Bromination of aromatic substrates

We have previously shown (ref. 1) that microporous solids are useful in the controlled bromination of aromatic substrates. In particular, we showed how a reagent system comprising V-bromosuccinimide (NBS) and silica is useful for the bromination of reactive aromatic systems such as indoles (Fig. 1) (ref. 2), carbazoles and iminodibenzyls (Fig. 2) (ref. 3). 

SELECTIVE BROMINATION OF AROMATIC SUBSTRATES Selective Bromination of Toluene... 

Zinc chloride was used as a catalyst in the Friedel Crafts benzylation of benzenes in the presence of polar solvents, such as primary alcohols, ketones, and water.639 Friedel-Crafts catalysis has also been carried out using a supported zinc chloride reagent. Mesoporous silicas with zinc chloride incorporated have been synthesized with a high level of available catalyst. Variation in reaction conditions and relation of catalytic activity to pore size and volume were studied.640 Other supported catalytic systems include a zinc bromide catalyst that is fast, efficient, selective, and reusable in the /wa-bromination of aromatic substrates.641... 

Table 6. Percentages of ortho- and para- products obtained from bromination of aromatic substrates containing — I, + M groups ...

The effects of a-CD on the bromination of other substrates have been studied recently (Javed, 1990 Tee et al., 1990a Tee and Javed, 1993), the object being to see if the catalytic effects observed earlier with phenols (Tee and Bennett, 1988a) are peculiar to these substrates or more general. Broadly speaking, various aromatic and heteroaromatic substrates (Table A4.4) showed behaviour (k /k2u = 1.7 to 10 XTS = 0.2 to 1.2 mM) very similar to that of phenols, and so the catalytic effect appears to be fairly general. The oxidation of formic acid by bromine also shows catalysis by a-CD (Han et al., 1989 Tee et al., 1990a). 

Tetrabutylphosphonium hydrogen difluoride [Bu4PF (HF)] and dihydrogen trifluoride [Bu4PF (HF)2] have been shown to be expedient reagents for nucleophilic fluorination of aromatic substrates containing a chlorine or bromine atom or a nitro group under mild conditions in non polar solvents. Thus, for example l-chloro-4-nitrobenzene (28) is converted to l-fluoro-4-nitrobenzene (29) in 90% yield.219... 

Many quantitative results regarding bromination of olefins and of aromatic substrates allow interesting comparisons to be made between the two reactions. 

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. 

For chlorination, the formation of the (7-complex would be expected to be the rate-determining step since the aromatic chlorination of other substrates does not appear to give rise to deuterium isotope effects (Baciocchi et al., 1960 de la Mare and Lomas, 1967). The effect of the experimental conditions on the rate-determining step in the aqueous bromination of aromatic amines has been investigated in detail by Dubois and his co-workers (Dubois et al., 1968a, b, c Dubois and Uzan, 1968). This work suggests that, for tertiary aromatic amines, the proton loss is fast for para-bromination but partly or wholly rate-determining for ortho-bromination. There is however some... 

After developing the optimal reaction conditions, a number of aromatic substrates were subjected to bromination and chlorination reactions with NaBr and NaCl (Table 4.10). Benzene, m-toluidine, benzonitrile, and chlorobenzene did not react in... 

Only small quantities of iron(III) bromide are required It is a catalyst for the brommation and as Figure 12 6 indicates is regenerated m the course of the reaction We 11 see later m this chapter that some aromatic substrates are much more reactive than benzene and react rapidly with bromine even m the absence of a catalyst... 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

Molecular bromine is believed to be the reactive brominating agent in uncatalyzed brominations. The brominations of benzene and toluene are first-order in both bromine and the aromatic substrate in trifluoroacetic acid solution, but the rate expressions become more complicated when these reactions take place in the presence of water. " The bromination of benzene in aqueous acetic acid exhibits a first-order dependence on bromine concentration when bromide ion is present. The observed rate is dependent on bromide ion concentration, decreasing with increasing bromide ion concentration. The detailed kinetics are consistent with a rate-determining formation of the n-complex when bromide ion concentration is low, but with a shift to reversible formation of the n-complex... 

The chain propagation step consists of a reaction of allylic radical 3 with a bromine molecule to give the allylic bromide 2 and a bromine radical. The intermediate allylic radical 3 is stabilized by delocalization of the unpaired electron due to resonance (see below). A similar stabilizing effect due to resonance is also possible for benzylic radicals a benzylic bromination of appropriately substituted aromatic substrates is therefore possible, and proceeds in good yields. 

