Nitration by nitric acid in acetic anhydride

The nature of the electrophile in this nitrating mixture is still not wholly agreed upon whereas kinetic evidence can be interpreted as consistent with nitration by nitronium ion, the fact that substituents with lone pairs of electrons or it-electrons give markedly different ortho para ratios from other nitrating mixtures is usually conceded to be consistent with the electrophile being something other than the nitronium ion. The balance of evidence at present is in favour of pro-tonated acetyl nitrate being the electrophile. 

Kinetic studies with benzene in acetic anhydride containing 0.4-2 M nitric acid at 25 °C show the reaction to be first-order in benzene and approximately second-order in nitric acid this falls to first-order in nitric acid on addition of sulphuric acid, which also increases the first-order rate coefficient (first-order in benzene) from 4.5 x 10-4 to 6.1 x 10 4. By contrast the addition of as little as 0.001 M sodium nitrate reduced the rate to 0.9 x 10-4 without affecting the kinetic order70. These results were, therefore, interpreted as nitration by nitronium ion via equilibria (21a) and (22). 

Bordwell and Garbisch71 contested this conclusion since they found that nitric acid in acetic anhydride prepared at —10 °C contained a much less effective nitrating species (the nitric acid could be recovered quantitatively) than when mixed at 25 °C and cooled to —10 °C (the nitric acid being then mostly unrecoverable). Further, these latter solutions reacted with alkenes to give predominantly cis addition products (nitro-acetates), whi h indicates association of the nitronium ion with some other species. It has been argued72 that this does not necessarily follow, since nitration of aromatics may involve a different 

A further observation is the fact that differences in rates of nitration between the reagents prepared at different temperatures tended to zero as the water concentration of the added nitric acid was decreased to zero73. It has been argued that, since the acid-catalysed hydrolysis of acetic anhydride must be very rapid at 25 °C and removes water which initially competes with acetic anhydride and acetyl nitrate for protons, this removal permits equilibria (30) and (31) to be displaced towards products. The more anhydrous the nitric acid, the less important is this initial hydrolysis of the acetic anhydride and so the difference in the nitrating power of the differently prepared mixtures becomes less. When reagents are mixed at low temperatures, the hydrolysis of the anhydride is very slow, but once this is accomplished, formation of the protonated acetyl nitrate and subsequent nitration is rapid as observed73. 

It should be noted that protonated acetyl nitrate can be regarded as a nitronium ion solvated by acetic acid74 (I) 

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Roberts and his associates (1954) re-examined the nitration of the halobenzenes using fuming nitric acid as the reagent in both acetic anhydride and nitromethane. These workers detected a significant solvent effect on the relative rate. Iodobenzene was nitrated by nitric acid in acetic anhydride at a rate 0.13 times that of benzene, in nitromethane this reagent provided a rate ratio of 0.22. 

Whereas pyrazoles are quite readily iV-nitrated by nitric acid in acetic anhydride or with nitronium fluoroborate, imidazoles are usually far too basic, and give the nitrate salts instead. A nitro substituent, however, decreases the basicity sufficiently to allow iV-nitration to occur. The A -nitro compounds are subject to thermal rearrangement to the 2- and 4-nitro isomers, pointing to an alternative route to such compounds [63]. 

Evidence developed in large measure by Ingold, Hughes, and their students provided strong support for the view that the nitration reactions of aromatic compounds proceeded via the ni-tronium ion under a variety of conditions including, for example, nitration by nitric acid in acetonitrile, nitration by nitric acid in acetic anhydride, and nitration by nitric acid in mixed acid.Each new investigation of the reaction yielded addi-... 

Fig. 7.1. Nitration of polynuclear hydrocarbons by nitric acid in acetic anhydride, (i) Plot of login (KijK against N. ,g-AnthryI positions A,

Acetoxylation is found to accompany nitration of fairly reactive aromatics by nitric acid in acetic anhydride and gives rise to zeroth-order kinetics76. The electrophile is believed to be protonated acetyl nitrate the formation of which is rate-determining, hence the kinetic order (see p. 37). Acetoxylation can also accompany halogenation by positive halogenating agents in acetic acid solvent, especially in the presence of sodium acetate137, but no kinetic studies have been carried out. 

Thus for the nitration of toluene by nitric acid in acetic anhydride at 0° kCtHsMJkCiHt was found to be 27, and the isomer distribution (%) o-, 61-5 m-, 1-5 p-, 37 0 the partial rate factors for nitration, under these conditions, are thus ... 

The partial rate factors for dibenzofuran relative to a benzene position, for protodetritiation, protodetrimethylsilyIation, nitration with nitric acid in acetic anhydride, and benzoylation with benzoyl chloride and aluminum chloride in nitrobenzene at 15°C are shown in Table VII along with the relevant values for diphenyl ether, It is seen that by introducing the biphenyl bond in diphenyl ether the reactivity is lowered at both the positions ortho (4-) and para (2-) to the oxygen of dibenzofuran. This lowering of reactivity has been attributed to the fact that the 2- and 4-positions, as... 

Thus for the nitration of toluene by nitric acid in acetic anhydride... 

