Nitration of Substituted Benzene Derivatives

BASF in Ludwigshafen, Germany, and university partners reported the nitration of several disubstituted benzene derivatives using a capillary flow microreactor [29]. The exact nature of these species, however, was not disclosed. 

Because the benzene derivative and nitric add are immiscible, the impact of mixing/distribution on slug formation was investigated. Uniform slugs of the aromatic compound/nitric acid were formed in a Y-piece [29]. The capillary attached has a stabilizing effect on the slug flow. The deviation of slug size distribution is very small (about 5%). Hence, interfacial area is nearly constant for this type of capillary flow. 

Conversion to the mononitrated benzene derivative increased linearly with increasing flow velocity due to enhanced mass transfer. The formation of phenol by-products increased in the same manner for similar reasons. In turn, consecutive by-products, dinitrated aromatics, were formed in a linear decreasing fashion. This was explained by a mass transfer-induced removal of the mononitrated product from the reacting slug. 

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A brief account of aromatic substitution may be usefully given here as it will assist the student in predicting the orientation of disubstituted benzene derivatives produced in the different substitution reactions. For the nitration of nitrobenzene the substance must be heated with a mixture of fuming nitric acid and concentrated sulphuric acid the product is largely ni-dinitrobenzene (about 90 per cent.), accompanied by a little o-dinitrobenzene (about 5 per cent.) which is eliminated in the recrystallisation process. On the other hand phenol can be easily nitrated with dilute nitric acid to yield a mixture of ortho and para nitrophenols. It may be said, therefore, that orientation is meta with the... 

Benzo[6 jthiophenes with nitro groups at the 4-, 5-, 6- or 7-positions may be synthesized by ring closure reactions of appropriately substituted benzene derivatives. Nitration of 5-acetaminobenzo[6]thiophene gives the 4-nitro derivative, which can be hydrolyzed and deaminated to yield 4-nitrobenzo[6]thiophene (equation 44). 5-Nitrobenzo[6]thiophene is conveniently available by decarboxylation of 5-nitrobenzo[6]thiophene-2-carboxylic acid, which in turn is available by a Perkin reaction of 4-nitro-2-formylphenylthioglycoIic ester (equation 45 Section 3.15.2.3). The 7-nitro isomer may be obtained similarly. 

However, in contrast to benzene, ferrocene is sensitive to oxidation, and the ferrocenium cation, FeCpj, a paramagnetic 17-electron species, is readily formed in the presence of various oxidants. The ferrocenium cation is reluctant to undergo electrophilic substitution, and therefore reactions such as halogenation and nitration, which are important routes to substituted benzene derivatives, cannot be used for the synthesis of substituted ferrocenes. Only electrophilic substitution under nonoxidizing conditions (e.g., Friedel-Crafts acylation, Mannich reaction, borylation, lithiation or mercuration), and radical substitution are available as an entry into the chemistry of substituted ferrocenes. 

Aromatic alcohols (phenols) can be prepared by treatment of a diazonium salt (ArN2 ) with water, acid, and heat. In this substitution reaction, water acts as a nucleophile and replaces the excellent nitrogen leaving group (N2) on the diazonium salt. The diazonium salt is prepared in three steps from benzene (or a substituted benzene derivative, but such compounds will be addressed in a later part of this book). First, nitration of benzene with HNO3 and H2SO4... 

TABLE 5.2 Nitrations of mono-substituted derivatives of benzene in solutions of acetyl nitrate in acetic anhydride ... 

If, on the other hand, the encounter pair were an oriented structure, positional selectivity could be retained for a different reason and in a different quantitative sense. Thus, a monosubstituted benzene derivative in which the substituent was sufficiently powerfully activating would react with the electrophile to give three different encounter pairs two of these would more readily proceed to the substitution products than to the starting materials, whilst the third might more readily break up than go to products. In the limit the first two would be giving substitution at the encounter rate and, in the absence of steric effects, products in the statistical ratio whilst the third would not. If we consider particular cases, there is nothing in the rather inadequate data available to discourage the view that, for example, in the cases of toluene or phenol, which in sulphuric acid are nitrated at or near the encounter rate, the... 

However, other studies on the nitration of a series of 3-methyl- and 3-ethyl-1,2-benzisoxazoles have shown that a mixture of the 5-nitro and 5,7-dinitro derivatives is formed (77IJC(B)1058, 77IJC(B)1061). The effect of substituents in the benzene ring is also of interest. If the 5-position is blocked, e.g. by a chloro group or by alkyl groups, nitration then occurs at the 4-position. 3-Alkyl-7-chloro and 3,7-dialkyl derivatives result in the formation of the appropriate 5-nitro derivative. The isomeric 3-alkyl-6-chloro- and 3,6-dialkyl-1,2-benzisoxazoles yield a mixture of the 5-nitro and 5,7-dinitro compounds. Both H NMR measurements and alternate syntheses were used in establishing the structures of these substitution products. 

This procedure illustrates a general method for converting substituted pyrylium salts to nitrobenzene derivatives. The reaction has been the subject of several reviews. - The yields are generally high, and under these conditions only a single product is formed, in contrast to the nitration of 1,3,5-triphenyl-benzene. The preparation of 2,4,6-triphenylnitrobenzene from the corresponding pyrylium salt eliminates isomer separation problems, which are encountered when the direct nitration procedure is used. Also, labeled compounds can readily be prepared by this method. ... 

Aniline is an important derivative of benzene that can be made in two steps by nitration to nitrobenzene and either catalytic hydrogenation or acidic metal reduction to aniline. Both steps occur in excellent yield. Almost all nitrobenzene manufactured (97%) is directly converted into aniline. The nitration of benzene with mixed acids is an example of an electrophilic aromatic substitution involving the nitronium ion as the attacking species. The hydrogenation of nitrobenzene has replaced the iron-... 

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