Salts diazonium

Aminothiazoles and their Derivatives C. Coupling with Diazonium Salts 

Yields can be very good Beyer (402) reports a 90% yield when coupling 2-amino-4-phenylthiazole with the diazonium salt of aniline. The coupling of diazotized anilines under modified conditions has been reported in a work treating the preparation of antineoplastics (403). 

At this point, we ll switch gears somewhat and discuss aspects of organic nitrogen chemistry, focusing on reactions that illustrate nitrogen s characteristic behavior. Diazonium cations (ArNj ) provide an excellent starting point for such a discussion. 

Aniline (PhNH2) and other aromatic amines (ArNH2) react with aqueous nitrous acid, or more accurately with NO (which is always present in aqueous solutions of HNOj, as shown in reaction 5A.8), to yield unstable diazonium ions (ArN2 ). They are almost never isolated but rather converted in situ to a variety of useful products. Some examples of these transformations are shown below  

The structure of a diazonium cation probably provides the most valuable clue to the mechanism of its formation. A N-N bond has to form, and for that ArNH2 is a plausible nucleophile and NO the likely electrophile there are really not many other choices. 

Successive protonation of the nitroso (N=0) oxygen and elimination of water then leads to the formation of a diazonium cation, as shown below  

The great synthetic utility of diazonium ions stems from the fact that they readily lose Nj, producing highly reactive aryl cations, which can be captured by a variety of nucleophiles (Nu )  

The -M effect cannot operate in the case of 3-nitroaniline, but this is still a weaker base than aniline because of the -I effect, although not as weak as the 2- and 4-isomers (Table 8.2). A second nitro group enhances these effects and 2,4-dinitroaniline is so weak a base that it does not dissolve in dilute hydrochloric acid. 

The trivial name for 2,4,6-trinitroaniline is picramide, which tells us that it lacks basic character. Its properties are more like those of an amide than those of an amine. 

The methoxy group is somewhat unusual in that in the 4-position its +M effect increases basicity, but only a -I effect operates in the 3-position and this decreases the basicity. 

Substituents in the ortho position may exert a steric effect on the amino group, twisting it out of the plane of the ring and so reducing mesomer-ic interaction between the nitrogen lone pair and the ring. The lone pair is more available for donation to a proton and the basicity is therefore greater. 

Diazonium salts can be stabilized to some extent by conversion to so-called double salts. The easiest to form are those with zinc chloride. Species such as [ArN ljIZnCI ] are reasonably stable in solution, especially if kept cold. 

Diazoni-UFTi salts can be to some hy conversion to so-called double sails. The easiest to lorm are those with 2inc chloricry. Species such as [AfN. l.[ZnClr l are reasonably stable in soluti in. ospeciaily if kepi iold- 

The conditions for successful diazotization depend upon the basicity of the amino group. Relatively highly basic amines such as aniline and the toluidines dissolve in aqueous hydrochloric acid. Treatment with aqueous sodium nitrite solution at 0-5 °C then very rapidly converts the amino group into the diazonium compound. Addition of nitrite is continued until there is a slight excess of nitrous acid, which is indicated by an instant dark blue colour with potassium iodide/starch paper. 

The synthesis of diazonium salts of less basic amines does not proceed satisfactorily under the above conditions because of the reduced nucleophilic nature of the amino group and the reaction is usually carried out in concentrated sulfuric acid. The addition of sodium nitrite to concentrated sulfuric acid produces the stable nitrosylsulfuric acid, (N0HS04). Diazotization of the most weakly basic amines is carried out using nitrosylsulfuric acid in a mixture of one part of propionic acid in five parts of acetic acid at 0 5 °C. The propionic acid prevents the mixture from freezing. 

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Azo-compounds can be obtained by reduction of nitro-compounds, or by oxidation of hydrazo-compounds. They are usually prepared, however, by reacting a phenol or amine with a diazonium salt. The coupling usually takes place in the position para to the hydroxyl or amino group, but if this position is occupied it goes to the ortho position, e.g. 

