Lecture № 1 1

1. Lecture № 11 • The most important derivatives of the fivemember heterocyclic compounds with one heteroatom. Fivemember heterocyclic compounds with two heteroatoms Ass. Medvid I.I

2. Outline: • The importantderivatives of pyrrole, furan and thiophene. • Physical and chemical properties of indole. • The importantderivatives of indole (indoxyl , indigo, isatin, tryptophan, serotonin, β- indolyl acetic acid) • Fivemember heterocyclic compounds with two heteroatoms • Structure, classification, nomenclature, izomery, methods of getting and chemical properties of imidazole. Histamine. Histidine.Benzimidazole. • Structure, classification, nomenclature, izomery, methods of getting and chemical properties of pyrazole. Analhine. • Structure, classification, nomenclature, izomery, methods of getting and chemical properties of oxazole.Isoxazole. • Structure, classification, nomenclature, izomery, methods of getting and chemical properties of thiazole. Thiamine. Isothiazole.

3. 1. The importantderivatives of pyrrole, furan and thiophene. 2-Pyrrolidone (2-Pyrrolidinone,2-Pyrol) is an organic compound consisting of a five-membered lactam. It is a colorless liquid which is used in industrial settings as a high-boiling non-corrosive polar solvent for a wide variety of applications. It is miscible with a wide variety of other solvents including water, ethanol, diethyl ether, chloroform, benzene, ethyl acetate and carbon disulfide. Derivatives of pyrrole

4. Polyvinylpyrrolidone (PVP) is a water-soluble polymer made from the monomer N-vinylpyrrolidone. PVP is soluble in water and other polar solvents. In water it has the useful property of Newtonian viscosity. When dry it is a light flaky powder, which readily absorbs up to 40% of its weight in atmospheric water. In solution, it has excellent wetting properties and readily forms films. This makes it good as a coating or an additive to coatings.

5. 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. The oxygen binds to the hemoglobin molecule in the vicinity of the iron, and the binding constant is proportional to the partial pressure of oxygen. In the lungs, where the partial pressure of oxygen is high, hemoglobin binds oxygen. In the tissues served by the blood stream, the oxyhemoglobin dissociates back into О, and hemoglobin, which returns to the lungs for another load. Carbon monoxide is а poison because it forms а tight complex with the iron of hemoglobin and prevents it from binding oxygen.

6. Vitamin B12 (cyanocobalamin), is an especially common vitamer of the vitamin B12 family. Cyanocobalamin is usually prescribed for the following reasons: after surgical removal of part, or all of the stomach or intestine to ensure there are adequate levels of vitamin B12 in the bloodstream; to treat pernicious anemia; vitamin B12 deficiency due to low intake from food; thyrotoxicosis, hemorrhage, malignancy, liver or kidney disease. Cyanocobamide is also used to perform the Schilling test to check your ability to absorb vitamin B12

7. Derivatives of furan Furfural is an industrial chemical compound derived from a variety of agricultural byproducts, including corncobs, oat and wheat bran, and sawdust. It is a colorless oily liquid with the odor of almonds, but upon exposure to air it quickly becomes yellow.Furfural's physical properties are summarized in the table at right. Furfural dissolves readily in most polar organic solvents, but is only slightly soluble in either water or alkanes. The method of extraction :

8. 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.

10. Synthesis of furacilin

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

12. 2. Physical and chemical properties of indole Indole (benzo [b] pyrrole) is an aromatic heterocyclic organic compound. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. The participation of the nitrogen lone electron pair in the aromatic ring means that indole is not a base, and it does not behave like a simple amine. Indole is a solid at room temperature. At very low concentrations, however, it has a flowery smell, and is a constituent of many flower scents (such as orange blossoms) and perfumes. It also occurs in coal tar. The indole structure can be found in many organic compounds like the amino acid tryptophan and in tryptophan-containing protein, in alkaloids, and in pigments. Indole undergoes electrophilic substitution, mainly at position 3.

13. Extraction of indole: 1. Cyclization of N-formyl-o-toluidine indole N-formyl-o-toluidine

14. 2. 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.

15. indole-3-sulfoacid 3-nitroindole indole 3-chlorindole 3-benzolazoindole

16. Oxidation of indole Due 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).

17. 3.The importantderivatives of indole.a) 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.

18. 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.

19. Sulfonation of indigo

20. Restoration of indigo and cubic dyeing

21. Change the colour is, until in a solution is present a glucose, which in alkaline medium cans to reduce of indigocarmine.

22. c) isatin Isatin 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.

25. d) tryptophan, serotonin, β- indolyl acetic acid For many organisms (including humans), tryptophan is an essential amino acid. This means that it cannot be synthesized by the organism and therefore must be part of its diet. Amino acids, including tryptophan, act as building blocks in protein biosynthesis. In addition, tryptophan functions as a biochemical precursor for the following compounds.

26. Serotonin H O С H С H N H 2 2 2 N H b Serotonin [5-hydroxy-3-( -aminoethyl)іndole] 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.

27. C H - C O O H 2 b a N H b- indolyl acetic acid (heteroauxin) It is a heterocyclic compound that is an phytohormone called auxins. This colourless solid is probably the most important plant auxin.

28. 4. 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.

29. 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 рzorbitals from each ring atom. Six  electrons (one from each carbon and from one nitrogen, two from the other nitrogen) complete the aromatic shell.

