Synthesis of Aryl Halides

Q Bromobenzene is readily synthesized from benzene by reaction with bromine in the presence of pyridine. Suggest a mechanism for this route. 

A Pyridine is behaving as a Lewis base, reacting with bromine at the nitrogen atom to generate. V-bromopyridinium bromide. This 

Increasing the reaction temperature and the amount of halogen used results in the introduction of further halogen atoms. It was noted in Chapter 2 that the halogen atom in chlorobenzene is ortholpara directing, but deactivating to electrophilic substitution as a result of opposing mesomeric (+M) and inductive (--I) effects. Consequently, disubstitution leads to a mixture of the 1,2- and, mainly, 1,4-isomers under conditions similar to those required to attack benzene. 

Aromatic systems substituted with electron-donating groups are more readily halogenated than benzene. Consequently, other synthetic routes or reagents are sometimes used to avoid polyhalogenation and the formation of isomeric mixtures. For example, the iodination of toluene gives a mixture of 2- and 4-iodotoluenes each isomer can be prepared individually from the appropriate toluidine via the diazonium salt (see Chapter 8). 

In the case of aromatic systems activated towards electrophilic attack by strongly electron-donating substituents, a catalyst may not be required. For instance, both phenol and aniline are tribrominated by bromine at room temperature. Even iodine attacks aniline in the presence of only a scavenger for the liberated hydrogen iodide. 

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The Sandmeyer procedure for the synthesis of aryl halides from arylamines has been applied, with modification, to the conversion of 5- and 8-aminoquinolines to the iodo and bromo derivative. 8-Aminoquinoline is converted to 8-bromoquinoline in good yield on treatment with /-butyl nitrite in the presence of CuBr in acetonitrile at 60 °C <2003JOC5123> and 5-amino-6-nitroquinoline is converted to the 5-iodo derivative under equally mild conditions using potassium nitrite and copper iodide in DMSO at 60 °C <2005JOC2445>. 

Diazonium salts are valuable reagents for the synthesis of aryl halides, nitriles, phenols, hydrazines and azo compounds. 

The advantages of the synthesis of aryl halides from diazonium salts will be discussed in detail in Sec. 25.3. Aryl fluorides and iodides cannot generally be prepared by direct halogenation. Aryl chlorides and bromides can be prepared by direct halogenation, but, when a mixture of 0- and p isomers is obtained, it is difficult to isolate the pure compounds because of their similarity in boiling point. Diazonium salts ultimately go back to nitro compounds, which are usually obtainable in pure form. 

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. 

The methods described above for alkyl halides (on sp hybridized carbons) cannot be applied to the synthesis of aryl halides (on sp hybridized carbons). The introduction of a halogen to benzene (or a benzene derivative) can be accomplished either by an electrophilic aromatic substitution reaction (Cy FeCls or Br2/FeBr3) or by treatment of a diazonium salt (ArNaO with a halide nucleophile (Cul, CuBr, HBF4, or KI). 

The reaction apparently involves free-radical mechanism, but arylcopper compounds take a part, at least under certain reaction conditions, as clearly demonstrated through Cohen s concise results [99,100]. The reaction was discovered as a side-reaction during probes of the Gatterman synthesis of aryl halides from diazonium salts and copper(l) halides. Probably the most known example is very practical preparation of diphenic acid (57) starting from anthranilic acid (58). The reaction is usually conducted by adding an aqueous diazotized anthranilic acid solution (diazonium salt 59) to the copper(l) reagent, in situ obtained by reduction of CUSO4 with an equimolar amount of hydroxylaminc in aqueous sodium hydroxide solution, to produce diphenic acid with a 80-90% yield [99,100], Scheme 25. 

SYNTHESIS OF ARYL HALIDES THROUGH THE FORMATION OF HALOGEN-CARBON(sp ) BONDS... 

Historically, aryl fluorides were prepared by either Balz-Schiemann-type reactions or though the Halex process [70-75], Although a number of these procedures were quite successful, many of them required the use of toxic reagents or harsh conditions. To address these issues and provide practical routes to aryl fluorides, a host of alternative protocols have been developed [6, 76-78]. In addition to this work, a number of methods for the synthesis of aryl halides have been developed. The following sections will highlight several practical versions. 

Given the value of aryl chlorides, bromides, and iodides as substrates in organic transformations, a host of protocols have been devised for their synthesis. One of the classic methods for the synthesis of aryl halides were versions of the halodediazoniation reactions [109-111]. For a range of electron-rich arenes as well as many common aromatic compounds, bromination is commonly achieved simply through the addition of NBS to the arene in DMF [112]. Yields are good to excellent, and no transition metal catalyst was needed. In addition to NBS, elemental bromine has also been successfully used for the bromination... 

Troubleshooting the Synthesis of Aryl Halides and Related Compounds... 

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