Diazotate ion

A continuing problem in this area has been the identification of the species X of Scheme 6, which plays a key role in the chain mechanism. The favoured view is that X is the diazotate ion, ArN=NO . 

Type II nitrosamines have two reaction pathways. One pathway involves nucleophilic attack at the carbon of C=0 to generate a tetrahedral intermediate which decomposes to an active diazotate ion (R-N=N-0 ). The other pathway involves the nucleophililc attack on the nitrogen of the nitroso group resulting in denitrosation (Scheme 3.5). The nucleophile can be a biologically prevalent thiol, therefore type II compounds are often used as NO donors for the formation of S-nitrosothiols [67, 68]. 

The pK, values of the two equilibria of equation (70) are pKi = 4.3 and pKj = 9.9, respectively. Therefore, in solutions of pH < 4.3 the relative concentration of the amino form 75/ will decrease by one power of ten per pH unit. As it is only the amino form which reacts with the diazonium ion, we expect that the logarithm of the rate of coupling at the 1-position will show a linear increase with pH (see Fig. 3, dotted line). An analogous situation exists for coupling at the 8-position. The rate will increase by one power of ten per pH unit up to pH 9.9 and then level off at higher pH values (Fig. 3, solid line). The decrease of bodi curves at pH > 11 is due to the diazonium ion diazotate ion equlibrium (see Sect. 4.1). 

Couplings between arenediazonium cations and phenols take place most rapidly in slightly alkaline solution. Under these conditions an appreciable amount of the phenol is present as a phenoxide ion, ArO , and phenoxide ions are even more reactive toward electrophilic substitution than are phenols themselves. (Why ) If the solution is too alkaline (pH > 10), however, the arenediazonium salt itself reacts with hydroxide ion to form a relatively unreactive diazohydroxide or diazotate ion ... 

The product of this series of steps is an alkyl diazonium ion, and the amine is said to have been diazotized Alkyl diazonium ions are not very stable decomposing rapidly under the conditions of their formation Molecular nitrogen is a leaving group par excel lence and the reaction products arise by solvolysis of the diazonium ion Usually a car bocation intermediate is involved... 

Aryl diazonium ions prepared by nitrous acid diazotization of primary arylamines are substantially more stable than alkyl diazonium ions and are of enormous synthetic value Their use m the synthesis of substituted aromatic compounds is described m the following two sections... 

Diazotization (Section 22 16) The reaction by which a pn mary arylamine is converted to the corresponding diazo mum ion by nitrosation... 

Diazotization Routes. Conventional Sandmeyer reaction conditions are not suitable to make fluoroaromatics. Phenols primarily result from high solvation of fluoride ion in aqueous media. 

This method is suitable only for the preparation of 4-substituted and/or 3,4-disubstituted derivatives, the substituents being only alkyl, aryl or heteroaryl groups. The presence of electron-withdrawing groups in the unsaturated side chain prevents the cyclization step. This is understandable if the influence of such groups on the stability of the intermediate carbonium ion is considered. Of more limited application is the analogous cyclization of diazotized o-aminophenylpropiolic acids, the reaction being referred to as the Richter synthesis (Scheme 70). A related synthesis (also referred to as the Neber-Bossel synthesis)... 

Pyridine-2- and -4-diazonium ions are far less stable than benzenediazonium ions. Azolediazonium salts generally show intermediate stability provided diazotization is carried out in concentrated acid, many of the usual diazonium reactions succeed. Indeed, azolediazonium salts are often very reactive in coupling reactions. 

When 6/3-aminopenicillanic acid (6-APA) is diazotized in the presence of chloride ion, the principal product obtained is 6a-chloropenicillanic acid (38) (62JOC2668), presumably by way of the diazo intermediate (39 Scheme 29) (72JCS(P1)895). If the diazotization is carried out in the presence of excess bromide instead of chloride, significant amounts of the 6,6-dibromo derivative are obtained, and in the case of excess iodide the 6,6-diiodopenicillanic acid becomes the predominant product (69JCS(C)2123). The 6,6-dihalo products presumably arise from nitrous acid oxidation of halide to halogen, which then reacts with (39). 

Nucleophilic substitution reactions that occur imder conditions of amine diazotization often have significantly different stereochemisby, as compared with that in halide or sulfonate solvolysis. Diazotization generates an alkyl diazonium ion, which rapidly decomposes to a carbocation, molecular nitrogen, and water ... 

Among the reagents that are classified as weak electrophiles, the best studied are the aromatic diazonium ions, which reagents react only with aromatic substrates having strong electron-donor substituents. The products are azo compounds. The aryl diazonium ions are usually generated by diazotization of aromatic amines. The mechanism of diazonium ion formation is discussed more completely in Section 11.2.1 of Part B. 

Because of the limited range of aromatic compounds that react with diazonium ions, selectivity data comparable to those discussed for other electrophilic substitutions are not available. Because diazotization involves a weak electrophile, it would be expected to reveal high substrate and position selectivity. 

Heavily fluonnated aminobenzenes, pyridines, and pyrimidines are diazotized in strong-acid media Solid sodium nitrite added directly to the fluonnated amine dissolved in 80% hydrofluonc acid, anhydrous hydrogen fluoride, or (1 1 wt/wt) 98% sulfuric acid in (86 14 wt/wt) acetic and propionic acids affords the electrophilic fluoroarenediazonium ion Addition of an electron rich aromatic to the resultant diazonium solution gives the fluoroareneazo compound [10 II] (equa tions 9 and 10)... 

