Unit 4 Pyridine

Pharmaceutical Organic Chemistry 3 IV SEM

1. Unit 4
Pyridine
Lecture by
SowmiyaPerinbaraj, M.Pharm
Assistant Professor
Dept of Pharmaceutical Chemistry
SVCP

2. Pyridine
❖PyridinealsocalledasAzabenzeneorAzine.
❖Pyridineisanunsaturatedsixnumberedheterocyclic
ringconsistsofnitrogenasheteroatom.
❖Itpossessplanarconjugatedringstructureconsistsof
sixdelocalizedπ-electrons.
❖Thearomaticnaturearisesfromthethreedoublebonds
presentintheringassixdelocalizedπ–electrons.
❖SoitfollowsHuckel’sruleandhenceitisaromatic
compound.

3. Pyridine
❖Molecularformula:C
5H
5N
1
❖Itiscolourlessliquidwithboiling
point115°C
❖Ithascharacteristicunpleasant
odour.
❖Nitrogenhavealonepairof
electrons,whichisavailablefor
protonation.
❖Thuspyridinebehavesasatertiary
base.

4. Synthesis
1.Hantzschsynthesis
▪Itinvolvescondensationofanaldehydewithtwomolesofa
dicarbonylcompoundorβ-ketoestersandammonia.

5. Synthesis
2. Guareschisynthesis
▪Itinvolvestreatingacyanoacetamidewithadiketone(acetoacetic
ester)yieldpyridonewhichconvertedintopyridine.
➔

6. Synthesis
3. From acetylene
▪Bypassingamixtureofacetyleneandhydrogencyanide
througharedhottube.

7. Synthesis
4. From aldehydes or ketones and ammonia
▪Aldehydesorketonesonreactionwithammoniaunder
suitableconditionssuchashightemperatureandpressure
givespyridine.

8. Synthesis
5.Frompentamethylenediaminehydrochloride
▪Pentamethylenediaminehydrochlorideonheatingaffords
piperidinewhichontreatmentwithacidcatalystgives
pyridine.

9. Synthesis
6.FromFurans
2-furylketonesgive3-hydroxy-2-alkylpyridineswhenheatedwith
ammonia.
▪Byheatingtetrahydrofurfurylalcoholwithammoniainthepresence
ofaluminiumoxideat500°C

10. Synthesis
7.FromPyrrole
▪Pyrroleonheatingwithdichloromethaneinpresenceof
sodiumethoxidegivespyridine.

11. Synthesis
8.FromPicolines
▪Picolineonoxidationwithpotassiumdichromateand
sulphuricacidyieldsNicotinicacidwhichon
decarboxylationwithcalciumoxideaffordspyridine.

12. Synthesis
9.FromPiperidine
▪Bydehydrogenationofpiperidinewithconcentrated
sulphuricacidat300°Cornitrobenzeneat260°Cgives
pyridine.

13. Reactions
1.Electrophilicsubstitution
▪Pyridineisconsiderablylessreactivethanbenzenetowards
electrophilicsubstitution.Because
i.Thenitrogenatominpyridine,becauseofitselectronegativity
lowerstheelectrondensityaroundtheringcarbons.
ii.Theusualelectrophilescancoordinatewiththelonepairof
electronsonnitrogentoformresonancestabilizedpyridinium
salts.

14. Reactions
1.Electrophilicsubstitution
▪Pyridine,howeverdoesundergoelectrophilicsubstitutionreactions
whenextremelyvigorousreactionconditionsareused.
▪SubstitutionoccursalmostexclusivelyatC-3position.

15. Reactions
1.Electrophilicsubstitution

16. 1. Electrophilic substitution
i.Nitration:Pyridineundergoesnitrationwithpotassiumnitrateinthe
presenceofsulphuricacidat300°Ctoyield3-nitropyridine.
ii.Sulfonation:Itundergoessulfonationwithfumingsulphuricacid
inthepresenceofmercuricsulphatetogivepyridine-3-sulphonicacid.

17. 1. Electrophilic substitution
iii.Bromination
Itmaybebrominatedbypassingthevaporsofpyridineand
bromineovercharcoalcatalysttoyield3-bromopyridine
and3,5-dibromopyridine.

