Heterocyclic compounds Unit-III.pptx

Heterocyclic compounds Unit-III

1. HETEROCYCLIC COMPOUNDS Mr.P.S.Kore Assistant Professor(Research Scholar) Department of Pharmaceutical Chemistry RCP, Kasegaon. R.C.P. KASEGAON

2. Heterocyclic compounds Ring compounds with elements other than carbon in the ring. The most common elements to appear in heterocyclic compounds are oxygen, nitrogen and sulfur. The saturated heterocycles are similar to the open chain analogues, ethers, amines and sulfides. The aromatic heterocycles are similar to other aromatic compounds. R.C.P. KASEGAON

3. Heterocyclic Nomenclature R ep l a c eme n t nom e ncl a tu r e ( IU P A C r ecommend e d 1957) Lowest number assigned to the hetero atom with the highest precedence : O > S > N S thiacyclobutane O N H 1-oxa-3-azacyclopentane R.C.P. KASEGAON

4. Hantzsch-Widman (1888) Sr. No Hetero atom Symbol Prefix 01 Oxygen O Oxa 02 Sulphur S Thia 03 Selenium Se Selena 04 Nitrogen N Aza 05 Phosphorous P Phospha 06 Arsenic As Arsa 07 Antimony Sb Stiba 08 Bismuth Bi Bisma 09 Silicon Si Silia Prefixes Used in Nomenclature of Heterocyclic Compounds R.C.P. KASEGAON

5. Hantzsch-Widman (1888) Ring No. Ring With Nitrogen Atom Ring Without Nitrogen Atom Unsaturated Saturated Unsaturate d Saturated 3 -irine iridine irene irine 4 ete etidine ete etane 5 -ole olidine ole olane 6 -ine Perhydro in e in ane 7 -epine Perhydro e pine epin epane Suffixes Used in Nomenclature of Heterocyclic Compounds R.C.P. KASEGAON

6. Nomenclature of Heterocyclic Compounds Name: Prefix + Stem + Suffix In this nomenclature the nomenclature of heterocyclic compounds are assigned by combining ‘prefix’ (that indicate the heteroatom present) with ‘stem’ (that indicate the ring size as well as the saturation and unsaturation in the ring) and ‘suffixes Nomenclature of heterocyclic compound starts with the heteroatom appears first If more than two different hetero atoms are present in any heterocyclic compound the prefixes are listed in Preceding order If there are two or more than two hetero atoms of same types are present in a heterocyclic compound they are indicated by di-, tri- etc. The position of saturated atom is numerically indicated with prefix ‘H - ’ as a part of the name of the ring system The size of a monocyclic ring (three to ten membered rings) is indicated by stem. The common ‘stem’ nomenclature R.C.P. KASEGAON

7. O S * oxirane ethylene oxide o xa c y c lo p r o p an e * thiirane ethylene sulfide t hi a c y clo p r o p an e N H * aziridine ethylene imine a z a c y cl o p r o p a n e N H N N diazirane N 1 - a zi r i n e O oxaziridine o x a z a c y cl o p r o p a n e You must know the * names R.C.P. KASEGAON

8. O S N H N N oxetane o xa c y c l o bu t a n e thietane t h i a c y c l o b ut a n e azetidine a z a c y c l o b u t a n e azete a z a c y c l o b u t a d i e ne 1-azetine 1-azacyclobutene R.C.P. KASEGAON

9. O O * furan oxole o x a c y c l o p e n t a n d i e n e S * thiophene thiole thiacyclopentandiene N H * pyrrole O 1,3-dioxolane 1,3-dioxacyclopentane O * tetrahydrofuran N H * pyrrolidine a z a c y c l o p en t an e R.C.P. KASEGAON

10. N N N H N N N N H N p y r a z o le N H imidazole 1,2,4-triazole O o x a z o l e N O isooxazole S thiazole R.C.P. KASEGAON

11. O O O O N H N H H N O 4-hydropyran O O 2-pyrone 4 - p y r o n e * 1,4-dioxane * piperidine piperazine R.C.P. KASEGAON