Tetramethyl-l,2-oxathietane (138) was prepared by diazotization of 139, which was prepared from the aziridine (140) (86JA3811).Tlie reaction presumably involves the decomposition of the sulfonium ion intermediate (141).Tire dichloromethane solution of 138 at -20°C is sufficiently stable to permit exploration of the chemical reactions. Tire oxathietane 138 undergoes a formal [[Pg.248]

Aliphatic primary amines also undergo the diazotization reaction in weakly acidic solution however the resulting aliphatic diazonium ions are generally unstable, and easily decompose into nitrogen and highly reactive carbenium ions. The arenediazonium ions are stabilized by resonance with the aromatic ring ... 

Most functional groups do not interfere with the diazotization reaction. Since aliphatic amines are stronger bases and therefore completely protonated at a pH < 3, it is possible that an aromatic amino group is converted into a diazonium group, while an aliphatic amino group present in the same substrate molecule is protected as ammonium ion and does not react. ... 

The reaction of nitrous acid with the amino group of the /3-amino alcohol—e.g. 1-aminomethyl-cyclopentanol 1—leads to formation of the nitrosamine 4, from which, through protonation and subsequent loss of water, a diazonium ion species 5 is formed " —similar to a diazotization reaction ... 

The NH2 groups can be diazotized and reduced in the presence of thiosulphates and different metal ions. The effect of some metal ions, namely Fe ", Sn, Cu +, and Co on the graft yield of cotton modified with aryl diazonium groups via its reaction with 2,4-dichloro-6-(p-nitroaniline)-5-triazine in the presence of alkali and followed by reduction of nitro group was studied [4]. 

Free radicals can be generated on the cellulose chain by hydrogen abstraction, oxidation, the ceric ion method, diazotization, introduction of unsaturated groups, or by y-irradiation. 

Diazotization (Section 24.8) The conversion of a primary amine, RNH2, into a diazonium ion, RN2+, by treatment with nitrous acid. 

It has been observed2 that the dropwise addition of an aqueous solution of potassium ethyl xanthate to a cold (0°) aqueous solution of diazotized orthanilic acid results in the immediate loss of nitrogen when a trace of nickel ion is present in the stirred diazonium solution.3 The catalyst can be added as nickelous chloride or simply by using a nichrome wire stirrer. When no nickel ion is added and a glass stirrer is employed, the diazonium xanthate precipitates and requires heat (32°) to effect decomposition. 

Bromo-6,7,8,9-tetrahydro-l//-3-benzazepin-2-amine(6) with thiocyanate ion undergoes substitution of bromide to give the thiocyanatotetrahydro-l//-3-benzazepine 7.105 Attempts to replace bromide by azide ion failed, as did diazotization of the amine group with sodium nitrite in 6 M sulfuric acid. Oddly, treatment of the aminobromo compound with sodium borohydride in methanol results not in reduction, but in methoxy-debromination to give the 2-methoxy derivative which, on the basis of HNMR spectral data, is best represented as the 2-imino tautomer 8. 

Griess (1864a) had already observed that the diazo compounds obtained from primary aromatic amines in acid solution are converted by alkalis into salts of alkalis. The reaction is reversible. The compounds which Hantzsch (1894) termed sjw-diazotates exhibit apparently the same reactions as the diazonium ions into which they are instantaneously transformed by excess of acid. Clearly the reaction depends on an acid-base equilibrium. 

Of course, in aqueous solution the reactants and the products exist wholly or partly in their ionized forms the acid, nitrite, and salt exist as H+X , Na+N02, and Na+X , while the diazonium salts are practically completely ionized and the amine is in equilibrium with the corresponding ammonium ion, Ar—NH3. The question of which of these various species are involved in the substitution proper will be dealt with in Chapter 3. Although it is generally desirable to introduce ionized forms into equations, this is inappropriate for the overall equation for the diazotization process, as will become apparent in the discussion of the reaction mechanism (Ch. 3) and from the following remarks. 

As described more fully in Sections 3.1-3.3, with increasing pH the reactive forms of the diazotizing agent are converted into ineffective ones, namely free nitrous acid, HN02, and the nitrite ion, N02. From the discussion of the mechanism of diazotization it will also become apparent why the reaction proceeds better, that is faster, in dilute hydrochloric than in dilute sulfuric acid. With very slow diazotizations for instance, because of high dilution as in nitrite titrations, the use... 

An increased hydrogen ion concentration, that is a considerably greater amount of acid than the theoretical two equivalents of Scheme 2-1, is necessary in the diazotization of weakly basic amines. The classic example of this is the preparation of 4-nitrobenzenediazonium ions 4-nitroaniline is dissolved in hot 5-10 m HC1 to convert it into the anilinium ion and the solution is either cooled quickly or poured onto ice. In this way the anilinium chloride is precipitated before hydrolysis to the base can occur. On immediate addition of nitrite, smooth diazotization can be obtained. The diazonium salt solution formed should be practically clear and should not become cloudy on standing in the dark. Some practice is necessary, and details can be found in the books emphasizing preparative aspects (Fierz-David and Blangey, 1952 Saunders and Allen, 1985 in Houben-Weyl, Vol. E 16a, Part II, the chapter written by Engel, 1990). These books give a series of detailed prescriptions for specific examples and a useful review of the principal variations of the methods of diazotization. Such reviews have also been written by Putter (1965) and Schank (1975). 

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). 

This diazotization is typical of many aminoazoles the diazonium ions formed are relatively strong acids. The pATa values of five di-, tri-, and tetrazolediazonium ions are reported to be between 3 and 4, i. e., about 10 units lower (more acidic) than those of the respective unsubstituted heterocycles (Vilarrasa et al., 1974). Therefore, deprotonation of the diazonium ion is easy and, depending on reaction conditions, yields either the diazonium salt or its conjugate base, the diazo compound. The electrophilic reactivity of the P nitrogen atom in the diazo group of the base is lower than the reactivity of the diazonio group of the cation (Diener and Zollinger, 1986 see Sec. 12.2). 

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