Coupling activity of diazonium salts

In coupling reactions of diazonium salts, nitrogen is retained and actually bonds to an activated aromatic ring in an electrophilic aromatic substitution reaction. This reaction is used to make azo dyes. 

B. Coupling of Diazonium Salts with Active Methylene Compounds... 

Intramolecular coupling of diazonium salts with ortho substituents bearing an active methylene grouping or its equivalent gives rise to cinnolines, which may be considered a class of cyclic azo compounds. Three name reactions are cited here for reference only. 

Generally the coupling of diazonium salt is carried out under neutral to slightly alkaline conditions. In coupling with amines or phenols, it has been demonstrated that the active species are the diazonium cation, the free amine,... 

As has been mentioned previously, the reactivity of halogeno- and methylsulfonyl-l,3,4-thiadiazoles toward nucleophilic reagents is in agreement with the low electron density on the carbon atoms in the ring. The high coupling activity of the diazonium salts can be ascribed to the same cause. 

Salts of primary aromatic amines react with nitrous acid to produce diazonium salts. The reaction is usually performed by adding a cold solution of sodium nitrite to a cold solution of the arylamine in aqueous mineral acid. The end point of the reaction is conveniently determined by the detection of excess nitrous acid with potassium iodide-starch paper. Sulfamic acid has long been used both in industry and in the laboratory to remove excess nitrous acid. It has been found to react with the more active diazo compounds. In most cases, high temperatures are avoided to prevent the formation of phenols and the decomposition of the unstable nitrous acid. An excess of mineral acid is necessary to prevent coupling between the diazonium salt and unreacted amine (cf. method 494). If the amine salt is somewhat insoluble, a fine crystalline form, which is produced by rapid crystallization from a warm aqueous solution, may be employed. ... 

The requirement for the occurrence of the Japp-Klingemann reaction is the presence of a hydrogen atom of sufficient activity to permit the coupling with the diazonium salt. A methinyl group in the a-position of a pyridyl acetic acid 11 is reactive enough to participate in the Japp-Klingemann process.7... 

In the..case of biphenylenes having activating substituents at the 2-position further electrophilic substitution takes place at the 3--position, as predicted by early molecular orbital calculations [158]. Tims, for example, 2-amino- and 2-hydroxy-biphenylene couple with benzene diazonium salts at the 3-position [159,160], and numerous other examples involving 2-acetamido- [161-163], 2-acetoxy- [163], 2-hydroxy- [163], 2-methoxy- [163,164], 2-methyl- [155] and 2-ethyl-[165] biphenylenes are known. Where the substituent is less strongly activating, as in the case of 2-ethylbiphenylene, some substitution occurs alternatively at the 6,7-positions [165], Friedel-Crafts benzoylation of 2-bromobiphenylene gave rise to a 7-benzoyl-2-bromo-biphenylene [157]. 

A reaction of aryl diazonium salts that does not involve loss of nitrogen takes place when they react with phenols and arylamines Aryl diazonium ions are relatively weak elec trophiles but have sufficient reactivity to attack strongly activated aromatic rings The reaction is known as azo coupling two aryl groups are joined together by an azo (—N=N—) function... 

Azo coupling (Section 22 18) Formation of a compound of the type ArN=NAr by reaction of an aryl diazonium salt with an arene The arene must be strongly activated toward... 

The triazinedione, triazuril (163) is active as a poultry coccidiostat. Diazonium salt 160, prepared from the appropriate aniline, is coupled with the active methylene group of N-carbethoxycyanoacetamide to give 161. Hydrolysis of the cyano group is accompanied by cyclization, and the resulting acid (162) is decarboxylated to triazuril (163) on heating.50... 

Several examples of the binding of enzymes to poly(vinyl alcohol) are in the literature. These could possibly be used to treat enzyme deficiency diseases. In a recent example, trypsin was immobilized on poly(vinyl alcohol) fibers using maleic dialdehyde or bromal. While the reaction was more complete with bromal, the reaction with maleic dialdehyde gave a better support which showed decreasing activity with increasing enzyme content. The activity of the bromal activated system was independant of the enzyme content (52 ). Trypsin and papain were attached to poly(vinyl alcohol) by the reaction sequence shown in Equation 13. In this case, the crosslinked poly(vinyl alcohol) is treated by the 1,3-dioxalone derivative and then converted to either the isothiocyanate or the diazonium salt for coupling with the enzyme. The bound enzymes showed significant, altho reduced, activity in each case (53). 

Two of these systems were studied as models—the acetylation of choline in brain to give acetyl choline (Hebb, Nachmansohn), and of sulfanilamide (the active component in prontosil, Chapter 3) in liver (Lipmann). Sulfanilamide is rapidly inactivated by acetylation on the p-amino group and then excreted. Sulfanilamide is easily diazotized the diazonium salt formed can be coupled with N-( 1 -naphthyl)ethylenedi-amine dihydrochloride to give a pink derivative (Bratton and Marshall, 1939). This formed the basis for an elegant colorimetric assay. Only the free p-amino group reacts, so that as acetylation proceeded color formation diminished. 

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