THEME: Condensed azines . Quinoline . Isoquinoline . Acridine . Diazines . Purine .

1. LECTURE № 13 THEME: Condensed azines. Quinoline. Isoquinoline. Acridine.Diazines.Purine. associate. prof. Ye. B. Dmukhalska, assistant. I.I. Medvid

2. Plane 1. Receipt of quinoline and his derivatives. Synthesis of Skraupa and synthesis of Debner—Miller. Physical and chemical properties of quinoline. 2. Receipt of isoquinoline. Synthesis of Bischler-Napieralski. Physical and chemical properties of isoquinoline. 3. Structure, nomenclature, methods of getting and physical and chemical properties of acridine. 4. Methods of getting of sixmember heterocyclic connections with two heteroatoms 5. Structure, nomenclature, physical and chemical properties of pyridazine, pyrimidine, barbituric acid, pyrazine, purine, uric acid. 6. Structure, nomenclature and properties of azepines. Benzazepine,diazepine. Benzodiazepine, Oxazepam. Radedrol (nitrazepam). Seduxen (diazepam). 7. Classification of alkaloids.

3. 1. Obtaining of quinoline and his derivatives. Synthesis of Skraup and synthesis of Debner—Miller. Physical and chemical properties of quinoline. The impotent condensed of sixmembered heterocycles connections are with one heteroatom is: quinolineisoquinoline acridine Quinoline, also known as 1-azanaphthalene, 1-benzazine, or benzo[b]pyridine, is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown.

4. Quinoline is only slightly soluble in cold water but dissolves readily in hot water and most organic solvents. Quinoline is mainly used as a building block to other specialty chemicals. Approximately 4 tonnes are produced annually according to a report published in 2005. Its principal use is as a precursor to 8-hydroxyquinoline, which is a versatile chelating agent and precursor to pesticides. Its 2- and 4-methyl derivatives are precursors to cyanine dyes. Oxidation of quinonline affords quinolinic acid (pyridine-2,3-dicarboxylic acid), a precursor to the herbicide sold under the name "Assert".

5. The Skraup synthesis is a chemical reaction used to synthesize quinolines. It is named after the Czech chemist Zdenko Hans Skraup (1850-1910). In the archetypal Skraup, aniline is heated with sulphuric acid, glycerol, and an oxidizing agent, like nitrobenzene to yield quinoline. The Skraup synthesis place is taken in three stages. On the first stage glycerin is under the action of сoncentrated H2S04 to dehydration with formation of akrolein:

6. On the second stage appearing akrolein enters into the reaction of condensation with an aniline: • H2O

7. On the third stage of reaction of 1,2-dihydroquinoline oxidizes nitrobenzol in to quinoline:

8. Synthesis of Debner —Miller. The reaction is opened in 1881. On the first stage there is krothonic condensation of two molecules of aldehyde. Further there is cooperation of krothonic aldehyde with aniline. 2-methyl-1,2-dihydroquinoline 2-methyl-quinoline

9. Chemical properties: quinoline chloride 1. Reactions of heteroatom. N-methylquinoline iodide N-acethylquinoline chloride

10. 2. Reactions of electrophilic and nukleophilic substitutions . Reactions ofelectrophilic substitution in the molecula of quinoline is entered in position of 5 and 8. 6- quinoline sulphatic acid Reactions of nukleophilic substitution (is entered in position of 2) . 2- aminoquinoline 2- hydroxyquinoline

11. 3. Reactions of reduction and oxidization. quinolinic acid

12. Derivatives of quinoline 8-Hydroxyquinoline is an organic compound with the formula C9H7NO. It is a derivative of the heterocycle quinoline by placement of an OH group on carbon number 8. This colorless compound is widely used commercially, although under a variety of names. It is usually prepared from quinoline-8-sulfonic acid and from the Skraup synthesis from 2-aminophenol. NaOH -Na2SO3

13. 8-Hydroxyquinoline is a monoprotic bidentate chelating agent. Related ligands are the Schiff bases derived from salicylaldehyde, such as salicylaldoxime and salen. The roots of the invasive plant Centaurea diffusa release 8-hydroxyquinoline, which has a negative effect on plants that have not co-evolved with it. The complexes as well as the heterocycle itself exhibit antiseptic, disinfectant, and pesticide properties. Its solution in alcohol are used as liquid bandages. It once was of interest as an anti-cancer drug.