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. 

The diazonium salts are by far the most important diazo-compounds. These are salts... 

They are prepared by the action of HNO2 on aromatic amines. The amine is dissolved in excess of mineral acid and sodium nitrite is added slowly until a slight excess of HNO2 is present. The reaction is usually carried out in ice-cold solution. The solution then contains the diazonium salt of the mineral acid used, anhydrous diazonium salts of unpredictable stability may be precipitated with complex anions like PF , SnCl6 BF4 . 

The diazonium salts usually decompose when warmed with water to give a phenol and nitrogen. When treated with CuCl, CuBr, KI, the diazo group is replaced by chlorine, bromine or iodine respectively (Sandmeyer reaction). A diazonium sulphate and hydroxyl-amine give an azoimide. The diazonium salt of anthranilic acid (2-aminobenzoic acid) decomposes to give benzyne. ... 

The most important reaction of the diazonium salts is the condensation with phenols or aromatic amines to form the intensely coloured azo compounds. The phenol or amine is called the secondary component, and the process of coupling with a diazonium salt is the basis of manufacture of all the azo dyestuffs. The entering azo group goes into the p-position of the benzene ring if this is free, otherwise it takes up the o-position, e.g. diazotized aniline coupled with phenol gives benzeneazophenol. When only half a molecular proportion of nitrous acid is used in the diazotization of an aromatic amine a diazo-amino compound is formed. 

Gattermann s reaction A variation of the Sandmeyer reaction copper powder and hydrogen halide are allowed to react with the diazonium salt solution and halogen is introduced into the aromatic nucleus in place of an amino group. 

It is extensively used in the preparation of dyestuffs. Combines with diazonium salts to form oxyazo-colouring matters. Gives rise to fluorescein dyes on fusion with phthalic anhydride. Used for production of plasticizers, resins, adhesives. 

Copper 1) chloride, bromide and cyanide were used by Sandmeyer to introduce a chlorine, a bromine atom and a cyanide group respectively into a benzene ring by addition to the phenyl diazonium salt. 

In preparing an aqueous sol ution of a diazonium salt, such as benzene-diazonium chloride, it is usual to dissolve the amine in a slight excess (about 2 2 molecular equivalents) of dilute hydrochloric acid (or alternatively to dissolve the crystalline amine hydrochloride in i 2 equivalents of the acid) and then add an aqueous solution of a metallic nitrite. Nitrous acid is thus generated in situ, and reacts with the amine salt to give the diazonium compound. For a successful preparation of an aqueous solution of the diazonium salt, however, two conditions must always be observed ... 

When potassium iodide or hydrogen iodide is added to an aqueous solution of a diazonium salt, nitrogen is readily evolved (no catalyst being necessary) and the corresponding iodo-compound is formed. lodo-compounds can thus... 

When a diazonium salt in aqueous solution is gently warmed, it reacts with the water, liberating nitrogen and forming the corresponding phenol ... 

When an aqueous solution of a diazonium salt is added to an alkaline solution of a phenol, coupling occurs with formation of an azo-compound (p. 188). If ho vc cr the ntiueous solution of the diazonium salt, t. . ., />-bromohenzene diazonium chloride, is mixed with an excess of an aromatic hydrocarbon, and aqueous sodium hydroxide then added to the vigorously stirred mixture, the diazotate which is formed, e.g., BrC,H N OH, dissolves in the hydrocarbon and there undergoes decomposition with the formation of nitrogen and two free radicals. The aryl free radical then reacts with the hydrocarbon to give a... 

Diazonium salts couple readily with aromatic primary amines, giving diazoamino compounds. If for instance an aqueous solution of aniline sulphate is diazotised with a deficiency of nitrous acid, only part of it is converted into benzenediazonium sulphate and the latter then couples with the unchanged aniline to give diazoaminobenzene. The reaction is carried out at the opti-CeHsNHj.HjSO + HONO = CbHsNjHSO, + zHaO... 

