Heterocyclic chemistry six membered ring systems

Pyridine, Pyrimidine, Pyrazine, and Pyridazine - Structure, aromaticity, basicity, preparation methods, and reactions

1. Heterocyclic Chemistry Six membered ring systems Mr. C. Naresh Babu Assistant Professor Email: [email protected]

2. 2 Pyridine – Molecular Formula – C 5 H 5 N In pyridine all ring atoms (5 carbons and 1 nitrogen) are SP 2 hybridized. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP Pyridine is a six membered aromatic with one hetero atom, Nitrogen.

3. Two SP 2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The third SP 2 orbital on each carbon atom overlaps with an S orbital of hydrogen and forms C-H σ bonds . The third SP 2 orbital of nitrogen is occupied by the nitrogen lone pair of electrons. All σ bonds in pyridine lie in one plane and all bond angles are approximately equal to 120 . Each ring atom possesses one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds. Overlap of these p – orbitals produces delocalized π – molecular orbital containing 6 electrons. Structure & Aromaticity Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 3

4. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 4

5. Pyridine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule). The nitrogen lone pair is not released into the aromatic system because it is perpendicular to the  system. The nitrogen withdraws electrons by resonance, resulting in an electron-deficient ring system. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 5

6. Preparations By passing a mixture of acetylene and hydrogen cyanide through a red hot tube. 2. By dehydrogenation of Piperidine with concentrated H 2 SO 4 at 300 C or with nitrobenzene at 260 C. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 6

7. 3. By heating pyrrole with dichloro methane in the presence of sodium ethoxide . 4. By heating tetrahydro furfuryl alcohol with ammonia in the presence of aluminium oxide at 500 C . Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 7

8. Basic Character: Pyridine behaves as a base , it reacts with acid to form stable salts. Basic character of pyridine is due to the lone pair of electrons in SP 2 orbital (Not involved in delocalized π – molecular orbital ). So lone pair of electrons readily makes a bond with a proton and forms N-H bond. Pyridine is more basic than pyrrole because in pyrrole lone pair of electrons involved in delocalized π – molecular orbital and forms a part of aromatic sextet. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 8

9. Pyridine is less basic than aliphatic amines: In both Pyridine & aliphatic amines the lone pair of electrons on N are available for reaction. In case of aliphatic amines, the nitrogen is SP 3 hybridized where as in pyridine, nitrogen is SP 2 hybridized . The SP 2 hybridized nitrogen is more electronegative than SP 3 hybridized nitrogen. The lone pair of electrons held more towards electronegative SP 2 hybridized nitrogen and is relatively less available for reaction. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 9

10. 10 Characteristic reactions Electrophilic aromatic substitution at C-3 or C-5: 6-position 5 -position In pyridine Electrophilic substitution reactions takes place extremely at vigorous conditions in C-3 or C-5 positions. At this points more stable 3 resonance structures were possible. At C-2, 4 & 6 th positions give only 2 stable resonance structures. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP

11. 11 Pyridine is less reactive than benzene towards electrophilic substitution. Pyridine contains nitrogen atom it is more electronegative, so it lowers the electron density around the ring carbons. The usual electrophiles can co-ordinate with the lone pair of electrons on nitrogen to form resonance stabilized pyridinium salts. > Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP

12. 12 The pyridine nitrogen is a meta director: HgSO 4 Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP

13. Aluminium chloride and other lewis acid catalysts co-ordinate with the pair of electrons of nitrogen, friedel – craft reaction i.e., alkylation and acylation fails with the pyridine. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 13

14. 14 Pyridine is reactive toward nucleophilic aromatic substitution because of the presence of the electronegative nitrogen: Nucleophilic substitution Reactions: Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP

15. 15 Pyridine undergoes nucleophilic aromatic substitution at C-2, C-4 and C-6: Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP

16. 16 If the leaving groups at C-2 and C-4 are different , the incoming nucleophile will preferentially substitute for the weaker base: Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP

17. Reaction with sodamide (Chichibabin reaction): Pyridine reacts with sodamide at C-2 and gives 2-amino pyridine and sodium hydride. Sodium hydride formed is removed by reaction with liq. Ammonia to give back sodamide. Reaction with sodium hydroxide Pyridine reacts with sodium hydroxide at C-2 and gives 2-hydroxy pyridine and upon keto-enol tautomerism it forms keto form of 2-pyridone. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 17

