Nitration under acidic conditions

3 DIRECT NITRATION OF AMINES 5.3.1 Nitration under acidic conditions 

The direct nitration of a primary amine to a nitramine with nitric acid or mixtures containing nitric acid is not possible due to the instability of the tautomeric isonitramine in strongly acidic solution (Equation 5.1). Secondary amines are far more stable under strongly acidic conditions and some of these can undergo electrophilic nitration with nitric acid in a dehydrating medium like acetic anhydride. 

A number of other amines containing electron-withdrawing groups undergo facile N-nitration (Table 5.1). The direct A-nitration of aniline derivatives is limited to amines of 

A/-Nitration of amines with nitric acid and its mixtures 

A large number of nitramine-based explosives have been synthesized via Mannich-type condensation reactions (Section 5.13.2). The amines generated from these reactions often have the powerful electron-withdrawing trinitromethyl or fluorodinitromethyl groups positioned on the carbon a to the amino group. This reduces amine basicity to an extent that A-nitration becomes facile. The energetic nitramines (17), (19) and (21) have been synthesized from the condensation of ethylenediamine with 2,2,2-trinitroethanol, 2-fluoro-2,2-dinitroethanol with ethanolamine, and 2-fluoro-2,2-dinitroethylamine with 2,2-dinitro-l,3-propanediol respectively, followed by A-nitration of the resulting amine bases (16), (18) and (20), respectively. 

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If nitration under acidic conditions could only be used for the nitration of the weakest of amine bases its use for the synthesis of secondary nitramines would be severely limited. An important discovery by Wright and co-workers " found that the nitrations of the more basic amines are strongly catalyzed by chloride ion. This is explained by the fact that chloride ion, in the form of anhydrous zinc chloride, the hydrochloride salt of the amine, or dissolved gaseous hydrogen chloride, is a source of electropositive chlorine under the oxidizing conditions of nitration and this can react with the free amine to form an intermediate chloramine. The corresponding chloramines are readily nitrated with the loss of electropositive chlorine and the formation of the secondary nitramine in a catalytic cycle (Equations 5.2, 5.3 and 5.4). The mechanism of this reaction is proposed to involve chlorine acetate as the source of electropositive chlorine but other species may play a role. The success of the reaction appears to be due to the chloramines being weaker bases than the parent amines. 

The nitration of active methylene compounds by the action of a nitrate ester under basic conditions has been found to be a general and convenient method for introducing a nitro group alpha to the activating group. By choosing the appropriate base-solvent system, we have been successful in applying the reaction to ketones, nitriles, amides, carboxyl esters, sulfonic esters, sul-fones, substituted toluenes, and heterocyclics. Usually the nitration under acidic conditions fails with these classes of compounds. 

Finally, in the last step, the chelating auxiliary had to be removed Ideally, one would like to convert 4.54 into ketone 4.55 via a retro Mannich reaction. Unfortunately, repeated attempts to accomplish this failed. These attempts included refluxing in aqueous ethanol under acidic and basic conditions and refluxing in a 1 1 acetone - water mixture in the presence of excess paraformaldehyde under acidic conditions, in order to trap any liberated diamine. Tliese procedures were repeated under neutral conditions in the presence of copper(II)nitrate, but without success. 

The observation already discussed ( 2.2, 2.3, 2.4) of nitrations, in concentrated and aqueous mineral acids and in pure nitric acid, which depend on the first power of the concentration of the aromatic compound, does not help much in elucidating the mechanisms of nitrations under these conditions. In contrast, the observation of zeroth-order... 

The theory that the catalysed nitration proceeds through nitrosation was supported by the isolation of some />-nitrosophenol from the interrupted nitration of phenol, and from the observation that the ortho.-para ratio (9 91) of strongly catalysed nitration under aqueous conditions was very similar to the corresponding ratio of formation of nitrosophenols in the absence of nitric acid. ... 

The observation of nitration at a rate independent of the concentration and the nature of the aromatic means only that the effective nitrating species is formed slowly in a step which does not involve the aromatic. The fact that the rates of zeroth-order nitration under comparable conditions in solutions of nitric acid in acetic acid, sulpholan and nitromethane differed by at most a factor of 50 indicated that the slow step in these three cases was the same, and that the solvents had no chemical involvement in this step. The dissimilarity in the rate between these three cases and nitration with acetyl nitrate in acetic anhydride argues against a common mechanism, and indeed it is not required from evidence about zeroth-order rates alone that in the latter solutions the slow step should involve the formation of the nitronium ion. 