12. N N N N N N N O pyridazine pyrimidine pyrazine * pyridine N H * morpholine R.C.P. KASEGAON

13. 6 7 8 5 N 1 2 3 4 6 7 5 N 2 3 4 * quinoline 8 1 * isoquinoline N H * indole R.C.P. KASEGAON

14. N H aziridine O oxirane O oxirene N H 1 H -azirine Classification of Heterocyclic Compounds 1.Three membered heterocyclic ring R.C.P. KASEGAON

15. 2.FIVE MEMBERED RING WITH ONE HETERO ATOM N H 1 H - p y r r o le S t h i o p h e n e O f u r an R.C.P. KASEGAON

16. 3.FIVE MEMBERED WITH 2 HETERO ATOM N N H 1 H -pyrazole N O isoxazole N S isothiazole A. 1 AND 2 POSITION N N H 1 H -imidazole N O oxazole N S th i a z ol e B. 1 AND 3 POSITION R.C.P. KASEGAON

17. 4.FIVE MEMBERED RING WITH MORE THAN TWO HETERO ATOM N N N H 1 H - 1, 2 ,3 - t r i az o l e N N N H 1 H -1,2,4-triazole N N N H N 1 H -tetrazole N N O 1,2,4-oxadiazole N N S 1,2,4-thiadiazole N N O 1,3,4-oxadiazole R.C.P. KASEGAON

18. 5.SIX MEMBERED RING WITH ONE HETERO ATOM N p y r idin e N H piperidine R.C.P. KASEGAON

19. 6.SIX MEMBERED RING WITH TWO HETERO ATOM N N pyrimidine N N pyrazine N N pyridazine R.C.P. KASEGAON

20. 7.FIVE MEMBERED HETEROCYCLIC RING FUSED WITH BENZENE(BENZFUSED HETEROCYCLE) N H 1 H -indole R.C.P. KASEGAON

21. 8.SIX MEMBERED HETEROCYCLIC RING ATTACHED WITH BENZENE N quinoline N isoquinoline N a c r i d i n e R.C.P. KASEGAON

22. 9. SEVEN MEMBERED RING WIT ONE HETERO ATOM N H N N H AZEPINE DIAZE P INE R.C.P. KASEGAON

23. 10. B EN Z ODI A Z E PINES N N H R.C.P. KASEGAON

24. Calculation of “n” Huckel Rule: 4n+2 π 1 Double bond gives 2 π electron and hetero atom contains 2 lone pair of electron. Examples of hetero atom N, O,S etc Hence Pyrrole, Furan, Thiophene contains 6 π Huckel rule=4n+2 6 π =4n+2 4n=6-2 4n=4 N=4/4= 1 Hence n=1 Huckel Rule: 4n+2 4(1)+2 Huckel rule = 6 π electron According to Huckel Rule Pyrrole, Furan and thiophene are aromatic because it Cyclic Planner Pressence alternate conjugate double bond Follows huckel rule: means it satisfy 2  , 6 π , 10 π ,14 π ,18 π ,22 π ,26 π , 30 π Aromaticity in Heterocyclic compounds N O fu r a n H py r rol e S th i oph e n e Aromaticity in Heterocyclic compounds R.C.P. KASEGAON

25. Resonance structure N H N H Resonance of pyrrole N H N H N H O O Resonance of furan O O O S S Resonance of Thiophene S S S R.C.P. KASEGAON

26. Comparison of Aromaticity Furan is less aromatic / Thiphene is more aromatic The more electro negative atom holds lone pair of electron more tightly. This will reduces delocalization(Aromaticity) Hence more electro negative atom decreases aromaticity and least electro negative increases aromaticity. Oxygen is more electronegative atom and sulphur is less electronegative atom Hence thiophene is more aromatic because of more delocalization, more resonance energy. R.C.P. KASEGAON

