Bromine continued substitution

Radical bromination of pyrrole and indole methyl substituents continues to be investigated, as does the substitution of the resulting bromo compound. Selective bromination of the 2-methyl group in 1-acetyl-2,3-dimethylindole can be achieved and the bromide ion displaced by malonate <85TL5253>. A recent example of an effective sequence of bromination and substitution is shown in Scheme 116 <928743, 930PP249,93TL3215>. 

Dibromide formation. Dissolve 0 2 ml. of styrene in 0 5 ml. of CCI4 in a test-tube. Add slowly, drop by drop, a 10% solution of bromine in CCI4. Note the decolorisation of the bromine and absence of HBr fumes (therefore reaction by addition and not by substitution). Continue to add the bromine solution until a faint brown colour persists. Scratch the sides of the tube and cool it in ice-water. Filter off the crystals that separate and recrystallise the styrene dibromide from methanol m.p. 72 . 

The fonnation of these substances contradicts common ideas on nucleophilic substitution. The presence of radical traps (oxygen or tetrabromobenzoquinone) decelerates the formation of both unexpected compounds and product of thioarylation. Consequently, the first stage of the reaction depicted in Scheme 4.5 produces phenylthiyl radical and anion-radical of the substrate. Both electron-transfer products undergo further conversions The phenylthiyl radical gives diphenyldi-sulfide, and the anion-radical of the substrate produces 9-fluorenyl radical. The latter reacts in two directions—dimerizing, it forms bifluorenyl reacting with the nucleophile, it gives the anion-radical of the substitution product. The chain continues because the electron from the anion-radical is transferred to the unreacted molecule of the substrate. The latter loses bromine and then reacts with the nucleophile, and so on (Scheme 4.6). 

Folate analogues continue to have importance in chemotherapy, especially heterocyclic analogues other than pteridines which are covered in Chapters 10.15-10.17 and 10.19. 1,3-Dimethyllumazine analogues of folates for use as model compounds have been prepared by side-chain elaboration of 6-bromomethyl-l,3-dimethyllumazine (Scheme 34) <1996JHC341>. More notable in this work, however, was the synthesis of the bromomethyl precursor itself in addition to routine bromination of the 6-methyllumazine 175 prepared by condensation of dihydroxyacetone with 5,6-diamino-l,3-dimethyluracil, a cycloaddition reaction between trimethylsilyl enol ethers and the pyrimidyl bisimine 177, via cycloadducts such as 176, afforded substituted pteridines in moderate to good yields. 

An Sjuyl-type (S l ) mechanism has been proposed in the synthesis of poly(2,6-dimethyl-l,4-phenylene ether) through the anion-radical polymerization of 4-bromo-2,6-dimethylphenoxide ions (204) under phase-transfer catalysed conditions269. Ions 204 are oxidized to give an oxygen radical 205. The propagation consists of the radical nucleophilic substitution by 205 at the ipso position of the bromine in 204 (equation 144). The anion-radical 206 thus formed eliminates a bromide ion to form a dimer phenoxy radical 207 (equation 145). A polymeric phenoxy radical results by continuation of this radical nucleophilic substitution. 

N-Bromosuccinimide (NBS) is a reagent that will continuously generate bromine molecules at a low concentration. This occurs when the HBr molecule from an allylic substitution reacts with NBS ... 

If the reaction is allowed to continue for a long time, other substitution products can also be obtained. But the action of chlorine or bromine on adds is very sluggish. It may be essentially fadlitated by certain conditions. If, e.g., the operation is conducted in direct sunlight, the reaction proceeds much more rapidly than in a dark place. The reaction is assisted more effectively by adding a so-called earner Iodine... 

Preparation of Eosin (SECTION 641).—In a small flask cover 5 grams of fluorescein with 20 cc. of alcohol. Add slowly in small portions, taking 10 minutes for the operation, 4 cc. of bromine. Shake the flask frequently. When about one-half of the bromine has been added most of the fluorescein passes into solution as the dibrom-substitution-product as the addition continues the tetrabrom-substitution-produet crystallizes out. (Eq.) Allow the mixture to stand for an hour filter and... 

Moving to bromination, represented by squares in the figure, we again see an increase of reactivity with alkyl substitution. Now, however, the total number of substituents is important. The rate continues to increase as substitution increases from ethene through 2,3-dimethyl-2-butene. This pattern is consistent with the more symmetrical (bridged) nature of the rate-determining TS. All of the substituents contribute to stabilization. 

In a study of coal halogenation (105), exhaustive bromination of two coals (one containing 77.7% C and the other 81.7% C) by treatment with Br-CHC13 at 0 °C, followed by hydrolysis of the brominated materials with 10% aqueous NaOH, yielded very different reaction products. In one case, hydrolysis ended after four Br atoms per 100 C atoms were replaced with -OH, while in the other it continued as an oxidation process that appeared to introduce =CO moieties and ended only after it had substituted 10 O atoms for five Br atoms per 100 C atoms. 

The electrophilic aromatic substitution of the pyridine ring continues to be explored as a way to prepare substituted pyridines. Bw-( 5y w-collidine)-iodine(I) and bromine (I) are effective iodinating or brominating agents, respectively, of pyridinols, although the di- or tri-halogenated products are obtained <97TL2467>. lodination of 3-pyridinol produces 5-hydroxy-... 

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