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Heterocyclic chemistry

Mumbai University T Y B Pharm Sem V
Organic chemistry

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Heterocyclic chemistry

  1. 1. Heterocyclic chemistry:Heterocyclic chemistry: Furan, Thiophene, Pyrrole, Imidazole, Indole Dr. Taj Khan Dept. of Pharmaceutical Chemistry, Oriental college of pharmacy Sanpada, New Mumbai.
  2. 2. Furan α β α' β’ Drugs: Furosemide, Nitrofurantoin, Nitrofurazone, Prazocin, Ranitidine Scheele 1780
  3. 3. Less stable than pyrrole & thiophene less reactive than pyrrole towards E+ Aromatic as lone pair of e participate in Pi cloud, follow Huckel’s rule of aromaticity 4n + 2π O and 4 C SP2 hybridised & lie in same plane
  4. 4. Synthesis of Furan: 1) From carbohydrate: Polysaccharide (Oat) Acid hydrolysis Furfuraldehyde 2-furoic acid Decarboxylation Furan
  5. 5. 2) Synthesis of furan from Oxazole
  6. 6. 3) Synthesis of 3-substituted furan from DA adduct
  7. 7. 4) Synthesis of furan by Paal –Knorr method: Ring closure mtd. Subst. open chain compd (1,4 diketone) cyclize by acid to give furan Mechanism via mono enol formation. Sterically hindered diketone do not cyclize to furan
  8. 8. Chemical reactions of furan: 1)Reaction with acid: F can be hydrolysed easily by acid to give aldehyde. Mild conditions shd be used otherwise protonated F undergoes polymerization can occur. F with EWD more stabile to acids
  9. 9. Chemical reactions of furan: 1)Reaction with Base:
  10. 10. Chemical reactions of furan: 2) Electrophilic aromatic substitution: more reactive than benzene. 2 position more reactive. Conditions need to be controlled. A) Halogenation: proceeds quickly to give mix of either mono and poly subs or resin % of 2 subst product can be increased by using less amt of Cl2 2- Bromo can be obtd by Br2 in dioxane
  11. 11. Chemical reactions of furan: 2)Electrophilic aromatic substitution: B) Nitration: Mild nitrating agents used acetyl nitrate (acetic anhydride + HNO3
  12. 12. Chemical reactions of furan: 2)Electrophilic aromatic substitution: C) Sulfonation: Mild sulfonating agents used Pyridine- SO3 complex If H2SO4 used, it gives resin
  13. 13. Chemical reactions of furan: 2)Electrophilic aromatic substitution: D) Friedel Crafts reaction: Anhydride and acyl halide need Lewis catalyst. But reactive anhydride like (CF3CO)2O work without catalyst. Alkylation not successful, polymerization. F containing EWD can be alkylated.
  14. 14. Chemical reactions of furan: 3) Carbene and nitrene: Cabene add across 2,3 C db. There is not much report of reactions of nitrene with furan
  15. 15. Chemical reactions of furan: 4) Reaction with reducing agents: dependent on catalyst, solvent & temp
  16. 16. Chemical reactions of furan: 5) Reaction with oxidizing agents: F is O2/air sensitive, 1,4 addition to diene system
  17. 17. Chemical reactions of furan: 6) DA Reaction : Furan as a diene reacts with dienophiles to give DA adduct. But due to aromatic character and ring strain in cycloadduct it is thermolabile, revert to SM.
  18. 18. Extra
  19. 19. 2 Position reactive Extra
  20. 20. O furan O CH=O O Br O HgCl O I 1. HCN, HCl 2. H2O Br2 dioxane HgCl2 CH3CO2Na I2 CH3COCl O C O CH3 Extra
  21. 21. Thipohene Have two pairs of nonbonding e but only 1 pair is in the unhybridized p orbital and is able to overlap with the C of the ring. Mayer 1882 Coal tar, pt and animal metabolite
  22. 22. Synthesis of Thiophene: 1)Using Na-Succinate Classical mtd Phos. trisulfide ( Red P +S) Industrial mtd use hydrocarbon (butane/butene/1,3-butadiene and elemental S 600 0 C
  23. 23. Synthesis of Thiophene: 2) Ring closure Mtd A) From unsaturated compds/ Fiesselmann mtd: Condensation Rxn
  24. 24. Synthesis of Thiophene: 2) Ring closure Mtd B) Paal Knor mtd: General mtd
  25. 25. Synthesis of Thiophene: 2) Ring closure Mtd C) Hinsberg Mtd: 1,2 dicarbonyl compound diethylthiodiacetate in presence of st base involved 2 aldol condensation betn reactant and forms half ester
  26. 26. Chemical reactions of thiophene: 1)Reaction with acid: T stable to acid. V. st acid can cause polymerization. Orthophosphoric acid under mild condition gives trimer.
