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Heterocyclic compounds Unit-III.pptx

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Heterocyclic compounds Unit-III.pptx

  1. 1. HETEROCYCLIC COMPOUNDS Mr.P.S.Kore Assistant Professor(Research Scholar) Department of Pharmaceutical Chemistry RCP, Kasegaon. R.C.P. KASEGAON
  2. 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. 3. Heterocyclic Nomenclature Replacementnomenclature (IUPAC recommended 1957) Lowest number assigned to the hetero atom with the highest precedence: O > S > N S thiacyclobutane O NH 1-oxa-3-azacyclopentane R.C.P. KASEGAON
  4. 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. 5. Hantzsch-Widman (1888) Ring No. Ring With Nitrogen Atom Ring WithoutNitrogen 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. 6. Nomenclature of Heterocyclic Compounds Name: Prefix + Stem + Suffix In this nomenclature the nomenclature of heterocyclic compounds are assignedby combining ‘prefix’ (that indicate the heteroatompresent) with ‘stem’ (that indicate the ring sizeaswell asthesaturation 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. Theposition 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. Thecommon ‘stem’nomenclature R.C.P. KASEGAON
  7. 7. O S * oxirane ethylene oxide oxacyclopropane * thiirane ethylene sulfide thiacyclopropane N H * aziridine ethylene imine azacyclopropane N H N N diazirane N 1-azirine O oxaziridine oxazacyclopropane You must know the * names R.C.P. KASEGAON
  8. 8. O S NH N N oxetane oxacyclobutane thietane thiacyclobutane azetidine azacyclobutane azete azacyclobutadiene 1-azetine 1-azacyclobutene R.C.P. KASEGAON
  9. 9. O O * furan oxole oxacyclopentandiene S * thiophene thiole thiacyclopentandiene N H * pyrrole O 1,3-dioxolane 1,3-dioxacyclopentane O * tetrahydrofuran N H * pyrrolidine azacyclopentane R.C.P. KASEGAON
  10. 10. N N N H N N N N H N pyrazole N H imidazole 1,2,4-triazole O oxazole N O isooxazole S thiazole R.C.P. KASEGAON
  11. 11. O O O O N H N H H N O 4-hydropyran O O 2-pyrone 4-pyrone * 1,4-dioxane * piperidine piperazine R.C.P. KASEGAON
  12. 12. N N N N N N N O pyridazine pyrimidine pyrazine * pyridine N H * morpholine R.C.P. KASEGAON
  13. 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. 14. N H aziridine O oxirane O oxirene N H 1H-azirine Classification of Heterocyclic Compounds 1.Three membered heterocyclic ring R.C.P. KASEGAON
  15. 15. 2.FIVE MEMBERED RING WITH ONE HETERO ATOM N H 1H-pyrrole S thiophene O furan R.C.P. KASEGAON
  16. 16. 3.FIVE MEMBERED WITH 2 HETERO ATOM N N H 1H-pyrazole N O isoxazole N S i s o t h i a z o l e A. 1 AND 2 POSITION N N H 1H-imidazole N O o x a z o l e N S t h ia z o l e B. 1 AND 3 POSITION R.C.P. KASEGAON
  17. 17. 4.FIVE MEMBERED RING WITH MORE THAN TWO HETERO ATOM N N N H 1H -1,2,3-triazole N N N H 1H-1,2,4-triazole N N N HN 1H-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. 18. 5.SIX MEMBERED RING WITH ONE HETERO ATOM N p y r i d i n e N H piperidine R.C.P. KASEGAON
  19. 19. 6.SIX MEMBERED RING WITH TWO HETERO ATOM N N pyrimidine N N pyrazine N N py ridazine R.C.P. KASEGAON
  20. 20. 7.FIVE MEMBERED HETEROCYCLIC RING FUSED WITH BENZENE(BENZFUSED HETEROCYCLE) N H 1H-indole R.C.P. KASEGAON
  21. 21. 8.SIX MEMBERED HETEROCYCLIC RING ATTACHED WITH BENZENE N quinoline N isoquinoline N acridine R.C.P. KASEGAON
