Pyrrole (o.c iv)

DETAILED INFO OF HETEROCYCLIC COMPUND-PYRROLE

1. ORGANIC CHEMISTRY CHEMISTRY OF FIVE-MEMBERED HETEROCYCLIC COMPOUND : PYRROLE Mr. Srinivas R. Bhairy B. Pharmacy (S.Y) (2012-2013) Student Organic Chemistry- IV Shivajirao S. Jondhle College Of Pharmacy Asangaon , Tal.Shahapur , Dist.Thane 12/02/2013 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 1

2. OBJECTIVES Introduction to Heterocyclic Compounds. Classification of Heterocyclic Compounds. Introduction to Pyrrole . Structure of Pyrrole . Preparation/ synthesis of Pyrrole . Properties of Pyrrole :- Physical Amphoteric Chemical Medicinal uses/ Medicinal Compounds of Pyrrole . 2 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY

3. Introduction to Heterocyclic Compounds. Cyclic compounds with one or more other elements along with carbon atoms are heterocyclic compounds. Non carbon atoms are the hetero atoms. Common hetero atoms are the N, S, O etc. Number of drugs in pharmaceutical science are heterocyclic compounds. Hetero cyclic compounds may be of natural origin or synthetically available. 3 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY

4. Classification of Heterocyclic Compounds SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 4

5. 5 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM. FURAN PYRROLE THIOPHENE 5-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS. PYRAZOLE IMIDAZOLE OXAZOLE ISOXAZOLE THIAZOLE

6. 6 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING ONE HETERO ATOM. PYRIDINE PIPERIDINE 6-MEMBERED HETEROCYCLIC COMPOUNDS HAVING MORE THAN ONE HETERO ATOMS. PYRIMIDINE PYIRIDAZINE PYRAZINE

7. 7 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 7-MEMBERED HETEROCYCLIC COMPOUNDS. OXEPINE 1-H-AZEPINE CONDENSED HETEROCYCLIC COMPOUNDS. INDOLE QUINOLINE ISOQUINOLINE PURINE

8. Introduction to Pyrrole . Pyrrole is an important five membered heterocyclic compound possessing a nitrogen atom as hetero atom. plays important role in the chemistry of living organisms. The essential structural feature of chlorophyll and heme is porphyrin , which consists of four Pyrrole rings held together by bridges. 8 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY

9. 9 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Hemoglobin

10. Structure of Pyrrole . Pyrrole has 3 pairs of delocalized ∏ electrons. Two of the pars are shown as bonds and third pair is shown as a pair of nonbonding electrons on the hetero atom (nitrogen). These non bonding electrons are in a SP 2 hybrid orbital perpendicular to the p- orbitals . Since it is cyclic, planar molecule with three pairs of delocalized electrons, fulfils the criteria for aromaticity . 10 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY

11. SOME DIFFERENT REPRESENTATION MODELS OF PYRROLE:- 11 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Continuous….. EXPLICIT STRUCTURE OF PYRROLE, WITH AROMATICITY INDICATED BY DASHED BONDS NUMBERED SKELETAL STRUCTURE OF PYRROLE BALL & STICK MODEL OF PYRROLE MOLECULE SPACE- FILLING MODEL OF PYRROLE MOLECULE ( 3D- MODEL)

12. Continuous….. Pyrrole is less aromatic than thiophene and more aromatic than furan. Therefore the total orbital diagram of Pyrrole is: 12 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY

13. Continuous….. According to the resonance theory Pyrrole is considered as a resonance hybrid of the following contributing structures. Among the resonance contributing structures 1. 2, and 3 are the main contributing structures to the resonance hybrid and hence resonance hybrid has a larger electron density at positions 2 and 5 than at 3 and 4. 13 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY

14. Preparation/ synthesis of Pyrrole . Parrole is obtained commertially by distillation of coal tar. It is synthesized in the laboratory by the following methods: From Furan. From Distillation of Succinimide . From Acetylene and Ammonia. Paal - Knorr Synthesis. 14 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY

15. From Furan Furan on heating with Ammonia in presence of Alumina (Al 2 O 3 ) gives Pyrrole . 15 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY FURAN PYRROLE

16. From distillation of succinimide Pyrrole is also obtained by the Distillation of Succinimide with Zinc dust. 16 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY SUCCINIMIDE PYRROLE ZINC OXIDE

17. From acetylene and ammonia Pyrrole can also be prepared by passing Acetylene and Ammonia through a Red-hot tube. 17 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Red- hot tube ACETYLENE AMMONIA ACETYLENE PYRROLE

18. Paal - Knorr Synthesis Pyrrole derivatives are synthesized by treating 1,4-diketone with Primary amine. 18 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 1,4-DIKETONE PRIMARY AMINE 1,2,5- TRIALKYL PYRROLE WATER

