By Direct Nitration

Nitration of a substituted quinoxaline usually occurs in the homocyclic ring and occasionally in an exocyclic substituent such as a phenyl group. The actual position(s) of nitration can seldom be forecast with any confidence analogy with reported nitrations is still the best guide. Accordingly, the following examples are classified, not by nitration sites but by the reagents used. 

Quinoxalines Supplement II, Chemistry of Heterocyclic Compounds, Volume 61, by Desmond J. Brown ISBN 0-471-26495-4 Copyright 2004 John Wiley Sons, Inc. 

5-Piperidino-7- 7-toluenesulfonaniidoqumoxalme (1, Q = R = H) gave a separable mixture of 5-nitro-8-piperidino-6-p-toluenesulfonamido- (1, Q = H, R = NO2) and 6-nitro-5-piperidino-7-p-toluenesulfonamidoquinoxaline (1, Q = 

6-Bromo-7-fluoro-3,4-dihydro-2(l//)-quinoxalinone (2) gave only 6-bromo- 

7-fluoro-5-nitro-2,3(l//, 4//)-quinoxalinedione (3) (excess 90% HNO3, F3CCO2H, 20°C, 12 h 85% note the additional oxidative introduction of a second 0x0 aubstituent) also analogous products likewise. 

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In the commonly used Welland process, calcium cyanamide, made from calcium carbonate, is converted to cyanamide by reaction with carbon dioxide and water. Dicyandiamide is fused with ammonium nitrate to form guanidine nitrate. Dehydration with 96% sulfuric acid gives nitroguanidine which is precipitated by dilution. In the aqueous fusion process, calcium cyanamide is fused with ammonium nitrate ia the presence of some water. The calcium nitrate produced is removed by precipitation with ammonium carbonate or carbon dioxide. The filtrate contains the guanidine nitrate that is recovered by vacuum evaporation and converted to nitroguanidine. Both operations can be mn on a continuous basis (see Cyanamides). In the Marquerol and Loriette process, nitroguanidine is obtained directly ia about 90% yield from dicyandiamide by reaction with sulfuric acid to form guanidine sulfate followed by direct nitration with nitric acid (169—172). 

Nitration. Naphthalene is easily nitrated with mixed acids, eg, nitric and sulfuric, at moderate temperatures to give mostly 1-nitronaphthalene and small quantities, 3—5%, of 2-nitronaphthalene. 2-Nitronaphthalene [581-89-5] is not made in substantial amounts by direct nitration and must be produced by indirect methods, eg, the Bucherer reaction starting with 2-naphthalenol (2-naphthol [135-19-3]). However, the 2-naphthylamine [91-59-8] made using this route is a carcinogen thus the Bucherer method is seldom used in the United States. 

Nitrated fluoro compounds are synthesized by electrophilic (NOz+), radical (NO2 ), or nucleophilic (NO2-) methods Indirect nitration routes can suppress the side reactions associated with severe reaction conditions and some nitration reagents Novel fluoronitro compounds, unobtainable by direct nitration, can also be pre pared For example, the nitration of (2-fluoro-2,2-dinitroethoxy)acetaldoxime followed by oxidation of the nitroso intermediate with hydrogen peroxide yields 2-fluoro-2,2-dinitioethyl 2,2-dinitroethyl ether [f] (equation 1)... 

Substituted nitrobenzotrifluondes useful as intermediates for agrochemicals, pharmaceuticals, and liquid crystals are prepared by direct nitration of the respec-... 

Mononitrophenols. OjN.CgH4.OH,mw 139.11, N 10.07%, OB to C02 —133.17%. Three isomers are possible but only two (o- and p-) are obtained by direct nitration. The nitration of phenol is much easier than that of aromatic hydrocarbons such as benz or toluene... 

P-Nitronaphthalene is not formed by direct nitration. For the preparation of p-naphthylamine, the Bucherer reaction may be applied to p-naphthol, i.e., by heating with ammoniacal ammonium sulphite solution at 150° (under pressure). The reaction involves the addition of the bisulphite to the keto form of p-naphthol ... 

Nitroveratraldehyde has always been prepared by direct nitration of the aldehyde. This preparation is a modification of that given by Salway.8... 

New isoxazoline derivatives of a-tocopherol, the main component of vitamin E, have been synthesized in a facile, two-step sequence consisting of nitration followed by 1,3-dipolar cycloaddition. 5-Nitromethyl-a-tocopheryl acetate, obtained from a-tocopheryl acetate by direct nitration in one step, act as the nitrile oxide precursor in the reaction with various alkenes. The facile conversion proceeds in the presence of equimolar amounts of PhNCO and catalytic amounts of triethylamine to give isoxazolines, 446 (489). 

Triphenylnitrobenzene may be prepared by direct nitration of 1,3,5-triphenylbenzene and by the reaction of 2,4,6-triphenylpyrylium tetrafluoroborate with nitromethane. The present procedure is an adaptation of the latter method. 

Similarly, acetylation of thieno[3,2-6]thiophene (2) afforded 2-acetyl-thieno[3,2-6]thiophene, which was converted into methyl n-hexyl ketone by desulfurization with Raney nickel. Oxidation of 2-acetylthieno-[3,2-i]thiophene followed by nitration gave 5-nitrothieno[3,2-6]-thiophene-2-carboxylic acid. Decarboxylation of the latter furnished 2-nitrothieno[3,2-ft]thiophene identical with the compound obtained by direct nitration of thienothiophene 2 [Eq. (60)]. 