18. Reaction with n-butyl lithium: Pyridine reacts with n-butyl lithium at C-2 and gives 2-(n-butyl) pyridine. Oxidation Like benzene pyridine is stable towards mild oxidizing agents. It does not react with chromic acid and nitric acid. However it may be oxidized by peracetic acid to give pyridine-N-oxide. 2-alkyl pyridine easily oxidized. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 18

19. Reduction Pyridine undergoes reduction with lithium aluminium hydroxide or hydrogen in the presence of nickel catalyst to form piperidine . Reaction with alkyl halides Pyridine reacts with alkyl halides to form N-alkyl pyridinium halide. Pyridine with methyl bromide yields crystalline N-methyl pyridinium bromide. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 19

20. 20 Diazotization of Aminopyridine Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP

21. Pyrazine all ring atoms (4 carbons & 2 nitrogens) are SP 2 hybridized. Two SP 2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The third SP 2 orbital on each carbon atom overlaps with an S orbital of hydrogen and forms C-H σ bonds . The third SP 2 orbital of two nitrogens is occupied by the nitrogen lone pair of electrons. All σ bonds in pyridine lie in one plane and all bond angles are approximately equal to 120 . Pyrazine - Structure & Aromaticity - Molecular Formula – C 4 H 4 N 2 Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP Pyrazine is a six membered aromatic ring system with two hetero atoms of Nitrogen at 1 st and 4 th positions. 21

22. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 22 Each ring atom possesses one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds. Overlap of these p – orbitals produces delocalized π – molecular orbital containing 6 electrons.

23. Pyrazine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule). The nitrogen lone pair is not released into the aromatic system because it is perpendicular to the  system. The nitrogen withdraws electrons by resonance, resulting in an electron-deficient ring system. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 23

24. Preparations From amino carbonyl compounds: Condensation of two molecules of α -amino carbonyl compounds followed by oxidation. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 24

25. 2 . From diamines: Pyrazine prepared by condensation of ethylene diamine and ethylene oxide followed by dehydrogenation. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 25

26. Basic Character: Pyrazine is a weak mono basic compound, since the available electrons of one nitrogen atom are shared with the other nitrogen atom. It gets protonated at N, Diprotonation is possible only in presence of strong acid. Basic character of pyrazine is due to the lone pair of electrons in SP 2 orbital (Not involved in delocalized π – molecular orbital ). So lone pair of electrons readily makes a bond with a proton and forms N-H bond. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 26

27. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 27 Characteristic reactions Electrophilic substitution reactions: Pyrazine is less reactive with electrophiles because of presence of two nitrogens, these atoms deactivate the ring. However presence of electron donating group at C-2 position, electrophilic substitution is possible. 2. Reaction of pyrazine with nucleophiles: Pyrazine undergoes reaction with nucleophilic reagent.

28. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 28 3. Reaction with oxidizing agents: Pyrazine is stable towards oxidizing agents, but presence of alkyl group at C-2 position it gets oxidized to carboxyl group. 4. Reduction: In the presence of Na/C 2 H 5 OH, pyrazine can be used to hexahydro pyrazine

29. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 29 5. Isomerization of Pyrazine: Pyrazine under photolytic conditions it gets isomerized to other diazine .

30. Pyrimidine all ring atoms (4 carbons & 2 nitrogens) are SP 2 hybridized. Two SP 2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The third SP 2 orbital on each carbon atom overlaps with an S orbital of hydrogen and forms 4 C-H σ bonds . The third SP 2 orbital of two nitrogens is occupied by the nitrogen lone pair of electrons. All σ bonds in pyridine lie in one plane and all bond angles are approximately equal to 120 . Pyrimidine - Structure & Aromaticity - Molecular Formula – C 4 H 4 N 2 Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP Pyrimidine is a six membered aromatic ring system with two hetero atoms of Nitrogen at 1 st and 3 rd positions. 30

31. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 31 Each ring atom possesses one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds. Overlap of these p – orbitals produces delocalized π – molecular orbital containing 6 electrons.

