Hetrocyclic chemistry

heterocyclic chemistry

1. Introduction: Heterocyclic Compounds Dr.GURUMEET C Wadhawa , Karmaveer Bhaurao Patil College,Vashi,Navimumbai

2. Contents Introduction: heterocyclic compounds Introduction: pyrrole Nomenclature Physical properties Chemical properties/ reaction Derivatives of pyrrole Synthesis of pyrrole Application References 2

3. Introduction: Heterocyclic Compounds 3

4. 4 A cyclic organic compound containing all carbon atoms in ring formation is referred to as a carbocyclic compound. Heterocyclic compounds are organic compounds that contain a ring structure containing atoms in addition to carbon, such as sulfur, oxygen or nitrogen, as the heteroatom. The ring may be aromatic or non-aromatica. Number of drugs in pharmaceutical science are heterocyclic compounds. Heterocyclic compounds may be of natural origin or synthetically available.

5. Classification of Heterocyclic compounds 5- Membered heterocyclic compounds One heterotom: Exam p l e -f uro ne pyrrole More than one heteroatom: Example- Pyrazole Imidazole Oxazole 6-Membered heterocyclic compounds One heteroatom Example- Pyridine, piperidine More than one heteroatom: Example- pyrimidine 7 - M e mb ered heterocyclic compounds Example: Oxepine Condensed het erocy c lic compounds Example: Indole, Quinoline Isoquinoline 5

6. 5- Membered heterocyclic compound having one heteroatom: 5- Membered heterocyclic compound having more than one heteroatom furan Pyrrole Thiophene Pyrazole 6 Oxazole Imidazole

7. 6-Membered heterocyclic compounds having one heteroatom: Pyridine Piperidine 6-Membered heterocyclic compounds having more than one heteroatom: Pyrim i dine 7 Pyrazine

8. 7-Membered heterocyclic compounds 1-H-Azpine Oxe p ine Condensed heterocyclic compounds Quinoline 8 Isoquinoline

9. Introduction: Pyr r ole 9

10. HISTORY 1834 Runge Distillation of coal tar, bone oil, and other product derived from proteins gave unknown product in ammonia & dipped in HCl, called PYRROLE 1857 Anderson Obtained pure compound from bone oil distillate and synthesized by the pyrolysis of ammonium mucate which is commercially used. 10

11. Pyrrole is the 5- membered ring containing N-atom replacement with C- atom. the pyrrole ring system soon become of great interest, as it was found in many compounds widely distributed in nature. Pyrrole rings are present in a number of natural products for eg. alkoloids and synthetic pharmaceuticals. Pyrroles having a following therapeutical activity 11

12. Nomenclature 12

13. In naming pyrrole and its derivatives, the nitrogen atom is assigned position-1. 1 13 2 3 4 5 α ‘ β’ β α The position of the substituent may be specified in Arabic numerals or in Greek letters.

14. Five - membered heterocycles containing nitrogen general end with ‘ ole’ Three dihydropyrroles or pyrrolines are theoretically possible and tetrahydropyrrole is called pyrrolidine. The pyrrole ring, when considered as asubstituent in another structure is called pyrryl. Pyrroline Pyrrolid i ne Pyrryl 14

15. Physical properties 15

16. It is a colourless volatile liquid. It’s boiling point is 131 ° C and melting point is -23 ° C. It turns brown in the air and gradually resinifies. Only slightly soluble in water but it is totally miscible with ether and ethanol. Pyrrole is weakly basic in nature. Pyrrole has a relatively high boiling point as compared to furan and thiophene, this is due to the presence of intermolecular hydrogen bonding in pyrrole. 16

17. 17 Aromaticity of pyrrole Pyrrole itself is completely planar and have molecular dimensions. The 5 Sp 2 hybridised C-atom sustained 6π electron system. From the molecular orbital standpoint is consisting of planar pentagoan with Sp 2 hybridised C-atoms. Each of the 4 C-atoms has one electron remaning in a p z orbital. The N-atom has 2 electron in p orbital. Th e se p o r bi t a ls ov e rla p to gi v e a tot a l o f s i x electro n s in π system and this shell provide stability. Pyrrole is an extremely weak base because its pair of non-bonding electrons are part of the π-cloud (K b = 2.5 x 10 -14 ). Therefore, if pyrrole is protonated, it loses its aromaticity.

