1. Pharmaceutical Organic Chemistry By Dr. Mehnaz Kamal Assistant Professor Pharmaceutical Chemistry Prince Sattam Bin Abdulaziz University

2. Heterocyclic Chemistry

3. 1-To know types of six membered heterocyclic ring 2- To know sources of six membered heterocyclic compounds 3- To know syntheses of six membered heterocyclic compounds 4-To understand chemical reactions of six membered heterocyclic compounds

4. Six Membered Aromatic Heterocycles

5. Structure and Properties The aromatic sextet is complete without participating of the lone pair of nitrogen Molecular orbital The unshared electrons is in sp 2 orbital and in the same plane of the ring but other Six membered heterocyclic compounds (one N ) Pyridine

6. Pyridine important solvent & base (~ 3 o amine) Reactions: 1) Electrophilic substitution in pyridine Electrophilic aromatic substitution (much less reactive than benzene) Six membered heterocyclic compounds (one N )

7. Substitution takes place at meta position

8. Comparison between benzene and pyridine 1- Benzene symmetrical non-polar but pyridine polar It resist electrophilic substitution only in N-atom or at meta-position It is highly susceptible to neucleophilic substitution Pyridine is less active, than benzene toward electrophilic agents, because nitrogen is more electronegative, than carbon and acts like an electron withdrawing substituent, including the meta-directing effect. Six membered heterocyclic compounds (one N )

9. 2- It is basic compound [its basicity less than aliphatic amine] Six membered heterocyclic compounds (one N ) Comparison between benzene and pyridine

10. Like that of benzene, pyridine is resistant to oxidation, side chain can be oxidized Similarity Comparison between benzene and pyridine Six membered heterocyclic compounds (one N )

11. It is found in coal tar. αβ γ Oxidation of picolines yields the pyridine carboxylic acids. Six membered heterocyclic compounds (one N ) Sources of Pyridine

12. Six membered heterocyclic compounds (one N ) α  

13. The Nicotinic acid is a Vitamin. B. The Isonicotinic acid has been used in the form of its hydrazide in treatment of TB. Six membered heterocyclic compounds (one N )

14. Hantzsch pyridine synthesis Six membered heterocyclic compounds (one N ) Synthesis of Pyridine The Hantzsch pyridine synthesis typically uses a 2:1:1 mixture of a β-keto acid (often acetoacetate), an aldehyde (often formaldehyde), and ammonia or its salt as the nitrogen donor. First, a double hydrogenated pyridine is obtained, which is then oxidized to the corresponding pyridine derivative.

15. Reactions of Pyridine It undergoes both Nucleophilic substitution and Electrophilic substitution Six membered heterocyclic compounds (one N ) Pyridine behaves as both

16. A: Electrophilic Substitution S E Reaction types of Pyridine Pyridine resemble highly deactivated benzene derivatives It undergo nitration, sulfonation, and halogenation. only under very vigorous condition chiefly at the 3- position Six membered heterocyclic compounds (one N )

17. Why mainly at c-3 ? Six membered heterocyclic compounds (pyridine ) mainly at c-3 Reaction types of Pyridine A: Electrophilic Substitution S E elec. (+ ve) par

18. In contrast to benzene, Pyridine is very unreactive to S E reaction ? 1- due to electron withdrawing effect of N in the ring 2- the intermediate is destabilized by electro negativity effect of N 3- rapid formation of pyridinium cation …. So resist further S E reaction Six membered heterocyclic compounds (one N ) A: Electrophilic Substitution S E Reaction types of Pyridine

19. B: Nucleophilic Substitution S N Six membered heterocyclic compounds (pyridine ) Reaction types of Pyridine Nu. (- ve) Ortho or para

20. Example 1- Chichibabin Reaction Six membered heterocyclic compounds (one N ) Reaction of Pyridine

21. Example 2- Alkylation or Arylation Reaction by Organolithium compounds Six membered heterocyclic compounds (one N ) Reaction of Pyridine

22. C: Reaction at N-1 Alkylation Six membered heterocyclic compounds (one N) Reaction types of Pyridine electrophilic

23. C: Reaction at N-1 Acylation Six membered heterocyclic compounds (one N ) Reaction types of Pyridine

24. C: Reaction at N-1 Rx with peracids Rx with lewis acid Six membered heterocyclic compounds (one N ) Reaction types of Pyridine

25. Electrophilic ( Nitration) Six membered heterocyclic compounds (one N ) Reaction types of Pyridine

26. D: Oxidation and Reduction Reduction Oxidation As before oxidation of Picolines Six membered heterocyclic compounds (one N ) Reaction types of Pyridine

27. Six membered heterocyclic compounds with two N (Diazines) - -Found in folic acid & cigarette derivative. - Less basic than the other two Used only in research as building block for more complex comp. Three nucleobases found in nucleic acid cytosine, thyamine, uracil

28. DNA A________ T G________ C RNA A________ U G________ C Chemical properties of Pyrimidines in common with pyridine, as number of N-atoms in the ring increase the ring π- electrons become less energetic So S E gets more difficult while S N gets easier In DNA & RNA, these bases form H-bonds with their complementary Purines Six membered heterocyclic compounds with two N (Diazines)

29. Quinoline Benzo[b]pyridine 1-azanaphthaline Isoquinoline Benzo[c]pyridine 2-azanaphthaline Both Quinoline and Isoquinoline are weak bases. Both undergo SE more easly than pyridine in position 5 and 8 on benzoid ring. Like pyridine, N-ring of quinoline and isoquinoline undergo SN at α position Six membered heterocyclic compounds (pyridine ) Fused ring

30. Six membered heterocyclic compounds (pyridine ) Quinoline

31. Six membered heterocyclic compounds (pyridine ) Isoquinoline

32. Skraup Synthesis Six membered heterocyclic compounds (pyridine ) Synthesis of Quinoline 1- Dehydration of glycerol by hot H 2 SO 4 2- Nuecleophlic addition

33. Six membered heterocyclic compounds (pyridine ) Synthesis of Quinoline (Skraup Synthesis) 3- Elecetrophlic attack on aromatic ring by electron deficient Carbonyl carbon of protonated aldehyde 4- Oxidation by nitrobenzene

34. Six membered heterocyclic compounds (pyridine ) (Bischler Nepieralski Synthesis) Synthesis of Quinoline

35. Nitration Halogenation Sulfonation Electrophilic Substitution Six membered heterocyclic compounds (pyridine ) Reactions of Quinoline

36. Nucleophilic Substitution Amination Hydroxylation Alkylation Or Arylation with organo- metallic compounds Six membered heterocyclic compounds (pyridine ) Reactions of Quinoline

37. Oxidation & Reduction Reduction Oxidation Six membered heterocyclic compounds (pyridine ) Reactions of Quinoline

38. Fused Six membered heterocyclic compounds with more than one N Purines Contain pyrimidine fused to imidazole ring

39. Fused Six membered heterocyclic compounds with more than one N

40. Miscellaneous Dibenzothiazine or Thiodiphenylamine Drugs containing this nucleus used as antipsychotic and adrenergic blocker Fused Six membered heterocyclic compounds Hypnotic, Sedative, Anxiolytic, Anticonvulsant, Muscle relaxant Properties Diazepam/ Valium H.W find 2 drugs and draw their structures