27. Bas i c i ty Furan is more basic and thiophene is least basic or not basic. Furan contains Oxygen and it pulls Lone pair of electron as o x yg en is m o r e el e ct r o ne g a ti v e a t om . H e nc e less delo c ali z a tion o f π electron or lone pair of electron. Electro negativity will localized and it is more basic Thiophene contains sulphur which is less electro negative and it pulls of π electron or lone pair of electron slowly. Hence more delocalization. Hence thiophene is least basic or not basic R.C.P. KASEGAON

28. Orbital structure of Pyrrole The delocalization of lone pair of nitrogen in pyrrole through conjugation also suggests that the pyrrole molecule should have planar geometry. This is only possible when the orbital's of carbon and nitrogen in pyrrole are sp2- hybridized. The unhybridized p-orbital of nitrogen contains lone pair of electrons. Two sp2- hybridized orbital's of nitrogen atom forms -bond with two carbon atoms of the ring . third sp2- hybridized orbital of nitrogen atom forms -bond with hydrogen atom. Similarly each sp2- hybridized carbon forms two -bonds with neighbouring carbon atoms and one -bond with hydrogen atom R.C.P. KASEGAON

29. Orbital structure R.C.P. KASEGAON

30. Orbital structure R.C.P. KASEGAON

31. Comparison stability and reactivity S t h i op h e ne O f u r a n N H 1 H -p y r ro le Electronegativity order: O>N>S Stability order < < Reactivity order: S thio p h en e O fur a n N H 1 H - py rr ole > > Oxygen has more electro negativity hence they have capacity to pull electron more than N and S Hence furan acquire less resonance stabilization than pyrrole and thiphene Thiphene is stable hence thiphene is very reactive than pyrrole and furan. R.C.P. KASEGAON

32. CO NTEN T Properties, synthesis, reactions & medicinal uses of… R.C.P. KASEGAON

33. Properties 1 . Aro m at i ci t y PYRRO LE R.C.P. KASEGAON

34. Properties 1 . Aro m at i ci t y PYRRO LE R.C.P. KASEGAON

35. Properties PYRRO LE R.C.P. KASEGAON

36. Physical properties of Pyrrole Pyrrole is colorless liquid, BP 131°C Rapidly turns brown on exposure to air. Its odour is like chloroform and pyrrole sparingly soluble in water but dissolves in ethanol and ether Chemical properties of Pyrrole Pyrrole is a weak base(pKa=3.4) R.C.P. KASEGAON

37. Chemical properties of Pyrrole N + HCl N H H Pyrrole is weak base(pKa=3.4) It reacts with dil. HCl to give crystalline hydrochloride reason for basic character is presence of lone pair of electron on nitrogen atom O 2 Polymerisation Brown Resin Cl Pyrrole hydrochloride H Pyrrole Pyrrole is also weak acid(pKa=15). It reacts with KOH to form pyrrole potassium. Reason for acidic character resonance structure shown positive charge on nitrogen because electron density on nitrogen decreases while delocalization of lone pair of electron N + KOH N H P yr r ol e K Pyrrole potassium + H 2 O R.C.P. KASEGAON

38. Basicity of Pyrrole From experimental studies it is observed that the pKb values of pyrrole, pyridine and Piperidine are ~14, ~8.7 and ~2.7, respectively. Pyrrole is the weakest base among these three heterocyclic bases the lone pair of electron on nitrogen atom exists in the sp2 hybridized orbital of nitrogen and participates in the delocalization, hence does not freely available to cause the basic character of pyrrole. the lone pair of electron on nitrogen atom of pyridine also exists in the sp2 hybridized orbital; however, it does not participate in the delocalization and available freely to cause the basic character. In case of Piperdine, the lone pair of electron of nitrogen atom lies in sp3 hybridized orbital of nitrogen . These electrons are less tightly bonded with nucleus. Therefore, these electrons are readily available for protonation. Thus, piperidine is the strongest base among the three. < < N H 1 H -pyrrole N pyridine N H piperidine R.C.P. KASEGAON

39. PYRRO LE Synthesis 1. From Acetylene Mixture of Acetylene and ammonia passed over red hot tube CH CH + N H 1 H - py r r o le C H C H Acetylene NH 3 Ammonoia R.C.P. KASEGAON