18. They tend to react by electrophilic substitution due appearance of –ve charge on carbon atoms. D ue to d e loc a li z a t ion of e lectron a s s h own in th e fo llowing resonance structures . 18

19. Chemical properties/ Reaction 5. 19

20. Pyrrole is aromatic and more reactive than benzene. It gives electrophilic substitution reactions such as halogenation , nitration ,etc. I t a lso un d e rgoe s dia z otiz at io n and Reimer - T i e ma n n r ea ct ions, while benzene does not. Acidity pKa = 17,5 Pyrrole is a weak acid Pyrrolyl anion is a strong base 20

21. Basicity Pyrrole is a weak base: Protonation breaks aromaticity (lone pair participates in conjugation)and thus it is not readily available 21

22. 1. Opening of the pyrrole ring: The pyrrole ring is not readily opened by acids or alkalis, but boiling with alcoholic hydroxylamine hydrochloride causes rupture, with the formation of succindialdehyde dioxime . N H H N H H 2 NH 2 OH - H N H H 2 N H O H H N H N O H H - H H N N O H NH 2 OH -NH 3 HON NOH succindialdehyde dio x ime 22

23. 23 The ozonoly s i s of py r rol e and d e riv a t i ve s a t - 60 chloroform breaks the ring. O C in Pyrrole in a q. S ilve r nitrat e is brok e n dow n by y u l tra s on i c vibration into acetylene and cyanide ion.

24. 2. Reaction with electrophiles 24 for example Nitration Sulfonation Halogenation

25. 3. Substitution reaction Substitution at nitrogen: A) Metallation of Pyrrole 25

26. B) Formation of N-substituted pyrrole 26

27. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 27 Pyrrole behaves both as a weak acid and exhibits the following chemical reactions. Reduction reaction. Oxidation reaction. Ring expansion reaction. Reimer-Tiemann reaction. Ring opening reaction. Electrophilic aromatic substitution reaction. (Nitration, Sulphonation, Chlorination, Iodination, Acetylation)

28. Reduction reaction. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 28 Pyrrole on reduction with Zinc and Acetic acid gives 2,5-dihydropyrrole which on reduction with HI and Red phosphorus gives Pyrrolidine. Zn/CH3COOH HI / P P Y R R O L E 2,5 -DIHYDROPYRROLE P Y R R O L IDINE

29. Oxidation reaction. Pyrrole is oxidized to Maleinimide (Imide of acetic acid) with chromium tri oxide in Acetic acid. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 29 CrO3 / CH 3 COOH P Y R R O L E NASANT OXYGEN ATOM Maleinimide (Imide of acetic acid)

30. Pyrrole ring expands on heating Potassium Pyrrole with Chloroform and Sodium Ethoxide . Ring expansion reaction. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 30 CHCl3 / C2H5ONa POTASSIUM PYRROLE 3-CHLORO PYRIDINE

31. d. Reimer-Tiemann reaction. In presence of a strong base and Chloroform Pyrrole undergoes Reimer- Tiemann reaction to form Pyrrole-2-aldehyde. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 31 CHCl3 / KOH P Y R R O L E PYRROLE-2-ALDEHYDE INTE R MIDI A TE

32. Ring opening reaction. Pyrrole ring structure opens and forms Succinaldehyde dioxime (addition product) on Refluxing with Ethanolic Hydroxylamine. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 32 NH2OH / C2H5OH REFLUX P Y R R O L E SUCCINALDEHYDE DIOXIME

33. pyrrole undergoes electrophilic aromatic substitution more readily at C-2 than C-3 position. Mechanism of electrophilic aromatic substitution : electrophilic aromatic substitution of pyrrole, involves the following steps: Electrophilic aromatic substitution reaction. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 33

34. Step-01) SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 34 Generation of electrophile : ELECTROPHILE Step-02) Attachment of electrophile to the aromatic ring to form intermediate carbocation : P Y R R O L E ELECTROPHILE INTE R MEDI A TE CARBOCATION

35. Step-03) Elimination of proton from carbocation to form substitution product : SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 35 INT ER M E DI A TE CARBOCATION SUB S TI T UTI O N PRODUCT P R O T O N