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

31. 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).

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

33. Amphotericity Imidiazole is amphoteric, i.e. it can function as both an acid and as a base. Preparation A ball-and-stick model of imidazole, showing carbon-carbon and a carbon-nitrogen double bonds. Imidazole can be synthesized by numerous methods besides the Debus method. Many of these syntheses can also be applied to different substituted imidazoles and imidazole derivatives simply by varying the functional groups on the reactants. In literature, these methods are commonly categorized by which and how many bonds form to make the imidazole rings. For example, the Debus method forms the (1,2), (3,4), and (1,5) bonds in imidazole, using each reactant as a fragment of the ring, and thus this method would be a three-bond-forming synthesis. A small sampling of these methods is presented below.

34. Formation of one bond The (1,5) or (3,4) bond can be formed by the reaction of an immediate and an α-aminoaldehyde or α-aminoacetal, resulting in the cyclization of an amidine to imidazole. The example below applies to imidazole when R=R1=Hydrogen. Formation of two bonds 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 dehydrogenating catalyst, such as platinum on alumina, is required.

35. The (1,2) and (3,4) bonds can also be formed from N-substituted α-aminoketones and formamide and heat. The product will be a 1,4-disubstituted imidazole, but here since R=R1=Hydrogen, imidazole itself is the product. The yield of this reaction is moderate, but it seems to be the most effective method of making the 1,4 substitution. Formation of four bonds 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 materials are substituted glyoxal, aldehyde, amine, and ammonia or an ammonium salt.

36. Formation from other heterocycles Imidazole 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.

38. chemical properties of Imidiazole • Imidiazole is amphoteric compound. Thanks to pyrrol type nitrogen atom imidazole has weak acidic properties and by pyridine type nitrogen atom imidazole – basic properties. • Azol tautomery is also peculiar to imidazole, as a result 4 and 5 location of imidazole cycle are equivalent.

39. 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).

40. Chemical reactions 1.Interaction of an imidazol with halogenalkanes (alkylation) 2. Nitrification and sulfonation

41. 3. Interactionwith halogens (bromine, iodine) 4. Oxidation

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

43. One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography (IMAC). Imidazole is used to elute tagged proteins bound to Ni ions attached to the surface of beads in the chromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel co-ordination, freeing the His-tagged proteins. Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many fungicides and antifungal, antiprotozoal, and antihypertensive medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, which stimulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities.

44. Industrial applications Imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion. Many compounds of industrial and technological importance contain imidazole derivatives. The thermostable polybenzimidazole PBI contains imidazole fused to a benzene ring and linked to a benzene, and acts as a fire retardant. Imidazole can also be found in various compounds which are used for photography and electronics.

45. Histidine is an amino acid that is used to develop and maintain healthy tissues in all parts of the body, particularly the myelin sheaths that coat nerve cells and ensure the transmission of messages from the brain to various parts of the body. It may be useful for treatment of mental disorders as well as certain types of sexual dysfunction. Histidine levels in the body must be balanced to ensure good mental and physical health. High levels of this amino acid have been linked to the presence of psychological disorders such as anxiety and schizophrenia, while low levels of histidine are thought contribute to the development of rheumatoid arthritis and the type of deafness that results from nerve damage. Taking histidine supplements may help relieve symptoms of rheumatoid arthritis. Histidine is important to normal sexual functioning, because it gets converted into histamine, a chemical needed to stimulate sexual arousal. When taken together with vitamin B3(niacin) and vitamin B6 (pyridoxine), histidine can increase sexual pleasure by boosting histamine levels in the body.

46. Histamine is also needed to help the immune system know when the body is experiencing an allergic reaction, and for the production of gastric juices needed for normal digestion. Research suggests that hsitidine also acts as a natural detoxifier, protecting against radiation damage, and removing heavy metals from the system. It may even help prevent the onset of AIDS—histidine is crucial to the production of both red and white blood cells. Like other amino acids, histidine is found in many high-protein foods, such as meat and dairy products, as well as grains such as rice, wheat, and rye. It is not certain if histidine is an essential or non-essential amino acid—most health experts agree that, although the body manufactures its own histidine, it is fairly easy for natural supplies to run short. The chronically ill, post-surgery, or arthritic individual may wish to consider supplementation with this amino acid. Histidine is available in both capsule and powder forms, as well as in combination amino acid formulas. Because it has a proven effect on the central nervous system and histamine production, people with manic (bipolar) depression should not take supplemental histidine without first consulting their physician. Anyone with liver or kidney disorders should not take histidine without first consulting with a licensed health care provider. Taking any one amino acid supplement may cause levels of nitrogen in the body to become imbalanced, as well as disrupt the Krebs cycle by which toxins are eliminated from the liver and kidneys.

47. 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.

48. Synthesis and metabolism Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme L-histidine decarboxylase. It is a hydrophilic 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.

49. Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in an extension of the well-elaborated imidazole system, has been used as carbon skeletons for N-heterocyclic carbenes. The NHCs are usually used as ligands for transition metal complexes. They are often prepared by deprotonating an N,N'-disubstituted benzimidazolium salt at the 2-position with a base. Preparation Benzimidazole is commercially available. The usual synthesis involves condensation of o-phenylenediamine with formic acid, or the equivalent trimethoxymethyl: C6H4(NH2)2 + HC(OCH3)3 → C6H4N(NH)CH + + 3 CH3OH