Bromine electrophilic attack

Because the position of electrophilic attack on an aromatic nng is controlled by the direct ing effects of substituents already present the preparation of disubstituted aromatic com pounds requires that careful thought be given to the order of introduction of the two groups Compare the independent preparations of m bromoacetophenone and p bromoace tophenone from benzene Both syntheses require a Friedel-Crafts acylation step and a bromination step but the major product is determined by the order m which the two steps are carried out When the meta directing acetyl group is introduced first the final product IS m bromoacetophenone... 

As might be expected from a consideration of electronic effects, an amino substituent activates pyrazines, quinoxalines and phenazines to electrophilic attack, usually at positions ortho and para to the amino group thus, bromination of 2-aminopyrazine with bromine in acetic acid yields 2-amino-3,5-dibromopyrazine (Scheme 29). 

Bromine in chloroform and bromine in acetic acid are the reagents used most often to brominate pyrazole. When nitric acid is used as a solvent, both bromine and chlorine transform pyrazoles into pyrazolones (Scheme 24). Thus 3-methyl-l-(2,4-dinitrophe-nyOpyrazole is brominated at the 4-position (309). The product reacts with chlorine and nitric acid to give the pyrazolone (310). The same product results from the action of bromine and nitric acid on (311). The electrophilic attack of halogen at C-4 is followed by the nucleophilic attack of water at C-5 and subsequent oxidation by nitric acid. 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

Bromonium ions can be also produced by an electrophilic attack by a species that should generate a positive bromine ... 

The presence of an TV-oxide group activates the 1,2,4-triazine ring toward electrophilic attack, for instance, in halogenation reactions. Thus, 3-methoxy- and 3-amino(alkylamino)-1,2,4-triazine 1-oxides 16 react easily with chlorine or bromine to form the corresponding 6-halo-1,2,4-triazine 1-oxides 17 (77JOC3498, 78JOC2514). 

Selective electrophilic attack has also been demonstrated, for example, during nitration,48 chlorination,37-49 bromination,32 acylation and formylation.32k... 

Most electrophilic substitutions in benzimidazole (31 R = H) occur primarily in the 5-position. In multiple bromination the order followed, 5 > 7 > 6,4 > 2, parallels molecular orbital calculations. In benzimidazole itself the 4(7)- and 5(6)-positions are tautomerically equivalent. Fusion of a benzene ring deactivates C-2 to electrophilic attack to such an extent that it is around 5000 times less reactive than the 2-position of imidazole. Strong electron donors at C-5 direct halogenation to the 4-position, whereas electron-withdrawing groups favor C-4 or C-6 substitution (84MI21). 

Although the reaction of ketones and other carbonyl compounds with electrophiles such as bromine leads to substitution rather than addition, the mechanism of the reaction is closely related to electrophilic additions to alkenes. An enol, enolate, or enolate equivalent derived from the carbonyl compound is the nucleophile, and the electrophilic attack by the halogen is analogous to that on alkenes. The reaction is completed by restoration of the carbonyl bond, rather than by addition of a nucleophile. The acid- and base-catalyzed halogenation of ketones, which is discussed briefly in Section 6.4 of Part A, provide the most-studied examples of the reaction from a mechanistic perspective. 

A mechanistic interpretation is based on the ring-opening principle deduced in the next chapter the very unusual electrophilic attack of bromine at carbonyl oxygen is followed by nucleophilic addition of bromide ion at elevated temperature and ring-opening by transfer of bromine to CljC2. 

No significant examples of electrophilic attack on. ///-pyrrolizincs were reported since CHEC-II(1996). Nevertheless, treatment of the tricyclic pyrrolizine 53 with aqueous bromine in THF afforded, as expected, the corresponding bromohydrin 54 <1997T4549>. 

Tanuer (1964) has shown that in polar solvents the mechanism of bromination is not free radical but involves an electrophilic attack by Br . 

Three salicylate (2-hydroxybenzoate) anions, which have unusual reactivity towards bromine that has been attributed to intramolecular proton transfer assisting electrophilic attack (Tee and Iyengar, 1985, 1990), exhibit modest catalysis (k /k2u = 3 to 10) and have KTS values similar to phenols. Pyridones and their /V-methyl derivatives, three heteroaromatic acid anions, and four phenoxy derivatives show comparable catalysis (k //c2u = 1.7 to 9.5) and Krs values (Table A4.4). 

To provide an example of a reaction that is very different to electrophilic aromatic substitution, the oxidation of formic acid by bromine was also studied. This reaction, which involves electrophilic attack on the formate anion (15) (Cox and McTigue, 1964 Smith, 1972 Herbine et al., 1980 Brusa and Colussi, 1980), is catalysed by a-CD (/c /k2u = 11) (Tee et al., 1990a), and the degree of transition state stabilization (Xts = 0.18 mM) is similar to that for phenols (Table A4.2) and most of the other substrates (Table A4.4). 