18. 2. Nucleophilic substitution
➢Pyridineundergoesnucleophilicsubstitutionreactions
becausethesameelectronegativitythatmakespyridine
unreactivetowardselectrophilicsubstitutionmakesit
highlyreactivetowardsnucleophilicsubstitution.
➢SubstitutionoccursalmostexclusivelyatC-2orC-4
positionifC-2isblocked.

20. 2. Nucleophilic substitution
i.Chichibabinreaction
❖Pyridinereactswithsodamideinliquidammoniaat
about100°Ctoform2-aminopyridine.

21. 2. Nucleophilic substitution
ii.ReactionwithSodiumhydroxide
❖Pyridinereactswithsodiumhydroxideatabout300°Cto
yieldanequilibriummixtureof2-hydroxypyridineand2-
pyridine.
❖Thereactioniscarriedoutinthepresenceofoxygen.

22. 2. Nucleophilic substitution
iii.Reactionwithn-butyllithium
❖Pyridinereactswithn-butyllithiumatabout100°Ctogive
2-n-butylpyridine.

23. Reaction
3.Oxidation
❖Pyridineisquitestabletowardsmildoxidizingagents.
❖Itdoesnotreactwithchromicacidornitricacid.
❖However,itmaybeoxidizedbyperaceticacidtogive
pyridine-N-oxide.

24. Reactions
4.Reduction
❖Pyridineundergoesreductionwithlithiumaluminium
hydride(LiAlH
4)orhydrogeninthepresenceofnickel
catalysttoformpiperidine.

25. Reaction
5.ReactionwithAlkylHalides
❖PyridinereactswithalkylhalidestoformN-alkyl-
pyridiniumhalides.
❖withmethylbromideityieldscrystallineN-
methylpyridiniumbromide.

26. Basicity of Pyridine
✓Pyridinebehavesasabase(pKa=5.2)
✓Itreactswithacidtoformfairlystablesalts.
✓Thereasonforthebasiccharacterofpyridineisthatthe
nitrogenlonepairofelectronsbeinginSp
2
hybridorbitalis
notinvolvedintheformationofthedelocalizedπ
molecularorbital.
✓ItisreadilyavailablefortheformationofanewN-Hbond
withproton.

27. Basicity of Pyridine
I) Pyridine is more basic than Pyrrole
✓Pyridineisastrongerbasethanpyrrole(oraniline)in
whichthebasicityisreducedbydelocalizationofthe
nitrogenlonepair.
✓Pyridine➔Ndoesnotinvolvedintheresonanceand
thoselonepairofelectronsarereadilyavailablefor
reactions.
✓Pyrrole➔Ninvolvedintheresonance(delocalization)
andthoselonepairofelectronsarenotreadilyavailable
forreactions.

28. Basicity of Pyridine
II) Pyridine is less basic than
aliphatic amines
✓Pyridineisaconsiderablyweakerbase
thantrimethylamine(aliphatictertiary
amine).
✓Thisisprobablyduetothedifferenceinthe
natureofhybridorbitalscontainingthe
nitrogenlonepairinthetwomolecules.
✓Pyridine➔sp
2
orbital(smaller)➔mores
character➔moreelectronegative
✓Trimethylamine➔sp
3
orbital➔lesss
character➔lesselectronegative

29. Basicity of Pyridine
II) Pyridine is less basic than aliphatic amines
✓Thismeansthatthelonepairofelectronsonnitrogenin
pyridineismorecloselyassociatedwiththenitrogen
nucleus.
✓Itistherefore,lessavailablefortheformationofabond
withproton(reactions)andconsequentlytherelative
basicityisreduced.

30. Medicinal Uses
1.Isoniazid and Ethionamide
•They are used to treat tuberculosis (TB) infections

31. Medicinal Uses
2. Pyridostigmine
•Anticholinesterase inhibitor used to treat the symptoms of
Myasthenia gravis (neuromuscular disorder that causes weakness
in the skeletal muscles)

32. Medicinal Uses
3. Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole
•They are proton pump inhibitors used to prevent and treat
ulcer conditions.

33. Medicinal Uses
4. Sulphapyridine, Sulphasalazine
▪It is used to treat bacterial infections.

34. Medicinal Uses
5. Pyridoxine
▪Pyridoxine (vitamin B6) is used to maintain the health of
nerves, skin and red blood cells.