14. Pyridine PDF

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Summary

Pyridine...

Description

PYRIDINE  

C5H5N Planar

Reactivity

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E- deficiency is greatest at posns 2,4,6

Electrophilic Substitution   

Pyridine is less reactive towards electrophilic substitution that benzene If substitution is ‘forced’, the ‘least unreactive’ posn is 3 (or 5) o So, electrophilic substitution is deactivated and meta directed Conditions for electrophilic substitution often require strong acid, which protonates N to give N+ o The intermediate would have two (+) charges!

Reactions at N   

High e- density at N o Due to lp in the sp2 orbital on N Behaves as base/nucleophile With no H-atoms on N, pyridine behaves as a 3o amine  reactions w/ electrophiles give N+ and forms salts with the counterion

Nucleophilic Catalysis

Nucleophilic Substitution

Substituent Modification  

Further substituted pyridines are accessible via modification of side-groups If a VERY powerful nucleophile is used, even the reluctant hydride (H -) can be displaced

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If the strong nucleophile phenyl lithium (Ph-Li) is used the intermediate can be detected or even isolated Warming or oxidation (e.g. O2) regenerates the aromatic ring Hydroxide (KOH) is not as strong a nucleophile, so requires vigorous conditions

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Hydroxypyridines and Pyridones

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Depending on exact solvent, the compound is in equilibrium with a zwitterion

Reactivity of pyridines

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Reacts w/ PCl5 or POCl3 Product: 2-chloro (can be substituted/removes by hydrogenation over Ni)

N-alkylpyridines  

Protonation of N reduces electrophilic substitution N-alkylated pyridine is more susceptible to nucleophilic substitution

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De-protonation is even easier for 4o salt – much weaker bases can be used

Reduction   

More easily reduced than benzene (more e- deficient than benzene) Birch reduction is analogous to benzene w/ an e- withdrawing group Pyridine is readily reduced by catalytic hydrogenation

Oxidation   

Less easily oxidised However, its lp reacts w/ peracids o Product: pyridine N-oxide Pyridine is regenerated by treatment w/ Ph3P or PCl3

Reactivity of N-oxides   

Re-visiting electrophilic substitution (again), the situation is now much better! There is again a (+) on the N (bad!) BUT, the new (+) resulting from attack of E + at C-4 can now be directly neutralised by the (-) on O

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N+ in N-oxides also facilitates nucleophilic substitution (see N-alkylpyridines ) So, an N-oxide allows access via electrophilic substitution, then nucleophilic substitution and/or functional group modification, to a much wider range of pyridines

Radical Reactions  

Reduced by Na/NH3/EtOH In aprotic solvent (THF) the intermediate radical-anion is not protonated and dimerization occurs

N-methylations gives paraquat

Reaction Sequence

Synthesis of Pyridine 

Often synthesised from acyclic precursors

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One of the most important routes is the Hantzch synthesis

Mechanism...