36. In Pyrrole Electrophilic Substitution takes place at 2 or 5 positions. If these positions are filled substitution takes place at 3 or 4 positions. This can be explained as follows : SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 36

37. Substitution occurs preferentially at C–2 because the intermediate carbocation obtained by putting a substituent at this position is more stable than the intermediate carbocation obtained by placing a substituent at C-3. The intermediate resulting from C-2 substitution has 3 resonance contributors; they both have a positive charge on a relatively stable secondary allylic carbon. The intermediate resulting from c-3 Substitution has only 2-resonance contributors and has positive charge on a primary carbon, which is unstable. Thus substitution at C-2 predominates. C o n tin u o u s….. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 37

38. HNO3/(C H 3 C O ) 2O 10* NITRATION SO3, PYRIDINE,100*C S ULPHONATI ON SO2Cl2 0*C CH L ORIN A TION I2 / Aq. KI IODI N A TION (CH3CO)2O /SnCl4 200*c P Y R R O L E SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 38 2-NITRO P YR R OLE 2-PYRROLE SULPHONIC ACID 2,3,4,5TETRACHLORO PYRROLE 2,3,4,5TE T RA IODO PYRROLE 2-ACETYL PYRROLE

39. Chemically procyclidine is α-cyclohexyl, α- phenyl-l-pyrrolidinepropanol. It is an anti-muscarinic drug used in the treatment of parkinsonism. Medicinal uses/ Compounds. The following medicinal compounds possess pyrrole heterocyclic ring system . SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 39

40. Anti-muscarionic Drugs are the agents that blocks the activity of muscarinic Acetylcholine receptors. SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 40 Acetylcholine receptors are of two types :- Muscarinic receptors which responds to muscarin neurotransmitters. Nicotinic receptors which responds to nicotine. PROCYCLIDINE C o n tin u o u s…..

41. Derivatives of pyrrole 41

42. The functional derivatives of pyrrole is Hydroxypyrroles : Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by insertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole. The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 2 - hydro x ymet h yl p yrrole 42

43. 2. Aldehydes and Ketones: Pyrrole aldehydes and ketones are somewhat less reactive than the corresponding benzenoid derivatives. They react with pyrroles under acidic conditions to form dipyrrylmethenes. dipyrrylmethenes 43

44. 44 Pyrrole Carboxylic Acids and Esters: The acids are considerably less stable than benzoic acid and often decarboxylate readily on heating. However, electron-withdrawing substituents tend to stabilize them toward decarboxylation. The pyrrole esters are important synthetically because they stabilize the ring and may also act as protecting groups. Thus, the esters can be utilized synthetically and then hydrolyzed to the acid, which can be decarboxylated by heating. Often β-esters are hydrolyzed more easily than the α-esters.

45. 4. Vinyl Pyrroles: Reaction between ketoximes and acetylene in an alkali metal hydroxide–dimethyl sulfoxide (DMSO) system havemade vinyl pyrroles. The 1-vinylpyrroles are highly reactive and are sensitive to oxygen. Conjugation of the vinyl group with the aromatic ring leads to a greater susceptibility to electrophilic attack. Vinyl Pyrroles 45 V i nyl

46. Condensed Pyrroles: Pyrroles can be condensed to compounds containing two, three, or four pyrrole nuclei. These are important in synthetic routes. Bipyrroles: 46

47. Synthesis of Pyrrole 47

48. 1. Knorr Synthesis: Condensation of an α-aminoketone with a carbonyl compound was first reported by Knorr. This reaction and its modifications are among the most important and widely used methods for the synthesis of pyrroles. α - amin o ketone 48 β-dicarbonyl derivative pyrrole

49. RO 2 C O R 2 R 3 O H N R 4 R 5 B a s e RO 2 C O R 2 R 3 O H N R 4 R 5 N R 5 H O R 2 H O H R 3 R 4 H 2 RO C 2 -2H O N R 5 R 4 R 2 2 RO C R 3 Can be removed; hydrol., decarbox. Alkyl, aryl May be H If R2=CO2R Can be removed; hydrol., decarbox Mechanism 49

50. 2. Hantzsch and Feist Syntheses: The Hantzsch synthesis of pyrroles involves condensation of an α- haloketone with a β-keto ester in the presence of ammonia or an amine. α-haloketone 50 β-keto ester pyrrole

51. Step I 51 Step II Mechanism

52. 52 3. Paal-Knorr Pyrrole Synthesis Generally Substituted pyrrole may be synthesized through the cyclization of 1,4-diketones in combination with ammonia (NH3) or amines. The ring-closure is proceeded by dehydration (condensation), which then yields the two double bonds and thus the aromatic π system. The formation of the energetically favored aromatic system is one of the driving forces of the reaction.

