid. A dehydrogenating catalyst, such as platinum on alumina, is required.dehydrogenating catalyst, such as platinum on alumina, is required.

The (1,2) and (3,4) bonds can also be formed from N-substituted The (1,2) and (3,4) bonds can also be formed from N-substituted αα--aminoketones and formamide and heat. The product will be a 1,4-aminoketones and formamide and heat. The product will be a 1,4-disubstituted imidazole, but here since R=Rdisubstituted imidazole, but here since R=R11=Hydrogen, imidazole itself is =Hydrogen, imidazole itself is the product. The yield of this reaction is moderate, but it seems to be the most the product. The yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution.effective method of making the 1,4 substitution.

Formation of four bonds Formation of four bonds

This is a general method which is able to give good yields for substituted This is a general method which is able to give good yields for substituted imidazoles. It is essentially an adaptation of the Debus method. The starting imidazoles. It is essentially an adaptation of the Debus method. The starting materials are substituted glyoxal, aldehyde, amine, and ammonia or an materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.ammonium salt.

Formation from other heterocyclesImidazole can be synthesized by the photolysis of 1-vinyltetrazole. This reaction will only give substantial yields if the 1-vinyltetrazole is made efficiently from an organotin compound such as 2-tributylstannyltetrazole. The reaction, shown below, produces imidazole when R=R1=R2=Hydrogen.

Imidazole can also be formed in a vapor phase reaction. The reaction occurs with formamide, ethylenediamine, and hydrogen over platinum on alumina, and it must take place between 340 and 480 °C. This forms a very pure imidazole product.

chemical properties of chemical properties of ImidiazoleImidiazole Imidiazole is amphoteric compound. Thanks to pyrrol type Imidiazole is amphoteric compound. Thanks to pyrrol type

nitrogen atom imidazole has weak acidic properties and by nitrogen atom imidazole has weak acidic properties and by pyridine type nitrogen atom imidazole – basic properties.pyridine type nitrogen atom imidazole – basic properties.

Azol tautomery is also Azol tautomery is also peculiar to imidazole, as peculiar to imidazole, as a result 4 and 5 location a result 4 and 5 location of imidazole cycle are of imidazole cycle are equivalent.equivalent.

Salts of imidazole

Salts of imidazole where the imidazole ring is in the cation are known as imidazolium salts (for example, imidazolium chloride). These salts are formed from the protonation or substitution at nitrogen of imidazole. These salts have been used as ionic liquids and precursors to stable carbenes. Salts where a deprotanated imidazole is an anion are also possible; these salts are known as imidazolide salts (for example, sodium imidazolide).

Chemical reactions1.Interaction of an imidazol with halogenalkanes (alkylation)1.Interaction of an imidazol with halogenalkanes (alkylation)

2. Nitrification and sulfonation

3. Interaction3. Interaction with halogens (bromine, iodine)with halogens (bromine, iodine)

4. Oxidation

Biological significance and applicationsBiological significance and applications

Imidazole is incorporated into many important biological Imidazole is incorporated into many important biological molecules. The most pervasive is the amino acid histidine, molecules. The most pervasive is the amino acid histidine, which has an imidazole side chain. Histidine is present in many which has an imidazole side chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Histidine can be binding functions of hemoglobin. Histidine can be decarboxylated to histamine, which is also a common biological decarboxylated to histamine, which is also a common biological compound. It is a component of the toxin that causes urticaria, compound. It is a component of the toxin that causes urticaria, which is another name for allergic hives. The relationship which is another name for allergic hives. The relationship between histidine and histamine are shown below:between histidine and histamine are shown below:

Histamine forms colorless hygroscopic crystals that melt at 84°C, and are easily dissolved in water or ethanol, but not in ether. In aqueous solution histamine exists in two tautomeric forms, Nπ-H-histamine and Nτ-H-histamine.

Tautomers of histamine

Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group will be protonated, whereas the second nitrogen of the imidazole ring will not be protonated. Thus, histamine is normally protonated to a singly-charged cation. Istidine was first isolated by German physician Albrecht Kossel in 1896.

Synthesis and metabolismSynthesis and metabolism

Histamine is derived from the decarboxylation of the amino acid histidine, a Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic vasoactive amine.vasoactive amine.

