Lecture 12

Ass. Medvid I.I.,Ass. Medvid I.I.,ass. Burmas N.I.ass. Burmas N.I.

Sixmember heterocyclic compounds with one heteroatom. Pyrane. Pyridine.

The most important derivatives of pyridine.

OutlineOutline1. 1. Structure, classification, nomenclature, izomery, methods of Structure, classification, nomenclature, izomery, methods of

getting and chemical properties of pyridine. getting and chemical properties of pyridine. 2. 2. Structure, nomenclature, methods of getting and chemical Structure, nomenclature, methods of getting and chemical

properties of pycoline. properties of pycoline. 3. 3. Structure, methods of getting and chemical properties of Structure, methods of getting and chemical properties of

hydroxypyridine and aminopyridine.hydroxypyridine and aminopyridine.4. Pyridine carbonic acids: 4. Pyridine carbonic acids: structure, classification, structure, classification,

nomenclature, izomery, methods of getting and chemical nomenclature, izomery, methods of getting and chemical properties.properties.

5. 5. Methods of receipt and property of heterocycles of group of Methods of receipt and property of heterocycles of group of pyran.α- and γ-pyrones. Synthesis and chemical properties pyran.α- and γ-pyrones. Synthesis and chemical properties of the condensed derivatives of pyrones (coumarin, of the condensed derivatives of pyrones (coumarin, chromone). chromone). Flavonoids.Flavonoids.

1. 1. Structure, classification, nomenclature, izomery, methods Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyridine.of getting and chemical properties of pyridine.

Heterocycles containing as a heteroatom atom of nitrogen, Heterocycles containing as a heteroatom atom of nitrogen, behave to the most widespread representatives of this group of behave to the most widespread representatives of this group of connections (azynes):connections (azynes):

pyridine quinoline isoquinoline acridine

Pyridine, obtained commercially by distillation of coal tar, is Pyridine, obtained commercially by distillation of coal tar, is the nitrogen – containing heterocyclic analog of benzene. Like the nitrogen – containing heterocyclic analog of benzene. Like benzene, pyridine is a flat, aromatic molecule with bond benzene, pyridine is a flat, aromatic molecule with bond angles of 120° and C-C bond lengths of 139 pm, intermediate angles of 120° and C-C bond lengths of 139 pm, intermediate between typical single and double bonds. The five carbon between typical single and double bonds. The five carbon atoms and atoms and spsp²²- hybridized nitrogen atom each contribute one π - hybridized nitrogen atom each contribute one π electron to the aromatic sextet. Unlike the situation in pyrrole, electron to the aromatic sextet. Unlike the situation in pyrrole, the lone pair of electrons on the pyridine nitrogen atom the lone pair of electrons on the pyridine nitrogen atom occupies an occupies an spsp²² orbital in the plane of the ring and is not orbital in the plane of the ring and is not involved in bonding (Figure 1).involved in bonding (Figure 1).

Figure 1Figure 1

Electronic structure of pyridine, a six-π-electon, nitrogen – containing analog of benzene. The electrostatic potential map shows that the nitrogen is the most negative atom (red).

The sp²- hybridized nitrogen atom in pyridine, with 33% s character, holds the lone-pair electrons more tightly than the sp³- hybridized nitrogen in an alkylamine (25% s character).

MMethods of getting:ethods of getting:1.1. Heating to 400 °C of acetone with ammonia.Heating to 400 °C of acetone with ammonia.

2. At heating of akroleine with an ammonia turns out β-picoline:2. At heating of akroleine with an ammonia turns out β-picoline:

3. 3. Cooperation of acethylene with the strong acid:Cooperation of acethylene with the strong acid:

α-picoline γ- picoline

β-picoline

pyridine

4. Condensation of acetaldehyde and formaldehyde with an 4. Condensation of acetaldehyde and formaldehyde with an ammonia:ammonia:

Chemical properties of pyridine.Chemical properties of pyridine.Characteristic for pyridine reactions can be divided into Characteristic for pyridine reactions can be divided into

three groups:three groups:I. Reactions which followings with participation of I. Reactions which followings with participation of

heteroatom.heteroatom.II. Reactions of substituting for the hydrogen atoms of II. Reactions of substituting for the hydrogen atoms of

pyridines ring.pyridines ring.III. Reactions of reduction and oxidization.III. Reactions of reduction and oxidization.

pyridine

I. Reactions which followings with participation of heteroatom.I. Reactions which followings with participation of heteroatom.

1. Cooperating with acids. 1. Cooperating with acids.

Due to the indivisible pair of electrons atom of nitrogen of Due to the indivisible pair of electrons atom of nitrogen of pyridine shows weak basic properties. At cooperating with strong pyridine shows weak basic properties. At cooperating with strong mineral and organic acids he forms soluble salt of pyridine.mineral and organic acids he forms soluble salt of pyridine.

