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Heterocyclic Compounds-2

Heterocyclic Compounds-2. Are cyclic with the ring containing more than one kind of atom or ring containing carbon and another elements O, S, N, P, ….. 1-Five membered Rings Containing More Than One Heteroatom Azoles Nomenclatures: التسمية

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Heterocyclic Compounds-2

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  1. Heterocyclic Compounds-2 • Are cyclic with the ring containing more than one kind of atom or ring containing carbon and another elements O, S, N, P, ….. • 1-Five membered Rings Containing More Than One Heteroatom • Azoles • Nomenclatures: التسمية • There are three systems are used: يوجد 3 انواع من التسمية • Common (trivial) name system الشائع • Chemical abstract name system • Systematic ( IUPAC). • 1- Common (trivial) name system (simple) • Pyrrole : gives red (pyro) fumes when its vapor is • exposed to HCl. • Thiophene: Sulfurated benzene • Furan : Bran (furfur) boiled with H2SO4, steam • distillation and the oil produced named furfural, • then they found aldehyde group and they named • (furfural) the furan. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  2. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  3. 2-Chemical abstract name system • Heterocyclic names are based on the name of carbocyclic system Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  4. 3- Systematic (IUPAC) Name System. The name is constructed as: Prefix + Stem + Suffix • Prefix + Stem + Suffix • Prefix:telling the name or names of heteroatoms as well as • their number (Kind, Number, Position). • Stem:Indicating the number of atoms in the ring (Ring • Size). • Suffix: Indicating the degree of saturation or unsaturation. • Prefix: • Kind of heteroatoms • One: Oxygen ≡ Oxa Nitrogen ≡ Aza Sulphur ≡ Thia • Number of heteroatoms • Two: Oxygen ≡ dioxa, diaza, dithia • When there are more than one H. atoms: * Nitrogen + Sulphur ≡ Thia + aza ≡ thiaza * Oxygen + Sulphur ≡ oxa + Thia ≡ oxathia Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  5. When there are more than one H. atoms: * Oxygen + Nitrogen ≡ oxa + aza ≡ oxaza * Nitrogen + Sulphur ≡ Thia + aza ≡ thiaza * Oxygen + Sulphur ≡ oxa + Thia ≡ oxathia O > S > N Position of H. atoms to each other Oxygen takes lowest number, then Sulphur and Nitrogen O > S > N Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  6. Stem: Ring contains 3 atoms [ir] Ring contains 4 atoms [et] Ring contains 5 atoms [ol] Ring contains 6 atoms [in] Ring contains 7 atoms [ep] Suffix: Specify the degree of unsaturation. Ring are classified into: 1- Nitrogen containing ring 2- No Nitrogen containing ring • 1- Nitrogen containing ring: • unsaturated rings • saturated rings A) Nitrogen Containing Ring and Unsaturated With: Stem [3] ir will have suffix ine ≡ irine Stem [4] et will have suffix e ≡ ete Stem [5] ol will have suffix e ≡ ole Stem [6] in will have suffix e ≡ ine Stem [7] ep will have suffix ine ≡ epine Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  7. Examples: B) Nitrogen Containing Ring and Saturated With: Stem [3] ir will have suffix idine ≡ iridine Stem [4] et will have suffix idine ≡ etidine Stem [5] ol will have suffix idine ≡ olidine Stem [6] in Perhydro Azine Stem [7] ep Perhydro Azepine Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  8. 2- NO Nitrogen Containing Rings: A) Unsaturated with: Stem [3] ir will have suffix ene≡ irene Stem [4] et will have suffix e≡ete Stem [5] ol will have suffix e≡ole Stem [6] in will have suffix - ≡ in Stem [7] ep will have suffix in ≡epin Example: B) Saturated Rings With: Stem [3] ir will have suffix ane ≡ irane Stem [4] et will have suffix ane ≡ etane Stem [5] ol will have suffix ane ≡ olane Stem [6] in will have suffix ane ≡ inane Stem [7] ep will have suffix ane ≡ epane Examples: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  9. * Partially Reduced Rings Are often referred to as: Dihydro or tetrahydro derivative of the parent unsaturated ring. Examples: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  10. Ring Numbering: تسمية المكبات الحلقية الخماسية الملتحمة: Naming of fused five-membered Rings تسمى الحلقة التي تحتوي الذرة الغير متجانسة التى لها الاولوية الحلقة الاساسية والتي ترقم بالحروف اما الحلقة الاولى فانها اخذ ارقام ويعبر عن موضع الالتحام بالارقام والحروف كما هو موضح في المثال التالي: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  