  22. 22. 9. SEVEN MEMBERED RING WIT ONE HETERO ATOM N H N N H AZEPI NE DIAZEPI NE R.C.P. KASEGAON
  23. 23. 10.BENZODIAZEPINES N N H R.C.P. KASEGAON
  24. 24. Calculationof “n” Huckel Rule: 4n+2π 1 Double bond gives 2 πelectron 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 1. Cyclic 2.Planner 3.Pressence alternate conjugate double bond 4. 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 furan H pyrrole S thiophene Aromaticity in Heterocyclic compounds R.C.P. KASEGAON
  25. 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. 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. 27. Basicity Furan is more basic and thiophene is least basic or not basic. Furan contains Oxygen and it pulls Lone pair of electron as oxygen is more electro negative atom. Hence less delocalization of πelectron 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 πelectron or lone pair of electron slowly. Hence more delocalization. Hence thiophene is least basic or not basic R.C.P. KASEGAON
  28. 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. 29. Orbital structure R.C.P. KASEGAON
  30. 30. Orbital structure R.C.P. KASEGAON
  31. 31. Comparison stability and reactivity S thiophene O furan N H 1H-pyrrole Electronegativity order: O>N>S Stability order < < Reactivity order: S thiophene O furan N H 1H-pyrrole > > 1. Oxygen has more electro negativity hence they have capacity to pull electron more than N and S 2. Hence furan acquire less resonance stabilization than pyrrole and thiphene 3. Thiphene is stable hence thiphene is very reactive than pyrrole and furan. R.C.P. KASEGAON
  32. 32. CO NTEN T Properties, synthesis, reactions & medicinal uses of… R.C.P. KASEGAON
  33. 33. Properties 1. Aromaticity PYRRO LE R.C.P. KASEGAON
  34. 34. Properties 1. Aromaticity PYRRO LE R.C.P. KASEGAON
  35. 35. Properties PYRRO LE R.C.P. KASEGAON
  36. 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. 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 O2 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 Pyrrole K Pyrrole potassium + H2O R.C.P. KASEGAON
  38. 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 1H-pyrrole N pyridine N H piperidine R.C.P. KASEGAON
  39. 39. PYRRO LE Synthesis 1. FromAcetylene Mixture of Acetylene and ammonia passed over red hot tube CH CH + N H 1H-pyrrole CH CH Acetylene NH3 Ammonoia R.C.P. KASEGAON
  40. 40. PYRRO LE Synthesis 2. From AmmoniumMucate Ammonium mucate heated with glycerol at 200°C HO OH HO H H4NOOC H COONH4 OH Ammonium Mucate Glycerol HO H H OH H H HO H HOOC H COOH OH Mucic acid + 2NH3 + 4H2O +2CO2 N H Pyrrole R.C.P. KASEGAON
  41. 41. PYRRO LE Synthesis 3. Succinimide Succinimide heated with Zn Dust C CH2 H2C C N H N H O O H H OH HO Zn Succinimide (Keto) Succinimide (Enol) N H Pyrrole + 2ZnO R.C.P. KASEGAON
  42. 42. PYRRO LE Synthesis 4. Succinic dialdehyde (Pal-Knor Synthesis Succinic dialdehyde warmed with ammonia HC CH2 H2C CH O O H H NH3 Succinic dialdehyde ENOL N H Pyrrole + 2H2O OH HO R.C.P. KASEGAON
  43. 43. + NH3 PYRRO LE Synthesis 5. From Furans Mixture of Furan and ammonia passed steam over aluminium oxide catalyst at 480°C-490°C Al2O3 Steam + H2O O furan N H 1H-pyrrole R.C.P. KASEGAON
  44. 44. PYRRO LE Synthesis 6.Paal-Knorr synthesis. 2,5 hexandione heated with Ammonium carbonate to form pyrrole C CH2 H2C C O H H NH3 O 2,5 hxanedione ENOL N H Pyrrole + 2H2O OH HO CH3 3 H C CH3 H3C CH3 3 H C R.C.P. KASEGAON
