Isolation of Diazonium Salts

The foimation of aromatic diazonium salts from aromatic primary amines is one of the oldest synthetic procedures in organic chemistry. Methods based on nitrosation of amine with nitrous acid in aqueous solution are die best known, but diere are variants which are of particular use widi weakly basic amines and for the isolation of diazonium salts fiom nonaqueous media. General reviews include a book by Saunders and AUen and a survey of preparative methods by Schank. There ate also reviews on the diazotization of heteroaromatic primary amines and on the diazotization of weakly basic amines in strongly acidic media. The diazotization process (Scheme 11) goes by way of a primary nitrosamine. 

The diazoamino-compounds are usually yellow in colour, and do not dissolve in acid they can usually be isolated and crystallized without decomposition. When treated with HNO2 two molecules of diazonium salt are formed. Form an azo compound when warmed with an amine and its hydrochloride, e.g. 

In most cases diazonium salts are not isolated, but are converted into products by reactions that can be carried out in situ. Moreover, it is actually recommended not to isolate these salts, not even for purification purposes, as many of them have a tendency to explode. In addition, the high solubility of most diazonium salts in water makes precipitation from this medium difficult. Therefore, to obtain solid diazonium salts the recommended method for many decades was to carry out diazotizations in ethanol followed by precipitation with ether. As inorganic salts of nitrous acid are scarely soluble in ethanol, Knoevenagel recommended alkyl nitrites (ethyl or isopentyl nitrite) as diazotization reagents as long ago as 1890. Various other solvents have subsequently been used for diazotizations with alkyl nitrites (see Saunders and Allen, 1985, p. 23 ff.), but as a method for obtaining solid diazonium salts this has been superseded by the isolation of diazonium tetrafluoroborates and, to a lesser degree, of hexafluorophosphates. 

Milner (1992) recently described a novel and versatile modification of the Balz-Schiemann reaction. The amine is diazotized with solid nitrosonium tetrafluoro-borate in CH2C12 and, without isolation, the diazonium salt is heated and yields the fluoroarene in good yield. The method is also applicable to aniline derivatives bearing carboxy and hydroxy substituents, compounds which give poor yields in the classical procedure. 

Entries 7 and 8 illustrate conversion of diazonium salts to phenols. Entries 9 and 10 use the traditional conditions for the Sandmeyer reaction. Entry 11 is a Sandmeyer reaction under in situ diazotization conditions, whereas Entry 12 involves halogen atom transfer from solvent. Entry 13 is an example of formation of an aryl iodide. Entries 14 and 15 are Schiemann reactions. The reaction in Entry 16 was used to introduce a chlorine substituent on vancomycin. Of several procedures investigated, the CuCl-CuCl2 catalysis of chlorine atom transfer form CC14 proved to be the best. The diazonium salt was isolated as the tetrafluoroborate after in situ diazotization. Entries 17 and 18 show procedures for introducing cyano and azido groups, respectively. 

The products produced by interaction of diazonium salts and iodides are unstable and liable to be explosive in the solid state. They are usually the triiodides, but monoiodides have been isolated under specific conditions from diazotised aniline and o-toluidine. Products prepared from diazotised o-, m- or p-nitroanilmes, m-chloro-, -methoxy-, or -methyl-aniline are too unstable to isolate, decomposing below 0°C. 

Diazotization has been reported for all the pyrazolopyridines, and in some cases the salts have been isolated. A 7-aminopyrazolo[4,3-c]pyridine (191a) was converted to the corresponding hydroxy compound with sodium nitrite in hot glacial acetic acid.159 Analogous products were obtained from a 3-aminopyrazolo[3,4-b]-15 and 2-aminopyrazolo[l,5-a]pyridine.186 Decomposition of diazonium salts with hydrobromic acid afforded 3-bromo-pyrazolo[3,4-c]-u0 or -[4,3-bjpyridines111 deamination of 3-aminopyra-zolo[3,4-h]pyridines was achieved via treatment of the diazonium salts with hypophosphorous acid,10 titanous chloride,238 or ferrous ammonium sulfate.238 Kocevar et al.236 have made a detailed study of the reactions of the latter diazonium salt. 

It is not usually necessary to isolate the diazonium salt from solution, although in some cases this separates out as the reaction proceeds. If sufficient acid is not present, an aminoazo compound may be precipitated, due to the coupling (see p. 282) of the diazonium compound with the excess of base. In fact, this is one method of forming aminoazo compounds—by diazotising in presence of about half the quantity of acid necessary for the complete diazotisation. 

On the other hand, the diazonium substitute acetyl-acetone complex 13 as well as the mixture of diazonium salts 14 and 15 seem to react with 2- and 1-naphthol, respectively, to give the corresponding azo dyes, which could, however, not be isolate as pure compounds. 

