Sodium nitrite formation

J. D. Hoffmann, D. Reaction of nicotine and sodium nitrite Formation of nitrosamines and fragmentation of the pyrrolidine ring. J. Org. Chem.. 1978, 72-76. 

Hecht, S.S., Chen, C.B., Ornaf, R.M., Jacobs, E., Adams, J.D. and Hoffmann, D., "Reaction of Nicotine and Sodium Nitrite Formation of Nitrosamines and Fragmentation of the Pyrrolidine Ring",... 

Azo-dye formation. Dissolve 2-3 drops of aniline in 1 ml. of cone. HCl and add 3 ml. of water. Shaike to dissolve any hydrochloride which may have separated and cool in ice. Add a few drops of 20% sodium nitrite solution. Add this cold diazonium solution to a cold solution of the phenol in an excess of aqueous NaOH solution. Solutions or precipitates of azo-dyes ranging in colour from orange through scarlet to dark red, according to the phenol used, are obtained. Note in particular that i-naphthol gives a brownish-red, 2-naphthol a scarlet precipitate. Catechol decomposes. 

Formation of nitrosaminey RgN NO. (a) From monomethylaniline. Dissolve I ml. of monomethylaniline in about 3 ml. of dil. HCl and add sodium nitrite solution gradually with shaking until the yellow oil separates out at the bottom of the solution. Transfer completely to a smdl separating-funnel, add about 20 ml. of ether and sh e. Run off the lower layer and wash the ethereal extract first with water, then with dil. NaOH solution, and finally with w ter to free it completely from nitrous acid. Evaporate the ether in a basin over a previously warmed water-bath, in a fume cupboard with no flames near. Apply Liebermann s reaction to the residual oil (p. 340). 

Note on the laboratory preparation of monoethylaniline. Although the laboratory preparation of monomethyl- or monoethyl-aniline is hardly worth whUe, the following experimental details may be useful to those who wish to prepare pure monoethylaniline directly from amline. In a flask, fitted with a double surface reflux condenser, place 50 g. (49 ml.) of aniline and 65 g. of ethyl bromide, and boU gently for 2 hours or until the mixture has almost entirely sohdified. Dissolve it in water and boil off the small quantity of unreacted ethyl bromide. Render the mixture alkaUne with concentrated sodium hydroxide solution, extract the precipitated bases with three 50 ml. portions of ether, and distil off the ether. The residual oil contains anihne, mono- and di-ethylaniline. Dissolve it in excess of dilute hydrochloric acid (say, 100 ml. of concentrated acid and 400 ml. of water), cool in ice, and add with stirring a solution of 37 g. of sodium nitrite in 100 ml. of water do not allow the temperature to rise above 10°. Tnis leads to the formation of a solution of phenyl diazonium chloride, of N-nitrosoethylaniline and of p-nitrosodiethylaniline. The nitrosoethylaniline separates as a dark coloured oil. Extract the oil with ether, distil off the ether, and reduce the nitrosoamine with tin and hydrochloric acid (see above). The yield of ethylaniline is 20 g. 

Special Precautions. Use of sodium nitrite or other nitrosating agents in formulations containing nikanolamines could lead to formation of suspected cancer-causing nitrosamines. 

Gas contact is typically carried out in absorption towers over which the alkaline solutions are recirculated. Strict control over the conditions of absorption are required to efficiendy capture the NO and convert it predominantly to sodium nitrite according to the following reaction, thereby minimizing the formation of by-product sodium nitrate. Excessive amounts of nitrate can impede the separation of pure sodium nitrite from the process. 

The reactivity of the 5-position of 2-aminothiophene in diazo coupling, which is present also in the acylated derivatives, complicates the formation of a diazonium salt from 2-aminothiophene. Thus Steinkopf and Miiller obtained only an azo dyestuff, although they proved, through the isolation of small amounts of 2-thienyl diazonium chloride, the diazotizability of 2-aminothiophene which had earlier been denied. However, recent Russian work claims the preparation of 2-thienyldiazonium chloride by treating the double salt in 10% hydrochloric acid with sodium nitrite. Amazingly high yields (over 90%) of azo compounds were then achieved by coupling the diazonium salt solution with y9-naphtol, w-toluidine or with the 2-aminothiophene double salt. These authors have also studied the... 

The nitrosation of primary aromatic amines 1 with nitrous acid 2 and a subsequent dehydration step lead to the formation of diazonium ions 3. The unstable nitrous acid can for example be prepared by reaction of sodium nitrite with aqueous hydrochloric acid. 

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

In contrast to the acid, sodium nitrite should not in general be added in excess. Firstly, as far as the ratio of amine to nitrite is concerned, diazotization is practically a quantitative reaction. In consequence, it provides the most important method for determining aromatic amines by titration. Secondly, an excess of nitrous acid exerts a very unfavorable influence on the stability of diazo solutions, as was shown by Gies and Pfeil (1952). Mechanistically the reactions between aromatic diazonium and nitrite ions were investigated more recently by Opgenorth and Rtichardt (1974). They showed that the primary and major reaction is the formation of aryl radicals from the intermediate arenediazonitrite (Ar —N2 —NO2). Details will be discussed in the context of homolytic dediazoniations (Secs. 8.6 and 10.6). 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

Recently, Robach et al. ( ) investigated the effects of various concentrations of sodium nitrite and potassium sorbate on N-nitrosamine formation in commercially prepared bacon. 

It is conceivable that nltrosamlnes can be synthesized In the Intestine, since the precursors are present. While the conditions for aqueous nltrosatlon reactions are not optimum at pH values encountered In the lower gastrointestinal tract, several studies have shown that these reactions can be catalyzed (39, 40, 41). It has been suggested that the Intestine might be a site for the formation of nltrosamlnes by bacterial action (42). Sander (43) has demonstrated the formation of nltrosamlnes by bacterial action from precursor amines and nitrate at neutral pH and Klubes and coworkers have reported the formation of NDMA. upon Incubation of l C-dlmethylamlne and sodium nitrite with rat fecal contents (44, 45). 

Figure 2, Formation of H-nitrosoglyphosate after treatment with sodium nitrite at pH 3,0 and 25°C ( 2), Initial concentrations glyphosate, 10,5mM sodium nitrite, 10,lmM (9), 7,5mM (Ah and 5,0mM (Wh...

Figure 5, Formation of H-nitrosoglyphosate in soils incubated at 25°C with 20 ppm of nitrite nitrogen as sodium nitrite and 740 ppm glyphosate (free acid equivalent) (6), Soil syrnbols , Fox A, Grandin Brookston and O, Granville,...

The effect of sodium nitrite on phthalic anhydride when it was hot ended with a violent detonation of the medium. It was explained by the formation of a derivative containing the following unstable group CO-ONO. 

The first two reaction types often lead to the formation of stable end-products, but (c) and (d) lead to the formation of new carbocations to which the whole spectrum of reaction types is still open. Most of these possibilities are neatly illustrated in the reaction of 1-amino-propane (11) with sodium nitrite and dilute hydrochloric acid [the behaviour of diazonium cations, e.g. (12), will be discussed further below, p. 119] ... 

---