Conversion of histidine to histamine by histidine decarboxylase

Once formed, histamine is either stored or rapidly inactivated. Histamine released into the synapses is broken down by acetaldehyde dehydrogenase. It is the deficiency of this enzyme that triggers an allergic reaction as histamines pool in the synapses. Histamine is broken down by histamine-N-methyltransferase and diamine oxidase.

Benzimidazole

IUPAC name 1H-benzimidazole

Properties

Molecular formula C7H6N2

Molar mass 118.14 g mol−1

Melting point 170–172 °C

Submitted by E. C. Wagner and W. H. Millett. Submitted by E. C. Wagner and W. H. Millett.

Benzimidazoles are a large chemical family used to treat nematode and Benzimidazoles are a large chemical family used to treat nematode and trematode infections in domestic animals. However, with the widespread trematode infections in domestic animals. However, with the widespread development of resistance and the availability of more efficient and easier development of resistance and the availability of more efficient and easier to administer compounds, their use is rapidly decreasing. They are to administer compounds, their use is rapidly decreasing. They are characterized by a broad spectrum of activity against roundworms characterized by a broad spectrum of activity against roundworms (nematodes), an ovicidal effect, and a wide safety margin. Those of interest (nematodes), an ovicidal effect, and a wide safety margin. Those of interest are mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, are mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, albendazole, albendazole sulfoxide, thiabendazole, thiophanate, febantel, netobimin, and triclabendazole. Netobimin, albendazole, and netobimin, and triclabendazole. Netobimin, albendazole, and triclabendazole are also active against liver flukes; however, unlike all the triclabendazole are also active against liver flukes; however, unlike all the other benzimidazoles, triclabendazole has no activity against roundworms.other benzimidazoles, triclabendazole has no activity against roundworms.

Benzimidazole gives a similar reactions of electrophilic Benzimidazole gives a similar reactions of electrophilic substitution as imidazole, radicals direct in 5 or 6 location substitution as imidazole, radicals direct in 5 or 6 location of benzole cycle. of benzole cycle.

6. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyrazole. Analhine.

Pyrazole refers both to the class of simple aromatic ring organic compounds of the heterocyclic series characterized by a 5-membered ring structure composed of three carbon atoms and two nitrogen atoms in adjacent positions and to the unsubstituted parent compound. Being so composed and having pharmacological effects on humans, they are classified as alkaloids, although they are rare in nature. Pyrazoles are produced synthetically through the reaction of α,β-unsaturated aldehydes with hydrazine and subsequent dehydrogenation.

In the industry pyrazole also produces by interaction of diazoalkans with acetylene

and by interaction hydrazine, alkylhydrazine or arylhydrazine with 1,3-dicarbonyl componds

Pyrazoles react with potassium borohydride to form a class of ligands known as Scorpionates. Structurally related compounds are pyrazoline and pyrazolidine.

Heterocycle formation from 1,3-dinitroalkanes. A novel pyrazole synthesis .

Physical properties of pyrazolePhysical properties of pyrazole Pyrazole is a colorless crystal compound Pyrazole is a colorless crystal compound

with weak pyridine smell, with weak pyridine smell, which is soluble in which is soluble in water, ethanol and ether. In inpolar solvents water, ethanol and ether. In inpolar solvents pyrazole forms dimers and trimers through pyrazole forms dimers and trimers through formation intermolecular hydrogen bonds. formation intermolecular hydrogen bonds.

Chemical properties of Chemical properties of pyrazolepyrazole

Pyrazole is amphoteric compound. Thanks to pyrrol type Pyrazole is amphoteric compound. Thanks to pyrrol type nitrogen atom imidazole has weak acidic properties and by nitrogen atom imidazole has weak acidic properties and by pyridine type nitrogen atom imidazole – basic propertiespyridine type nitrogen atom imidazole – basic properties

Hence, pyrazole can react with acids and bases

Azol tautomery is also peculiar to Azol tautomery is also peculiar to pyrazole, as an imidazole, as a result 3 pyrazole, as an imidazole, as a result 3 and 5 location of pyrazole cycle are and 5 location of pyrazole cycle are equivalent.equivalent.