Nitration is almost always carried out under acidic conditions. If the compound being nitrated is basic, the problem arises of deciding whether the free base or its conjugate acid is being nitrated, or if both of these species are reacting. 

Ha.logena.tlon, One review provides detailed discussion of direct and indirect methods for both mono- and polyhalogenation (20). As with nitration, halogenation under acidic conditions favors reaction in the benzenoid ring, whereas reaction at the 3-position takes place in the neutral molecule. Radical reactions in the pyridine ring can be important under more vigorous conditions. 

Quinoxaline is resistant to nitration under mild conditions. On treatment with a mixture of oleum and nitric acid at 90°C for 24... 

Quinoxalin-2-ones, unlike quinoxaline itself, may be nitrated under mild conditions. Nitration of quinoxalin-2-one in acetic acid gives mainly the 7-nitro derivative in sulfuric acid, the 6-nitro compound is formed (Scheme 6). ... 

Ethyl formate34,52 or orthoformate5 3,54 reacts with two equivalents of phenylhydrazine to yield 1,5-diphenylformazan (11) the reaction takes place under acidic conditions and involves an oxidation. Under basic conditions, ethyl nitrate reacts at the methylene position to yield 3-methyl-1,5-diphenylformazan (37) which can also be obtained from the reaction of phenyl-azoethane (38) with isoamyl nitrite (Scheme 4).8,68 Aryl hydrazines react with a variety of s-triazines (39) to yield 1,5-diaryl formazans with hydrogen, methyl, or phenyl groups in the 3-position as in 40 (Eq. 6).56 Hydrazines have also been reported to react with benzotrichloride55,658 and sym-diamino tetrazine659 to yield formazans. 

The presence of N02, the nitronium ion, both in this solution and in a number of salts (some of which, e.g. NOz C104e, have actually been isolated) has been confirmed spectroscopically there is a line in the Raman spectrum of each of them at 1400 cm"1 which can only originate from a species that is both linear and triatomic. Nitric acid itself is converted in concentrated sulphuric acid virtually entirely into N02, and there can be little doubt left that this is the effective electrophile in nitration under these conditions. If the purpose of the sulphuric acid is merely to function as a highly acid medium in which NOz can be released from HO—N02, it would be expected that other strong acids, e.g. HC104, would also promote nitration. This is indeed found to be the case, and HF plus BF3 are also effective. The poor performance of nitric acid by itself in the nitration of benzene is thus explained for it contains but little N02 the small amount that is present is obtained by the two-stage process... 

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 ... 

Matthews and Riley [99] preconcentrated iodide by co-precipitation with chloride ions. This is achieved by adding 0.23 g silver nitrate per 500 ml of seawater sample. Treatment of the precipitate with aqueous bromine and ultrasonic agitation promote recovery of iodide as iodate which is caused to react with excess iodide under acid conditions, yielding I3. This is determined either spectrophotometrically or by photometric titration with sodium thiosulfate. Photometric titration gave a recovery of 99.0 0.4% and a coefficient of variation of 0.4% compared with 98.5 0.6% and 0.8%, respectively, for the spectrophotometric procedure. 

Spencer and Brewer [144] have reviewed methods for the determination of nitrite in seawater. Workers at WRc, UK [ 145] have described an automated procedure for the determination of oxidised nitrogen and nitrite in estuarine waters. The procedure determines nitrite by reaction with N-1 naphthyl-ethylene diamine hydrochloride under acidic conditions to form an azo dye which is measured spectrophotometrically. The reliability and precision of the procedure were tested and found to be satisfactory for routine analyses, provided that standards are prepared using water of an appropriate salinity. Samples taken at the mouth of an estuary require standards prepared in synthetic seawater, while samples taken at the tidal limit of the estuary require standards prepared using deionised water. At sampling points between these two extremes there will be an error of up to 10% unless the salinity of the standards is adjusted accordingly. In a modification of the method, nitrate is reduced to nitrite in a micro cadmium/copper reduction column and total nitrite estimated. The nitrate content is then obtained by difference. 