2. Reaction with the oxide of sulphur (VI). 2. Reaction with the oxide of sulphur (VI).

pyridine bromide

II. Reactions of substituting for the hydrogen atoms of II. Reactions of substituting for the hydrogen atoms of pyridines ring.pyridines ring.

1. Reactions of electrophilic substitution (S1. Reactions of electrophilic substitution (SEE).). The reactions of nitration, sulphonation and halogenation pass The reactions of nitration, sulphonation and halogenation pass slowly drastic and with low exits. Thus an electrophilic reagent is slowly drastic and with low exits. Thus an electrophilic reagent is direct in position 3.direct in position 3.

3-nithropyridine

3-pyridinesulphure acid

2. Reactions of nucleophilic substitution.2. Reactions of nucleophilic substitution.

The substitution goes on positions 2,4,6, most easy of nucleophilic The substitution goes on positions 2,4,6, most easy of nucleophilic reagent is entered in position of 2,6 (α-position ). The prime reagent is entered in position of 2,6 (α-position ). The prime example of reaction of this type is an amination of pyridine with example of reaction of this type is an amination of pyridine with sodium of amide on Chychybabyne. The reaction flows to the sodium of amide on Chychybabyne. The reaction flows to the mechanism Smechanism SNN2:2:

σ- complex 2- aminopyridine

III. Reactions of reduction and oxidization.III. Reactions of reduction and oxidization. 1.1. Reduction .Reduction .

2. Oxidization .2. Oxidization .

pyperedine

nicotinic acid

By action of peroxiacids of pyridine oxidizes on the atom of By action of peroxiacids of pyridine oxidizes on the atom of nitrogen with organized of N-oxide.nitrogen with organized of N-oxide.

N-oxide of pyridine

N-oxide-4-nitropyridine

4-nitropyridine

4-aminopyridine

N-oxide-4-chloride pyridine 4-chloride pyridine

2. Structure, nomenclature, methods of getting and chemical

properties of pycoline. Picoline refers to three different methylpyridine isomers, Picoline refers to three different methylpyridine isomers, all with the chemical formula Call with the chemical formula C66HH77N and a molar mass N and a molar mass of 93.13 g mol−1. All three are colourless liquids at of 93.13 g mol−1. All three are colourless liquids at room temperature and pressure and are miscible with room temperature and pressure and are miscible with water and most organic solvents. water and most organic solvents. alpha-picoline, beta-alpha-picoline, beta-picoline, and gamma-picoline. The three compounds are picoline, and gamma-picoline. The three compounds are structural isomers. The names of the three compounds structural isomers. The names of the three compounds indicate which of the hydrogens on the benzene ring indicate which of the hydrogens on the benzene ring portion of the molecule have been replaced. They are portion of the molecule have been replaced. They are obtained from coal tar or petroleum. Because the boiling obtained from coal tar or petroleum. Because the boiling points of these three compounds are nearly the same, a points of these three compounds are nearly the same, a separation of a mixture of the three into its pure separation of a mixture of the three into its pure components is impractical. components is impractical.

Picolines are useful as solvents and as raw materials for various chemical products used in the industry of polymers, textiles, fuels, agrochemicals, pharmaceuticals and colorants.

α- picoline β-picoline γ-picoline

At oxidization β-picoline nicotine acid appears:

nicotinic acid

α- picoline and γ-picoline opposite to β-picoline give reaction of condensation with aldehyds and ketons, by acting of sodium amide form metalorganic compounds.

3. Structure, methods of getting and chemical properties of hydroxypyridine and aminopyridine.

Depending on position of hydroxylic group distinguish three isomers:Depending on position of hydroxylic group distinguish three isomers:

Hydroxypyridine are crystalline matters, well Hydroxypyridine are crystalline matters, well dissolve in an ethanol, acetone, undersoluble in dissolve in an ethanol, acetone, undersoluble in diethyl ether and benzoldiethyl ether and benzol..

α- hydroxypyridine β- hydroxypyridine γ- hydroxypyridine

The special feature of α- and σ-isomers is that they exist in The special feature of α- and σ-isomers is that they exist in two tautomeric forms:two tautomeric forms:

β- hydroxypyridine in water solutions exist in neutral and β- hydroxypyridine in water solutions exist in neutral and bipolar forms in correlation 1:1.bipolar forms in correlation 1:1.

hydroxyform oxoform hydroxyform oxoform

neutral form bipolar form

The alcylhalohenyde react with 2- and 4- hydroxypyridine The alcylhalohenyde react with 2- and 4- hydroxypyridine form gives of N-alcylpyridone, and 3- hydroxypyridine - form gives of N-alcylpyridone, and 3- hydroxypyridine - salts N-alkilpiridiniya:salts N-alkilpiridiniya:

pyridinole-2 N-methylpyridinole pyridinole-3 N-methyl-3-hydroxpyridinole iodid

To the derivatives of hydroxypyridine belong to pyridoxyne( vitamine B6).