14. O [H] C H = C H - C H 2 N O N H 2 2 O H O H O H H SO 2 4 2- + SO N N 4 2 O H O H H quinozol

15. 2. Receipt of isoquinoline. Synthesis of Bischler-Napieralski. Physical and chemical properties of isoquinoline. Isoquinoline, also known as benzo[c]pyridine or 2-benzanine, is a heterocyclic aromatic organic compound. It is a structural isomer of quinoline. Isoquinoline and quinoline are benzopyridines, which are composed of a benzene ring fused to a pyridine ring. In a broader sense, the term isoquinoline is used to make reference to isoquinoline derivatives. 1-Benzylisoquinoline is the structural backbone in naturally occurring alkaloids including papaverine and morphine. The isoquinoline ring in these natural compound derives from the aromatic amino acid tyrosine. Isoquinoline is a colourless hygroscopic liquid at room temperature with a penetrating, unpleasant odour. Impure samples can appear brownish, as is typical for nitrogen heterocycles. It crystallizes platelets that have a low solubility in water but dissolve well in ethanol, acetone, diethyl ether, carbon disulfide, and other common organic solvents. It is also soluble in dilute acids as the protonated derivative.

16. In the Bischler-Napieralski reaction an β-phenylethylamine is acylated and cyclodehydrated by a Lewis acid, such as phosphoryl chloride or phosphorus pentoxide. The resulting 1-substituted-3,4-dihydroisoquinoline can then be dehydrogenated using palladium. The following Bischler-Napieralski reaction produces papaverine. 1-substituted-3,4- dihydroisoquinoline 1-substituted isoquinoline

17. Chemical properties: 1. Reactions of electrophilic and nukleophilic substitutions . Reactions ofelectrophilic substitution in the molecula of isoquinoline is entered in position of 5 and 8. Reactions of nukleophilic substitutions tare place in position of 1. isoquinoline of chloride N-methylisoquinoline of iodide

18. 2. Reaction of reduction 1,2,3,4- tetrahydroisoquinoline 3. Reaction of oxidization 3,4- pyridinedicarbonic acid

19. Methods of getting: 1. Condensation of diphenylamine with carbonic acids : 2. Cyclization N-fenilanthranilic acid on the reaction of Drozdov—Mahidson—Hrihorovsky: diphenylamine acridine anhidride chloride N-fenilanthranilic acid N-fenilanthranilic acid acridone-9

20. acridole-9 9-chloracridine 9,10-dihydroacridine acridine

21. acridinium chloride • Reactions of heteroatom. 2. Reactions of electrophilic and nukleophilic substitutions . N-oxide of acridine N-methylacridine iodide 9-hydroxacridine, 9- oxoacridine, acridole-9 acridone-9

22. 3.Reactions of oxidization. 4. Reactions of reduction. acridinic acid 9,10-dehydroacridine, acridane

23. Derivatives of acridine 9- Aminoacridine is an antiseptic and disinfectant. Acidylating flows on aminogroup: 9-N-acethylaminoacridine 9-aminoacridine chloride

24. arcihine rivanol medicinal preparations

25. 9-amino-2-ethoxy-6-nitroacridine

26. ethacridine lactate, rivanol, 6,9 – diamimo-2-ethoxyacridine lactate

27. Sixmembered heterocycles connections are with two heteroatoms In addition to these three diazines, the bicyclic tetraaza compound, purine, is an important heterocyclic system. These ring systems, particularly that of pyrimidine, occur commonly in natural products. The pyrimidines, cytosine, thymine, and uracil are especially important because they are components of nucleic acids, as are the purine derivatives adenine and guanine.

