Substitution reactions of aryl diazonium salts

Aryl diazonium salts undergo two general reactions  

Coupling of a diazonium salt with another benzene derivative to form an azo compound, a compound containing a nitrogen-nitrogen double bond. 

Aryl diazonium salts react with a variety of reagents to form products in which Z (an atom or group of atoms) replaces Ng, a very good leaving group. The mechanism of these reactions varies with the identity of Z, so we will concentrate on the products of the reactions, not the mechanisms. 

A diazonium salt reacts with HgO to form a phenol. 

A diazonium salt reacts with copper(I) chloride or copper(I) bromide to form an aryl chloride or aryl bromide, respectively. This is called the Sandmeyer reaction. It provides an alternative to direct chlorination and bromination of an aromatic ring using CI2 or Br2 and a Lewis acid catalyst. 

A diazonium salt reacts with fluoroboric acid (HBF4) to form an aryl fluoride. This is a useful reaction because aryl fluorides cannot be produced by direct fluorination with F2 and a Lewis acid catalyst, as F2 reacts too violently (Section 18.3). 

Many different nucleophiles can react with aryl diazonium salts, often by different mechanisms that range Tom SnI type processes to those involving radicals.288 Heating 398 in aqueous acid generates phenol.289 This reaction is also illustrated by the conversion of 3-nitroaniline (400) to the diazonium salt (401), which was tollowed by heating in aqueous sulfuric acid to give 3-nitrophenol (402).290 

Treatment of diazonium salts with cuprous, Cu(I), salts generates aryl halides. When 398 reacts with CuCl (cuprous chloride) or CuBr (cuprous bromide), the products are chlorobenzene or bromobenzene via what is probably a radical reaction.29l jhis conversion is known as the Sandmeyer reaction. 2 The use of copper powder rather than cuprous salts for this transformation is often called the Gattermann reaction. 93,292b,c Aryl iodides are also produced from diazonium salts by reaction with potassium iodide (KI) but the actual reactive species may be l3-.294,295 Treatment of aniline derivative 403 with sodium nitrite and HCl followed by treatment with KI, for example, gave a 89% yield of 404.Aryl nitriles are generated under Sandmeyer conditions using cuprous cyanide (CuCN), as in the conversion of 405 to benzonitrile derivative 407 via diazonium chloride, 406. 

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Other Substitution Reactions of Aryl Diazonium Salts... 

The Pd )-catalyzed reaction of aryl diazonium salts with mono-substituted alkenes [1] was found to be an interesting alternative to the well-known Pd - catalyzed arylhalide alkene coupling (Heck type reaction) or the copper mediated reaction of aryl diazonium salts with alkenes (Meerwein arylation) [2], The reaction can be run without isolation of the diazonium salt in presence of only 0.5 to 1 mol% of the Palladium catalyst in a one pot procedure, in high yield and under nuld conditions. The resulting styrene is reduced in a subsequent hydrogenation step with an in situ generated heterogeneous Pd-catalyst. The combination of three reaction steps without isolation of intermediates and the virtually complete recovery of the Pd-metal at the end of the reaction sequence makes this process [4] extremely efficient. 

The first widely used intermediates for nucleophilic aromatic substitution were the aryl diazonium salts. Aryl diazonium ions are usually prepared by reaction of an aniline with nitrous acid, which is generated in situ from a nitrite salt.81 Unlike aliphatic diazonium ions, which decompose very rapidly to molecular nitrogen and a carbocation (see Part A, Section 4.1.5), aryl diazonium ions are stable enough to exist in solution at room temperature and below. They can also be isolated as salts with nonnucleophilic anions, such as tetrafluoroborate or trifluoroacetate.82 Salts prepared with 0-benzenedisulfonimidate also appear to have potential for synthetic application.83... 

Amino-substituted 1,2,3,4-thiatriazoles 87 were first prepared by a similar reaction starting from the readily available thiosemicarbazides <1895CB74>. In subsequent work this method has been widely used to prepare a variety of derivatives <1981JIC1087>. A modification of this method is to use the aza transfer reaction between aryl diazonium salts and 4-substituted thiosemicarbazide 139 (Equation 10) <19780PP59>. 

In contrast to classical Meerwein arylations, non-activated alkenes are well suited for this reaction type for two reasons. First, due to the relatively slow formation of azo compounds by addition of aryl radical 49 to 48, this undesired pathway cannot compete successfully with the attack of 49 on the alkene to give radical adduct 50. Second, a nucleophilic alkyl radical 50 arises from the addition step, which is effectively trapped by electrophilic salt 48 to give azo compound 51. As a result of several improvements, the methodology is now applicable for a wide range of polar to non-polar alkenes with almost no restrictions on the substitution pattern of the diazonium salt [101, 102]. Moderate diastereoselectivities have been obtained in first attempts with chiral auxiliaries [103]. The azo compounds accessible, such as 51, can be converted to carboamination products 52 by hydrogenation and to various other heterocycles. 

To exploit the synthetic versatility of aryl diazonium salts, be prepared to reason backward. When you see a fluorine attached to a benzene ring, for example, realize that it probably will have to be introduced by a Schiemann reaction of an arylamine realize that the required arylamine is derived from a nitroarene, and that the nitro group is introduced by nitration. Be aware that an unsubstituted position of a benzene ring need not have always been that way. It might once have borne an amino group that was used to control the orientation of electrophilic aromatic substitution reactions before being removed by reductive deamination. The strategy... 