Aminopyridine.

Depending on position of aminogroup distinguish:

α-aminopyridine β- aminopyridine γ- aminopyridine

Aminopiridiny is white crystalline matters, easily dissolved in water, ethanol and other organic solvents.

3-aminopyridine- dichloride

2 and 4-aminopyridine react with halogenalkanes 2 and 4-aminopyridine react with halogenalkanes by the cyclic atom of nitrogen and with acylation by the cyclic atom of nitrogen and with acylation agents by atom of nitrogen of aminogroup:agents by atom of nitrogen of aminogroup:

4-acethaminopyridine 4-amino-1-methyl-pyridine iodid

4. Pyridine carbonic acids: structure, classification, nomenclature, izomery, methods of getting and chemical properties.Depending on position of carboxyl group a- in a molecule is distinguish of α- ,β- ,y- pyridine carbonic acids:

Pyridine carbonic acids are white crystal of matters, dissoled in the hot water. Nicotine acid and its amide (Nicotinamidum) is known in medicine as a provitamin of vitamin PP.

picoline acid nicotine acid isonicotinic acid

Presences of acid and basic centrs of pyridinkarbonic Presences of acid and basic centrs of pyridinkarbonic acids show amphoteric properties, so, thee acids can react acids show amphoteric properties, so, thee acids can react with acids and alkalis:with acids and alkalis:

Derivatives of isonicotinic acid:Derivatives of isonicotinic acid: Synthesis of Synthesis of phthyvazide and isoniazide

Derivatives of isonicotinic acid:Derivatives of isonicotinic acid:

isoniazide phthyvazidePyperidine

Piperidine — colourless liquid substance with a strong ammoniac smell.

N-acethylpyperidine N-methylpyperidine

N

COOHSOCl2

N

Cl

O

N

NH2

O

N

N(C2H5)2

O- HCl, -SO 2

C

NH3

-HCl

-HCl

C

C(C2H5)2

NH

Nicotinamidum (vitamin РР)

N,N-diethylamide nicotinic acid cordiamine

N

COOH

SOCl2

N

ClO

N

OC2H5O

N

NHNH2O

- HCl, -SO2

C2H5OH

- HCl

C

- C2H5 OH

NH2NH2

C

isoniazid

N

NHNH2O

OH

O H

N

NH-NO

OH

HC

isoniazid

+

C

CH3O

vanillin

- H2O

C C

4-hydroxy-3-methoxybenzyl-iden-hydrazid of isonicotinic acidphthivazid

OCH3

5.5. Methods of getting and propertiesof α,γ-pyrans and α,γ- Methods of getting and propertiesof α,γ-pyrans and α,γ-pyrones. Synthesis and chemical properties of the condensed pyrones. Synthesis and chemical properties of the condensed

derivatives of pyrones (coumarin, chromone). derivatives of pyrones (coumarin, chromone). Flavonoids.Flavonoids.

Pyrones or pyranones are the class of cyclic chemical compounds. They contain an unsaturated six member ring containing one oxygen atom and a ketone functional group. There are two isomers denoted as 2-pyrone and 4-pyrone. The 2-pyrone structure is found in nature as part of the coumarin ring system. 4-Pyrone is found in some natural chemical compounds such as meconic and helidonic acid.

α-pyran γ-pyran

2-Pyrone (α-pyrone or pyran-2-one) is an unsaturated cyclic chemical compound with the molecular formula C5H4O2. It is isomeric with 4-pyrone .

α-pyrone or pyran-2

4-Pyrone (γ-pyrone or pyran-4-one) is an unsaturated cyclic chemical compound with the molecular formula C5H4O2. It is isomeric with 2-pyrone. 4-Pyrone forms the central core of several natural chemical compounds including maltol and kojic acid and of the important class of the Flavones.

γ-pyrone or pyran-4

4-hydroxpyrylyu chloride

Tautomeric forms

4-methoxpyrylyu iodide

Reactions of nucleophilic additionsReactions of nucleophilic additions

Interaction of Interaction of γγ-pyrone with mineral acids -pyrone with mineral acids and alkylhalogenidesand alkylhalogenides