40. PYRRO LE Synthesis 2. From Ammonium Mucate Ammonium mucate heated with glycerol at 200°C H O O H H O H H 4 NOOC H COONH 4 O H Ammonium Mucate G l y ce r o l H O H H O H H H H O H H OO C H C OO H O H Mucic acid + 2NH 3 + 4H 2 O + 2CO 2 N H Pyrrole R.C.P. KASEGAON

41. PYRRO LE Synthesis 3. Succinimide Succinimide heated with Zn Dust C CH 2 H 2 C C N H N H O O H H O H H O Z n S u c c ini m i de (Keto) Su c c ini m ide (Enol) N H P y rr ole + 2ZnO R.C.P. KASEGAON

42. PYRRO LE Synthesis 4. Succinic dialdehyde (Pal-Knor Synthesis Succinic dialdehyde warmed with ammonia H C CH 2 H 2 C C H O O H H NH 3 Succinic d i a ld e h yd e E N O L N H P y r rol e + 2H 2 O O H H O R.C.P. KASEGAON

43. + NH 3 PYRRO LE Synthesis 5. From Furans Mixture of Furan and ammonia passed steam over aluminium oxide catalyst at 480°C-490°C Al 2 O 3 S t e a m + H 2 O O f u r a n N H 1 H - p y r r ole R.C.P. KASEGAON

44. PYRRO LE Synthesis 6.Paal-Knorr synthesis. 2,5 hexandione heated with Ammonium carbonate to form pyrrole C CH 2 H 2 C C O H H NH 3 O 2,5 hxanedione E NO L N H P y r r ole + 2H 2 O OH H O CH 3 3 H C CH 3 H 3 C CH 3 3 H C R.C.P. KASEGAON

45. Synthesis 6. Paal-Knorr synthesis PYRRO LE R.C.P. KASEGAON

46. Synthesis 7. Hantzsch Pyrrole synthesis PYRRO LE R.C.P. KASEGAON

47. Synthesis 7. Hantzsch Pyrrole synthesis PYRRO LE R.C.P. KASEGAON

48. Synthesis 8. Knorr synthesis PYRRO LE R.C.P. KASEGAON

49. Synthesis 8. Knorr synthesis Mechanism PYRRO LE R.C.P. KASEGAON

50. Reactions 1. Electrophilic substitution PYRRO LE R.C.P. KASEGAON

51. substitution reaction Reactions 1. Electrophilic substitution Pyrrol e underg o e s electr o ph i l i c at 2 nd position PYRRO LE R.C.P. KASEGAON

52. Reactions 1. Electrophilic substitution PYRRO LE R.C.P. KASEGAON

53. Mech a nism CH 3 C O O NO 2 + CH 3 COOH CH 3 O C O + NO 2 Step - I generation of electrophile(NO 2 + ) O O CH 3 C O C CH 3 + HNO 3 Step - -II - Attack of electrophile on C 2 of pyrrole to form resonance stabilised structure N H + NO 2 N H NO 2 + H N H H NO 2 N H H NO 2 Step-III - Deprotonation by acetate anion to form stable pyrrole N H N O 2 + H + O O C CH 3 2 N H Pyrrole N O + CH 3 COOH R.C.P. KASEGAON

54. Reactions 2. Reduction PYRRO LE R.C.P. KASEGAON

55. Reactions 3. Reimer Tiemann reaction PYRRO LE R.C.P. KASEGAON

56. Reactions PYRRO LE R.C.P. KASEGAON

57. PYRRO LE + CH 3 ONa + CH 2 I 2 N H P y r ro l e + 2NaI + CH 3 COOH N Pyridine Reactions: Ring expansion reaction Pyrrole treated with sodium methoxide and methylene iodide to form pyridine R.C.P. KASEGAON

58. PYRRO LE + NH 2 OH + C 2 H 5 OH N H P yr r ol e C H C H Reactions: Ring Opening reaction Pyrrole treated with hot ethanolic hydroxyl amine undergo ring opening reaction and to get dioxime of succindialdehyde H 2 C C H 2 NOH NOH Succindialdehyde R.C.P. KASEGAON