28. The рurine nucleus also occurs in such compounds as caffeine (coffee and tea) and theobromine (cacao beans).

29. C H H N H N H H C C 2 2 - H O N C O 2 N H O pyridazine O H O O H H C O C H N H N 2 5 C H O N a N C H 2 2 5 C H + C O 2 H O N O H - C H O H O N O 2 5 C O C H H N 2 5 2 H O barbituric acid барбітурова Cl N 6H (Zn) P O C l N 3 N Cl N Cl pyrimidine 4. Methods of getting of sixmember heterocyclic connections with two heteroatoms maleinaldehide urea Malene ephir

30. These method use for obtaining pyridazine and his derivatives

31. ethylendiamine glyoxal 2,3- dihydropyrazine pyrazine purine

32. 5. Structure, classification, nomenclature, physical and chemical properties of pyridazine. Pyridazine is a heteroaromatic organic compound with the molecular formulaC4H4N2, sometimes called 1,2-diazine. It contains a six-membered ring with two adjacent nitrogen atoms. It is a colorless liquid with a boiling point of 208 °C. Pyridazine has no household use. It is mainly used in research and industry as building block for more complex compounds. The pyridazine structure is found within a number of herbicides such as credazine, pyridafol and pyridate. It is also found within the structure of several pharmaceutical drugs such as cefozopran, cadralazine, minaprine, hydralazine, and cilazapril.

34. N-methylpyridazine iodide Pyridazine chloride N-oxide pyridazine thethramethyleldiamine

35. Derivatives of pyridazine

36. 6. Structure, nomenclature, physical and chemical properties of pyrimidine. Three nucleobases found in nucleic acids (cytosine, thymine, and uracil) are pyrimidine derivatives: In DNA and RNA, these bases form hydrogen bonds with their complementary purines. Thus the purines adenine (A) and guanine (G) pair up with the pyrimidines thymine (T) and cytosine (C), respectively.

38. HCl pyrimidine chloride 4-amino-2-hydroxypyridine 2- aminopyridine

39. Derivatives of pyrimidine Barbituric acid (2,4,6-trihydroxypyrimidine) Keto-enole and lactam-lactim tautomery

40. 7. Structure, nomenclature, physical and chemical properties of barbituric acid. • Barbituric acid or malonylurea or 4-hydroxyuracil is an organic compound based on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in hot water. Barbituric acid is the parent compound of a large class of barbiturates that have central nervous system depressant properties, although barbituric acid itself is not pharmacologically active. • The compound was discovered by the German chemist Adolf von Baeyer on 4. December 1864—the feast of St Barbara and therefore the name given to the compound—by combining urea and malonic acid in a condensation reaction. Malonic acid has since been replaced by diethyl malonate.

41. Bases of pyrimidine (important derivatives ) These bases are present in nucleinic acids

42. Vitamin B1 (thiamine)contain pyrimidine and thyazole ring connect through methyl group. Physiological active form of vitaminB1 in living organisms is cocarboxilaza, which take part in enzyme processes, in hydrocarbon exchange Orotic acid is primary compound in biosynthesis of pyrimidine bases

44. The Gastaldi synthesis (1921) is another variation:

45. Chemical properties of pyrazine pyperazine 2-aminopyrazine N- oxide pyrazine

47. Synthesis of purine Traube method: condnsation 4,5-diaminopyrimidines with carbonic acids

48. The Traube purine synthesis (1900) is a classic reaction (named after Wilhelm Traube) between an amine substutited pyrimidine and formic acid

49. N H 2 Cl N H 2 N N H N N N H N N 3 Cl Cl N H N (1:1) N H N H Cl Cl N N adenine K O H O H O H O H N H N N N N H N N 3 Cl Cl N H (1:1) H N N N H N H H N N 2 Cl N 2 guanine H H N O 2 O O N N H N H N N N N N O H H H hypoxanthine xanthine Chemical properties of purine.For purine is characteristic of azole tautomery :

50. Purine is an amphoteric compound