Coumarin Coumarin is a chemical compound (benzo[b]pyrone-2); a toxin is a chemical compound (benzo[b]pyrone-2); a toxin found in many plants, notably in high concentration in the cacao found in many plants, notably in high concentration in the cacao bean, vanilla grass, woodruff, mullein, and bison grass. It has a bean, vanilla grass, woodruff, mullein, and bison grass. It has a sweet scent, readily recognised as the scent of newly-mown hay, sweet scent, readily recognised as the scent of newly-mown hay, and has been used in perfumes since 1882. It has clinical medical and has been used in perfumes since 1882. It has clinical medical value as the precursor for several anticoagulants, notably warfarin, value as the precursor for several anticoagulants, notably warfarin, and is used as a gain medium in some dye lasers. The biosynthesis and is used as a gain medium in some dye lasers. The biosynthesis of coumarin in plants is via hydroxylation, glycolysis and of coumarin in plants is via hydroxylation, glycolysis and cyclization of cinnamic acid. Coumarin can be prepared in a cyclization of cinnamic acid. Coumarin can be prepared in a laboratory in a Perkin reaction between salicylaldehyde and acetic laboratory in a Perkin reaction between salicylaldehyde and acetic anhydride.anhydride.

Synthesis of coumarineSynthesis of coumarine

Chemical propertiesChemical properties

disodium salt of coumarin acid

On the benzol ring of coumarin enters into the reactions of electrophilic substitution to position 6.

6- coumarin sulphatic acid

ChromoneChromone ( (benzo[b]pyrone-4benzo[b]pyrone-4) is a ) is a derivative of benzopyran with a substituted derivative of benzopyran with a substituted keto group on the pyran ring. Derivatives keto group on the pyran ring. Derivatives of chromone are collectively known as of chromone are collectively known as

chromoneschromones. . Most, though not all, chromones are Most, though not all, chromones are also also flavonoids. flavonoids.

Cromoglicate is used as an mast cell stabilizer in allergic rhinitis, asthma and allergic conjunctivitis.Khellin is a naturally occurring chromone extracted from the medicinal plant Amni visnaga long used in Egypt and the Eastern Mediterranean countries for the treatment of respiratory disorders. It however has many side effects making it unsuitable.Roger Altounyan studied chromones and eventually found disodium cromoglycate. This drug was found to inhibit antigen challenge as well as stress induced symptoms. Comparatively free of side-effects, unfortunately the short half-life limited its value.Nedocromil sodium was found to have a somewhat longer half-life.

O

O

O

O

flavoneisoflavone

1/

1

1/

Flavones are mainly found in cereals and herbs. In the West, the Flavones are mainly found in cereals and herbs. In the West, the estimated daily intake of flavones is in the range 20-50 mg per day. estimated daily intake of flavones is in the range 20-50 mg per day. In recent years, scientific and public interest in flavones has grown In recent years, scientific and public interest in flavones has grown enormously due to their putative beneficial effects against enormously due to their putative beneficial effects against atherosclerosis, osteoporosis, diabetes mellitus and certain cancers. atherosclerosis, osteoporosis, diabetes mellitus and certain cancers. Flavones intake in the form of dietary supplements and plant extracts Flavones intake in the form of dietary supplements and plant extracts has been steadily increasing.has been steadily increasing.

Derivatives of chromone:

Isoflavone differs from flavone (2-phenyl-4Isoflavone differs from flavone (2-phenyl-4HH-1-benzopyr-4-one) -1-benzopyr-4-one) in location of the phenyl group. Isoflavones are produced via a in location of the phenyl group. Isoflavones are produced via a branch of the general phenylpropanoid pathway that produces branch of the general phenylpropanoid pathway that produces flavonoid compounds in higher plants. Soybeans are the most flavonoid compounds in higher plants. Soybeans are the most common source of isoflavones in human food; the major common source of isoflavones in human food; the major isoflavones in soybean are genistein and daidzein. The isoflavones in soybean are genistein and daidzein. The phenylpropanoid pathway begins from the amino acid phenylpropanoid pathway begins from the amino acid phenylalanine, and an intermediate of the pathway, naringenin, is phenylalanine, and an intermediate of the pathway, naringenin, is sequentially converted in to the isoflavone genistein by two sequentially converted in to the isoflavone genistein by two legume-specific enzymes, isoflavone synthase, and a dehydratase. legume-specific enzymes, isoflavone synthase, and a dehydratase. Similarly, another intermediate naringenin chalcone is converted Similarly, another intermediate naringenin chalcone is converted to the isoflavone daidzein by sequential action of three legume-to the isoflavone daidzein by sequential action of three legume-specific enzymes: chalcone reductase, type II chalcone isomerase, specific enzymes: chalcone reductase, type II chalcone isomerase, and isoflavone synthase. Plants use isoflavones and their and isoflavone synthase. Plants use isoflavones and their derivatives as phytoalexin compounds to ward off disease-causing derivatives as phytoalexin compounds to ward off disease-causing pathogenic fungi and other microbes. In addition, soybean uses pathogenic fungi and other microbes. In addition, soybean uses isoflavones to stimulate soil-microbe rhizobium to form nitrogen-isoflavones to stimulate soil-microbe rhizobium to form nitrogen-fixing root nodules.fixing root nodules.

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