Substitution, electrophilic bromination

As a further electrophilic substitution the bromination of selenazoles has been investigated. This is not as complicated as nitration. Bromination was carried out in several solvents and with various amounts of bromine. In spite of the great variation in conditions, monobromo derivatives containing the bromine atom in the 5-position are always formed. This could be established, for example, by the bromination of the 2-amino-4-p-nitrophenylselenazole (Scheme 34) and its 2-benzamino compound (98). The 2-benzamido bromo compound gives the same bromo... 

The six-position may be functionalized by electrophilic aromatic substitution. Either bromination (Br2/CH2Cl2/-5°) acetylation (acetyl chloride, aluminum chloride, nitrobenzene) " or chloromethylation (chloromethyl methyl ether, stannic chloride, -60°) " affords the 6,6 -disubstituted product. It should also be noted that treatment of the acetyl derivative with KOBr in THF affords the carboxylic acid in 84% yield. The brominated crown may then be metallated (n-BuLi) and treated with an electrophile to form a chain-extender. To this end, Cram has utilized both ethylene oxide " and dichlorodimethyl-silane in the conversion of bis-binaphthyl crowns into polymer-bound resolving agents. The acetylation/oxidation sequence is illustrated in Eq. (3.54). 

Other electrophilic substitutions proceed with difficulty, or not at all. Nitrosation and diazo coupling require the presence of the strongly activating dimethylamino group (see Section VIII). Bromine adds, in the presence of sunlight, to give tetrabromotetrahydrobenzofuroxan (48) the initial attack is probably free-radical in nature. The product can be dehydrobrominated to form 4,7-, or a mixture of 4,5- and 4,6-dibromobenzofuroxan, depending upon the conditions. More conventional electrophilic bromination conditions have been tried in an attempt to obtain a monosubstituted product, but without success. 

There are many other kinds of electrophilic aromatic substitutions besides bromination, and all are thought to occur by the same general mechanism. Let s look at some of these other reactions briefly. 

Electrophilic bromination (and nitration) of pyrido[l, 2-a]benzimidazole (analogous to 132) cannot take place in the imidazole moiety. Initial substitution, using NBS as reagent, was shown to occur at the 8-position, and subsequently at C-4 and C-6 (90JOU1166). 

Systematic studies of the selectivity of electrophilic bromine addition to ethylenic bonds are almost inexistent whereas the selectivity of electrophilic bromination of aromatic compounds has been extensively investigated (ref. 1). This surprising difference arises probably from particular features of their reaction mechanisms. Aromatic substitution exhibits only regioselectivity, which is determined by the bromine attack itself, i.e. the selectivity- and rate-determining steps are identical. 

Apart from a few studies (ref. 7), the use of deuterium kinetic isotope effects (kie s) appears to have had limited use in mechanistic studies of electrophilic bromination of olefins. Secondary alpha D-kie s have been reported for two cases, trans-stilbene fi and p-substituted a-d-styrenes 2, these giving relatively small inverse kie s of... 

Recent studies by Pincock and Yates (32, 33) have demonstrated the intermediacy of vinyl cations in the electrophilic bromination of arylmethyl-acetylenes in acetic acid. The rates of addition of Brj to a number of substituted phenylmethylacetylenes in acetic acid follow the general equation... 

In fact, the analogy between the mechanisms of heterolytic nucleophilic substitutions and electrophilic bromine additions, shown by the similarity of kinetic substituent and solvent effects (Ruasse and Motallebi, 1991), tends to support Brown s conclusion. If cationic intermediates are formed reversibly in solvolysis, analogous bromocations obtained from bromine and an ethylenic compound could also be formed reversibly. Nevertheless, return is a priori less favourable in bromination than in solvolysis because of the charge distribution in the bromocations. Return in bromination implies that the counter-ion, a bromide ion in protic solvents, attacks the bromine atom of the bromonium ion rather than a carbon atom (see [27]). Now, it is known (Galland et al, 1990) that the charge on this bromine atom is very small in bridged intermediates and obviously nil in /f-bromocarbocations [28]. 

Free halogens are generally inconvenient to use, owing to their toxic and corrosive nature, but can be replaced by quaternary ammonium polyhalides. Quaternary ammonium tribromides are well established [e.g. 1] as solid, readily handled and relatively non-toxic alternatives for electrophilic bromine. More recently, other quaternary ammonium polyhalides have been produced, which together with the tribromides, have wide application as catalysts or in stoichiometric quantities in electrophilic substitution and addition reactions, oxidations, etc. 

Construction of the carbazole framework was achieved by slightly modifying the reaction conditions previously reported for the racemic synthesis (641,642). The reaction of the (R)-arylamine 928 with the iron complex salt 602 in air provided by concomitant oxidative cyclization the tricarbonyliron-complexed 4b,8a-dihydro-9H-carbazole (931). Demetalation of the complex 931, followed by aromatization and regioselective electrophilic bromination, afforded the 6-bromocarbazole 927, which represents a crucial precursor for the synthesis of the 6-substituted carbazole... 