59. Medicinal uses PYRRO LE R.C.P. KASEGAON

60. Properties 1 . Aro m at i ci t y FU RA N R.C.P. KASEGAON

61. F u ran Slightly Furan is colorless liquid , bp 32°C with chloroform like smell. soluble in water but soluble in organic solvent It is weak base and form unstable salt with mineral acid. This salt may produce to brown resin or undergo hydrolysis to form succindialdehyde + HCl O Cl O 2 Polymerisation Brown Resin H O O H H Succindialdehyde Furan hydrochloride O F u r an R.C.P. KASEGAON

62. Properties 1 . Aro m at i ci t y FU RA N R.C.P. KASEGAON

63. FU RA N Synthesis 1. Paal-Knorr synthesis of furan C C O O 3 CH H 3 C H H -H 2 O O 3 H C CH 3 2,5 Dimethyl furan H + /HCl CH CH R.C.P. KASEGAON

64. CH CH C C O O 3 CH H 3 C A C I D H C C H C C O H H O 3 CH H 3 C 2 -H O O H 3 C CH 3 H H KETO hexane-2,5-dione ENOL (2 E ,4 E )-hexa-2,4-diene-2,5-diol 2,5 Dimethyl furan FU RA N Synthesis 1. Paal-Knorr synthesis of furan Mechanism: R.C.P. KASEGAON

65. Synthesis 2 . Feist – Benary Synthesis FU RA N R.C.P. KASEGAON

66. Synthesis 2. Feist – Benary Synthe s is Mechanism FU RA N CH COOC 2 H 5 C O CH 3 H H C COOC 2 H 5 C H O CH 3 + H C C CH 3 CH 3 O C COOC H 2 5 C H O CH 3 H C C CH 3 C l C H 3 O H COOC 2 H 5 C H H 3 C O H C C CH 3 C l CH 3 H O O C 2 H 5 OOC H 3 C CH 3 CH 3 H C - HCl , H2O H ethyl 2,4,5-trimethylfuran-3-carboxylate ethyl 3-oxobutanoate Cl 3-chlorobutan-2-one R.C.P. KASEGAON

67. FU RA N Synthesis 3. From carbohydrate Step-I Distillation of CH with Sulphuric acid Step-II: Catalytic Decomposition of furfural in steam H C O H H O H O H H O H O H H H H/H 2 SO 4 O C O H -3H 2 O, -H 2 CaO, steam O f u r a n R.C.P. KASEGAON

68. FU R AN Synthesis: 4. From Mucic acid:Dry distillation of Mucic acid and heating of to get furan H O H O H H H O H H OO C H CO O H O H Mucic acid Dry Distill -3H2O, -CO2 O Furoic acid O F ur a n -CO 2 COO H R.C.P. KASEGAON

69. FU R AN O Furoic acid O F u r a n -CO 2 COO H C O F urfu r a l Synthesis: 5. From Oxidation Furfural : Oxidation of furfural with potassium dichromate to give furoic acid and subsequent decarboxylation at 200-300°C O H [O] K 2 Cr 2 O 7 R.C.P. KASEGAON

70. FU R AN Ag 2 O S t e a m C O Furfural Synthesis: 6. From Decarboxylation Furfural : Decarboxylation of furfural in steam in the presence of silver oxide catalyst O H O f u r a n + C O R.C.P. KASEGAON

71. FU R AN Synthesis: 7. From Succinic dialdehyde : Pal-Knor synthesis Dehydration of succinic dialdehyde by heating with P 2 O 5 H C CH 2 H 2 C C H O O O H H P 2 O 5 Succinic di a ld e hyd e E N O L F ur an + H 2 O O H H O R.C.P. KASEGAON

72. Reactions 1. Electrophilic substitution furan undergoes electrophilic substitution reaction at 2 nd position FU RA N R.C.P. KASEGAON