53. Mechanism 53 1,4-diketones pyrrole

54. 4. Pyrrole is obtained by distillation of succinimide over zinc dust 54

55. 5. By heating a mixture of furan, ammonia and steam over alumina catalyst 55

56. 6 . B y pa s s in g a mix t ure o f a c etyl e n e and a m m o ni a o v er red hot tube. 56

57. The r ea ct i o n of a n i t r oalk e n e wit h a n α - is o cy a no a cet a t e u nder basic conditions. 57 7. Barton-Zard Pyrrole Synthesis nitroalkene α-isocyanoacetate Pyrrole

58. Mechanism 58

59. Applications 59

60. 60 Pyrrole is essential to the production of many different chemicals. N-methylpyrrole is a precursor to N-methylpyrrolecarboxylic acid, a building-block in pharmaceutical chemistry. Although there is a claim that pyrrole is used as an additive to cigarettes, it is typically listed as a constituent of tobacco smoke and not as an ingredient. Pyrrole is also use in commercial and pharmaceuticals.

61. Pyrrole subunit has diverse applications in therapeutically active compounds including fungicides, antibiotics, anti- inammatory drugs,cholesterol reducing drugs, antitumor agents and many more. for example Pyrocyclidine act as anti-muscarinic agent use in the treatment of parkinsonism. Pyrocyclidine 61

62. References 62

63. 63 1. Mor r i n Ach e son: A n I n tro d u c tio n to The Che mistry of H e terocy c lic Compoun d s, Wiley stude n t e di t i on, Third edition,2008, 89-113. Th o mas G i l ch ris t : H e tero c yc l i c Chemi s try , P e a rso n e ducatio n , Third edition,2007, 12, 192-205. Raj Bansal: Heterocyclic Chemistry, New age international publishers, Fifth edition, 2012, 1-8, 152-177. Joule and Mills: Heterocyclic Chemistry, Blackwell Publishing, Fourth edition, 2008, 237. D r . M u k he r j e e K . S . :T e x t b ook o f Org a ni c Ch e mi s try , N C B A, Third edition, 2010, 440-448.

64. 64 Tewari K. S., Vishnoi N. K.: A Textbook of Organic Chemistry, Vikas publishing house, Second edition, 2004, 1025-1029. Ghosh S. K.: Advaced General Organic chemistry- A Modern Approch Part II, NCBA, Third edition, 2013, 1105-1113. Solomons and Fryhle: Organic chemistry, Wiley student edition, Eighth edition, 2007, 644. Fabio Bellina and Renzo Rossi: Synthesis and biological activity of pyrrole, pyrroline and pyrrolidine derivatives with two aryl groups on adjacent positions, Elsevier Ltd,2006 , 7213–7256. Varun Bhardwaj: Pyrrole: a resourceful small molecule in keymedicinal hetero-aromatics, The Royal Society of Chemistry , 2015, 15233.

65. 65 11 . Shri n iva s Jos h i , U . Mor e : Pyr r o l e : Ch em i ca l sy n th e sis, m i crow a v e assisted sy n th e sis, r e a c t i ons a n d a pp li c a tio n s : A r e v i e w , Ar t ic l e in cu r r e n t or g anic 2304 · January 2013. 12. Pragi arora, varun arora , H.S. Lamba che mi s tr y 1 7:2279- and deepak wadhwa: Importance Of Heterocyclic Chemistry: A Review, IJPSR, 2012; vol. 3(9): 2947-2954 . 13. Dr. Usha Yadav 1 and Dheeraj Kumar2: Study Of Heterocyclic Compound – Pyrrole (IJRST) 2015, Vol. No. 5, Issue No. I, Jan-Mar , ISSN: 2249-0604 .