  45. 45. Synthesis 6. Paal-Knorr synthesis PYRRO LE R.C.P. KASEGAON
  46. 46. Synthesis 7. Hantzsch Pyrrole synthesis PYRRO LE R.C.P. KASEGAON
  47. 47. Synthesis 7. Hantzsch Pyrrole synthesis PYRRO LE R.C.P. KASEGAON
  48. 48. Synthesis 8. Knorr synthesis PYRRO LE R.C.P. KASEGAON
  49. 49. Synthesis 8. Knorr synthesis Mechanism PYRRO LE R.C.P. KASEGAON
  50. 50. Reactions 1. Electrophilicsubstitution PYRRO LE R.C.P. KASEGAON
  51. 51. substitution reaction Reactions 1. Electrophilic substitution Pyrrole undergoes electrophilic at 2nd position PYRRO LE R.C.P. KASEGAON
  52. 52. Reactions 1. Electrophilicsubstitution PYRRO LE R.C.P. KASEGAON
  53. 53. Mechanism CH3 C O O NO2 + CH3COOH CH3 O C O + NO2 Step-I generation of electrophile(NO2 +) O O CH3 C O C CH3 + HNO3 Step--II- Attack of electrophile on C2 of pyrrole to form resonance stabilisedstructure N H + NO2 N H NO2 + H N H H NO2 N H H NO2 Step-III- Deprotonation by acetate anion to form stable pyrrole N H NO2 + H + O O C CH3 2 N H Pyrrole NO + CH3COOH R.C.P. KASEGAON
  54. 54. Reactions 2. Reduction PYRRO LE R.C.P. KASEGAON
  55. 55. Reactions 3. Reimer Tiemannreaction PYRRO LE R.C.P. KASEGAON
  56. 56. Reactions PYRRO LE R.C.P. KASEGAON
  57. 57. PYRRO LE + CH3ONa + CH2I2 N H Pyrrole + 2NaI + CH3COOH N Pyridine Reactions: Ring expansion reaction Pyrrole treated with sodium methoxide and methylene iodide to form pyridine R.C.P. KASEGAON
  58. 58. PYRRO LE + NH2OH + C2H5OH N H Pyrrole CH CH Reactions: Ring Opening reaction Pyrrole treated with hot ethanolic hydroxyl amine undergo ring opening reaction and to get dioxime of succindialdehyde H2C CH2 NOH NOH Succindialdehyde R.C.P. KASEGAON
  59. 59. Medicinal uses PYRRO LE R.C.P. KASEGAON
  60. 60. Properties 1. Aromaticity FU RA N R.C.P. KASEGAON
  61. 61. Furan Slightl y 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 O2 Polymerisation Brown Resin H O O H H Succindialdehyde Furan hydrochloride O Furan R.C.P. KASEGAON
  62. 62. Properties 1. Aromaticity FU RA N R.C.P. KASEGAON
  63. 63. FU RA N Synthesis 1. Paal-Knorr synthesis of furan C C O O 3 CH H3C H H -H2O O 3 H C CH3 2,5 Dimethyl furan H+ /HCl CH CH R.C.P. KASEGAON
  64. 64. CH CH C C O O 3 CH H3C ACID HC CH C C OH HO 3 CH H3C 2 -H O O H3C CH3 H H KETO hexane-2,5-dione ENOL (2E,4E)-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. 65. Synthesis 2. Feist – Benary Synthesis FU RA N R.C.P. KASEGAON
  66. 66. Synthesis 2. Feist – Benary Synthesis Mechanism FU RA N CH COOC2H5 C O CH3 H HC COOC2H5 C HO CH3 + HC C CH3 CH3 O C COOC H 2 5 C HO CH3 HC C CH3 Cl CH3 O H COOC2H5 CH H3C OH C C CH3 Cl CH3 HO O C2H5OOC H3C CH3 CH3 HC -HCl, H2O H ethyl 2,4,5-trimethylfuran-3-carboxylate ethyl 3-oxobutanoate Cl 3-chlorobutan-2-one R.C.P. KASEGAON
  67. 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 COH H OH OH H O H OH H H H/H2SO4 O C O H -3H2O, -H2 CaO, steam O furan R.C.P. KASEGAON
  68. 68. FURAN Synthesis: 4. From Mucic acid:Dry distillation of Mucic acid and heating of to get furan HO H OH H HO H HOOC H COOH OH Mucic acid Dry Distill -3H2O, -CO2 O Furoic acid O Furan -CO2 COOH R.C.P. KASEGAON
  69. 69. FURAN O Furoic acid O Furan -CO2 COOH C O Furfural 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] K2Cr2O7 R.C.P. KASEGAON
