Aromatic Heterocyclic

Compounds
Reactions and Synthesis
1- Pyridine
a) Reactions of pyridine
• In pyridine we have a stable imine—stable because of its aromaticity.
• All imines are less basic than saturated amines.
• Pyridine is a weak base with a pKa (for its conjugate acid) of 5.5.
• Pyridinium ion is about as strong an acid as a carboxylic acid.
• The lone pair of electrons on N are not part of the ring aromatic electrons and are readily donated
for electrophiles.
• Pyridine is an electron-deficient aromatic azine system.
• Electrophiles attack preferably at the N-atom.
• The ring-C-atoms can also react by EAS reactions.
• Nucleophiles attack occur at the ring carbons and undergo NAS reactions.
1) Electrophilic reactions at nitrogen:
Pyridine is a very unreactive aromatic imine

Pyridine is nucleophilic at the nitrogen atom because the lone pair of electrons on nitrogen
cannot be delocalized around the ring. They are in sp2 orbital orthogonal to the p orbitals in
the ring and there is no interaction between orthogonal orbitals.

a) Reaction with Lewis acids :

Lewis acid (L) such as AlCl3, SbCl5 form stable N-adducts of type 1 with pyridine.
The chlorochromate (2, X = CrO3Cl) and the dichromate (2, X = Cr2O7/2) used as oxidants.
b) Protonation of Nitrogen
• Pyridine, with pKa 5.5 in water, is a much weaker base than saturated aliphatic amines.
• The presence of electron donating groups generally increase the basic strength ( Table 1)
• The increased basicities of substituted pyridines can be explained by resonance effect as
well as inductive effect of substituent on pyridine ring.
• For example 2–methoxypyridine is a weaker than 4-methoxypyridine which is a stronger
base than pyridine; the effect of inductive withdrawal of electrons by the electronegative
oxygen is felt more strongly when it is closer to the nitrogen, i.e. at C - 2.

Table 1
Compound pKa
Pyridine 5.5
2-Methylpyridine 5.97
3-Methylpyridine 5.68
4-Methylpyridine 6.02
2-Methoxypyridine 3.3
4-Methoxypyridine 6.6
3-Chloropyridine 2.8
c) Alkylation and Acylation
Pyridine reacts with acyl chlorides, or acid anhydrides, to form N-acylpyridinium
salts, which are readily hydrolysed.

Alkyl halides and related alkylating agents react with pyridines to form N-alkylpyridinium
salts. These compounds are much more stable than their N-acylpyridinium equivalents
and can often be isolated as crystalline solids,
d) Oxidation of Nitrogen

Pyridine N-oxides are frequently used in place of pyridines to facilitate electrophilic substitution.
Pyridines react smoothly with percarboxylic acids (e.g. hydrogen peroxide in acetic acid, forming peracetic
acid in situ, orrn-chloroperbenzoic acid, MCPBA) to give N – oxides:

e) Sulfonation of Nitrogen
Pyridine reacts with sulfur trioxide (SO3) to give the crystalline, zwitterionic pyridinium-1-sulfonate, usually known as
the pyridine sulfur trioxide complex. This compound is hydrolysed in hot water to sulfuric acid and pyridine.
 N - oxide chemistry
• The structure of N - oxides means that they are both more susceptible to electrophilic
substitution and react more easily with nucleophiles .
• Note that, the formally negatively charged oxygen can release electrons to stabilize an
intermediate for electrophilic attack.

• The positively charged ring nitrogen can act as an electron sink to encourage nucleophilic addition.
f) Halogenation at Nitrogen
• Pyridines react easily with halogens and inter - halogens to give crystalline compounds, largely
undissociated when dissolved in solvents such as carbon tetrachloride. Structurally they are best
formulated as resonance hybrids related to trihalide anions.
• 1 - Fluoropyridinium triflate is also crystalline and serves as an electrophilic fluorinating agent.

