Halogenation reactions aromatic compounds

Reaction LXXL Replacement of Halogen by Hydroxyl. (B., 14, 2394 16, 2954 25, 3290 J. pr 11, 229 A. Ch., [3], 55, 400.)—When alkyl halides are refluxed with dilute caustic alkali or alkali carbonate, hydro-xylation occurs smoothly. If the halide be tertiary the replacement takes place with great ease, warming with water being sufficient a secondary halide reacts less readily, but more so than a primary. Halogen in aromatic compounds is replaced with great difficulty unless there be present negative substituents in the ortho- or para-position. The replacement, however, can be effected under pressure (U.S.P., 1996745). 

The halogenation of aromatic compounds has probably a mechanism similar to that of the Friedel-Crafts reaction, a Lewis acid acting as catalyst. For example ... 

A recently reported procedure for a Lewis acid-catalyzed selective halogenation of aromatic compounds was applied to the synthesis of 2-fluoropyrrole (57). Thus, reaction of pyrrole with NFSi in the presence of a catalytic amount of ZrCLi in CH2CI2 for 12 h gave a 55% yield of 2-fluoropyrrole (Fig. 3.25). 

The sodium periodate-mediated oxidation of alkali halides is a useful method to accomplish the halogenation of aromatic compounds. Accordingly, NaCl is successfully employed as a chlorine source for the chlorination of various aromatic compounds, although mixtures of regioisomers are sometimes obtained on the other hand, the related sodium periodate-mediated bromina-tion reaction, which uses lithium bromide or sodium bromide as halogen source, affords the expected brominated products in a regioselective fashion (eq 33). ... 

Such long ago known in organic chemistry reactions as nitration, sulfonation, and halogenation of aromatic compounds are reactions of electrophilic substitution. 

The halogenation of aromatic compounds in acidic media or in the presence of Lewis acids proceeds via the Se2 mechanism. The following species can be electrophilic agents in chlorination (arranged in decreasing their activity) Cl, ClOH, CI2, and CIOH. In nonaqueous solvents, CI2 acts most often as the main agent. In aqueous acidic solutions, it is Cr, which is formed ftom CIOH by the reactions... 

Radiolysis and photodecomposition of chlorite and chlorate have been studied in aqueous solution. Reaction schemes, rate constants, and quantum yields are reported.The first stage in the reaction of chlorine with phenol is the second-order formation of [CI2 PhOH], with a rate constant 2 = 2.3 x 10 lmol- s at 5 °C. This [Clg-PhOH] intermediate, whose properties are similar to those of known charge-transfer compounds of halogens with aromatic compounds, decomposes by three parallel pathways. Chlorine reacts more slowly with chlorophenols than with phenol itself. The reaction of chlorine dioxide with phenol follows a comparable rate law ... 

Aromatic compounds may be chlorinated with chlorine in the presence of a catalyst such as iron, ferric chloride, or other Lewis acids. The halogenation reaction involves electrophilic displacement of the aromatic hydrogen by halogen. Introduction of a second chlorine atom into the monochloro aromatic stmcture leads to ortho and para substitution. The presence of a Lewis acid favors polarization of the chlorine molecule, thereby increasing its electrophilic character. Because the polarization does not lead to complete ionization, the reaction should be represented as shown in equation 26. 

The isoxazole nucleus is also halogenated in the 4-position by N-bromosuccinimide provided there is no substituent in this position. This reaction does not proceed homolytically, as might have been expected, and appears to represent a simple electrophilic substitution by the bromine cation. Similar cases have been previously described for the bromination of certain aromatic compounds with A -bromo-succinimide. ... 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

Hydro-de-diazoniation seems to be an unnecessary reaction from the synthetic standpoint, as arenediazonium salts are obtained from the respective amines, reagents that are normally synthesized from the hydrocarbon. Some aromatic compounds, however, cannot be synthesized by straightforward electrophilic aromatic substitution examples of these are the 1,3,5-trichloro- and -tribromobenzenes (see below). These simple benzene derivatives are synthesized from aniline via halogenation, diazotization and hydro-de-diazoniation. Furthermore hydro-de-diazoniation is useful for the introduction of a hydrogen isotope in specific positions. 

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