  70. 70. FURAN Ag2O Steam C O Furfural Synthesis: 6. From Decarboxylation Furfural: Decarboxylation of furfural in steam in the presence of silver oxide catalyst O H O furan + CO R.C.P. KASEGAON
  71. 71. FURAN Synthesis: 7. From Succinic dialdehyde: Pal-Knor synthesis Dehydration of succinic dialdehyde by heating with P2O5 HC CH2 H2C CH O O O H H P2O5 Succinic dialdehyde ENOL Furan + H2O OH HO R.C.P. KASEGAON
  72. 72. Reactions 1. Electrophilic substitution furan undergoes electrophilic substitution reaction at 2n d position FU RA N R.C.P. KASEGAON
  73. 73. Reactions 1. Electrophilicsubstitution FU RA N R.C.P. KASEGAON
  74. 74. Reactions 1. Electrophilicsubstitution FU RA N R.C.P. KASEGAON
  75. 75. Reactions 2. Reduction FU RA N R.C.P. KASEGAON
  76. 76. Reactions 3. Diels-Alder reaction FU RA N R.C.P. KASEGAON
  77. 77. Reactions 3. Diels-Alder reaction FU RA N R.C.P. KASEGAON
  78. 78. FU RA N + NH3 Reactions 4. Pyrrole synthesis Mixture of Furan and ammonia passed steam over aluminium oxide catalyst at 480°C- 490°C Al2O3 Steam + H2O O furan N H 1H-pyrrole R.C.P. KASEGAON
  79. 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 CH2 H2C C O O O Diacetyl Succinic dialdehyde Furan 3 + + 2CH OH 2 HCl H3CO OCH3 R.C.P. KASEGAON
  80. 80. Medicinal uses FU RA N R.C.P. KASEGAON
  81. 81. Properties 1. Aromaticity TH IOPH EN E R.C.P. KASEGAON
  82. 82. TH IOPH EN E Thiophene is a colorless liquid, bp 84°C it is insoluble in water. Thiophene does not shows any basic properties. It more stable to acid than pyrrole or furan. Thiophene does not undergo Diels –Alder reaction R.C.P. KASEGAON
  83. 83. Properties 1. Aromaticity TH IOPH EN E R.C.P. KASEGAON
  84. 84. Properties 1. Aromaticity TH IOPH EN E R.C.P. KASEGAON
  85. 85. Synthesis 1. Paal-Knorr synthesis of thiophene TH IOPH EN E R.C.P. KASEGAON
  86. 86. Synthesis 1. Paal-Knorr synthesis of furan Mechanism TH IOPH EN E R.C.P. KASEGAON
  87. 87. Mechanism CH CH C O O C 3 CH H3C ACID HC CH C C OH HO 3 CH H3C 2 -H O S H3C CH3 H H KETO hexane-2,5-dione ENOL (2E,4E)-hexa-2,4-diene-2,5-diol 2,5 Dimethyl Thiphene P2S5 R.C.P. KASEGAON
  88. 88. Synthesis 2. From sod. succinate TH IOPH EN E R.C.P. KASEGAON
  89. 89. Synthesis 3. Hinsberg Synthesis TH IOPH EN E R.C.P. KASEGAON
  90. 90. THIOPHENE 4. From Acetylene: Mixture of acetylene and hydrogen sulphide passed over aluminium oxide at 400°C CH CH CH CH S + Acetylene Hydrogen sulphide H H S thiophene Al2O3 R.C.P. KASEGAON
  91. 91. THIOPHENE 5. From Furoic acid: Distillation of furoic acid with barium sulfide. O C OH + BaS + BaCO3 O Furoic acid S Thiophene R.C.P. KASEGAON
  92. 92. THIOPHENE 6. From n-butane: Reaction of n-butane with sulphur in the gas phase at 650°C. + 4S 650°c H2C CH2 CH3 CH3 n- Butane S Thiophene + 3H2S R.C.P. KASEGAON
  93. 93. Reactions 1. Electrophilic substitution thiophene undergoes electrophilic substitution reaction at 2nd position TH IOPH EN E R.C.P. KASEGAON
  94. 94. Reactions 1. Electrophilicsubstitution TH IOPH EN E R.C.P. KASEGAON
  95. 95. Reactions 1. Electrophilicsubstitution TH IOPH EN E R.C.P. KASEGAON
  96. 96. Reactions 2. Reduction TH IOPH EN E R.C.P. KASEGAON
  97. 97. Reactions 3. Reaction with organo lithium TH IOPH EN E R.C.P. KASEGAON
  98. 98. Medicinal uses TH IOPH EN E R.C.P. KASEGAON
  99. 99. Medicinal uses TH IOPH EN E R.C.P. KASEGAON

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