Examples of the three mechansims are, respectively (a) hydrolysis of aryl diazonium salts to phenols (b) reaction of aryl diazonium ions with Ns to give the aryl azides " and (c) the Sandmeyer reaction, involving cuprous chloride or bromide for synthesis of aryl halides. Specific synthetically important substitution processes are considered in the succeeding sections. 

When Pschorr reported more than a century ago on the first intramolecular homolytic aromatic substitution [25], he showed that biaryls could be readily prepared by intramolecular homolytic aromatic substitution using reactive aryl radicals and arenes as radical acceptors. The aryl radicals were generated by treatment of arene-diazonium salts with copper(l) ions. Today, this reaction and related processes are referred to as Pschorr reactions. It was later found that radical biaryl synthesis could be conducted without copper salts by photochemical or thermal generation of the aryl radical from the corresponding diazonium salt [26], Moreover, the reduction of aryl diazonium salts offers another route to generate reactive aryl radicals. Hence, electrochemistry [27], titanium(lll) ions [28], Fe(II)-salts [29], tet-rathiafulvalene [30] and iodide [31] have each been used successfully for the reduction of diazonium salts to generate the corresponding aryl radicals [32]. As an example, the iodide-induced cycUzation of diazonium salt 6 to phenanthrene derivative 7 is presented in Scheme 13.3 [31]. For further information on the... 

The most significant radical substitution reaction of ferrocene is noted upon reaction with aryl diazonium salts giving an arylation product, equation (6-4). 

The diazonium salts 145 are another source of arylpalladium com-plexes[114]. They are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature. In addition, they can be used for alkene insertion in the absence of a phosphine ligand using Pd2(dba)3 as a catalyst. This reaction consists of the indirect substitution reaction of an aromatic nitro group with an alkene. The use of diazonium salts is more convenient and synthetically useful than the use of aryl halides, because many aryl halides are prepared from diazonium salts. Diazotization of the aniline derivative 146 in aqueous solution and subsequent insertion of acrylate catalyzed by Pd(OAc)2 by the addition of MeOH are carried out as a one-pot reaction, affording the cinnamate 147 in good yield[115]. The A-nitroso-jV-arylacetamide 148 is prepared from acetanilides and used as another precursor of arylpalladium intermediate. It is more reactive than aryl iodides and bromides and reacts with alkenes at 40 °C without addition of a phosphine ligandfl 16]. 

This procedure has been used to prepare a variety of substituted a-bromohydrocinnamic acids 2 p-acetyl-a-bromohydro-cinnamic acid was prepared for the first time by this method. The method illustrates a typical application of the Meerwein reaction for the arylation of unsaturated substrates.3 In this reaction a catalytic amount of a copper(I) salt is used to reduce an aryl diazonium salt forming an aryl radical and a copper(II) halide. Addition of the aryl radical to an unsaturated substrate forms an alkyl radical that is reoxidized by the copper(II) halide present forming an alkyl halide and regenerating the copper(I) salt catalyst. In this preparation, the product, an a-bromo acid, is formed in an acidic reaction mixture and dehydro-halogenation does not occur. However, dehydrohalogenation... 

The Balz-Schiemann and Wallach reactions The Balz-Schiemann reaction (the thermal decomposition of an aryl diazonium salt. Scheme 46) was for many years the only practical method for the introduction of a fluorine atom into an aromatic ring not bearing electron-withdrawing substituents. This reaction, first reported in the late 1800s, was studied in fluorine-18 chemistry as early as 1967 [214]. It involves the generation of an aryl cation by thermal decomposition, which then reacts with solvent, nucleophiles or other species present to produce a substituted aromatic compound. Use of fluorine-18-labelled... 

Normally, the most practical vinyl substitutions are achieved by use of the oxidative additions of organic bromides, iodides, diazonium salts or triflates to palladium(0)-phosphine complexes in situ. The organic halide, diazonium salt or triflate, an alkene, a base to neutralize the acid formed and a catalytic amount of a palladium(II) salt, usually in conjunction with a triarylphosphine, are the usual reactants at about 25-100 C. This method is useful for reactions of aryl, heterocyclic and vinyl derviatives. Acid chlorides also react, usually yielding decarbonylated products, although there are a few exceptions. Likewise, arylsulfonyl chlorides lose sulfur dioxide and form arylated alkenes. Aryl chlorides have been reacted successfully in a few instances but only with the most reactive alkenes and usually under more vigorous conditions. Benzyl iodide, bromide and chloride will benzylate alkenes but other alkyl halides generally do not alkylate alkenes by this procedure. 

The diazonium sulphate is used in preference to the diazonium chloride, since the presence of chloride ions gives rise to small quantities of the aryl chloride as a by-product. The solution must be acidic in order to avoid the coupling reaction between unreacted diazonium salt and the phenol (see Section 6.7.2, p. 946). For the preparation of phenols and cresols, the aqueous solution of the diazonium compound is warmed to about 50 °C 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. boiling 40 60% sulphuric acid) is necessary to decompose the diazonium salt... 

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