32. Pyrimidine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule). The nitrogen lone pair is not released into the aromatic system because it is perpendicular to the  system. The nitrogen withdraws electrons by resonance, resulting in an electron-deficient ring system. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 32

33. Preparations From alkyl pyrimidines: Alkyl pyrimidines on oxidation followed by decarboxylation gives pyrimidine. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 33 2. From chloro pyrimidines: Catalytic reductive dechlorination of 2,4-dichloro pyrimidine gives pyrimidine.

34. 3. From barbituric acid: Pyrimidine is synthesized from barbituric acid by the following steps. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 34

35. Basic Character: Pyrimidine is a weaker base than pyridine, because of electron withdrawing effect of the second nitrogen atom present in pyrimidine. Pyrimidine gets protonated in acidic medium. Presence of electron donating groups like alkyl, alkoxy enhance the basicity. Under normal conditions only one nitrogen of pyrimidine is protonated. But under strong acidic conditions both nitrogens are protonated to form deprotonated pyrimidine. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 35

36. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 36 Characteristic reactions Electrophilic substitution reactions: Pyrimidine is less reactive than pyridine due to two electron withdrawing groups towards electrophilic substitution. However presence of electron donating groups on ring, electrophilic substitution is possible at 5 th position ( the least electron-deficient ). Nitration, Sulphonation , Bromination , Formylation and azo coupling have been observed with substituted pyrimidines.

37. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 37

38. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 38 2. Nucleophilic Substitution reactions: Pyrimidine easily undergoes nucleophilic substitution. Nucleophilic attack takes place at 2,4 or 6 th positions. The amino group at C-2 or C-4 positions may conveniently replaced by hydroxyl group on heating with water. 3 . Nucleophilic Addition reactions: Pyrimidine undergo reaction with nucleophiles to form nucleophilic addition products.

39. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 39 4 . Reaction with oxidizing agents: Pyrimidine is oxidized slowly while alkyl substituted pyrimidines are oxidized readily to N-oxide with peroxy acids.

40. Pyridazine all ring atoms (4 carbons & 2 nitrogens) are SP 2 hybridized. Two SP 2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The third SP 2 orbital on each carbon atom overlaps with an S orbital of hydrogen and forms 4 C-H σ bonds . The third SP 2 orbital of two nitrogens is occupied by the nitrogen lone pair of electrons. All σ bonds in pyridine lie in one plane and all bond angles are approximately equal to 120 . Pyridazine - Structure & Aromaticity - Molecular Formula – C 4 H 4 N 2 Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP Pyridazine is a six membered aromatic ring system with two hetero atoms of Nitrogen at 1 st and 2 nd positions. 40

41. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 41 Each ring atom possesses one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds. Overlap of these p – orbitals produces delocalized π – molecular orbital containing 6 electrons.

42. Pyridazine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule). The nitrogen lone pair is not released into the aromatic system because it is perpendicular to the  system. The nitrogen withdraws electrons by resonance, resulting in an electron-deficient ring system. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 42

43. Preparations From 1,4-diketones: Pyridazines are prepared by reacting hydrazine hydrate with unsaturated 1,4-diketones. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 43 2. From maleic dialdehyde : Pyridazines are also prepared by reacting hydrazine hydrate with maleic dialdehyde .

44. Basic Character: Pyridazine is a weak base it reacts with strong acids to yield salts. The second nitrogen can not be protonated because it needs high energy to develop positive charge on the adjacent nitrogen atoms. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 44

45. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 45 Characteristic reactions Electrophilic substitution reactions: Pyridazine undergoes electrophilic substitution reactions only under drastic conditions because of electron withdrawing nature of nitrogen atoms. Hence, when activating groups are present in pyridazine ring then electrophilic substitution reactions are possible

46. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 46 2. Reaction with Nucleophilic reagents: The two nitrogen atoms present in pyridazine make all other carbon atoms (3,4,5 and 6) electron deficient. So, pyridazine is easily reacts with nucleophilic reagents. 3 . Reduction: Pyridazine upon reduction it gives hexahydro pyridazine

47. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 47 4 . Reaction with oxidizing agents: Pyridazine has been resistant towards oxidizing agents because of electron deficiency in the ring system. However peroxy benzoic acid is able to convert pyridazine to pyridazine oxide. 5. Hofmann’s reaction: Pyridazine undergoes reaction with one mole of methyl iodide to yield quarternary ammonium halide.

48. Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 48 6. Rearrangement: Substituted Pyridazine under UV irradiation rearrangement takes place.