The 5-unsubstituted-l,2,3-triazol-4-ones (176, R = H) participate in electrophilic substitution reactions. Bromination in chloroform of anhydro-4-hydroxy-l,3-dimethyl-1,2,3-triazolium hydroxide (180) gave its 5-bromo derivative (182). The meso-ionic 3-aryl-1,2,3-triazol-4-ones (176, R = Me, R = Ar, R = H) gave 5-bromo derivatives (176, R = Me, R = Ar, R = Br) with bromine in acetic acid. Their reaction with sulphur monochloride gave the sulfide (189, X = S), and with thionyl chloride they gave the sulfoxide (189, X = SO). ... 

Nearly every substrate bears donor groups (OH, NH2) in position 5 or 7 or both these groups activate C-6 for possible substitution reactions (Table XI). Electrophilic brominations occur at the unprotonated species (68JOC1087). 

In agreement with MO calculations (V-acylation of 5H- dibenz[6,/]azepine alters considerably the pattern of electrophilic substitution. In the N-unsubstituted heterocycle the sites of electrophilic substitution are at C-2 and C-8 i.e. ortho and para to the free NH see Section 5.16.3.9.1). However, as predicted theoretically, IV-acylation deactivates the car-bocyclic nuclei towards substitution via mesomers of structure (32). As a result Friedel-Crafts acetylation furnishes the 5,10-diacetyl derivative (108). Electrophilic bromination (Br2/CHC13), unlike the free radical process (see Section 5.16.3.7), yields the 10,11-dibromo compound. In contrast, nitration of the (V-acetyl derivative at low temperature affords only the 3-nitro isomer (74CRV101). 

Bromination The five-membered aromatic heterocycles are all more reactive toward electrophiles than benzene is, and the reactivity is similar to that of phenol. These compounds undergo electrophilic bromination. However, reaction rates vary considerably, and for pyrrole, furan and thiophene the rates are 5.6 x 10, 1.2 x 10 and 1.00, respectively. While unsubstituted five-membered aromatic heterocycles produce a mixture of bromo-derivatives, e.g. bromothiphenes, substituted heterocycles produce a single product. 

Electrophilic aromatic substitution Electrophilic aromatic substitution of indole occurs on the five-membered pyrrole ring, because it is more reactive towards such reaction than a benzene ring. As an electron-rich heterocycle, indole undergoes electrophilic aromatic substitution primarily at C-3, for example bromination of indole. 

Bromination of benzene follows the same general mechanism of the electrophilic aromatic substitution. The bromine molecule reacts with FeBr3 by donating a pair of its electrons to it, which creates a more polar Br—Br bond. 

Since the reactivity of double bonds in electrophilic bromination increases drastically with increasing alkyl substitution, selective monoaddition to the more substituted double bond in nonconjugated dienes can be accomplished with pyridin hydrobromide perbromide.264 Chlorination265 and bromination266 of c/s,cis-1,5-cyclooctadiene lead to the expected dihalogen and tetrahalogen derivatives. 

Substituents at the 3-position, if capable of stabilizing an adjacent positive charge by resonance and/or inductive effects, direct strongly to the adjacent (i.e. 2) position (equation 3). Stabilization of the allylic carbonium ion intermediate is obviously involved. This effect can be quite pronounced for R = Ph in equation (3) the ratio of 2- to 5-bromo derivatives for electrophilic bromination is ca. 660 (68JOC2902). Even more striking is the exclusive formation of the 2,2 -dibrominated product (19) from 3,3 -dithienyl (equation 4) (69JOC343). As expected, substituents not capable of stabilizing the cationic intermediate direct substitution to the 5-position. 

For alkyl substituents, electrophilic substitution (chlorination, bromination, acetylation, trifluoroacetylation, formylation, hydrogen exchange) of 2-alkylthiophenes happens mainly... 

The normal reactions of benzo[6]thiophene 1,1-dioxides have been reviewed (70AHC(11)177). Electrophilic substitution (nitration, bromination) takes place at position 6. 3-Halo derivatives undergo normal nucleophilic displacement reactions, but 2-bromobenzo[6]thiophene dioxide gives the 3-ethoxy derivative in ethanolic NaOH. The reaction of 3-methoxy derivatives with secondary amines can give rise either to enamines... 

Most of the reports in the literature discuss electrophilic substitution of 1,3,6-triazacycl[3.3.3]azine (80) and the 2-methyl, 4-cyano and 4-ethoxycarbonyl derivatives. Electrophilic bromination occurs preferentially at the 4-position (if available), and subsequently at the 9- and 7-positions. These data support the electron charge density calculations (see Section 2.20.2) (73ACS3264). Nitrations are carried out using copper(II) nitrate and acetic anhydride. The central nitrogen is completely non-basic, and in the triazacycl-azines protonation occurs initially at position 6 (80) (77ACS(B)239). Ceder and Vernmark have reported that piperidine reacts with (81) via the aryne intermediate the A-E cine-substitution mechanism is an attractive alternative (equation 40). 

Almost all electrophilic substitutions known to proceed in solution with isopropylbenzene can also be performed with polystyrene, using solvents such as nitrobenzene, carbon disulfide, or carbon tetrachloride. These substitutions include bromination [42], nitration [43,44], sulfonylation, Friedel-Crafts acylations [45 49], and alkylations... 

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