19. Properties of Pyrrole Physical Properties :-- 19 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY CHARECTERISTICS INFORMATION Compound name pyrrole IUPAC name 1H-Pyrrole synonym Azole State Liquid/ solid Appearance colourless Solubility Water- sparingly Organic solvents- easily soluble Molecular formula C 4 H 5 N Molar mass 67.09 g mol −1 Melting point 23 °C, 250 K, -9 °F Boiling point 129-131 °C, 402-404 K, 264-268 °F Density 967.00 kg/m³ Vapour pressure 7 mmHg at 23 °C viscosity 0.001225 Pa s Chemical nature Weak acid & weak base ( amphoteric )

20. pyrrole is weak base because the lone pair of electrons of nitrogen atom contributes to the (4n+2) π-electron cloud (aromatic sextet). Hence the availability of these electrons is decreased and consequently it is a very weak base. Pyrrole also exhibit weak acidic properties. The weak acidic property is due to its formation of potassium pyrrole with potassium hydroxide . 20 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Amphoteric Properties :-- KOH PYRROLE POTASSIUM PYRROLE

21. 21 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Chemical Properties :-- 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 )

22. Reduction reaction. Pyrrole on reduction with Zinc and Acetic acid gives 2,5-dihydropyrrole which on reduction with HI and Red phosphorus gives Pyrrolidine . 22 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Zn /CH3COOH HI / P PYRROLE 2,5 -DIHYDROPYRROLE PYRROLIDINE

23. Pyrrole is oxidized to Maleinimide ( Imide of acetic acid) with chromium tri oxide in Acetic acid. 23 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Oxidation reaction. CrO3 / CH 3 COOH PYRROLE NASANT OXYGEN ATOM Maleinimide ( Imide of acetic acid)

24. Pyrrole ring expands on heating Potassium Pyrrole with Chloroform and Sodium Ethoxide . 24 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Ring expansion reaction. CHCl3 / C2H5ONa POTASSIUM PYRROLE 3-CHLORO PYRIDINE

25. In presence of a strong base and Chloroform Pyrrole undergoes Reimer- Tiemann reaction to form Pyrrole-2-aldehyde . 25 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Reimer- Tiemann reaction. CHCl3 / KOH PYRROLE PYRROLE-2-ALDEHYDE INTERMIDIATE

26. Pyrrole ring structure opens and forms Succinaldehyde dioxime (addition product) on Refluxing with Ethanolic Hydroxylamine . 26 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Ring opening reaction. NH2OH / C2H5OH REFLUX PYRROLE SUCCINALDEHYDE DIOXIME

27. 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: 27 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Electrophilic aromatic substitution reaction.

28. 28 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Step-01) Generation of electrophile : ELECTROPHILE Step-02) Attachment of electrophile to the aromatic ring to form intermediate carbocation : PYRROLE ELECTROPHILE INTERMEDIATE CARBOCATION

29. 29 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Step-03) Elimination of proton from carbocation to form substitution product : INTERMEDIATE CARBOCATION SUBSTITUTION PRODUCT PROTON

30. 30 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY 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 :

31. 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. 31 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Continuous…..

32. 32 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY HNO3/(CH3CO)2O 10* NITRATION SO3, PYRIDINE,100*C SULPHONATION SO2Cl2 0*C CHLORINATION I2 / Aq. KI IODINATION (CH3CO)2O /SnCl4 200*c PYRROLE 2-NITRO PYRROLE 2-PYRROLE SULPHONIC ACID 2,3,4,5TETRACHLORO PYRROLE 2,3,4,5TETRA IODO PYRROLE 2-ACETYL PYRROLE

33. Medicinal uses/ Compounds. 33 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY Chemically procyclidine is α- cyclohexyl , α- phenyl-l- pyrrolidinepropanol . It is an anti- muscarinic drug used in the treatment of parkinsonism. The following medicinal compounds possess pyrrole heterocyclic ring system . PROCYCLIDINE

34. Anti- muscarionic Drugs are the agents that blocks the activity of muscarinic Acetylcholine receptors. Acetylcholine receptors are of two types :- Muscarinic receptors which responds to muscarin neurotransmitters. Nicotinic receptors which responds to nicotine. 34 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY PROCYCLIDINE Continuous…..

35. BIBLIOGRAPHY A text book of Heterocyclic Chemistry, Rama Rao . Heterocyclic Chemistry, J. A. Joule and K. Mills, 4 th Ed., Blackwell Publishing, 2005. Wikipedia, the free encyclopedia. (file:///G:/under%20cop/PYRROLE/Pyrrole.htm) Graphical Images from www.google.com/pyrrole. 35 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY

36. 36 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY ANY QUESTIONS ?

37. 37 SRINIVAS R. BHAIRY ORGANIC CHEMISTRY THANK YOU

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