Reaction of epoxides with nitrate anion under acidic conditions... 

Unsymmetrical epoxides (39) can form two isomers, (40) and (41), on reaction with nitrate anion and so raise the issue of regioselectivity. Under acidic conditions terminal epoxides are found to predominantly yield the primary nitrate ester (41) although this is not clear cut and propylene oxide is reported to yield an ill defined mixture of isomers. A comprehensive study on the regioselectivity of epoxide opening with nitrate anion under acidic conditions was conducted on glycidol. ... 

Unlike the direct nitration of amines under acidic conditions, nucleophilic nitration is an excellent route to both primary and secondary nitramines. In these reactions the amine or the conjugate base of the amine is used to attack a source of NO2. This source may be a nitrogen oxide, nitronium salt, cyanohydrin nitrate, alkyl nitrate ester or any other similar source of nitronium ion. 

Wright and co-workers prepared a number of alkyldichloramines from the action of hypochlorous acid on primary amines and found these stable enough in acidic solution to undergo nitration with acetic anhydride-nitric acid mixtures to give the corresponding N-chloronitramines (Equation 5.13). A-Chloronitramines are isolatable intermediates and stable under acidic conditions, although some are sensitive and violent explosives. The presence of... 

Moore and Willer reported the synthesis of some nitramine explosives containing a furazan ring fused to a piperazine ring. The tetranitramine (46) is synthesized from the condensation of 3,4-diaminofurazan (DAF) (24) with glyoxal under acidic conditions followed by A-nitration of the resulting heterocycle (45). The calculated performance for the tetranitramine (46) is very high but the compound proves to be unstable at room temperature. Instability is a common feature of heterocyclic nitramines derived from the nitration of aminal nitrogens. 

The nitration of benzocyclobutene under neutral conditions has not been examined, and ititration under acidic conditions leads to considerable ring cleavage. See Homer, L Schmelzer, H.-G. Thompson, B. Chem. Ber. 1960,93,1774 (b) Ref. 46. 

This automated procedure for the determination of nitrate and nitrite uses the procedure whereby nitrate is reduced to nitrite by a copper-cadmium reduc-tor column.52 The nitrite ion then reacts with sulphanilamide under acidic conditions to form a diazo compound. This compound then couples with N-1 -naphthylethylenediamine dihydrochloride to form a reddish-purple azo dye. 

For the same reasons as outlined for pyrrole (Section 6.1.2), there is preference for 2- rather than 3-substitution. However, conventional electrophilic reactions, such as nitration, sulfonation, etc., carried out under acidic conditions, are very difficult to control. 

Essentially the same route is followed for the synthesis of the triphenylethylene nitromifene (8-5). The sequence starts with Friedel-Crafts acylation of the alkylation product (8-1) from phenol and 1,2-dibromoethane with the acid chloride from anisic acid (8-2). The displacement of bromine in the product (8-3) with pyrrolidine leads to the formation of the basic ether and thus (8-4). Condensation of that product with benzylmagnesium bromide gives the tertiary alcohol (8-5). This product is then treated with a mixture of nitric and acetic acids. The dehydration products from the first step almost certainly consist of a mixture of the E and Z isomers for the same reasons advanced above. The olefin undergoes nitration under reaction conditions to lead to nitromifene (8-6) as a mixture of isomers [8] the separated compounds are reported to show surprisingly equivalent agonist/antagonist activities. 

Peroxynitrite is capable of initiating many of the reactions commonly attributed to hydroxyl radical, particularly under acidic conditions. Halfpenny and Robinson (1952a,b) showed that nitrous acid plus hydrogen peroxide in aqueous solutions at pH 2, which generates peroxynitrous acid, initiated the polymerization of methylmethacrylate (the precurser to Plexiglas) as well as the hydrox-ylation, nitration, and polymerization of benzene. 

Activated positions (e.g., ZCH2Z compounds) can be nitrated by fuming nitric acid in acetic acid, by acetyl nitrate and an acid catalyst,264 or by alkyl nitrates under alkaline conditions.265 In the latter case it is the carbanionic form of the substrate that is actually nitrated. What is isolated under these alkaline conditions is the conjugate base of the nitro... 

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