  27. 27. Chemical reactions of Thiophen: 1)Reaction with Base:
  28. 28. Chemical reactions of Thiophene: 2)Electrophilic aromatic substitution: more reactive than benzene. Pyrrole>furan>Thiophene>Benzene 2 position more reactive. A) Halogenation: Rxn with NBS gives 2- bromo T
  29. 29. Chemical reactions of Thiophene: 2)Electrophilic aromatic substitution: more reactive than benzene. Pyrrole>furan>Thiophene>Benzene 2 position more reactive. B) Nitration:
  30. 30. Chemical reactions of furan: 2)Electrophilic aromatic substitution: C) Sulfonation: 95% H2SO4 used at rt readily occurs
  31. 31. Chemical reactions of furan: 2)Electrophilic aromatic substitution: D) Friedel Crafts reaction: wide variety of choices available
  32. 32. Chemical reactions of furan: 3) Reaction with carbene & Nitrene: caboethoxy carbene adds to C2-C3 bond to give cyclopropane compd, which can be opened with acid to give thiophene Beta- acetic ester R=C: R–N: acts as E+
  33. 33. Ethyxycarbonylnitrene reacts with T to give 1,4-adduct which loses S to form N-carboethoxypyrrole
  34. 34. Chemical reactions of furan: 4) Reaction with Nu: Every positional combination of Nitro and Halo T actiavate system towards SN rxn Seems like normal displacement Rxn
  35. 35. Chemical reactions of furan: 5) Reaction with free radicals/ Gomberg Bachmann rxn: 1 of the best & simple mtd for synthesis of aryl thiophenes
  36. 36. Chemical reactions of furan: 6) Reaction with oxidising agents: Resistant to mild oxidising agents. HNO3 breaks ring to maleic acid and oxalic acid. Peracid (perbenzoic acid attacks S atom) Initial sulfoxide ca not be isolated due to dimerization & further oxidation to Thiophene 1,1’ dioxide/ Thiolane can form it’s also reactive but isolable
  37. 37. Chemical reactions of furan: 7) Reaction with reducing agents:
  38. 38. Chemical reactions of furan: 8) Diels-Alder reaction: Acetylenic dienophiles. Chelotropic expulsion of S from unstable intermediate, which gives benzene derivative
  39. 39. Pyrrole α β α' β’ Ketorelac, atorvastatin Hb, Chlorophyl, Vit B12, bile pigment Runge 1837 Greek: Red
  40. 40. Synthesis methods: 1) From Furan
  41. 41. 2)From Primary amine:
  42. 42. The Knorr Synthesis: Imp & widely used mtd Condensation of Alfa amino ketone with another dicarbonyl compound with active methylene grp in presence of acetic acid
  43. 43. Hantzch synthesis of pyrrole: Alfa halo ketone/aldehyde react with beta keto ester (Beta chloro ketone) In presence of N containing base (NH3 or amine) which acts as base as well as solvent. Yield moderate to good.
  44. 44. The Paal Knorr Synthesis of Pyrrole: General mtd Condensation of 1,4 diketone with NH3 or primary amine.
  45. 45. The Piloty Robinsons Synthesis: Monocyclic version of Fischer indole synthesis. Ketazine with st acid to give pyrrole through [3,3] sigmatropic rearrangement of tautomeric divinyl hydrazine
  46. 46. Chemical reactions of Pyrrole: 1) Reaction with acid: H attached at N undergoes rapid exchange in acid & alkali Similar exchange also possible for H at C under more acidic condition Exchange rate of α proton is double than that of β proton Isolation of trimer of pyrrole could be achieved by controlled addition of acid
  47. 47. Chemical reactions of Pyrrole: 2) Reaction with base: pKa 17.5 which is larger than imidazole so pyrrole is wk acid than imidazole. Weaker than phenol but equal to EtOH It reacts with K to liberate H2 and form salt Acidity of P can be increased by putting EWG at position 3 which stabilizes anion by resonance
  48. 48. Resonance structures of furan Thiphene and Pyrrole
  49. 49. Mono-C-alkylation of pyrroles cannot be achieved by direct reaction with simple alkyl halides, either alone or with a Lewis-acid catalyst, e.g. pyrrole does not react with methyl iodide even above about 150 °C, gives further heating leads to a complex mixture made up mostly of polymeric material together with some poly-methylated pyrroles. The more reactive allyl bromide reacts with pyrrole at room temperature, but mixtures of mono- to tetra-allyl-pyrroles together with oligomers and polymers are obtained. Chemical reactions of Pyrrole: 3) Alkylation:
  50. 50. Chemical reactions of Pyrrole: 3) Electrophilic Aromatic substitution: π e density is more as compared to benzene. ES Rxn occurs similar to benzenoid system Occurs at 2 position if blocked to other position Max resonance max stability/probability 2 position Followed by 3
  51. 51. Chemical reactions of Pyrrole: 3) Electrophilic Aromatic substitution: A)Halogenation: Extremely reactive Chlorination (SO2Cl2) Bromination (Br2 CH3COOH) Iodination (I2/KI3) All these gives tetra halo derivatives Hard to get mono halo derivative Halo-pyrroles are v. unstable, decompose in air & light