11. AZoles There are three types of these compounds having two heteroatoms وجود ذرة النيتروجين في مثل هذه المركبات وهى ذره ساحبه للالكترونات يقلل نشاط الحلقة تجاه الـ +E Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  12. General Preparation of These compounds From 1,3-dicarbonyl compounds Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  13. Which rings were produced by the reaction of the following compounds: With the following reagents How can you prepare : Thiazole, imidazole or oxaoles from 1-From α-aminoketone Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  14. II- From α -bromoketone Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  15. ٍSynthesis of a variety of 1,3-Azoles Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  16. 1- Pyrazole Synthesis i- By passing acetylene into a cold ethereal solution of diazomethane. Such cyclo-addition occurs in one step and is referred as 1,3-dipolar addition. ii- By the condensation of 1,1,3,3-tetraethoxypropane (malonoaldehyde diethyl acetal) with hydrazine dihydrochloride. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  17. iii- By the decarboxylation of various pyrazolecarboxylic acid, e.g., by heating pyrazole-3,4,5-tricarboxylic acid. Properties of Pyrazole: Pyrazole is a colourless solid, m.p., 70oC, this high value is due to intermolecular hydrogen bonding which results in a dimer. Pyrazole is a tautomeric substance, therefore, positions 3 and 5 are equivalent. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  18. The nucleophilic attacking group enters at position 4 The following resonating structures are possible for pyrazole. Electrophilic attack should occur equally well at positions 3,4 and 5 (in pyrazole itself, position 3 and 5 are equivalent). In nitration, the pyrazole is protonated and again was shown that position 4 is the favoured site for attack by the nitronium ion because of the electrostatic repulsion between the protonated substrate and the positive charge of nitronium ion.Even so, the rate of reaction is decreased . Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  19. Pyrazole is very resistance to oxidizing and reducing agents, but it may be hydrogenated catalytically, first to pyrazoline and then to pyrazolidine. Both compounds are stronger bases than pyrazole. Synthesis of Pyrazole Derivatives i- A very important method for preparing pyrazole derivatives is by the reaction between β-diketones and hydrazines. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  20. β-ketoaldehydes may also be used (instead of β-diketones) particularly in their vinyl ether If β-diketones are used then 5-pyrazolones are formed Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  21. By 1,3-dipolar cycloadditions The reaction between diazoacetic acid ester and acetylenes propargaldehyde reacts with diazomethane to form 3(5)-formylpyrazole (pyrazol-3(5)-aldehyde). ethylenic compound is used instead of the acetylenic one, a pyrazoline derivative is obtained. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  22. Pyrazoles are obtained by the reaction between acetylenic carbonyl compounds and hydrazines; Pyrazolines are produced by the condensation of a,b-unsaturated ketones or aldehydes with hydrazines, Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  23. If either carbon atom of the double bond is attached to a halogen atom, a pyrazole is obtained. Properties of the Pyrazole Derivatives Pyrazoles with substituent methyl group may be oxidized by potassium permanganate Although pyrazole itself is not reduced by sodium metal, N-phenyl substituted pyrazoles are readily reduced to the corresponding pyrazolines, e,g. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  24. Pyrazole-3- and 5-carboxylic acids are readily decarboxylated by heating above their melting points Chloromethylation of 1-unsabstituted pyrazoles gave carbinls. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  25. Quaternary pyrazoles are converted into hydrazines when boiled with concentrated aqueous KOH, e.g., Ethyl pyrazoline-3-carboxylate, eliminates nitrogen on heating to give cyclopropane derivative, e.g., Antipyrine (2,3-dimethyl-1-phenylpyrazol-5-one): Antipyrine is a solid compound, m.p., 127 oC, is very much used in medicine as a febrifuge Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  26. It prepared industrially by the condensation of ethyl acetoacetate with phenylhydrazine, and methylating the product (3-methyl-1-phenylpyrazol5-one): Antipyrine can be obtained directly from the condensation of 1-methyl-2-phenylhydrazine with ethyl actoacetate, e.g., Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  27. Indazoles (Benzopyrazoles): Indazole is a solid compound, m.p. 146 oC, Indazole may be prepared by heating o-(N-nitroso-N-benzoyl)toludine in benzene e.g., Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  28. Another synthesis: • Imidazoles: Synthesis: • By action of ammonia on glyoxal: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  29. by the reaction between an α-dicarbonyl compounds, ammonia and an aldehyde. • From tartaric acid dinitrate: Imidazole itself is best prepared by the action of ammonia on a mixture of formaldehyde and tartaric acid dinitrate Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  30. From Paraldehyde: Another good method is to brominates paraldehyde in ethylene glycol and to heat the product, 2-bromomethyl-1,3-dioxolan, with formamide in the presence of ammonia; bromoacetaldehyde is probably an intermediate: • action of potassium thiocyanate (KNCS) on α-aminoaldhydes (as hydrochlorides) and the product (imidazoline thione) is desulphurised with rany nickel or by oxidation with nitric acid. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  31. A shorter route starts with α-bromoketone and amidine: Properties of Imidazole Imidazole is a solid compound, m.p., 90 oC Since position 4 and 5 are equivalent (positions 4,5 and 2 have also been designated α,β- and μ, respectively. Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  32. Methylation of imidazole in KOH gave 1-methylimidazole which when strongly heated, isomerse to 2-methylimidazole, e.g., The imidazole ring is extremely stable towards oxidising and reducing agents; however, hydrogen peroxide readily opens the ring to form oxamide Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  33. but benzoyl chloride in the presence of NaOH opens the ring to form dibenzoyldiaminoethylene bromination of imidazole proceeds as the following Benzimidazole: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  34. Oxazoles • - Isoxazoles Isoxazoleitself may be prepared by the action of hydroxylamine on propargylaldehyde, e.g., Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  35. The 1,3-dipolar cycloaddition of a nitrile N-oxide to an acetylene, e.g., Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  36. acetylenic carbonyl compound and hydroxylamine hydrochloride Properties of Isoxazole Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  37. Isoxazoles undergo electrophilic substitution at the 4-position Oxazoles: Oxazoles can be prepared by the action of an acid on an α-acylaminoketone, e.g., Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  38. Properties of Oxazoles 5-Oxazolones Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  39. Benzoxazoles: ammonia on o-chloroacetanilide • Thiazoles Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  40. Thiazole If thiourea α-acylaminocarbonyl compounds Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  41. Properties of Thiazoles thiazole can be nitrated (HNO3/H2SO4) and sulphonated (with oleum) Thiazolines: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  42. Thiazolidines: carbonyl compounds with cysteine. Benzothiazoles o-acylaminophenols Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  43. Isothiazoles: • Triazoles: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  44. Triazoles Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  45. Benzotriazole, • Oxadiazoles: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  46. Tetrazoles: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  47. Azine Group: Are six-membered rings containing two nitrogen atoms: Pyridazines: 1,4-diketones and hydrazines Pyridazine itself prepared from maleic dialdehyde and hydrazine Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  48. Saturated 1,4-diketones and hydrazines Synthesis of 4-aminopyridazine Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  49. Pyrimidines: Mp: 225 oC Preparation: From 2,4-dichloropyrimidine: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

  50. From 1,1,3,3-tetraethoxypropane (malonodialdehyde diacetals): Properties: Neutral in solution but forms salts with acids: Reactions: Prof. Dr. Ahmed M. El-Saghier Heterocyclic-2

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