Diazotization mechanisms

Contrary to earlier assumptions, the aryl ammonium ion is not able to undergo diazotization since the crucial step in the diazotization mechanism is the electrophilic nitrosation of the free amino group in the free-base primary aromatic amine 12  

The diazotization reaction requires an excess of acid formation of the active ni-trosating agent XNO proceeds via the underlying equilibrium  

The reaction mechanism is reviewed in more detail by Zollinger [2], 

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Treatment of aniline 1 with nitric acid in the presence of tetrafluoroboric acid leads to a relatively stable benzenediazonium tetrafluoroborate 2 by the usual diazotization mechanism. There are several variants for the experimental procedure. Subsequent thermal decomposition generates an aryl cation species 4, which reacts with fluoroborate anion to yield fluorobenzene 3 " ... 

A widely significant and crucial investigation of the mechanism of diazotization was made in 1899 by Hantzsch and Schumann widely significant because it was one of the first mechanistic investigations using appropriate methods of organic chemistry - extremely crucial because it influenced all subsequent investigations in the field of diazotization mechanisms until 1958. 

Schmid s work marks the start of a change in the way in which the mechanism of diazotization was regarded, although it seems surprising that Schmid did not discuss further the contrast between his result indicating a reaction of third order and Hantzsch s claiming a second-order reaction. The diazotization mechanism in dilute HC1 and HBr will be discussed in Section 3.3. 

We will first discuss these two problems in a general way, and afterwards we will use the results for the diazotization mechanism in region B of Figure 3-1. 

This type of scheme for the nitrosation of primary aromatic amines was first used by Ridd in 1959. The comparison of the present scheme with that from 1959 demonstrates how much more diversified the knowledge on diazotization mechanisms has become in three decades. 

A study of the diazotization mechanism of 2-aminothiazole has shown that 2-aminothiazole is protonated at the endocyclic nitrogen and then attacked by the NO ion, the final status of the process being an equilibrium between the protonated form and the diazonium salt <89hcA800>. 

The free radical mechanism is confirmed by the fact that if a substituted aromatic hydrocarbon is used in this reaction, the incoming group (derived from the diazotate) may not necessarily occupy the position in the benzene ring normally determined by the substituent present—a characteristic of free radical reactions. 

Some recent general reviews deal with the mechanism of N-nitrosation in aqueous solution (345), the nitrosation of secondary amines (346). the effect of solvent acidity On diazotization (347) and the reactivity of diazonium salts (1691). Therefore, a complete rationalization of the reactivity of amino azaaromatics would be timelv. 

Guaiacols. Cresote, obtained from the pyrolysis of beechwood, and its active principles guaiacol [90-05-1] (1) and cresol [93-51-6] (2) have long been used ia expectorant mixtures. The compounds are usually classed as direct-acting or stimulant expectorants, but their mechanisms of action have not been well studied. Cresol is obtained by the Clemmensen reduction of vanillin (3), whereas guaiacol can be prepared by a number of methods including the mercuric oxide oxidation of lignin (qv) (4), the ziac chloride reduction of acetovanillone (5), and the diazotization and hydrolysis of o-anisidine (6). 

To a cold mixture of 800 cc. of 95 per cent ethyl alcohol and 200 cc. of concentrated sulfuric acid (Note i) in a 5-I. round-bottom flask, provided with an efficient mechanical stirrer, is added 250 g. (1.33 moles) of crude 3-bromo-4-aminotoluene (p. 8). The solution is stirred and cooled to 10° and a solution of 148 g. (2.05 moles) of d.s.p. sodium nitrite in 260 cc. of water is added from a separatory funnel. During this addition, the temperature of the mixture must not be allowed to rise above 10°. After all of the nitrite solution has been added, the mixture is stirred twenty minutes longer to complete the diazotization. 

In a 600-ml. beaker fitted with a thermometer and mechanical stirrer are placed 150 ml. of concentrated hydrochloric acid and 55 g. (0.32 mole) of o-bromoaniline. After brief stirring, 100 g. of ice is added and the beaker is surrounded by an ice-salt bath. The solution is then diazotized by the dropwise addition with stirring of a solution of 24.3 g. (0.35 mole) of sodium nitrite in 100 ml. of water, the temperature being kept at 0-5°. 

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. 

Forty-three grams (0.25 mole) of />-bromoaniline (Note 1) and 20 cc. of water are warmed in a 400-cc. beaker until the bromoaniline melts, and then 50 cc. of concentrated hydrochloric acid (sp. gr. 1.19) is added with mechanical stirring. The mixture is heated and stirred until solution is practically complete (Note 2). The beaker is then set in a dish of ice water and the solution is stirred as it cools in order to precipitate the />-bromoaniline hydrochloride in fine crystals. A few small pieces of ice are added and the cold (about 0-5 °) suspension is diazotized with a solution of 18 g. of sodium nitrite in 36 cc. of water to an end point with starch-iodide paper. 