Bromination of bicyclopropenyl system 369 at ambient temperature in absolute CHCI3 leads either to diene 372 (15%) and trienes 374-376 (15%, 35% and 10%, respectively) when R = H, or to the stable cyclopropenium salt 371 (95%) when R = Ph (equation 134)188. The electrophilic attack of bromine on compounds 369 creates the cationoid intermediates 370 which undergo either fragmentation to salt 371 (path a) or an electrocyclic ring opening (path b). When diene 372 is heated at about 150 °C in the solid state it rearranges to 1,2,3,5-tetraphenylbenzene 373 with concomitant loss of bromine. 

If (a) these compounds are the initial products of the reaction and (b) the first step in the reaction is an electrophilic attack by bromine (either Br+ or Br+—Bi") then these structures are not consistent with the initial attack being at the gold atom since the electrophilic gold(III) so formed would then be required to attack the olefin. This step would be governed by Markownikov s rule and would give 6 and 7 membered ring... 

Because halogenation involves electrophilic attack, substituents on the double bond that increase electron density increase the rate of reaction, whereas electron-withdrawing substituents have the opposite effect. Bromination of simple alkenes is an extremely fast reaction. Some specific rate data are tabulated and discussed in Section 6.3 of Part A. 

A detailed examination of OSO4 reactions with A -steroids has been reported." The A-ring conformation of the reactant or derived complex is important in determining the stereoselectivity of these reactions, and the major role of the proximate substituents is to anchor the appropriate conformation favouring a- or /3-attack. Studies on the stereochemistry of electrophilic attack on cholest-5-en-3-one continue." As with bromine chloride," appreciable /3-attack occurs and the 5/3,6j8-epoxide was isolated along with the previously reported 5a,6a-epoxide and the Baeyer-Villiger product, the A-homo-enol lactone (58). Base-catalysed... 

When there is an electron-releasing substituent in the 4-position, the electrophile attacks the 1-position. This has been used as a convenient way of preparing 1-substituted dibenzofurans by removal of an amino group at the 4-position. Bromination, chlorination, and diazo coupling of 4-dibenzofuranol occur at the 1-position. Bromination and Vilsmeier-Haack formylation of 4-methoxydibenzofuran provide the 1-substituted derivatives. Nitration and bromination of 4-acetylaminodibenzofuran take a similar course. ... 

Electrophilic addition to 9-vinylcarbazole occurs in the Markovnikov sense, thus hydrogen chloride,hydrogen bromide,chlorine, and bromine in carbon tetrachloride, and iodine chloride in pyridine are recorded as adding with initial electrophilic attack at the methylene. Mercuric acetate in methanol gave 9-(2-acetoxymercuri-l-methoxyethyl)carbazole. Although 9-vinylcarbazole gave an iodohydrin, comparable reaction with methanolic sodium hypochlorite led to 9-(2-chlorovinyl)carbazole. Catalytic reduction of the latter produced 9-(2-chloroethyl)carbazole. Tri-phenyltin hydride gave 96. ... 

The 2,3-double bond of compound 145 can be dibrominated with bromine <1982AP761>. The reaction is an analog of the dibromination of 126 described in Section 8.06.5.3. The 2-bromination of 152 to give 153 (Equation 6) was claimed to be a radical reaction, but is more likely to be an electrophilic attack, as a base catalyst was used and the reaction needed the presence of a 2-alkoxycarbonyl group to proceed <1984H(22)2789>. In a similar way, the a-carbons of dihydrooxazin-2-ones and dihydrooxazin-3-ones can also be deprotonated and then reacted with electrophiles these reactions are described in Section 8.06.6.5. 

Bromination of pyridine is much easier than chlorination. Vapour phase bromination over pumice or charcoal has been studied extensively (B-67MI20500) and, as with chlorination, orientation varies with change in temperature. At 300 °C, pyridine yields chiefly 3-bromo-and 3,5-dibromo-pyridine (electrophilic attack), whilst at 500 °C 2-bromo- and 2,6-dibromo-pyridine predominate (free radical attack). At intermediate temperatures, mixtures of these products are found. Similarly, bromination of quinoline over pumice at 300 °C affords the 3-bromo product, but at higher temperatures (450 °C) the 2-bromo isomer is obtained (77HC(32-1)319). Mixtures of 3-bromo- and 3,5-dibromo-pyridine may be produced by heating a pyridine-bromine complex at 200 °C, by addition of bromine to pyridine hydrochloride under reflux, and by heating pyridine hydrochloride perbromide at 160-170 °C (B-67MI20500). 

The oxide group mildly activates 3-substituted 1,2,3-triazole 1-oxides to electrophilic attack. Thus, 3-benzyl-1,2,3-triazole 1-oxide reacted much more rapidly than the unoxidized compound in giving the 5-bromo derivative, and there have been a number of other examples of 5-bromination and 5-chlorination of triazole oxides, including that of the 3-phenyl-l-oxide, which was not para-halogenated [87ACS(B)724]. 

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