  52. 52. Chemical reactions of Pyrrole: 3) Electrophilic Aromatic substitution: B) Nitration: Extremely reactive
  53. 53. Chemical reactions of Pyrrole: 2)Electrophilic aromatic substitution: C) Sulfonation: If H2SO4 used at rt forms polymer So mild sulfonating agent (Pyridine sulfur trioxide complex) used
  54. 54. Chemical reactions of Pyrrole: 4) Reaction with oxidising agents: Easy Autoxidation by air, light red brown colour. Ozonolysis at low temp breakdown of ring. If ring does survive it forms maleinimide deri. With H2O2 also it gives similar prodt
  55. 55. Chemical reactions of Pyrrole: 5) Reaction with reducing agents: P won’t respond to rxn with LAH, Na/Liq NH3 But reduction is possible in acidic media Species under attack protonated
  56. 56. Chemical reactions of Pyrrole: 6) Diels Alder reaction: DA adduct
  57. 57. Chemical reactions of Pyrrole: 7) Reaction with carbene & nitrene: Halocyclopropyl int
  58. 58. Rx with carbene
  59. 59. Rx with Nitrene: Gives homoazopyrrole which rearranges to give final prdt
  60. 60. 5 Membered Heterocyclic ring containing 2 hetero atoms Imidazole
  61. 61. Aka Iminazoline Azopyrrole 2 N atom separated by C Histamine, Histidine, Pilocarpine & allantoin Benzimidazole in Vit B12
  62. 62. Resonance structure of Imidazole:
  63. 63. Attack at 5 If blocked then on 4
  64. 64. 1) Synthesis from imidazoline: Dehydrogenation of imidazoline in +ce of S Another variation is use of Barium mangnate
  65. 65. 2)Synthesis from α Haloketone: 2,4 disubs Imidazole from Benzimidine & α Haloketone
  66. 66. 3)Radiszewski method: Imp mtd Condensation of diketone with aldehyde in +ce of NH3
  67. 67. Reaction of imidazole with acid & base Base and form crystalline salt with acid. More acidic than pyrroles and thus forms salts of the following type with Grignard reagent or metal ions.
  68. 68. Reaction of imidazole with oxidising agents: stable to auto oxidation and to the action of chromic acid Can be oxidised by KmnO4 . H2O2 Readily opens the ring to form oxamide N N H NH N H O2 / MeOH O MeO MeO Oxygen in the presence of a sensitizer (single oxygen) reaction gives an imidazolidine derivative
  69. 69. Reactions of imidazole -Electrophilic substitution Rxn: E + would attack the unshared electron pair on N-3, but not that on the ‘pyrrole’ nitrogen since it is the part of the aromatic sextet. It is more susceptible to E + attack than thiazole, furan and thiophene. Attack takes place at the 4th and 5th position
  70. 70. Reactions of imidazole -Nitration: Bromination
  71. 71. Reactions of imidazole - Sulfonation:
  72. 72. N N CH3 BuLi RX N N R N N ph N N ph Li ph R BuLi N N CH3 R Li N N H N N N N H N N Ac2O COCH3 CH2N2 CO2CH3 H3C CH3 H3C CO2CH3 Acylation Alkylation Lithiation Reactions of imidazole -
  73. 73. Catalysis role of imidazole - Ester Hydrolysis. Inspired by evidence that the imidazole ring of histidine residues present in various hydrolytic enzymes is responsible for their proteolytic activities, imidazole itself has been shown to be an excellent catalyst of ester hydrolysis In intramolecular transesterifications and hydrolyses of 2-hydroxymethylbenzoic acid derivatives the accelerating role of imidazole is due to its ability to act as a proton transfer catalyst rather than as a nucleophile.
  74. 74. Indole: abundant in nature tryptophan, indole-3-acetic acid, serotonin, natural products, drugs Isolated industrially from coal tar Biosynthesis of tryptophan Isoelectronic with naphthalene Very weakly basic: pKa of protonated indole: 2.4 Protonation occurs at C–3 preferentially Easily oxidized (atmospheric oxygen) very e rich Electrophilic attack occurs at C–3 (site of most electron density) N–1 isthe m ostnucleophilicsite C–2 is the second most reactive site C–3 is more reactive to electrophilic attack than benzene
  75. 75. Resonance structure of indole:
  76. 76. Intramolecular cyclization of N-phenylamides using strong base at high temperature.
  77. 77. The Fischer indole synthesis : best methods for preparing indoles. converts arylhydrazones into indoles in the presence of an acid catalyst.
  78. 78. Reactions of indole: Protonation
  79. 79. Bischler indole synthesis: 2-aryl-indole from α-bromo-acetophenone and excess aniline
  80. 80. Reissert indole synthesis: Basic condensation of o-nitrotoluene with oxalic ester to o- nitrophenylpyruvic ester, reduction of the nitro group to an amino group, cyclization to indole-2-carboxylic acid and final decarboxylation
  81. 81. Reactions of indole:
  82. 82. Reactions of indole: Indoles – Electrophilic Substitution
  83. 83. Reactions of indole:
  84. 84. Reactions of indole:
  85. 85. Reactions of indole:
  86. 86. Reactions of indole:
  87. 87. Oxidative cleavage of 2,3 db Reactions of indole:

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