Reactions of Heterocycles
Reactions of Pyrrole, Furan and Thiophene
(i) Electrophilic Substitution Reactions: Pyrrole, furan and thiophene undergo electrophilic substitution reactions like nitration, sulphonation, halogenation etc. characteristic of aromatic rings. It has already been described in Sec. 1.1 that carbons in 5-membered heterocyclic rings have higher electron density compared to benzene and hence undergo electrophilic substitution more readily than benzene (eq. 28). The electrophilic substitution takes place preferentially at 2-position (C-2).
The attack of an electrophile on pyrrole, for example, will lead to formation of 2- and 3-substitution products by way of carbocations XXXI and XXXII, respectively (Fig. 12). The substitution occurs preferably at C-2 position because the
intermediate obtained by attack at this position is more stable than the intermediate obtained by attack at C-3. The positive charge in intermediate XXXI is more delocalized than intermediate XXXII and hence is more stable and preferred intermediate.
The electrophilic substitution at C-2 in furan and thiophene can also be accounted in the same manner. Furan is not as reactive as pyrrole in electrophilic substitution reactions because the oxygen in furan is more electronegative than nitrogen in pyrrole and therefore does not enhance the electron density of carbons as much as pyrrole. Thiophene is less reactive than furan towards electrophilic substitution because the p-electrons of sulphur are in 3p orbital which overlaps less effectively than the 2p orbital of nitrogen or oxygen with 2p orbitals of carbon. The relative reactivities towards electrophilic substitution follows the order:
Some typical examples of electrophilic substitution of pyrrole, furan and thiophene are given below (Fig. 12).
Both the Mannich reaction (reaction with Me2NH, H2CO and H+) and azo coupling fail with furan, showing its lower reactivity compared with pyrrole.
(ii) Reduction: Pyrrole, furan and thiophene can be reduced to pyrrolidine (eq. 29), tetrahydrofuran (eq. 30) and tetrahydrothiophene (eq. 31), respectively by catalytic hydrogenation.
(iii) Diels-Alder Reaction: Furan is least aromatic of the three heterocycles and therefore behaves as a diene in a number of Diels-Alder reactions (eq. 32).
Pyrrole and thiophene do not undergo Diels-Alder reactions. However, N-carbomethoxy pyrrole reacts with highly reactive dienophiles e.g., dimethylacetylene dicarboxylate (DMAD) to give Diels-Alder product (eq. 33). The electron
withdrawing group reduces the availability of nitrogen lone pair for the ring and so it behaves more like a diene. Pyrrole and N-alkyl pyrrole undergo Michael-type addition reactions (eq. 34).
(iv) Ring Expansion of Pyrrole: Pyrrole adds on dichlorocarbene generated in situ from chloroform and base to give a bicyclic compound which undergoes ring expansion to give 3-chloropyridine (Scheme 4).
Reactions of Pyridine
(i) Electrophilic Substitution Reactions: Pyridine is a six-membered aromatic heterocycle and undergoes electrophilic substitution (eq. 35) e.g., nitration, sulfonation, halogenation, formylation etc. but the ring
is highly deactivated (about million times) compared to benzene because the more electronegative nitrogen pulls the electrons towards itself, thus reducing the electron density on the ring carbons.
The electrophilic substitution takes place at C-3 in pyridine. This orientation can be explained by comparing the relative stabilities of the intermediates arising from attack at C-3, C-4 or C-2 (Fig. 13). The electrophilic attack at C-3 gives a carbocation which is hybrid of three resonance structures in which the positive charge is on the carbon atoms only.
The electrophilic attacks at C-4 or C-2 also give an ion which is hybrid of three resonances structures but one of the resonance structures in each contains positively charged nitrogen which is a sextet and so unstable and hence does not contribute significantly to the resonance hybrid. Thus the resonance hybrid resulting from electrophilic attack at C-3 is more stable and the preferred site of electrophilic attack.
Some typical examples of electrophilic substitutions in pyridine are given below (Fig. 14). All these reactions involve substitution of a pyridinium cation. Friedel-crafts alkylation and acylation does not proceed with pyridine. Alkyl halides on heating with pyridine give pyridinium salts. Nitration also gives poor yields.
(ii) Nucleophilic Substitution Reactions: Pyridine undergoes nucleophilic substitution reactions much more readily than benzene because the ring has lower electron density than benzene due to electron withdrawal by nitrogen which is also responsible for its lower reactivity towards electrophiles. The high reactivity of pyridine towards nucleophilic substitution can cause displacement of even powerful hydride (H–) ion, e.g., the reaction of pyridine with sodamide gives 2-aminopyridine and is known as Chichibabin reaction (eq. 36).
The nucleophilic substitution in pyridine takes place at C-2 and C-4 positions compared to electrophilic substitution at C-3. Attack of nucleophile at C-2, C-3 and C-4 gives different resonating structures (Scheme 5).
It is obvious from the above structures that nucleophilic attack at C-2 and C-4 gives hybrid of three resonance structures in which one of the contributory structures contains negative charge on nitrogen which is more electronegative atom and therefore contributes significantly towards its stabilization unlike nucleophilic attack at C-3 in which the negative charge is present on only carbon atoms. Since the intermediate resulting from nucleophilic attack at C-2 and C-4 is more stable, nucleophilic substitution at these positions is preferred. Other nucleophilic substitution reactions of pyridine are given below (eqs. 37-38). If the leaving group at C-2 and C-4 are different, the incoming nucleophile will preferentially substitute for the weaker base (the better leaving group) (eqs. 39-40).