Halogens, reactive aromatic

Molecular iodine is not a very powerful halogenating agent. Only very reactive aromatics such as anilines or phenolate anions are reactive toward iodine. Iodine monochloride can be used as an iodinating agent. The greater electronegativity of the... 

It should be pointed out that the existence of stable structures of the intermediate-complex type (also known as a-complexes or Wheland complexes) is not of itself evidence for their being obligate intermediates in aromatic nucleophilic substitution. The lack of an element effect is suggested, but not established as in benzene derivatives (see Sections I,D,2 and II, D). The activated order of halogen reactivity F > Cl Br I has been observed in quantita-tivei36a,i37 Tables II, VII-XIII) and in many qualitative studies (see Section II, D). The reverse sequence applies to some less-activated compounds such as 3-halopyridines, but not in general.Bimolecular kinetics has been established by Chapman and others (Sections III, A and IV, A) for various reactions. 

Acetoxylation is found to accompany nitration of fairly reactive aromatics by nitric acid in acetic anhydride and gives rise to zeroth-order kinetics76. The electrophile is believed to be protonated acetyl nitrate the formation of which is rate-determining, hence the kinetic order (see p. 37). Acetoxylation can also accompany halogenation by positive halogenating agents in acetic acid solvent, especially in the presence of sodium acetate137, but no kinetic studies have been carried out. 

Kinetic studies have been carried out using the 1 1-complex iodobenzene dichloride as a source of molecular chlorine. In acetic acid solutions, the dissociation of this complex is slower than the rate of halogenation of reactive aromatics such as mesitylene or pentamethylbenzene, consequently the rate of chlorination of these is independent of the aromatic concentration. Thus at 25.2 °C first-order chlorination rate coefficients were obtained, being approximately 0.2 x 10-3 whilst the first-order dissociation rate coefficient was 0.16 xlO-3 from measurements at 25.2 and 45.6 °C the corresponding activation energies... 

The introduction of the halogens onto aromatic rings by electrophilic substitution is an important synthetic procedure. Chlorine and bromine are reactive toward aromatic hydrocarbons, but Lewis acid catalysts are normally needed to achieve desirable rates. Elemental fluorine reacts very exothermically and careful control of conditions is required. Molecular iodine can effect substitution only on very reactive aromatics, but a number of more reactive iodination reagents have been developed. 

Iodination of moderately reactive aromatics can be effected by mixtures of iodine and silver or mercuric salts.26 Hypoiodites are presumably the active iodinating species. Bis(pyridine)iodonium salts can iodinate benzene and activated derivatives in the presence of strong acids such as HBF4 or CF3S03H.27 Scheme 11.2 gives some specific examples of aromatic halogenation reactions. 

GSH may also be coupled to electrophilic reaction intermediates nonenzymatically or by GSH transferase (GST)-catalyzed reactions. Many different types of substrates will undergo GSH conjugation, including epoxides, halogenated compounds, aromatic nitro compounds, and many others. In these reactions, GSH can interact with an electrophilic carbon or heteroatom (O, N, and S) [35]. One such substrate is a reactive metabolite of acetaminophen (APAP), N-acetyl-p-benzoquinonimine (NAPQI), which will readily form a GSH conjugate (Scheme 3.2). Other examples of Phase II bioactivation reactions that lead to toxic endpoints are shown in Table 3.1. 

The reacting species is a rather weak electrophile and, therefore, only particularly reactive aromatics are suitable substrates. Consequently, the reaction is restricted for polyhydric phenols and their ethers, and reactive heterocycles. With strong acidic systems, such as AICI3 in halogenated benzene solvents, alkylben-zenes can react at more elevated temperatures (>50°C). Trichloroacetonitrile works also well with nonactivated aromatics. The 12 chloroimine, the protonated nitrile (13), or the nitrile coordinated with the Lewis acid are possible involved electrophiles. 

Strong differences in the reactivity of the aromatic C=C double bond compared to the reactivity of the C=C double bond of olefins are observed olefinic electrophilic additions are faster than aromatic electrophilic substitutions. For instance, the addition of molecular bromine to cyclohexene (in acetic acid) is about 1014 times faster than the formation of bromobenzene from benzene and bromine in acetic acid113,114. Nevertheless, the addition of halogens to olefins parallels the Wheland intermediate formation in the halogenation of aromatic substrates. 

D. Effects of Halogens in Aromatic Systems upon Reactivity... 

The amide N-H may also be halogenated, oxidized and nitrosated. A -Bromosuccinimide (NBS), like a number of other iV-halo compounds, readily undergoes a radical fission to give a bromine radical. This provides a useful reagent for radical bromination at, for example, allylic or benzylic positions. In the presence of acid, NBS is also a mild source of the halonium ion, which is used for the addition of hypobromous acid (Scheme 3.74) to alkenes or for the bromination of reactive aromatic rings. 

Halogenation of aromatic compounds differs from the halogenation of alkenes, which do not require a Lewis Acid catalyst. The formation of the arenium ion results in the temporary loss of aromaticity, which has a higher activation energy compared to carbocation formation in alkenes. In other words, alkenes are more reactive and do not need to have the Br-Br or Cl-Cl bond weakened. Also, if the ring contains a strongly activating substituent such as -OH, -OR or amines, a catalyst is not necessary, however if a catalyst is used with excess bromine then a tribromide will be formed. 

This reaction could be of interest for substituting chlorine for bromine or for iodine in certain aromatic compounds. Indeed, in the halogenation by aromatic electrophilic substitution, the chlorinated reagents are more effective [2] and cheaper than brominated and iodinated reagents. However, bromo or iodo compounds are generally more interesting if the haloaromatic compounds are intended to be used in subsequent reactions because they are generally more reactive [2],... 

Electrophilic Substitution Iodine labeling can be obtained by using molecular iodine and oxidation reagents, such as peracetic acid, imides and amides, which increase the electrophilic reactivity of the halogen toward aromatic compounds. 

Substitution for hydrogen by halogen is a synthetically important electrophilic aromatic substitution reaction. The reactivity of the halogens increases in the order I2 < Br2 < CI2. The molecular halogens are only reactive enough to halogenate quite reactive aromatics. Many reactions are run in the presence of Lewis acids, in which case a complex of the halogen with the Lewis acid is probably the active electrophile. 

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