The most noteworthy reaction of azo-compounds is their behaviour on reduction. Prolonged reduction first saturates the azo group, giving the hydrazo derivative (C NH-NH C), and then breaks the NH NH linkage, with the formation of two primary amine molecules. If method (1) has been employed to prepare the azo-compound, these two primary amines will therefore be respectively (a) the original amine from which the diazonium salt was prepared, and (6) the amino derivative of the amine or phenol with which the diazonium salt was coupled. For example, amino-azobenzene on complete reduction gives one equivalent of aniline, and one of p-phenylene diamine, NHaCeH NH benzene-azo-2-naphthoI similarly gives one equivalent of aniline and one of... 

Arylarsonic acids are most readily prepared by the Bart Reaction, in which a diazonium salt in aqueous solution is run into a solution of sodium arsenite in an excess of sodium carbonate. The addition of copper sulphate to the +. ... 

Primary aromatic amines differ from primary aliphatic amines in their reaction with nitrous acid. Whereas the latter yield the corresponding alcohols (RNHj — ROH) without formation of intermediate products see Section 111,123, test (i), primary aromatic amines 3neld diazonium salts. Thus aniline gives phcnyldiazonium chloride (sometimes termed benzene-diazonium chloride) CjHbNj- +C1 the exact mode of formation is not known, but a possible route is through the phenjdnitrosoammonium ion tlius ... 

The experimental conditions necessary for the preparation of a solution of a diazonium salt, diazotisation of a primary amine, are as follows. The amine is dissolved in a suitable volume of water containing 2 5-3 equivalents of hydrochloric acid (or of sulphuric acid) by the application of heat if necessary, and the solution is cooled in ice when the amine hydrochloride (or sulphate) usually crystallises. The temperature is maintained at 0-5°, an aqueous solution of sodium nitrite is added portion-wise until, after allowing 3-4 minutes for reaction, the solution gives an immediate positive test for excess of nitrous acid with an external indicator—moist potassium iodide - starch paper f ... 

The precipitated amine hydrochloride (or sulphate), if any, dissolves during the diazotisation to give a clear solution of the highly soluble diazonium salt. The general reaction may be written ... 

The excess of acid (0-5-1 equivalents) maintains a proper condition of acidity required to stabilise the diazonium salt solution by reducing the secondary... 

The amines are comparatively weak bases, so that a certain amount of free amine will be produced by salt hydrolysis unless an excess of acid is present. The reaction mixture must be kept very cold during the process (which is exothermic in character), otherwise the diazonium salt may be partially converted into the corresponding hydroxy compound ... 

Some amines, such as the nitroanilines and the naphthylamines, give somewhat more stable diazonium compounds and may be diazotised at room temperature, when the reaction proceeds more rapidly. If the amine salt is only sparingly soluble in water, it should be suspended in the acid in a fine state of division (this is generally attained by cooling a hot solution and stirring vigorously), and it passes into solution as the soluble diazonium salt is formed. 

To prepare the solid phenyldlazonlum chloride or sulphate, the reaction is conducted in the absence of water as far as possible. Thus the source of nitrous acid is one of its organic esters (e.g., amyl nitrite) and a solution of hydrogen chloride gas in absolute alcohol upon the addition of ether only the diazonium salt is precipitated as a crystalline solid, for example ... 

Solid diazonium salts are very sensitive to shock when perfectly dry and detonate violently upon gentle heating they are, therefore, of little value for preparative work. Happily, most of the useful reactions of diazonium compounds can be carried out with the readily-acoeasible aqueous solutions, so that the solid (explosive) diazonium salts are rarely requir. ... 

Gattermann (1890) found that the preparation of the cuprous halide may be avoided by making use of the fact that finely-divided copper (e.g., freshly-precipitated or reduced by hydrogen or copper bronze) acts catal3d.ically in the decomposition of solutions of diazonium salts, for example ... 