The stable pyridinum tribromide is commercially available salt can be used as a source of molecular
bromine, especially where small accurately known quantities are required.
2) Electrophilic substitution reactions at C

Pyridine is bad at electrophilic aromatic substitution

•EAS reactions of pyridine proceed much more slowly than those of benzene; they usually require
drastic conditions and occur exclusively at the 3-position.
•The relative reactivity of pyridine is comparable to that of nitrobenzene in EAS reactions operating in
strongly acidic medium.
•Electron donating substituents, increase the reactivity of the pyridine system.
•The nitrogen atom destabilizes the cationic intermediate, especially when it can be delocalized onto
nitrogen.
How electrophilic substitution of pyridine occurs?
• It is a two step mechanism that resembles same steps in EAS reactions of benzene. In all cases,
the electrophile should be prepared in situ, then
• 1st step: Addition of electrophile, electrophile attacks the aromatic ring, then
• 2nd step: Elimination of a good leaving group (usually H+) to restore the aromatic system.
• Remember that EAS of pyridine is very difficult, due to the reasons shown below:
Comparison of the σ-complexes resulting from the addition of electrophiles to the 2-, 3-, and 4-positions in
pyridine shows that only electrophilic attack at the 3-position avoids participation of energy-rich nitrenium
forms, which destabilize σ-complexes 9/11 relative to 10.
EAS of pyridine is very difficult, due to the following reasons :

• Once pyridine is exposed to an electrophile (E+), it is converted to pyridinium cation (highly

unreactive, more electron deficient than pyridine to word E+ attack). Concentration of
neutral pyridine will be very low
• The carbons of a pyridine are even more electron poor especially at α - and γ – positions
(formation of the intermediate between a pyridine and an electrophile is disfavored) .

• The best option for electrophilic attack is β - position – (Justify why? Draw all
possible resonance structures)
Effect of substituents on reactivity of pyridine towards EAS reactions
• Substituents effect is similar to that observed for benzene, depending on the type of substituent.
• Electron withdrawing groups (EWG): are deactivating groups, EAS becomes more difficult as compared to
neutral pyridine.
• Electron donating groups (EDG): these are activating groups (examples: -NH2 or substituted amine, -OR, -R).
These substituents activate pyridine ring towards EAS reactions. even in the protonated heterocycle (via a
dicationic intermediate:Write the structure of the dicationic intermediate).
• Halogen substituents: halogens have a base - weakening effect (EWD) & are only weakly deactivating. Halogens
can allow substitution to take place in a different way – by allowing an appreciably larger concentration of the
free neutral pyridine to be present (Write how this can be done?).
a) Nitration
• Treatment of pyridine with the usual mixture of HNO3 and H2SO4 mainly protonates the nitrogen
atom. Pyridine itself is not very reactive towards electrophiles: the pyridinium ion is totally
unreactive.

• Unsubtituted Pyridine can be converted into 3-nitropyridine only inefficiently by direct nitration,
even with extremely vigorous conditions.

• Ring activating groups facilitate electrophilic substitution sufficiently to allow nitration.

b) Sulfonation
• Pyridine is very resistant to sulfonation using concentrated sulfuric acid or oleum, only very low
yields of the 3 - sulfonic acid being produced after prolonged reaction periods at 320 ° C.
• sulfonation of pyridine with fuming sulfuric acid at 250 °C with Hg(II) catalysis leads to the pyridine-
3-sulfonic acid.
• The effect of the Hg(II) in this reaction is attributed to N-coordination and suppression of the
strongly deactivating N-protonation.
c) Halogenation
• Halogenation of pyridine occurs with elemental chlorine or bromine at high temperature.
• 3-Halo- and 3,5-dihalopyridines are formed at about 300 ◦C as a result of an EAS process

• 3-Bromopyridine is produced in good yield by the action of bromine in oleum (fuming sulfuric
acid). The process is thought to involve pyridinium-1-sulfonate as the reactive species, since no
bromination occurs in 95% sulfuric acid.
• 3 - Chloropyridine can be produced by chlorination at 200° C, or at 100 °C in the presence of
aluminium chloride (AlCl3).
d) Friedel–Crafts acylation's

• It require Lewis acids and these react at nitrogen.