73. Reactions 1. Electrophilic substitution FU RA N R.C.P. KASEGAON

74. Reactions 1. Electrophilic substitution FU RA N R.C.P. KASEGAON

75. Reactions 2. Reduction FU RA N R.C.P. KASEGAON

76. Reactions 3. Diels-Alder reaction FU RA N R.C.P. KASEGAON

77. Reactions 3. Diels-Alder reaction FU RA N R.C.P. KASEGAON

78. FU RA N + NH 3 Reactions 4. Pyrrole synthesis Mixture of Furan and ammonia passed steam over aluminium oxide catalyst at 480°C- 490°C Al 2 O 3 S t e a m + H 2 O O f u r a n N H 1 H -pyrrole R.C.P. KASEGAON

79. FU RA N Reactions 5. Ring Opening reaction When furan treated with methanol and HCl,Furan undergoes ring opening reaction to form diacetal succindialdehyde C CH 2 H 2 C C O O O Diacetyl Succinic dialdehyde F u r a n 3 + + 2 CH OH 2 HCl H 3 CO O C H 3 R.C.P. KASEGAON

80. Medicinal uses FU RA N R.C.P. KASEGAON

81. Properties 1 . Aro m at i ci t y TH IOPH EN E R.C.P. KASEGAON

82. TH IOPH EN E Thiophene is a colorless liquid, bp 84°C it is insoluble in water. Thioph e n e doe s no t s how s any basi c propert i e s . It more stable to acid than pyrrole or furan. Thiophene does not undergo Diels – Alder reaction R.C.P. KASEGAON

83. Properties 1 . Aro m at i ci t y TH IOPH EN E R.C.P. KASEGAON

84. Properties 1 . Aro m at i ci t y TH IOPH EN E R.C.P. KASEGAON

85. Synthesis 1. Paal-Knorr synthesis of thiophene TH IOPH EN E R.C.P. KASEGAON

86. Synthesis 1. Paal-Knorr synthesis of furan Mechanism TH IOPH EN E R.C.P. KASEGAON

87. Mech a nism CH CH C O O C 3 CH H 3 C A C I D H C C H C C O H H O 3 CH H 3 C 2 -H O S H 3 C CH 3 H H KETO hexane-2,5-dione ENOL (2 E ,4 E )-hexa-2,4-diene-2,5-diol 2,5 Dimethyl Thiphene P 2 S 5 R.C.P. KASEGAON

88. Synthesis 2. From sod. succinate TH IOPH EN E R.C.P. KASEGAON

89. Synthesis 3 . Hinsb e r g Synthesis TH IOPH EN E R.C.P. KASEGAON

90. THIOPHENE 4. From Acetylene: Mixture of acetylene and hydrogen sulphide passed over aluminium oxide at 400°C C H C H C H C H S + Acetylene Hydrogen sulphide H H S thiophene Al 2 O 3 R.C.P. KASEGAON

91. THIOPHENE 5. From Furoic acid: Distillation of furoic acid with barium sulfide. O C OH + B a S + BaCO 3 O Furoic acid S T h ioph e ne R.C.P. KASEGAON

92. THIOPHENE 6. From n-butane: Reaction of n-butane with sulphur in the gas phase at 650°C. + 4 S 650° c H 2 C CH 2 CH 3 CH 3 n- Butane S T h i oph e n e + 3H 2 S R.C.P. KASEGAON

93. Reactions 1. Electrophilic substitution thiophene undergoes electrophilic substitution reaction at 2 nd position TH IOPH EN E R.C.P. KASEGAON

94. Reactions 1. Electrophilic substitution TH IOPH EN E R.C.P. KASEGAON

95. Reactions 1. Electrophilic substitution TH IOPH EN E R.C.P. KASEGAON

96. Reactions 2. Reduction TH IOPH EN E R.C.P. KASEGAON

97. Reactions 3. Reaction with organo lithium TH IOPH EN E R.C.P. KASEGAON

98. Medicinal uses TH IOPH EN E R.C.P. KASEGAON

99. Medicinal uses TH IOPH EN E R.C.P. KASEGAON