Diazotization in organic solvents allows solid diazonium salts to be isolated. Diazotization can be carried out using an ester of nitrous acid, such as pentyl nitrite, in a solvent such as acetic acid or methanol. A procedure has also been described for isolating diazonium tetrafluoroborates, in excellent yield, by carrying out the diazotization with boron trifluoride etherate and f-butyl nitrite in ether or dichlorometh-ane at low temperature. Another method for the preparation of a variety of diazonium salts in a nonaqueous medium makes use of the chemistry of bis(trimethylsilyl)amines (8). These compounds react in dichloromethane with nitrosyl chloride and other nitrosating agents which are generated in situ. Thus, benzenediazonium chloride was isolated (96%) from bis(trimethylsilyl)aniline. 

Sodium nitrite, lOju.1 10 mM 1 nmol [i25i]Aniline, 5.0 nmol in 0.1 M HCl Protein, 10 mg 10 ml of 1 mg/ml solution at pH 10 Procedure. Add the sodium nitrite to the [ I]aniline. The solution of diazonium salt is added dropwise to the stirred solution of protein, and the. pH is maintained at 9-10 for 1 hr. Isolate the I-labeled product either by dialysis against 10 mM phosphate-buffered saline, pH 7.2, or by chromatography on a BioGel P column (2.5 x 30 cm) wet-packed and eluted with this same buffer. 

If it is desired to isolate the diazonium salt, the amine is dissolved in alcohol or glacial acetic acid and diazotized by adding amyl or butyl nitrite and then the acid. Diazonium salts are unstable and explosive, and are not prepared in the dry state in any considerable quantities. Diazotization is usually carried out in aqueous solutions. In most cases the base is suspended in water and 2.2 moles of acid is added. One mole of acid is required to form the amine... 

Nucleophilic introduction of nitro functions seems to be confined to reactions of diazonium salts which offer a useful entry, particularly to 2-nitroimidazoles (from the diazonium fluoroborates see Section 3.02.7.1.6). This method, though, depends on the ease of synthesis, isolation, and stability of aminoimidazoles. The 4- and 5-amino isomers in particular are frequently unstable in air, and aminoimidazoles are usually made either by ring synthetic methods or by reduction of nitro compounds. Oxidation of amino groups to nitro is seldom a useful option. 

Hantzsch, who put forward this hypothesis as to the way in which diazonium compounds undergo decomposition, has isolated in the case of certain diazonium derivatives the intermediate s2/n-diazo compounds. When p-chlorobenzenediazonium chloride, CIC6H4N2CI, is treated with a cyanide, p-chlorobenzo-nitrile, CIC6H4CN, is not immediately formed. The resulting product reacts energetically when treated with copper-powder and nitrogen and the nitrile are formed. This intermediate compound is considered to be the syn-diazo cyanide, as it does not possess the properties of diazonium salts. The syn-compound is unstable and on standing is converted into an isomer, which does not react with copper-powder this appears to be the anti-diazo compound. 

Diazotetrazole (16) was obtained by dropwise addition of 2-pentyl nitrite to a solution of 5-amino-l//-tetrazole in a 4 1 mixture of tetrahydrofuran and aqueous hydrochloric acid. The diazonium chloride can be extracted into ether. Shevlin obtained the extremely explosive solid diazonium salt (16) by evaporation of that solution. He has recommended that not more than 0.75 mmol of diazonium salt be isolated at one time. An explosion during the diazotization of 5-aminotetrazole on a laboratory scale was described by Gray and coworkers. The structure 17 (equation 5) indicates clearly that this diazo compound may have the tendency to decompose into atomic carbon and three equivalents of dinitrogen—a reaction which is clearly highly exothermic. The decomposition of the tetrazole-5-diazonium chloride (16) has been studied by Shevlin by coating the salt on the walls of a 500 ml flask in the presence of two substrates, ethene and ethylene oxide. With ethene the products found after heating the flask to 80 °C are shown in equation 6, and with ethylene oxide in equation 7. The products correspond to those found with atomic carbon formed by completely different methods (see references cited by Shevlin). 

Most arenediazonium salts are unstable at temperatures above 5—10 °C, and many explode when dry. Fortunately, however, most of the replacement reactions of diazonium salts do not require their isolation. We simply add another reagent (CuCI, CuBr, Kl, etc.) to the mixture, gently warm the solution, and the replacement (accompanied by the evolution of nitrogen) takes place ... 

Only in the replacement of the diazonium group by — F need we isolate a diazonium salt. We do this by adding HBF4 to the mixture, causing the sparingly soluble and reasonably stable arenediazonium fluoroborate, ArN2 BF4, to precipitate. 

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