Synthesis, reactivity, aromatic character and importance of Pyridine

Synthesis, reactivity, aromatic character and importance of 6-membered heterocycle containing one heteroatom - Pyridine

1. Synthesis, reactivity, aromatic character and importance of Pyridine Prepared by Dr. Krishna swamy Faculty DOS & R in Organic Chemistry Tumkur University

2. Pyridine is the simplest heterocycle of the azine type. It is derived from benzene by replacement of a CH group by a N-atom. From heat of combustion measurements, the aromatic stabilization energy of pyridine is 21 kcal/mole.

3. Nomenclature of heterocyclic rings will be done by three ways Common names Pyridine (2) Replacemnet nomenclature

4. (3) Hantzsch-Wideman nomenclature

5. Electron donating substituents will increase the basicity of a pyridine, and that substituents on the 2 and 4-positions will influence this basicity more than an equivalent 3-substituent.  Pyridine and its derivatives are weak bases ( pK a =5.2 ), reflecting the sp 2  hybridization of the nitrogen . Pyridine is aromatic with unshared electron pair is not part of the aromatic sextet.

6. Synthesis Hantzsch pyridine synthesis Condensation approaches From other heterocyclic ring systems

7. Hantzsch pyridine synthesis It is a four component reaction between 2 equivalents of keto esters, 1 equivalent of aldehyde and ammonia results in reduced pyridines which upon oxidation (or) dehydrogenation gives the corresponding pyridines.

8. Hantzsch pyridine synthesis involves the following mechanisms Aldol condensation of aldehyde with β - keto ester

9. Michael addition of β - keto ester with enone Addition of ammonia to form imine or enamine followed by cyclization

10. Dehydrogenation of dihydropyridine gives the corresponding pyridines

11. Dihydropyridine intermediates prepared from aromatic aldehydes are calcium blocking agents and therefore valuables drugs for heart disease.

12. Condensation approaches to prepare pyridines Condensation of 1,5 diones followed by oxidation Condensation of 1,5 diones with hydroxylamine instead ammonia avoids oxidation step

13. Synthesis from 1,3 dicarbonyls and 3-aminoenones From other heterocyclic ring systems Ciamician-Dennstedt Rearrangement

14. Reactions of pyridines Pyridine undergoes reaction at Nitrogen as well as at Carbon Reaction at C is usually difficult and slow than at N

15. Reactions at Nitrogen Electrophilic addition at Nitrogen Lone pair of electrons on the ring nitrogen undergoes electrophilic addition reaction with electrophiles such as protonation , nitration, alkylation and acylation . Pyridine reacts as a base or a nucleophile and forms a pyridinium cation in which the aromatic sextet is retained and the nitrogen acquires a formal positive charge. BOTH ARE AROMATIC

16. Protonation at Nitrogen Pyridine nitrogen form salt with most protic acids. Acid chlorides react rapidly with pyridines generating 1-acyl-pyridinium salts in solution. Acylation at Nitrogen

17. Alkyl halides react readily with pyridines giving quaternary pyridinium salts. Alkylation at Nitrogen Reaction of pyridines with nitronium salts such as nitronium tetrafluoroborate leads to nitration at nitrogen. Protic nitrating agents such as HNO 3 leads to N- protonation . Nitration at Nitrogen

18. Electrophilic substitution of pyridines at a carbon is very difficult. Two factors seem to be responsible for this unreactivity : Pyridine ring is less nucleophilic than the benzene ring because nitrogen atom is more electronegative than carbon atoms and therefore it pulls electrons away from the carbon atoms inductively leaving a partial positive charge on the carbon atoms . When pyridine compound is exposed to an acidic medium, it forms pyridinium salt. This increases resistance to electrophilic attack since the reaction will lead to doubly positive charged species . Hence pyridine is bad at electrophilic aromatic substitution but under drastic condition pyridine ring reacts with electrophile only at 3 rd position. Reactions at Carbon

19. The positive charge residing on an electronegative element with sextet configuration is unfavoured. The positive charge residing on an electronegative element with sextet configuration is unfavoured. In pyridine, β substitution is favoured but the reaction is slower than that of benzene Electrophilic aromatic substitution at carbon

20. Nitration of Pyridine Sulfonation of Pyridine Electrophilic aromatic substitution at carbon

21. Nucleophilic substitution is easy with pyridines Nitrogen atom makes pyridines more reactive towards nucleophilic substitution, particularly at the 2- and 4-positions. Nitrogen acts as electron sink hence favoured Nitrogen acts as electron sink hence favoured

22. Nucleophilic substituents favoured by electron-withdrawing substituents that are also good leaving groups. The position of the leaving group influences reaction rate i.e. Nucleophilic aromatic substitution

23. Nucleophilic substitution also occurs through Pyridyne intermediate similar to benzyne and are very reactive not isolable. Pyridyne Pyridyne formation

24. Halogenopyridines can undergo metal-halogen exchange when treated with butyllithium . Metal-halogen exchange The lithium derivatives then behave in a similar manner to arylithiums and Grignard reagents and react with electrophiles such as aldehydes, ketones and nitriles . Lithium derivative of pyridine reaction with ketones

25. Lithium derivative of pyridine reaction with nitriles

26. Deprotonation of alkyl pyridines Deprotonation of alkyl pyridines occurs in presence of strong base and deprotonation occurs only with alkyl groups at α and γ position not with β position.

27. If the pyridine ring attached to alkene then conjugate addition occurs.

28. Pyridine undergoes nucleophilic reaction with hydrides and the reaction with Li/NaNH 2 is referred to as the Chichibabin reaction. Chichibabin reaction

29. Nicotine is pharmacologically active constituent of tobacco –toxic and addictive Isoniazide has been an important agent to treat tuberculosis Bioactive Pyridines