Since the aerobic degradation of halogenated phenols takes place by monooxygenation and is discussed in Part 2 of this chapter, it is not discussed here except to note the production of chlorocat-echols from chlorophenols and chloroanilines. Emphasis is placed on chlorinated substrates, and reference may be made to a review (Allard and Neilson 2003) for details of their brominated and iodinated analogs. The degradation of aromatic fluorinated compounds is discussed in Part 3 of this chapter. 

Fluorine has been used for the generation of extremely strong electrophilic halogenating agents in electrophilic iodination and bromination of deactivated aromatic substrates in highly acidic reacton media. Polyhalogenation of more activated aromatic substrates is also possible (Fig. 90) [231-233]. 

Cross-linked polystyrene can be acylated with aliphatic and aromatic acyl halides in the presence of A1C13 (Friedel-Crafts acylation, Table 12.1). This reaction has mainly been used for the functionalization of polystyrene-based supports, and only rarely for the modification of support-bound substrates. Electron-rich arenes (Entry 3, Table 12.1) or heteroarenes, such as indoles (Entry 5, Table 15.7), undergo smooth Friedel-Crafts acylation without severe deterioration of the support. Suitable solvents for Friedel-Crafts acylations of cross-linked polystyrene are tetrachloroethene [1], DCE [2], CS2 [3,4], nitrobenzene [5,6], and CC14 [7]. As in the bromination of polystyrene, Friedel-Crafts acylations at high temperatures (e.g. DCE, 83 °C, 15 min [2]) can lead to partial dealkylation of phenyl groups and yield a soluble polymer. 

The extension of the Srn 1 reaction to polycyclic aromatic substrates has been limited almost entirely to the simple halogenated derivatives (see tables and references in Section 2.2.3). The substrates used include 4-halobiphenyls, 1- and 2-halonaphthalenes, 9-bromoanthracene and 9-bromophenanthrene. There appears to be only one report on the effect of additional substituents on these ring systems the ionized phenolic group in l-bromo-2-naphthoxide causes substitution of the bromine by CH2CN to be completely supplanted by a reductive process.39... 

An instance of an apparent electrophilic aromatic substitution (in this case 61 is an aromatic substrate, of Scheme 31), which actually is an electrophilic addition, is the halo-genation of 2-aminothiazole derivatives which was usually considered a simple attack of the electrophilic reagent on the heterocyclic aromatic substrate activated by the amino group see reaction 12. When the bromination of 2-aminothiazole derivatives is carried out in nucleophilic solvents (ROH) and at low temperatures, the partially saturated derivatives (64) of Scheme 33 were isolated in 80-95% yields133. By heating 64, the usual halogenated 2-aminothiazoles are obtained, as indicated by Scheme 33. An apparent electrophilic aromatic substitution is actually an addition reaction to the C=C double bond the elimination reaction is the following, separate step. 

The limiting reaction rate does not arise from the rate of formation of the electrophile since the reactions remain first-order with respect to the aromatic substrate. The limiting rate does not arise from a general breakdown in the additivity principle, e.g. as a result of the saturation of substituent effects, since the limiting rate is not found in some related reactions in which the substituent effects in deactivated systems are similar to those in nitration. This is illustrated by the results for bromination by positive bromine discussed in Section 5. Coombes et al. suggest that the limit arises from rate-determining formation of an encounter pair (ArH.NOJ between the nitronium ion and the aromatic substrate (Scheme 5). 

Most of the rate comparisons in the halogenation of aromatic amines refer to bromination rate coefficients for para-substitution are collected in Table 10. Further results for o/7/io-substitution are provided in the cited references. Some of the early calculation based on (39) and (40) may be in error, because it was not then realized that the appropriate acidity function in (40) depends on the structure of the substrate (cf. Bell and Ramsden., 1958 Bell and Ninkov, 1966). The appropriate acidity function was used for the results listed in Table 10 but it is still advisable for rate comparisons to be based on experiments carried out under the same conditions. 

On the other hand, if only catalytic amounts of A1C13 are added, the acetyl group of the acetophenone is brominated. Under these conditions the carhonyl oxygen of a fraction of acetophenone can be complexed. The bulk of the substrate still contains uncomplexed carhonyl oxygen. It allows acetophenone to equilibrate with its tautomeric enol (for details see Figure 12.5). The enol is a better nucleophile than the aromatic ring because it is brominated elec-trophilically without intermediate loss of aromaticity. HBr is the stoichiometric by-product of this substitution. Just like the HC1 that is formed initially, it catalyzes the enolization of unreacted acetophenone and thus keeps the reaction going. 

---