• Pyridine is a good ligand for metals such as Al(III) or Sn(IV) and, once again, the complex with its
cationic nitrogen is completely unreactive towards electrophiles.
Pyridine N-oxides are reactive towards both electrophilic and nucleophilic substitution

Because the nitrogen atom is nucleophilic,

pyridine can be oxidized to pyridine N-oxide
with reagents such as m-CPBA or just H2O2 in
acetic acid.

These N-oxides are stable dipolar species with the electrons on oxygen delocalized round the pyridine ring.
Reaction with electrophiles occurs at the 2-(ortho) and 4-(para) positions, chiefly at the 4-position to keep
away from positively charged nitrogen.
Pyridine-N-oxides and their reactions

Pyridine-N-oxide undergoes electrophilic and nucleophilic substitution reactions at the 2- and 4-positions,
as predicted from its resonance description

Now the oxide must be removed and best way with trivalent
phosphorus compounds such as (MeO)3P or PCl3.
The phosphorus atom detaches the oxygen atom in
a single step to form the very stable P=O double bond.
In this reaction the phosphorus atom is acting as both
a nucleophile and an electrophile.
3) Reactions with Nucleophilic Reagents
• Pyridine is very reactive towards nucleophiles than benzene it resembles benzene having
strong EWG due to the withdrawing effect of the electronegative N atom .

• As appeared from the resonance structures of pyridine positions 2, 4 and 6 carry partial
positive charges thus nucleophilic substitution proceeds readily at the 2-position followed
by 4-position but not at the 3-position.

• Nucleophilic substitution of hydrogen has to involve a hydride transfer, which needs the
presence of an oxidizing agent as hydride acceptor.

• Nucleophilic substitution of an atom or group at an 2 - or 4 - position, that is a good leaving

group, is, however, usually an easy and straightforward process.
The attack at positions 2, 4 or 6 results in resonance structure in which the -ve charge is delocalized at N thus it
is more preferred while attack at position 3 or 5 results in resonance structures in which the -ve charge is
delocalized over C only.
(a) Halogenopyridines

• Halogenopyridines undergo displacement reactions with a large number of N-, O-,S-, and C-nucleophiles.
• It occur preferentially in positions 2 and 4,less readily in 3-position.
• With 2- and 4-halogenopyridines, the SNAr process follows an addition/elimination mechanism

• The intermediate anion is stabilized by electronegative nitrogen and by delocalization round the ring.
• These reactions have some similarity to nucleophilic aromatic substitution but are more similar to
carbonyl reactions. The intermediate anion is a tetrahedral intermediate that loses the best leaving
group to regenerate the stable aromatic system.
 Nucleophiles such as amines or thiolate anions suitable for these reactions.

With 3-halogenopyridines, nucleophilic substitution takes place by an benzyne mechanism.

Nucleophilic substitution is more facile with good leaving group mainly Halogen, other good
leaving group such as OSO2R, NO2, OR can be replaced by NAS.
Substitution of a 2-ethoxypyridine allows the synthesis of flupirtine.
b) Amination of pyridine

Pyridines are capable of utilizing hydride as leaving groups in SNAr processes, for example, in the
Chichibabin reaction.

The Chichibabin reaction involves reaction of pyridine with NaNH2 (in toluene or N,N-dimethylaniline)
and leads regioselectively to 2-aminopyridine(s), for example

The ‘hydride’ transfer and production of hydrogen involve interaction of amino - pyridine
product, acting as an acid, with the anionic intermediate. The preference for α - substitution
may be associated with an intramolecular delivery of the nucleophile, guided by complexation
of ring nitrogen with metal cation.
4) Reactions with Oxidizing Agents

• The pyridine ring is generally resistant to oxidizing agents, vigorous conditions

being required for its breakdown, thus pyridine itself is oxidized by neutral
aqueous potassium permanganate at about the same rate as benzene (sealed
tube, 100 ° C), to give carbon dioxide.
• In acidic solution, pyridine is more resistant, but in alkaline media more rapidly
oxidized, than benzene.
• In most situations, carbon substituents can be oxidized with survival of the ring,
thus alkyl - pyridines can be converted into pyridine carboxylic acids with a variety
of reagents.
• Some selectivity can be achieved: only α - and γ - groups are attacked by selenium
dioxide; the oxidation can be stopped at the aldehyde oxidation level.