Nitration of quinoline

The preparative nitration of quinoline in mixed acid has been described several times, and has usually been carried out under unnecessarily severe conditions good yields of 5- and 8-nitroquinoline in roughly... 

The first quantitative studies of the nitration of quinoline, isoquinoline, and cinnoline were made by Dewar and Maitlis, who measured isomer proportions and also, by competition, the relative rates of nitration of quinoline and isoquinoline (1 24-5). Subsequently, extensive kinetic studies were reported for all three of these heterocycles and their methyl quaternary derivatives (table 10.3). The usual criteria established that over the range 77-99 % sulphuric acid at 25 °C quinoline reacts as its cation (i), and the same is true for isoquinoline in 71-84% sulphuric acid at 25 °C and 67-73 % sulphuric acid at 80 °C ( 8.2 tables 8.1, 8.3). Cinnoline reacts as the 2-cinnolinium cation (nia) in 76-83% sulphuric acid at 80 °C (see table 8.1). All of these cations are strongly deactivated. Approximate partial rate factors of /j = 9-ox io and /g = i-o X io have been estimated for isoquinolinium. The unproto-nated nitrogen atom of the 2-cinnolinium (ina) and 2-methylcinno-linium (iiiA) cations causes them to react 287 and 200 more slowly than the related 2-isoquinolinium (iia) and 2-methylisoquinolinium (iii)... 

Ochiai and Okamoto showed that nitration of quinoline i-oxide in sulphuric acid at o °C gave 5- and 8-nitroquinoline i-oxides with a trace of the 4-isomer, but that at 60-100 °C 4-nitration became overwhelmingly dominant. The orientation depends not only upon temperature but also upon acidity, and kinetic studies (table 8.4 table 10.3) show that two processes are occurring the nitration of the free base (vil, R = O at C(4), favoured by low acidities and high temperatures, and the nitration of the cation (vil, R = OH), favoured by high acidities and low temperatures. ... 

Nitration of quinoline 144 leads to the nitro derivative 145. Reduction of the nitro group leads to... 

The conclusion that the nitration of quinoline in sulphuric acid takes place via the conjugate acid has been confirmed by Moodie et al.50, who measured the rates of nitration of a wide range of heterocyclic compounds in nitric acid-sulphuric acid mixtures at a range of temperatures. A summary of the second-order rate coefficients and Arrhenius parameters is given in Table 4. From an analysis of the shapes of the plots of log k2 versus sulphuric acid acidity (or some function of this), it was concluded that all of the compounds starred in Table 4... 

However, the rate of nitration of quinoline in 80-99% sulfuric acid is of the same order as that of A-methylquinolinium salts, suggesting that here the quinolinium cation may be the target for attack. 

The first nitration of 1,10-phenanthroline in one of the pyridine rings has been accomplished by the use of fuming nitric acid in acetic anhydride.252 In this way 3-nitro-1,10-phenanthroline was obtained in very low yield. The mechanism proposed for the nitration is the same as that previously proposed for the similar nitration of quinoline.277 4,5-Diazafluorenone was again a coproduct. 

In other compounds, reaction can occur in both rings. Under such circumstances the orientation can depend on the conditions frequently reaction in the benzene ring involves the cationic species, whereas that in the pyridine ring involves the free base. Thus, the temperature dependent nitration of quinoline 1-oxide (578) reflects the decrease in intrinsic acidity as the temperature rises, which in turn increases the available amount of free base species. 

Nitration of quinolines in the benzo ring is seldom a problem, especially if the benzo ring contains an electron donating group. For some undisclosed reason, 6-methoxy-4-methylquinoline was subjected to fuming nitric acid for 3 days at room temperature, and this gave a 20% yield of the lactone 1. 

For instance, nitration of quinoline gives an equal mixture of regioisomers 6.20 and 6.21. However, nitration of isoquinoline is reasonably selective (10 1) for the C5 position over the C8, affording mainly 6.22. 

Nitration of quinoline with nitric acid or metal nitrates in acetic anhydride gives the 3-nitro derivative, together with some of the 6- and 8-isomers (40JA1640 57JCS2521) the 3-derivative (—30%) is also obtained by reaction with tetranitratotitanium(IV) [74JCS(P1) 1751 ]. These reactions almost certainly involve the free base, for which the expected positional reactivity order is 5 > 8 = 6 > 3 all of these positions are of closely similar reactivity (Section 7). Steric hindrance may reduce the amount of... 

The quinolinium ion is at least 10s times more reactive in nitration than the pyridinium ion (63JCS4204). The ratio of the reactivity of quinolinium to benzene and to naphthalene has been derived as 1.2 x 10 7 and 1 x 10 l0, respectively [63CI(L)1283 68ZC201], A detailed study of the products of nitration of quinoline by nitric acid in 80 wt% sulfuric acid at 25°C yielded the partial rate factors shown in 11.63 [71 JCS(B) 1254] so that the positional reactivity order for the quinolinium ion is 5 > 8 > 6 > 7 > 3, which is almost exactly that which applies to the free base, although the relative differences are much greater (Section 7). Likewise, partial rate factors for nitration on the isoquinolinium ion are given in... 

High yields of 5- and 8-nitro derivatives have been reported for nitration of quinoline with strongly activating groups at the 6-position (which direct into the 5-position). Electron-withdrawing groups at the 4-position... 

Quinoline forms part of quinine (structure at the head of this chapter) and isoquinoline forms the central skeleton of the isoquinoline alkaloids, which we will discuss at some length in Chapter 51. In this chapter we need not say much about quinoline because it behaves rather as you would expect—its chemistry is a mixture of that of benzene and pyridine. Electrophilic substitution favours the benzene ring and nucleophilic substitution favours the pyridine ring. So nitration of quinoline gives two products—the 5-nitroquinolines and the 8-nitroquinolines—in about equal quantities (though you will realize that the reaction really occurs on protonated quinoline. 

The first three reactions are all electrophilic substitution a bromination of a pyrrole, the nitration quinoline, and a Friedel-Crafts acylation of thiophene. Bromination occurs on the pyrrole at only remaining site. Nitration of quinoline occurs on the benzene rather than the quinoline r-fi (actually giving a mixture of 5- and 8-nitroquinolines, but don t worry if you didn t see t- Mi p. 1174), and the acylation would occur next to sulfur. 

Nitration of quinoline with HNO3 in acetic anhydride furnishes only small amounts of identifiable products such as 4 and 5 (< 1 %) and 3-nitroquinoline 6 (6%), probably resulting from an initial 1,2-addition (cf the bromination, p 319). Transition metals can exert special directional effects. For instance, Zr(N03)4 nitrates quinoline to give the 7-nitro derivative 7 ... 

Af-Oxide chemistry in these bicyclic systems largely parallels the processes described for pyridine 7V-oxide, with the additional possibility of benzene ring electrophilic susbstitution, for example mixed acid nitration of quinoline A -oxide takes place at C-5 and C-8 via the O-protonated species, but at C-4 at lower acid strength nitration of isoquinoline A/ -oxide takes place at C-5. ... 

The observed kinetic law, the type of rate profile (plot of log k vs. sulfuric acid concentration), the values of the Arrhenius parameters, the comparison of the observed reaction rates with the calculated encounter rates, and the agreement with the features of the nitration of quinoline are in favor of a reaction of nitronium ions with the azolium cations. Only at lower acidities ( < 90% H2SO4) can the reaction of the neutral azole molecules become important,... 

Nitration. Nitration of quinoline using HNO3 in H2SO4 promotes the formation of 5- and 8-nitroquinoline in an almost 1 1... 

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