Electrophilic substitution quinoline

The use of q and tt separately as reactivity indices can lead to misleading results. Thus, whilst within the approximations used, the use of either separately leads to the same conclusions regarding electrophilic substitution into halogenobenzenes ( 9.1.4), the orientation of substitution in quinoline ( 9.4.2) cannot be explained even qualitatively using either alone. By taking the two in combination, it can be shown that as the values of Sa are progressively increased to simulate reaction, the differences in SE explain satisfactorily the observed orientation. ... 

Numerous m.o.-theoretical calculations have been made on quinoline and quinolinium. Comparisons of the experimental results with the theoretical predictions reveals that, as expected (see 7.2), localisation energies give the best correlation. jr-Electron densities are a poor criterion of reactivity in electrophilic substitution the most reactive sites for both the quinolinium ion and the neutral molecule are predicted to be the 3-, 6- and 8-positions. ... 

Electrophilic substitution reactions of unsubstituted quinoxaline or phenazine are unusual however, in view of the increased resonance possibilities in the transition states leading to the products one would predict that electrophilic substitution should be more facile than with pyrazine itself (c/. the relationship between pyridine and quinoline). In the case of quinoxaline, electron localization calculations (57JCS2521) indicate the highest electron density at positions 5 and 8 and substitution would be expected to occur at these positions. Nitration is only effected under forcing conditions, e.g. with concentrated nitric acid and oleum at 90 °C for 24 hours a 1.5% yield of 5-nitroquinoxaline (19) is obtained. The major product is 5,6-dinitroquinoxaline (20), formed in 24% yield. 

During indolization of the 3, 6 and 7-quinolylhydrazones, formation of the new C-C bond occurs between the appropriate carbon atom of the ketone/aldehyde moiety and the 4, 5 and 8 carbon atoms of the quinoline nucleus. It is consistent with the mechanism of formation of the C-C bond during indolization and the direction of electrophilic substitution in the quinoline nucleus. °... 

Udenfriend et al. observed that aromatic compounds are hydroxyl-ated by a system consisting of ferrous ion, EDTA, ascorbic acid, and oxygend Aromatic and heteroaroinatic compounds are hydroxylated at the positions which are normally most reactive in electrophilic substitutions. For example, acetanilide gives rise exclusively to the o-and p-hydroxy isomers whereas quinoline gives the 3-hydroxy prod-uct. - The products of the reaction of this system w ith heterocyclic compounds are shown in Table XIII. 

The chemistry of these polycyclic heterocycles is just what you miglu expect from a knowledge of the simpler heterocycles pyridine and pyrrole Quinoline and isoquinoline both have basic, pyridine-like nitrogen atoms, anc both undergo electrophilic substitutions, although less easily than benzene Reaction occurs on the benzene ring rather than on the pyridine ring, and r mixture of substitution products is obtained. 

Chlorination. Electrophilic chlorination of quinoline (66) in neutral medium showed a positional selectivity order of 3 > 6 > 8. The 5- and 8-positions should be sterically hindered to some extent. Hammett cr+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. Treatment with chlorine at 160-190°C converted quinoline into a mixture of 3-chloro-, 3,4-dichloro-, 3,4,6- and 3,4,8-trichloro-, 3,4,6,8-tetrachloro-, and 3,4,6,7,8-pentachloro-quinolines. At lower temperatures ( 100°C) the major product was 3-chloroquinoline, albeit in low yield. The 4-substituted species may have arisen from an addition-elimination or radical process (70JHC171). 

A striking demonstration of the reduced activity towards electrophiles for the pyridine ring compared with the benzene ring will be seen later when we consider the fused heterocycles quinoline and isoquinoline (see Section 11.8.1). These contain a benzene ring fused to a pyridine ring electrophilic substitution occurs exclusively in the benzene ring. 

Quinoline is much more reactive towards electrophilic substitution than pyridine, but this is because substitution occurs on the benzene ring, not on the pyridine. We have already seen that pyridine carbons are unreactive towards electrophilic reagents, with strongly acidic systems protonating the nitrogen... 

Isoquinoline, like quinoline, is protonated and alkylated at the nitrogen atom, but electrophilic substitution in the benzene ring is also easily achieved (Scheme 3.14). Sulfonation with oleum gives mainly the 5-sulfonic acid, but fuming nitric acid and concentrated sulfuric acid at 0 C produce a 1 1 mixture of 5- and 8-nitroisoquinolines. Bromination in the presence of aluminium trichloride at 75 °C gives a 78% yield of 5-bromoisoquinoline. 

Pyridine is converted into perfluoropiperidine (82) in low yield by reaction with fluorine in the presence of cobalt trifluoride (50JCS1966) quinoline affords (83) under similar conditions (56JCS783). Perfluoropiperidine can be obtained electrochemically. This is useful, as it may be readily aromatized to perfluoropyridine by passing it over iron or nickel at ca. 600 °C (74HC(14-S2)407). Recently, pyridine has been treated with xenon difluoride to yield 2-fluoropyridine (35%), 3-fluoropyridine (20%) and 2,6-difluoropyridine (11%), but it is not likely that this is simply an electrophilic substitution reaction (76MI20500). 