Fig. 7.1. Nitration of polynuclear hydrocarbons by nitric acid in acetic anhydride, (i) Plot of logio (KJKo) against N. , 9-Anthryl positions A,a-napthyl positions V, 4-phenanthryi positions O, other positions. (From Dewar et a/.286) (ii) and (iii) Relative electrophilic localization energies vs. logarithms of partial rate factors for nitration (a) Hiickel, (6) PPP with fixed p. (From Dewar Thompson.83 ) (iv) Plot of log K vs. AEiac- (From Dewar.23 )...

Nitroindazoles, the products of nitration with nitric acid in acetic anhydride, are easily rearranged to 3-nitro derivatives that make these isomers fairly accessible [28], This method has been modified by Pozharskii [38] with a main goal to increase the yield of the reaction product. So 3-nitroindazole has been obtained without the intermediate 2-nitroindazole. 

When the acetic acid was replaced by acetic acid anhydride under otherwise unchanged conditions, the reaction became extremely fast. Within a one-minute reaction time the starting material was consumed completely and only a small amount of the wanted para-mononitro compound was found besides a higher nitrated compound as the major product Even if a more favorable selectivity would have been observed, and although a nitration with nitric acid in acetic anhydride can be carried out safely [17] with the micromixer, these conditions have to be avoided because the entire reaction heat is evolved immediately and very probably cannot be controlled on a larger scale. 

This salt appears to be stable indefinitely in air. It is unattacked by bromine, hydrogen bromide or hydrogen iodide, [34], but is nitrated by dinitrogen tetroxide or by nitric acid in acetic anhydride [35]. Other examples of substituted cyclopentadienide anions which can be handled in air include aroyl-, [20-22], fomyl-, [36], methoxycarbonyl-, [24,37-40], cyano-, [41-44], and methyl-sulphonyl-cyclopentadienides [45]. 

Also obtained from 3,4-dimethylbenzophenone by nitration with nitric acid in acetic anhydride at 70°, then at 5° overnight. The diene obtained (2-benzoyl-4,5-dimethyl-4-nitro-l,4-dihydrophenyl acetate as cis and trans mixture) was added to a concentrated solution of sodium methoxide in methanol [727]. 

Because of the chemical similarity between benzoyl nitrate and the acetyl nitrate which is formed in solutions of nitric acid in acetic anhydride, it is tempting to draw analogies between the mechanisms of nitration in such solutions and in solutions of benzoyl nitrate in carbon tetrachloride. Similarities do exist, such as the production by these reagents of higher proportions of o-substituted products from some substrates than are produced by nitronium ions, as already mentioned and further discussed below. Further, in solutions in carbon tetrachloride of acetyl nitrate or benzoyl nitrate, the addition of acetic anhydride and benzoic anhydride respectively reduces the rate of reaction, implying that dinitrogen pentoxide may also be involved in nitration in acetic anhydride. However, for solutions in which acetic anhydride is also the solvent, the analogy should be drawn with caution, for in many ways the conditions are not comparable. Thus, carbon tetrachloride is a non-polar solvent, in which, as has been shown above,... 

Aromatic Ring Reactions. In the presence of an iodine catalyst chlorination of benzyl chloride yields a mixture consisting mostly of the ortho and para compounds. With strong Lewis acid catalysts such as ferric chloride, chlorination is accompanied by self-condensation. Nitration of benzyl chloride with nitric acid in acetic anhydride gives an isomeric mixture containing about 33% ortho, 15% meta, and 52% para isomers (27) with benzal chloride, a mixture containing 23% ortho, 34% meta, and 43% para nitrobenzal chlorides is obtained. 

Another useful medium for nitration is a solution prepared by dissolving nitric acid in acetic anhydride, which generates acetyl nitrate. This reagent tends to give high ortho. para ratios for some nitrations.2... 

Nitroimidazoles substituted by an aromatic ring at the 2-position are also active as antitrichomonal agents. Reaction of p-fluorobenzonitrile (83) with saturated ethanolic hydrogen chloride affords imino-ether 84. Condensation of that intermediate with the dimethyl acetal from 2-aminoacetaldehyde gives the imidazole 85. Nitration of that heterocycle with nitric acid in acetic anhydride gives 86. Alkylation with ethylene chlorohydrin, presumably under neutral conditions, completes the synthesis of the anti-... 

Nitration of ketones or enol ethers provides a useful method for the preparation of a-nitro ketones. Direct nitration of ketones with HN03 suffers from the formation of a variety of oxidative by-products. Alternatively, the conversion of ketones into their enolates, enol acetates, or enol ethers, followed by nitration with conventional nitrating agents such as acyl nitrates, gives a-nitro ketones (see Ref. 79, a 1980 review). The nitration of enol acetates of alkylated cyclohexanones with concentrated nitric acid in acetic anhydride at 15-22 °C leads to mixtures of cis- and rrans-substituted 2-nitrocyclohexanones in 75-92% yield. 4-Monoalkylated acetoxy-cyclohexanes give mainly m-compounds, and 3-monoalkylated ones yield fra/w-compounds (Eq. 2.40).80... 

The role of dialkylchloramines as intermediates in the chloride-catalyzed nitration of secondary amines is discussed in Section 5.3.1. Wright and co-workers" studied this reaction further and prepared a number of dialkylchloramines by treating secondary amines with aqueous hypochlorous acid (Equation 5.12). Treatment of these dialkylchloramines with nitric acid in acetic anhydride forms the corresponding secondary nitramine, a result consistent with the chloride-catalyzed nitration of amines." ... 

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