The Sandmeyer reaction may also be applied to the preparation of nitriles. The solution of the diazonium salt is added to a solution of cuprous cyanide in excess of sodium or potassium cyanide solution (sometimes improved yields are obtained by substituting nickel cyanide for cuprous cyanide), for example CH3 CH, CH3... 

By adding a concentrated solution of sodium borofluoride to a solution of a diazonium salt, the diazonium fluoborate is precipitated this decomposes into the aryl fluoride when cautiously heated, for example ... 

When a solution of a diazonium salt is heated, the diazo group is replaced by hydroxyl and nitrogen is evolved ... 

The solution must be strongly acid in order to avoid the coupbng reaction between the undecomposed diazonium salt and the phenol (see under Azo Dyes). For the preparation of phenol and the cresols, the aqueous solution of the diazonium compound is warmed to about 50° at higher temperatures the reaction may become unduly vigorous and lead to appreciable quantities of tarry compounds... 

For certain substituted amines, a higher temperature (e.g., boding 40-60 per cent, sulphuric acid) is necessary to decompose the diazonium salt completely, for example ... 

An interesting coupling reaction with the diazonium salt derived from anthranilic acid leads to an excellent method for the preparation of dlphenic acid. The reaction occurs with cuprous salts in ammoniacal solution ... 

Dissolve 3-5 g. of aniline hydrochloride in 20 ml. of absolute ethyl alcohol contained in a 50 ml. conical flask, and add 0-5 ml. of a saturate solution of hydrogen chloride in absolute ethyl alcohol. Cool in ice and add 4 g. (4 -6 ml.) of iso-amyl nitrite (compare Section 111,53) gradually. Allow the mixture to stand for 5-10 minutes at the room temperature, and precipitate the diazonium salt by the gradual addition of ether. Filter ofiF the crystals at the pump on a small Buchner funnel, wash it with 5 ml. of alcohol - ether (1 1), and then with 10 ml. of ether. Keep... 

Dissolve 36 g. of p-toluidine in 85 ml. of concentrated hydrochloric acid and 85 ml. of water contained in a 750 ml. conical flask or beaker. Cool the mixture to 0° in an ice-salt bath with vigorous stirring or shaking and the addition of a httle crushed ice. The salt, p-toluidine hydrochloride, will separate as a finely-divided crystalline precipitate. Add during 10-15 minutes a solution of 24 g. of sodium nitrite in 50 ml. of water (1) shake or stir the solution well during the diazotisation, and keep the mixture at a temperature of 0-5° by the addition of a httle crushed ice from time to time. The hydrochloride wUl dissolve as the very soluble diazonium salt is formed when ah the nitrite solution has been introduced, the solution should contain a trace of free nitrous acid. Test with potassium iodide - starch paper (see Section IV,60). 

The diazonium salt solution decomposes on standing and hence must be mixed with the Cuprous chloride solution without delay. Mechanical stirring is an advantage. 

Dissolve 46-5 g. (45-5 ml.) of aniUne in a mixture of 126 ml. of concentrated hydrochloric acid and 126 ml. of water contained in a 1-htre beaker. Cool to 0-5° in a bath of ice and salt, and add a solution of 36-5 g. of sodium nitrite in 75 ml. of water in small portions stir vigorously with a thermometer (1) and maintain the temperature below 10°, but preferably at about 5° by the addition of a httle crushed ice if necessary. The diazotisation is complete when a drop of the solution diluted with 3-4 drops of water gives an immediate blue colouration with potassium iodide - starch paper the test should be performed 3-4 minutes after the last addition of the nitrite solution. Prepare a solution of 76 g. of sodium fluoborate (2) in 150 ml. of water, cool, and add the chilled solution slowly to the diazonium salt solution the latter must be kept well stirred (1) and the temperature controlled so that it is below 10°. Allow to stand for 10 minutes with frequent stirring. Filter... 

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