To 375 cc. (4.3 moles) of hydrochloric acid (sp. gr. 1.18) and 200 g. of ice is added 139.6 g. (1.5 moles) of aniline. The resulting solution is diazotized with a solution of 103.5 S (x-5 moles) of c. p. sodium nitrite, ice being added to the reaction mixture, as necessary, in order to keep the temperature below 50. The final volume of the diazotized solution is about 1 1. This solution is added in a slow stream from a dropping funnel to the potassium selenide solution, which is being vigorously stirred with a mechanical stirrer. When all the diazotized solution has been added, the red aqueous solution is decanted from the dark oil which forms and is heated to boiling (Note 4). It is then poured back on the oil, the mixture is well stirred (Note 5), 200 cc. of chloroform is added, and the selenium collected on a filter and washed with a little more chloroform (Note 6). After the chloroform layer is separated, the aqueous layer is again... 

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... 

A characteristic property of most diazotizations of aminoazoles is the occurrence of a relatively stable transient intermediate (probably the A-nitrosoamine), in contrast with the diazotization of carbocyclic aromatic amines, where A-nitrosoamines have been considered to be unstable intermediates. This problem will be discussed in the context of the mechanism of diazotization in Section 3.4. 

As the amines become more weakly basic, the normal method of diazotization becomes progressively more difficult. The equilibrium between amine and ammonium salt increasingly favors the former which, usually because of its poor solubility in water, is prevented from taking part in the reaction. Research into the mechanism of diazotization has demonstrated that the important step is the addition of the nitrosating agent to the base of the amine. Thus, the acidity for each diazotization should be so chosen that the equilibrium concentration of base corresponds to that of its saturated solution. This rule leads to the use of higer concentrations of aqueous mineral acid for weakly basic amines. 

Another redox reaction leading to arenediazonium salts was described by Morkov-nik et al. (1988). They showed that the perchlorates of the cation-radicals of 4-A,A-dimethylamino- and 4-morpholinoaniline (2.63) react with gaseous nitric oxide in acetone in a closed vessel. The characteristic red coloration of these cation-radical salts (Michaelis and Granick, 1943) disappears within 20 min., and after addition of ether the diazonium perchlorate is obtained in 84% and 92% yields, respectively. This reaction (Scheme 2-39) is important in the context of the mechanism of diazotization by the classical method (see Sec. 3.1). 

It is worthwhile to briefly discuss the history of investigations into the mechanism of diazotization. Its progression between 1894 and 1958 demonstrates that it may take more than 60 years to correct a false mechanistic interpretation of good experimental results followed by many supporting conclusions. 

Research into the mechanism of diazotization was based on Bamberger s supposition (1894 b) that the reaction corresponds to the formation of A-nitroso-A-alkyl-arylamines. The TV-nitrosation of secondary amines finishes at the nitrosoamine stage (because protolysis is not possible), but primary nitrosoamines are quickly transformed into diazo compounds in a moderately to strongly acidic medium. The process probably takes place by a prototropic rearrangement to the diazohydroxide, which is then attacked by a hydroxonium ion to yield the diazonium salt (Scheme 3-1 see also Sec. 3.4). 

This statement does not mean, however, that the mechanism of diazotization was completely elucidated with that breakthrough. More recently it was possible to test the hypothesis that, in the reaction between the nitrosyl ion and an aromatic amine, a radical cation and the nitric oxide radical (NO ) are first formed by a one-electron transfer from the amine to NO+. Stability considerations imply that such a primary step is feasible, because NO is a stable radical and an aromatic amine will form a radical cation relatively easily, especially if electron-donating substituents are present. As discussed briefly in Section 2.6, Morkovnik et al. (1988) found that the radical cations of 4-dimethylamino- and 4-7V-morpholinoaniline form the corresponding diazonium ions with the nitric oxide radical (Scheme 2-39). 

Analogies for such a mechanism in diazotization are found in the nitrous acid-catalyzed nitration of A,A-dimethylaniline, mesitylene, 4-nitrophenol, and some related compounds, which were investigated by 15N NMR spectroscopy in Ridd s group (Ridd and Sandall, 1981 Ridd et al., 1992 Clemens et al., 1984a, 1984b, 1985 Johnston et al., 1991 review Ridd, 1991). Ridd and coworkers were able to demonstrate clearly that not only the nitration proper, but also the preceding C-nitrosation, is accompanied by a marked 15N nuclear polarization. This was at-... 

Influence of Acidity on the Rate and Mechanism of Diazotization in Aqueous Sulfuric and Perchloric Acids... 

Acidity has an important influence on diazotization. Correlations of rates of diazotization with acidity and their implications regarding the reaction mechanism were first evaluated by Ridd (reviews Ridd, 1959, 1961, 1965, 1978 Williams, 1983, 1988). In this section we will concentrate mainly on aqueous solutions of sulfuric acid and perchloric acid, as the weakly nucleophilic anions of these acids do not interact with the nitrosating species. The mechanism of diazotization in the presence... 

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