Lecture 12

1. Sixmember heterocyclic compounds with one heteroatom. Pyrane. Pyridine. The most important derivatives of pyridine. Lecture 12 Ass. MedvidI.I., ass. Burmas N.I.

2. Outline 1. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyridine. 2. Structure, nomenclature, methods of getting and chemical properties of pycoline. 3. Structure, methods of getting and chemical properties of hydroxypyridine and aminopyridine. 4. Pyridine carbonic acids: structure, classification, nomenclature, izomery, methods of getting and chemical properties. 5. Methods of receipt and property of heterocycles of group of pyran.α- and γ-pyrones. Synthesis and chemical properties of the condensed derivatives of pyrones (coumarin, chromone). Flavonoids.

3. 1. Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyridine. Heterocycles containing as a heteroatom atom of nitrogen, behave to the most widespread representatives of this group of connections (azynes): quinoline isoquinoline acridine pyridine

4. Pyridine, obtained commercially by distillation of coal tar, is the nitrogen – containing heterocyclic analog of benzene. Like benzene, pyridine is a flat, aromatic molecule with bond angles of 120° and C-C bond lengths of 139 pm, intermediate between typical single and double bonds. The five carbon atoms and sp²- hybridized nitrogen atom each contribute one π electron to the aromatic sextet. Unlike the situation in pyrrole, the lone pair of electrons on the pyridine nitrogen atom occupies an sp² orbital in the plane of the ring and is not involved in bonding (Figure 1). Figure 1

5. 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).

6. Methods of getting: • Heating to 400 °C of acetone with ammonia. 2. At heating of akroleine with an ammonia turns out β-picoline: 3. Cooperation of acethylene with the strong acid: α-picoline γ- picoline β-picoline pyridine

7. 4. Condensation of acetaldehyde and formaldehyde with an ammonia: Chemical properties of pyridine. Characteristic for pyridine reactions can be divided into three groups: I. Reactions which followings with participation of heteroatom. II. Reactions of substituting for the hydrogen atoms of pyridines ring. III. Reactions of reduction and oxidization. pyridine

8. I. Reactions which followings with participation of heteroatom. 1. Cooperating with acids. Due to the indivisible pair of electrons atom of nitrogen of pyridine shows weak basic properties. At cooperating with strong mineral and organic acids he forms soluble salt of pyridine. 2. Reaction with the oxide of sulphur (VI). pyridine bromide

9. II. Reactions of substituting for the hydrogen atoms of pyridines ring. 1. Reactions of electrophilic substitution (SE). The reactions of nitration, sulphonation and halogenation pass slowly drastic and with low exits. Thus an electrophilic reagent is direct in position 3. 3-nithropyridine 3-pyridinesulphure acid

10. 2. Reactions of nucleophilic substitution. The substitution goes on positions 2,4,6, most easy of nucleophilic reagent is entered in position of 2,6 (α-position ). The prime example of reaction of this type is an amination of pyridine with sodium of amide on Chychybabyne. The reaction flows to the mechanism SN2: 2- aminopyridine σ- complex

11. III. Reactions of reduction and oxidization. • Reduction . 2. Oxidization . pyperedine nicotinic acid

12. By action of peroxiacids of pyridine oxidizes on the atom of 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

13. 2. Structure, nomenclature, methods of getting and chemical properties of pycoline. Picoline refers to three different methylpyridine isomers, all with the chemical formula C6H7N and a molar mass of 93.13 g mol−1. All three are colourless liquids at room temperature and pressure and are miscible with water and most organic solvents. alpha-picoline, beta-picoline, and gamma-picoline. The three compounds are structural isomers. The names of the three compounds indicate which of the hydrogens on the benzene ring portion of the molecule have been replaced. They are obtained from coal tar or petroleum. Because the boiling points of these three compounds are nearly the same, a separation of a mixture of the three into its pure components is impractical.

14. 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 γ-picoline β-picoline At oxidization β-picoline nicotine acid appears: nicotinic acid

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

16. 3. Structure, methods of getting and chemical properties of hydroxypyridine and aminopyridine. Depending on position of hydroxylic group distinguish three isomers: Hydroxypyridine are crystalline matters, well dissolve in an ethanol, acetone, undersoluble in diethyl ether and benzol. α- hydroxypyridine β- hydroxypyridine γ- hydroxypyridine

17. The special feature of α- and σ-isomers is that they exist in two tautomeric forms: β- hydroxypyridine in water solutions exist in neutral and bipolar forms in correlation 1:1. hydroxyform oxoform hydroxyform oxoform neutral form bipolar form

18. The alcylhalohenyde react with 2- and 4- hydroxypyridine form gives of N-alcylpyridone, and 3- hydroxypyridine - salts N-alkilpiridiniya: pyridinole-3 pyridinole-2 N-methylpyridinole N-methyl-3- hydroxpyridinole iodid To the derivatives of hydroxypyridine belong to pyridoxyne ( vitamine B6).

19. 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

20. 2 and 4-aminopyridine react with halogenalkanes by the cyclic atom of nitrogen and with acylation agents by atom of nitrogen of aminogroup: 4-acethaminopyridine 4-amino-1-methyl- pyridine iodid

21. 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

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

23. Derivatives of isonicotinic acid: • Synthesis of phthyvazide and isoniazide

24. Derivatives of isonicotinic acid: isoniazide phthyvazide Pyperidine Piperidine — colourless liquid substance with a strong ammoniac smell. N-acethylpyperidine N-methylpyperidine

25. O NH C 3 N H O -HCl 2 C O O H C N S O C l 2 Cl Nicotinamidum (vitamin РР) - HCl, -SO O N 2 N C (C H NH 2 5)2 N ( C H ) 2 5 2 -HCl N N,N-diethylamide nicotinic acid cordiamine O Cl O O C O O H N H N H O C H 2 2 5 C C S O C l C H OH NH NH 2 5 2 2 2 - HCl, -SO - HCl 2 - C H OH N N 2 5 N N isoniazid

26. O N H N H O H O 2 C H C N H - N C C + - H O 2 N CH O 3 N OCH isoniazid 3 O H O H vanillin 4-hydroxy-3-methoxybenzyl-iden- hydrazid of isonicotinic acid phthivazid

27. 5. Methods of getting and propertiesof α,γ-pyrans and α,γ-pyrones. Synthesis and chemical properties of the condensed derivatives of pyrones (coumarin, chromone). 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

28. 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

29. Tautomeric forms 4-hydroxpyrylyu chloride 4-methoxpyrylyu iodide

30. Reactions of nucleophilic additions

31. Interaction of γ-pyrone with mineral acids and alkylhalogenides

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

33. Synthesis of coumarine

34. Chemical 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

35. Chromone (benzo[b]pyrone-4) is a derivative of benzopyran with a substituted keto group on the pyran ring. Derivatives of chromone are collectively known as chromones. Most, though not all, chromones are also 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.

36. Derivatives of chromone: O O 1 / 1 / O O 1 flavone isoflavone 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. In recent years, scientific and public interest in flavones has grown enormously due to their putative beneficial effects against atherosclerosis, osteoporosis, diabetes mellitus and certain cancers. Flavones intake in the form of dietary supplements and plant extracts has been steadily increasing.

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

38. Thank you for attention!