Nitration of isoquinoline

Nitration of isoquinoline with nitric and sulfuric acids occurs preferentially at positions 5 and 8, the former predominating, in the approximate ratio of 9 1 at 0 °C. The amount of 8-nitro isomer is slightly increased at higher temperatures. Electrophilic localization energies predict the reactivity order 5>8>others. Over the range 71—85% sulfuric acid it has been shown that the reaction proceeds via the isoquinolinium cations (Scheme 6) (63CI(L)1283, 60T(8)23, 57JCS2521). 

The nitration of isoquinoline AT-oxide gives 5-nitroisoquinoline AAoxide and kinetic studies suggest that the reaction proceeds through the conjugate acid (66JCS(B)870>. In... 

The nitration of isoquinoline also occurs predominantly at the 5- and 8-positions and may be achieved in tandem with bromination to give access to bromonitroisoquinolines in a one-pot procedure <20050S98>. Isoquinoline is selectively brominated at the 5-position using A-bromosuccinimide (NBS) in sulfuric acid and nitration, without isolation of 5-bromoisoquinoline, occurs on addition of potassium nitrate to afford moderate yields of 5-bromo-8-nitroisoquinoline 6 (Equation 3). 

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. 

II. 64 (64MI2), and the differences in the i-Q/Q-rate ratios for the 5- and 8-positions (52 and 7, respectively) show the effect of conjugation between nitrogen and the 5-position in quinoline and the 8-position in isoquinoline. Nitration of isoquinoline with nitric acid in acetic anhydride almost certainly involves the free base and consequently gives the 4-derivative in 14% yield (720PP9) the 4-position is the most reactive site (see Section 7). 

This is obviously rather unsatisfactory but nitration is actually one of the better behaved reactions. Chlorination gives ten products (at least ), of which no fewer than five are chlorinated quinolines of various structures. The nitration of isoquinoline is rather better behaved, giving 72% of one isomer (5-nitroisoquinoline) at 0°C. 

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 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)... 

Nitration of 2-cyclohexyl-8-hydroxy-2,3,4,6,11,11 u-hexahydro-1 //-pyra-zino[l,2-6]isoquinoline-l,4-dione with 70% HNO3 at room temperature for 30 min afforded an 1 1 mixture of 7- and 9-nitro derivatives (98MIP7). 

Reactions. In general, isoquinoline undergoes electrophilic substitution reactions at the 5-position and nucleophilic reactions at the l-posilion. Nitration with mixed acids produces a 9 1 mixture of 5-nitroisoquinoline and 8-nitroisoquinoline. Sulfonation of isoquinoline gives a mixture with 5-isoquinolinesulfonic acid as the principal product. 

Bromination and nitration of some annulated thieno[3,2-6]pyridines were investigated. The reaction of thieno[3,2-c]isoquinoline A-oxide (181) with bromine yields 2,3-disubstituted product 182, whereas treatment of 181 with HN03 affords 2-nitro derivative 183 (1989CS305, 1989CS309). 

Electrophilic substitution (bromination, nitration) of 2-substituted 1,2,3,6,7,116-hexahydro-4//-pyrazino[2,l -a]isoquinolin-4-ones occurred on the aromatic moiety to give either 11- or 8-substituted derivatives the site was not determined (76GEP2441261). The nitro group was reduced to an amino group, which was alkylated, acylated, and converted to different groups via a diazonium group, and involved in diazonium coupling. 

The ct+ values show that the position in quinoline should be between 10 and 2 x 106 times less reactive than naphthalene toward nitration. The observed value is 10 °, confirming that, under these conditions, nitration takes place on the conjugate acid and not on the free base [71JCS(B)2382], Likewise, the partial rate factors for nitration of the 5-and 8-positions in isoquinoline require a+ values of 0.77 and 0.92, confirming that reaction takes place on the conjugate acid [75JCS(P2) 1783]. 

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. 

A solution of 387 g. (3.0 moles) of isoquinoline in 350 ml. of 48% hydrobromic acid is evaporated to near dryness, and 480 g. (3.0 moles) of bromine is added slowly. (Hood.) The resulting mixture is heated under an air reflux condenser at 180-190° for 7 hours, during which evolution of hydrogen bromide is complete. After cooling, excess sodium hydroxide solution is added and the mixture is steam-distilled. Water is decanted from the distillate until approximately 5 1. remains, and nitric acid is added to the hot mixture until the bromoisoquinoline is in solution. Upon cooling the nitrate salt precipitates and is filtered off and redissolved in hot water. Addition of excess ammonium hydroxide precipitates the 4-bromoisoquinoline which upon recrystallization from ether melts at 39-40°. The yield varies between 45% and 74%. 

A solution of 43 g. (0.33 mole) of isoquinoline in 200 ml. of concentrated sulfuric acid is cooled to 0°, and a mixture of 35 g. of potassium nitrate in 200 ml. of sulfuric acid is added over a period of 2 hours. The reaction mixture is held below 50° for 6 additional hours and then poured on ice and neutralized with ammonium hydroxide solu-... 

The nitration of aromatic compounds is a fundamental reaction [7] of utmost importance to the chemical industry. Many different regimens for this unit-process are known [8]. Nitrations have been described in microreactors [9-11] and during our own work with microreactors we have also gained experience with nitrations [12]. We have shown that it is possible to generate, in the laboratory, smaller amounts of chemicals using micro reactors, exemplified by the continuous nitration of 8.6 g of N-methoxycarbonyl-l,2,3,4-tetrahydro-isoquinoline over 6 full days. In an unlimited period of time one could produce unlimited amounts of chemicals with a single microsystem. Since this is unrealistic we are not... 

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