Chemical reactions 1. Interaction with alkyl- and acylradicals 1. Interaction with alkyl- and acylradicals

2. Nitrification and sulfonation

3. Halogenation of pyrazole3. Halogenation of pyrazole

4. Reduction

Main derivatives of pyrazoleMain derivatives of pyrazole Pyrazolone-5 is colorless crystal compound, Pyrazolone-5 is colorless crystal compound, which is which is

soluble in water and ethanol, bad soluble in ether and soluble in water and ethanol, bad soluble in ether and toluene. Pyrazolone-5 is tautomeric compound and can toluene. Pyrazolone-5 is tautomeric compound and can exists in CH2-, OH- and NH-forms. exists in CH2-, OH- and NH-forms.

Main derivatives of pyrazole are antipyrine, amidopyrine and analgine. As primery compound for obtaining medicine of pyrazolone chain using 3-methyl-1-phenylpyrazolone-5.

Obtaining of Obtaining of antipyrine

Antipyrine – colorless crystal compound with bitter taste, colorless crystal compound with bitter taste, which is which is soluble in water. Used in medicine as antipyretic and analgesic soluble in water. Used in medicine as antipyretic and analgesic agent.agent.

Obtaining of Obtaining of amidopyrine

Synthesis of analgineSynthesis of analgine

Amidopyrine and analgineAmidopyrine and analgine used in medicine as antipyretic and used in medicine as antipyretic and analgetic drugs. Analgine has biggest analgetic properties and analgetic drugs. Analgine has biggest analgetic properties and amidopyrine – antipyreticamidopyrine – antipyretic

NN

C6H5

CH3

CH3

O

NCH2NaO3SCH3

Analgin2,3-dymethyl-4-methylamino-

1-phenilpyrazolone-5-N-methansulfonate of sodium

The Fischer oxazole synthesis is a chemical synthesis of the aromatic heterocycle oxazole from cyanohydrins and aldehydes in the presence of anhydrous hydrochloric acid. This method was discovered by Hermann Emil Fischer in 1896.

Method of getting oxazole by Method of getting oxazole by cyclodehydratation of cyclodehydratation of αα-acylaminoketons -acylaminoketons at the presents of mineral acidsat the presents of mineral acids

BiosynthesisBiosynthesis

In biomolecules, oxazoles result from the cyclization and oxidation of serine or In biomolecules, oxazoles result from the cyclization and oxidation of serine or threonine nonribosomal peptides:threonine nonribosomal peptides:

Where X = H, CH3 for serine and threonine respectively, B = base.(1) Enzymatic cyclization. (2) Elimination. (3) [O] = enzymatic oxidation.

Reactions :

1. Deprotonation of oxazoles at C2 is often accompanied by ring-opening to the isonitrile.

2. Electrophilic aromatic substitution takes place at C5 requiring activating groups.

3. Nucleophilic aromatic substitution takes place with leaving groups at C2.

4. Diels-Alder reactions with oxazole dienes can be followed by loss of oxygen to form pyridines.

5. The Cornforth Rearrangement of 4-acyloxazoles is a thermal rearrangement reaction with the organic acyl residue and the C5 substituent changing positions.

6. Various oxidation reactions. One study] reports on the oxidation of 4,5-diphenyloxazole with 3 equivalents of CAN to the formamide and benzoic acid:

Isoxazole

IUPAC name isoxazole

Properties

Molecular formula C3H3NO

Molar mass 69.06202

Density 1.075 g/ml

Boiling point 95 °C

Isoxazole is an azole with an oxygen atom next to the nitrogen. Isoxazoles are found in some natural products, such as ibotenic acid. Isoxazoles also form the basis for a number of drugs, including the COX-2 inhibitor valdecoxib (Bextra). Furoxan is a nitric oxide donor.

Synthesis of isoxazoleSynthesis of isoxazole Reaction of 1,3-dicarbonil compounds with Reaction of 1,3-dicarbonil compounds with

hydroxylaminehydroxylamine

8. 8. Structure, classification, nomenclature, izomery, methods of Structure, classification, nomenclature, izomery, methods of getting and chemical properties of thiazole. Thiamine. getting and chemical properties of thiazole. Thiamine.

Isothiazole.Isothiazole.

