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6-Membered Aromatic Heterocycles

Containing one

Heteroatom

88

Pyridines

Pyridine is the simplest heterocycle of theazine type. It is derived from benzene byreplacement of a CH group by a N-atom.

89

The structure of pyridine is completely analogous to that ofbenzene, being related by replacement of CH by N.

The key differences are:

I. The departure from perfectly regular hexagonalgeometry caused by the presence of the hetero atom, inparticular the shorter carbon-nitrogen bonds,

II. The replacement of a hydrogen in the plane of the ringwith an unshaired electron pair, likewise in the plane ofthe ring, located in an sp2 hybrid orbital, and not at allinvolved in the aromatic p-electron sextet; it is thisnitrogen lone pair which is responsible for the basicproperties of pyridines, and

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III.A strong permanent dipole, traceable to thegreater electronegativity of the nitrogencompared with carbon.

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I. The heteroatom make pyridines very unreactiveto normal electrophilic aromatic substitutionreactions. Conversely pyridines are susceptible tonucleophilic attack. Pyridines undergoelectrophilic substitution reactions (SEAr) morereluctantly but nucleophilic substitution (SNAr)more readily than benzene.

II. Electrophilic reagents attack preferably at the N-atom and at the b-C-atoms, while nucleophilicreagents prefer the a- and c-C-atoms.

The following reactions can be predicted forpyridines on the basis of their electronic structure:

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In reactions which involve bond formation using thelone pair of electrons on the ring nitrogen, such asprotonation and quaternisation, pyridines behave justlike tertiary aliphatic or aromatic amines.

Electrophilic Addition at Nitrogen

Reactions of Pyridine

When a pyridine reacts as abase or a nucleophile itforms a pyridinium cation inwhich the aromatic sextet isretained and the nitrogenacquires a formal positivecharge.

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Protonation at Nitrogen

Nitration at Nitrogen

Pyridines form crystalline,frequently hygroscopic,salts with most protic acids.

This occurs readily byreaction of pyridineswith nitronium salts,such as nitroniumtetrafluoroborate.

Protic nitrating agents such as nitric acid of courselead exclusively to N-protonation.

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Acid chlorides and arylsulfonic acids react rapidlywith pyridines generating 1-acyl- and 1-arylsulfonylpyridinium salts in solution.

Acylation at nitrogen

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Alkylation at nitrogenAlkyl halides and sulfates react readily with pyridinesgiving quaternary pyridinium salts.

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Electrophilic substitution at Carbon atoms of the pyridine ring

Electrophilic substitution of pyridines at a carbon isvery difficult. Two factors seem to be responsible forthis unreactivity:I. Pyridine ring is less nucleophilic than the benzene

ring; nitrogen ring atom is more electronegativethan carbon atoms and therefore it pulls electronsaway from the carbon atoms inductively leaving apartial plus on the carbon atoms.

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II. When pyridine compound is exposed to an acidicmedium, it forms pyridinium salt. This increasesresistance to electrophilic attack since the reactionwill lead to doubly positive charged species.

Less reactive than pyridine

98

When an electrophile attacks the pyridine ring, onlyposition 3 is attacked.

Hint: draw resonance structures that result fromelectrophilic attack at various positions. The positivecharge residing on an electronegative element withsextet configuration is unfavoured.

Why?

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For example, 3-bromopyridine is formed whenpyridine is reacted with bromine in the presence ofoleum (sulfur trioxide in conc. sulfuric acid) at 130°C.

100

N

SO3

H

Br

Br

Mechanism of bromination of pyridine

101

Pyridine can be activated to electrophilicsubstitution by conversion to pyridine-N-oxides.

A series of preparatively interesting reactions onpyridine can be carried out by means of pyridine N-oxides such as the introduction of certain functionsinto the ring and side-chain which cannot beachieved in the parent system by direct methods.

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The activating oxygen atom can be removed byreacting the pyridine N-oxide withphosphorous trichloride.

103

In such reactions there is a balance between electronwithdrawal, caused by the inductive effect of the oxygenatom, and electron release through resonance from thesame atom in the opposite direction. Here, the resonanceeffect is more important, and electrophiles react at C-2(6)and C-4.

N

O

2

34

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Thionyl chloride, for example, gives a mixture of 2-and 4-chloropyridine N-oxides in which the 4-isomeris predominant.

PCl3

N Cl N+

Cl

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However, pyridine N-oxide reacts with aceticanhydride first to give 1-acetoxypyridinium acetateand then, on heating, to yield 2-acetoxypyridinethrough an addition-elimination process.

N

O

2

34

O

O

O

N O

O

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When a similar reaction is carried out upon the 2,3-dimethyl analogue, the acetoxy group rearrangesfrom N-1 to the C-2 methyl group, at 1800C, to form2-acetoxymethyl-3-methylpyridine.

N

O

O

O

O

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H2 Pd/EtOH

N

NH2

108

NH

H

NH

H

Resonance stabilized

Anion Chemistry of Pyridine

Works for 2(6)- and 4-alkylpyridines not for 3(5)-alkylpyridines, why?

The negative chargegenerated on thecarbon goes to theelectronegativenitrogen, which canbetter accommodateit.

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110

R Br

NR

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Another approach to electrophilic substitutioninvolves the chemistry of 2-pyridone and 4-Pyridones which are obtained from the diazotizationof the corresponding 2-aminopyridine and 4-aminopyridines, respectively.

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Both pyridones can react with electrophiles at positionsortho and para to the activating oxygen atom. Reaction withphosphorous oxychloride gives chloropyridines.

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Nucleophilic substituition of pyridine

a) X=Hb) X=Good leaving group

X=H, Substitution with “hydride” transfer

Nu: NaNH2 - aminationNu: BuLi, PhLi etc - alkylation / arylationNu: NaOH - “hydroxylation”

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At high temperature the intermediate anion canaromatize by loss of a hydride ion, eventhough, it is apoor leaving group.

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b) X=LG, The nucleophilic substitution is much morefacile when good leaving group such as X:Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR, areemployed.

116

117

-H: is a bad leaving group

N

Cl

Nu

SLOW

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N X

N SPhN OMe

N NN NH2

Ph

Me

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Halogenopyridines can undergo metal-halogenexchange when treated with butyllithium. Thelithium derivatives then behave in a similar mannerto arylithiums and Grignard reagents and react withelectrophiles such as aldehydes, ketones and nitriles.

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NaOMe

MeOH N

O

NOO

OMe

- NO2

N

O

OMe

121