Only a little 3,5-di- and penta-iodopyridine is obtained when pyridine reacts with iodine in the vapour phase. Treatment of pyridine with iodine in 50% oleum furnishes 3-iodo-(18%) and some 3,5-di-iodo-pyridine. This is probably the result of electrophilic substitution by I+, with oleum performing in the role already discussed (57JCS387). The products of iodination of quinoline are not well defined however, a reviewer (77HC(32-1)319) has pointed out that one such product (formed by heating quinoline with iodine and potassium iodide at 160-170 °C in the presence of mercury(II) chloride) has a melting point identical with that of 3-iodoquinoline. 

Replacement of the proton by deuterium represents the simplest electrophilic substitution the process is effected by concentrated deuteriosulfuric acid. Deuteration studied over the ranges 45-96% acid and 150-250 °C showed that for both quinoline and quinoline AT-oxide reaction occurs in the positions 8>5,6>7>3 and rates increased both with increasing acid concentration and with temperature. The mechanism proceeds via the conjugate acid (Scheme 4) (75TL1395, 72IZV2092, 71JCS(B)4, 67CPB826). 

A systematic and intensive theoretical study of reactivity has been reported by Brown and his colleagues,8,115,139-142 who discussed the reactivity of pyridine, quinoline, and isoquinoline in terms of localization energies. They investigated the values of these indices, first of all for electrophilic substitution, with regard to the value of the Coulomb integral of the heteroatom orbital and the orbitals adjacent to it (auxiliary inductive parameters). They demonstrated that the course of electrophilic substitution can be estimated from theoretical reactivity indices if 77-electron densities are used for reactions that occur readily and localization energies for those occurring only reluctantly. 

Electrophilic chlorination of quinoline under neutral conditions occurs in the orientation order 3 > 6 > 8. Hammett ct+ values predict an order for electrophilic substitution of 5 > 8 = 6 > 3. The reactivity order can be affected by substitution of an electron-withdrawing group in the benzene ring, which directs the chlorination to the pyridine ring. Thus, NCS in acetic acid or sulfuryl chloride in o-dichlorobenzene converts 8-nitroquinoline into 3-chloro-8-nitroquinoline in high yield (91M935). 

The relative reactivity of different positions toward electrophilic substitution is conveniently studied by acid-catalyzed deuterium exchange reaction rates can be followed by NMR and introduction of deuterium hardly affects the reactivity of the remaining positions. In D2S04 both quinoline and quinoline 1-oxide react as the conjugate acid at positions 8 > 5, 6 > 7 > 3. 

Substituents on the benzene rings exert their usual influence on the orientation and ease of electrophilic substitution reactions. For example, further nitration (HN03-H2S04-S03) of nitroquino-lines occurs meta to the nitro group as shown in diagrams (593) and (594). Friedel-Crafts acylation of 8-methoxyquinoline succeeds (cf. 595) although this reaction fails with quinoline itself. 

C(8a)—C(9) are elongated. The common bond C(3a)—C(9a) is also lengthened. A comparison of the 7r-electron densities reveals that all three procedures show almost the same trends. The calculated 7r-electron densities for thieno[2,3-6]quinoline (378) and thieno[3,4-6]quinoIine (379) do not differ significantly from the corresponding thienopyridines provided that the same set of parameters is used. Calculated reactivity indices indicate that electrophilic substitution reactions should occur predominantly in the thiophene unit. 

Although there are several studies of the reactions of quinolines, there is a paucity of data on electrophilic substitutions. In the case of quinoline, with the exception of the 5-position, all of the others are deactivated relative to benzene, but only by a slight amount [71JCS(B)4, 71JCS(B)2382], The partial rate factors for quinoline have also been determined [71JCS(B)1254],... 

These systems nitrate aromatic compounds by a process of electrophilic substitution, the character of which is now understood in some detail ( 6.1). It should be noted, however, that some of them can cause nitration and various other reactions by less well understood processes. Among such nitrations that of nitration via nitrosation is especially important when the aromatic substrate is a reactive one ( 4.3). In reaction with lithium nitrate in acetic anhydride, or with fuming nitric acid, quinoline gives a small yield of 3-nitroquinoline this untypical orientation (cf. 10.4.246) may be a consequence of nitration following nucleophilic addition.5... 

The azametallocenes, such as 206 and 208, are less stable than their cyclopentadienyl analogs.158 The pKa for azaferrocene (206) is similar to that of quinoline, whereas the manganese compound was a much weaker base.158 Azaferrocene yields a picrate and a methiodide, but, as might be expected, it does not undergo electrophilic substitution.158 The mass spectra of azametallocenes have been discussed.1636 The preparation of cyclopentadienyliodobis(imidazole)cobalt(III)iodide has been reported.1630... 

---