Thiazole, or 1,3-thiazole, is a clear to pale yellow flammable liquid with a Thiazole, or 1,3-thiazole, is a clear to pale yellow flammable liquid with a pyridine-like odour and the molecular formula C3H3NS. It is a 5-membered pyridine-like odour and the molecular formula C3H3NS. It is a 5-membered ring, in which two of the vertices of the ring are nitrogen and sulfur, and the ring, in which two of the vertices of the ring are nitrogen and sulfur, and the other three are carbons . Thiazole is used for manufacturing biocides, fungicides, other three are carbons . Thiazole is used for manufacturing biocides, fungicides, pharmaceuticals, and dyes. Thiazoles are a class of organic compounds related to pharmaceuticals, and dyes. Thiazoles are a class of organic compounds related to azoles with a common thiazole functional group. Thiazoles are aromatic. The azoles with a common thiazole functional group. Thiazoles are aromatic. The thiazole moiety is a crucial part of vitamin B1 (thiamine) and epothilone. Other thiazole moiety is a crucial part of vitamin B1 (thiamine) and epothilone. Other important thiazoles are benzothiazoles, for example, the firefly chemical important thiazoles are benzothiazoles, for example, the firefly chemical luciferin. Thiazoles are structurally similar to imidazoles. Like imidazoles, luciferin. Thiazoles are structurally similar to imidazoles. Like imidazoles, thiazoles have been used to give N-S free carbenes nd transition metal carbene thiazoles have been used to give N-S free carbenes nd transition metal carbene complexes.complexes.

Structure of thiazoles (left) and thiazolium salts (right)

Organic synthesisVarious laboratory methods exist for the organic synthesis of thiazole.1. The Hantzsch thiazole synthesis (1889) is a reaction between haloketones and thioamides. Example is given below:

2. In an adaptation of the Robinson-Gabriel synthesis, a 2-acylamino-ketones reacts with phosphorus pentasulfide.3. In the Cook-Heilbron synthesis, an α-aminonitrile reacts with carbon disulfide.4. Certain thiazoles can be accessed though application of the Herz reaction.

ReactionsReactions

Thiazoles are characterized by larger pi-electron delocalization Thiazoles are characterized by larger pi-electron delocalization than the corresponding oxazoles and have therefore greater than the corresponding oxazoles and have therefore greater aromaticity. This is evidenced by the position of the ring aromaticity. This is evidenced by the position of the ring protons in proton NMR (between 7.27 and 8.77 ppm), clearly protons in proton NMR (between 7.27 and 8.77 ppm), clearly indicating a strong diamagnetic ring current.indicating a strong diamagnetic ring current.

The calculated pi-electron density marks C5 as the primary The calculated pi-electron density marks C5 as the primary electrophilic site, and C2 as the nucleophilic site.electrophilic site, and C2 as the nucleophilic site.

Chemical reactionsChemical reactions 1. Thiazole is a weak base and can reacts with 1. Thiazole is a weak base and can reacts with

halogenalkans and mineral acidshalogenalkans and mineral acids

2. With amides

3. Oxidation by peroxiacids

4. Electrophilic aromatic substitution at C5 requires activating groups such as a methyl group in this bromination:

5.Nucleophilic aromatic substitution often requires an electrofuge at C2, such as chlorine with

6. Organic oxidation at nitrogen gives the thiazole N-oxide; many oxidizing agents exist, such as mCPBA; a novel one is hypofluorous acid prepared from fluorine and water in acetonitrile; some of the oxidation takes place at sulfur, leading to a sulfoxide :

Main derivatives of thiazoleMain derivatives of thiazole

2-aminothiazole2-aminothiazole

Penicillin – widely used antibiotic

Thiamine

Thiamine is a colorless compound with a chemical formula C12H17N4OS. Its structure contains a pyrimidine ring and a thiazole ring linked by a methylene bridge. Thiamine is soluble in water, methanol, and glycerol and practically insoluble in acetone, ether, chloroform, and benzene. It is stable at acidic pH, but is unstable in alkaline solutions. Thiamine is unstable to heat, but stable during frozen storage. It is unstable when exposed to ultraviolet light and gamma irradiation. Thiamine reacts strongly in Maillard-type reactions.

IUPAC name Isothiazole

Other names 1,2-thiazole

Properties

Molecular formula C3H3NS

Molar mass 85.13 g/mol

Boiling point 114 °C

Isothiazole

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