Kiirschner et al (Refs 7, 8 11) prepd nitrolignin by direct nitration of wood pulp. 

GuTh was formerly one of the most common salts of Gu,serving as the parent of other salts thru metathetical reactions. It also served as starting material for NGu by direct nitration with mixed acid. The NGu obtd proved to be unsuitable for use with NC because of the sul-furous impurities which reacted with the NC in storage. A strong aq soln of GuTh will dissolve cellulose (Ref 4)... 

For many years (before and for sometime after WWI), NGu, as well as many other derivs of Gu, was prepd from Gu thiocyanate, one of the cheapest and easiest id prepare of the Gu salts. The thiocyanate used to be the principal industrial product of Gu. However, NGu prepd from thiocyanate by direct nitration with mixed acids always contained traces of sulfur compds. When such NGu was used with NC in smokeless pro plot, the sulfur compds attacked the NC and thus lowered the stability of the proplnt. This was one reason why NGu powder did not come into earlier use (Ref 6d, p 375)... 

Aminoferrocene (XXXV) can be prepared in low yield by treatment of O-methylhydroxylamine or O-benzylhydroxylamine with ferrocenyllithium (1, 65). Nitroferrocene (XXXVI), unattainable by direct nitration of ferrocene, can be isolated from the reaction of ferrocenyllithium and either n-propyl nitrate or dinitrogen tetroxide at —70° (30, 36). A similar reaction between ferrocenyllithium and nitrous oxide leads to azoferrocene (XXXVII) (08). 

HO.Ci0H2(NO2)4.OH mw 340.16, N 16.47% yel ndls (from acet), mp-decamp violently between 250-65° depending on rate of heating was prepd by nitrating 2,4-dinitro-5-acetoxy-1-naphthol with HN03(d 1.5) at 0°, or by direct nitration of 1,5-dihydroxynaphthalene in acetic anhydride by diacetyl orthonitric acid in acet anhyd at 0° during l%hrs (Refs 1, 2 3). No expl props were reported... 

It was prepd in 1874 by Austen (Refs 1 St 2) by nitrating Picryl-p-nitroaniiine and in the same year by Gnehm (Refs 1 St 3) by the nitration of methyldiphenylamine. Mertens (Ref 4) was the first to prep it by direct nitration of DPhA. 

The large scale prepn of HNDPhA by direct nitration of DPhA was conducted, accdg to Davis (Ref 26, pl84), in 1910 in Germany... 

Herz succeeded in preparing RDX by direct nitration of hexamine, but the yields were low and the process was expensive and unattractive for large scale production. Hale, at Picatinny Arsenal in 1925, developed a process for manufacturing RDX which produced yields of 68%. However, no further substantial improvements were made in the manufacture of RDX until 1940 when Meissner developed a continuous method for the manufacture of RDX, and Ross and Schiessler from Canada developed a process which did not require the use of hexamine as a starting material. At the same time, Bachmann developed a manufacturing process for RDX (1.5) from hexamine which gave the greatest yield. 

Mononltroanllines or Nitroanilines, OjN.Q" H4.NHj, exist in three isomeric forms ortho-, meta-, and para. They are commercially available and extensively used in industry. None of these isomers can be obtained in good yield by direct nitration of aniline and it is necessary to employ indirect methods such as che Holleman method of acetylation of aniline to acetanilide followed by nitration(Ref 2) or by ammonolysis... 

TNAns is hygroscopic and is decompd by hot water with the formation of iso-picric acid (qv) (Ref 26). TNAns was prepd in 1849 by Cahours by direct nitration of anisole (Ref 6). This method according to Davis (Ref 51) is dangerous as it may produce an... 

Nitroalkanes. A process was developed and operated for a time for the manufacture of s-caprolactam based on the nitration of cyclohexane.197 Nitrocyclohexane thus prepared was transformed to e-caprolactam via cyclohexanone oxime. At present the only industrial process to produce nitroalkanes by direct nitration is the manufacture of nitromethane, nitroethane, 1-nitropropane, and 2-nitropropane. 

On the other hand, Elliott and his co-workers 4 maintain that the evidence for the nitro- structure is unsatisfactory, and that the p-nitro-dimethylaniline produced with dimethylaniline is a secondary product obtained either by oxidation of the nitroso-compound or by direct nitration of the amine. The addition of ethyl hydrogen sulphate to a solution of nitrosulphonic acid in sulphuric acid does not yield nitro -ethane. Elliott suggests that the crystalline acid is essentially the nitroso- form, ON. O. SO 2. OH, but that in the molten condition and in sulphuric acid solution this form is in equilibrium with another of yO ... 

However, de Bruin and Witte [55c] found that the solubility of partly denitrated nitrocellulose is abnormal. Thus, nitrocelluloses of 13.43 and 12.98% N prepared by direct nitration had solubilities in ethanol-ether (1 2 by volume) of 5 and 100% respectively. 

The 2,4- and 2,5-dinitrothiophenes are prepared by direct nitration of mononitrothio-phenes. Nitration of 2-nitrothiophene with nitric acid and sulfuric acid at 10 °C gives 2,5-dinitrothiophene, with only traces of 2,4-dinitrothiophene. Similar treatment of 3-nitrothiophene gives the 2,4-dinitrothiophene in good yield (Section 3.14.2.4). 

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