Reactions of Indole
Indole is a very weak base like pyrrole because of the involvement of lone pair of nitrogen in aromatization. However, in dilute solutions it undergoes protonation of nitrogen to give indolium cation in which the aromaticity of benzene ring is retained (eq. 41). Indole does not undergo easy alkylation of nitrogen unlike amines for the same reason.
(i) Electrophilic Substitution of Indole: The electron density of carbons in heterocyclic ring of indole is higher due to contribution from nitrogen as in case of pyrrole. Therefore, the heterocyclic ring of indole is more reactive towards electrophiles compared to its benzene ring. The electrophilic substitution in indole takes place at C-3 and not at C-2 as in pyrrole. This can be explained from the following observations. Electrophilic attack at C-2 and C-3 gives different intermediates as shown below (Scheme 6):
The carbocation resulting from electrophilic attack at C-2 is less favourable than the carbocation resulting from electrophilic attack at C-3 because though the former has more resonance structures, the aromaticity is completely lost whereas in the latter intermediate, the positive charge resides on heterocyclic ring carbon or the nitrogen atom without affecting the benzene ring. Some typical examples of electrophilic substitution of indole are given below (Fig. 15):
Acylation of indole at C-3 does not take place as the reaction with acyl halide leads to acylation of nitrogen. If C-3 of indole is blocked, then electrophilic substitution takes place at C-2 and if both C-2 and C-3 are blocked, then electrophilic substitution takes place preferably at C-6 in aromatic ring.
(ii) Oxidation and Reduction of Indole: Indoles are easily oxidized by air and give a mixture of products. The C2-C3 double bond of indole is labile and can be easily cleaved by ozonolysis, peracids and sodium hypoiodate etc. Indole gives a resinous material whereas 3-substituted or 2,3-disubstituted indoles undergo C2-C3 cleavage as in case of ozonolysis (eqs. 42-43).
Indoles can be selectively reduced in five membered ring or six membered ring. The five membered ring is reduced by a number of reagents in acidic media e.g., Zn, Sn, BH3-NMe3 complex (eq. 44) while six membered ring can be reduced by Birch reduction using Li-ammonia in ethanol to give 4,7-dihydroindole (eq. 45).
(iii) Reaction with Carbenes: Indole and substituted indoles undergo addition of dihalocarbene on electron rich C2-C3 double bond to give an intermediate which undergoes ring expansion to give 3-chloroquinoline or 3-membered ring cleavage to give 3-substituted indole derivative (eq. 46).
Reactions of Quinoline and Isoquinoline
Quinolines and isoquinolines behave similar to pyridine. Both are weakly basic and undergo protonation of nitrogen without affecting the aromaticity of the ring. Quaternary ammonium salts are formed on nitrogen by alkylation.
(i) Electrophilic Aromatic Substitution: The nitrogen of the quinoline and isoquinoline has deactivating effect on the ring towards electrophilic substitution as in case of pyridine as discussed earlier. However electrophilic substitution of quinoline and isoquinoline requires less vigorous conditions than pyridine. Electrophilic substitution of protonated quinoline and isoquinoline takes place on the carbocyclic ring at C-5 or C-8 positions. Some typical examples of electrophilic substitution in quinoline (Fig. 16) and isoquinoline (Fig. 17) are given below.
Quinoline and isoquinoline undergo reaction with nitric acid in presence of acetic anhydride to give 3-nitroquinoline and 4-nitroisoquinoline, respectively (eqs. 47-48).
(ii) Nucleophilic Aromatic Substitution: Quinoline and isoquinoline undergo facile nucleophilic substitution as in pyridine. Quinoline undergoes Chichibabin reaction to give 2-aminoquinoline (eq. 49) while isoquinoline undergoes Chichibabin reaction to give 1-amino isoquinoline (eq. 50). Isoquinoline undergoes substitution faster than quinoline. The reaction proceeds in a manner analogues to pyridine.
(iii) Reductions: Quinoline can be selectively reduced at 1,2-bond by reaction with lithium aluminium hydride but the 1,2-dihydro quinolines are unstable and disproportionate easily to give quinoline and 1,2,3,4-tetrahydroquinoline (eq. 51). Quinoline can be converted to 1,2,3,4-tetrahydroquinoline by catalytic hydrogenation or with tin and hydrochloric acid (eq. 52).
Isoquinoline can also be converted to 1,2-dihydro or 1,2,3,4-tetrahydroisoquinoline with diethyl aluminium hydride and sodium-ethanol, respectively (eq. 53).
(iv) Oxidations: Quinoline and isoquinoline undergo oxidative cleavage with alk. potassium permangnate to give pyridine-2,3-dicarboxylic acid (eq. 54) and pyridine-3,4-dicarboxylic acid (eq. 55), respectively. However, pyridine-2,3-dicarboxylic acid is not stable and undergoes decarboxylation to give nicotinic acid (eq. 54). Quinoline and isoquinoline both form N-oxides when treated with hydrogen peroxide in acetic acid or with organic peracids.