Diazonium coupling reactions

Diazonium coupling reactions are typical electrophilic aromatic substitutions in which the positively charged diazonium ion is the electrophile that reacts with the electron-rich, ring of a phenol or arylamine. Reaction usually occurs at the para position, although ortho reaction can take place if the para position is blocked. 

Diazonium coupling reaction (Section 24.8) the coupling reaction between an aromatic diazonium salt and a phenol or aniline. 

Many common synthetic dyes, such as alizarine yellow R, para red, and Congo red, are azo compounds, prepared by the diazonium coupling reaction described in Section 25.15. 

The preparation of unsymmetrical biaryls,6 the Sandmeyer reaction,6 the replacement of an aromatic diazonium group by hydrogen,7 and the reaction of diazonium salts with ,0-unsaturated carbonyl compounds 8 appear to proceed by free radical mechanisms and will not be discussed. Diazonium coupling reactions, however, have the characteristics of ionic processes. 

Diazonium Coupling Reactions. The union of a diazonium ion with a phenol or an amine is known as a diazonium coupling reaction. The process appears to be an example of aromatic substitution in which the reactive species are the diazonium cation and phenoxide ion or the substituted aniline molecule 9... 

In the light of this mechanism, several well-known facts concerning diazonium coupling reactions are readily explicable. Sodium acetate or sodium carbonate is usually necessary for coupling to lower the acidity of the reaction mixture and to increase correspondingly the concentration of free base or phenoxide ion. There is little probability of reaction between diazonium and substituted anilinium ions since they are of like charge and the aromatic nucleus of the anilinium ion is deactivated ... 

The above studies emphasize the ability of diazonium-coupling reactions to modify proteins with extremely high efficiency, but one of the limitations of this method is the lack of selectivity that can be obtained when there are multiple tyrosines on the surface of a single protein. This has not been problematic for the viral capsids shown above, as only one tyrosine is accessible on each monomer, but many applications demand higher levels of selectivity than allowed by these coupling reactions. To address this need, and to increase the substrate scope for bioconjugation reactions in general, a versatile Mannich-type reaction has been developed for tyrosine modification, Fig. 10.3-5 [25]. In this reaction, aldehydes and anilines are mixed to form... 

There are numerous multistep processes that generate electrophiles. As examples of these types of reactions, we will consider the diazotization of anilines and the formation of chloroiminium ions in the Vilsmeier-Haack reaction. Aryl diazonium ions are useful in the modification of arenes by the Sandmeyer reaction and as electrophilic intermediates in diazonium coupling reactions for the synthesis of dyes and pigments. Several types of synthetic methods have been developed for this chemistry, and the mechanism varies depending on the methodology [13]. Under some conditions, the nitrosonium ion (18) initiates the process (Scheme 1.5). NjOj and NOCl have also been proposed as intermediates in diazotization—both are considered as nitrosonium ion carriers. The aniline reacts... 

The final step in the S Ar reaction mechanism involves deprotonation of the a-complex intermediate to regenerate the aromatic x-system, and this is expected to be a very fast step. Since the C—H bond is not being broken in a rate-determining step, there is usually little or no detectable kinetic isotope effect (KIE) for S Ar reactions [61]. Thus, studies of KlEs are also consistent with the involvement of the a-complex. Larger KIEs have been observed in conversions involving weak electrophiles, such as nitrosations and diazonium coupling reactions [61c]. 

---