Radicals bromine, selectivity

The forward scheme is shown here. Methylcyclopentane will undergo radical bromination selectively at the tertiary position, giving a tertiary alkyl bromide. This aUcyl bromide will undergo an elimination reaction upon treatment with a strong base, such as sodium ethoxide. Ozonolysis of the resulting alkene gives a dicarbonyl compound, which can then be converted into the product upon treatment with methyl amine and sodium cyanoborohydride (with acid catalysis) ... 

Free-radical bromination is an important method of selective functionalization of hydrocarbons. The process is a chain reaction involving the following steps ... 

As we saw when discussing allylic bromination in Section 10.4, A-bromosuccin-imide (NBS) is a convenient free-radical brominating agent. Benzylic brominations with NBS are nonnally perfonned in carbon tetrachloride as the solvent in the presence of peroxides, which are added as initiators. As the exanple illustrates, free-radical bromination is selective for substitution of benzylic hydrogens. 

There are a few things to keep in mind when using this technique. First of all, radical bromination will selectively place a Br on the most substituted position. Therefore, you should always look for the tertiary position to see where the Br will go. Then, when doing the elimination, make sure to choose the base carefully, in order to achieve the desired regiochemistry. Let s get some practice with this. 

Generated from diacetyl peroxide, methyl radicals attack 2-methylfuran at position 5 preferentially if both 2- and 5-positions are occupied as in 2,5-dimethylfuran there is still little or no attack at the 3(4)-position. If there is a choice of 2(5)-positions, as in 3-methylfuran, then that adjacent to the methyl substituent is selected.249 These orientation rules are very like those for electrophilic substitution, but are predicted for radical attack by calculations of superdelocalizability (Sr) by the simple HMO method. Radical bromination by IV-bromsuccinimide follows theory less closely, presumably because it does not occur through a pure radical-chain mechanism.249... 

Table 4.1 weighs the positional selectivity of the side-chain cation-radical acetoxylation against the side-chain pure radical bromination. 

The selectivity of radical bromination reactions depends, in part, on the increased stability of secondary or tertiary radical intermediates compared with primary radicals. In Section 9.2 we noted that allyl and benzyl radicals were especially... 

Radical bromination of 3,4-dimethyl-1,2,5-thiadiazole (55) has been extensively studied. While, under forcing conditions a mixture of mono-, di-, tri-, and tetrabromo derivatives can form, by careful control the monobromide (59) can be selectively formed (Equation (9)) <84JHC1157, 87CB1593, 89CCC2176>. 

Free radical brominations can be conducted effectively in SC-CO2 as solvent. The high product yields and selectivities usually found for brominations in conventional solvents are not compromised by the use of this nontoxic, less environmentally threatening medium. The results demonstrate that supercritical fluid solvents retain virtually all of the chemical advantages associated with conventional organic solvents (Tanko et al., 1994). 

Bromine selectively suhstitutes for a henzylic hydrogen in toluene in a radical suhstitution reaction to produce hromomethylhenzene or henzylhro-mide. A-hromosuccinimide is used to carry out henzylic hromination of toluene. 

Novel results were reported for allylic bromination. In radical bromination of cyclohexene in CCI4 under light the selectivity of substitution over addition was shown to be controlled by bromine concentration.304 Substitution via the corresponding allyl radical, while relatively slow, is irreversible and fast enough to maintain the concentration of bromine at a sufficiently low level to prevent significant addition. The reaction of two strained alkenes, fZ)-1,2-dimethyl-1,2-di-ferf-butylethylene and the -isomer (14), leads to the corresponding bromosubstituted product, instead of addition 305... 

Table 9.12 compares partial rate factors for substitution by phenyl radical with those for electrophilic bromination. Selectivity is clearly much lower for the radical substitution furthermore, for attacking phenyl radical, nearly all positions in the substituted benzenes are more reactive than in benzene itself, a finding that reflects the tendency for most substituents to stabilize a radical, and thus to lower transition state energy for formation of the cyclohexadienyl intermediate, when compared with hydrogen. The strong polar effects, which cause the familiar pattern of activation and deactivation in the electrophilic substitutions, are absent. One factor that presumably contributes to the low selectivity in radical attack is an early transition state in the addition step, which is exothermic by roughly 20 kcal mole-1.178... 

The first step constitutes a che mo selective radical bromination of the methyl group in quinoline 10 using A-bromosuccinimide (33), leading to compound 34. Here benzoyl peroxide (32) acts as the radical initiator. A rule of thumb for chemoselectivity states that heat and light produce side-chain halogenation, whereas cold and catalysis favor halogenation of the aromatic nucleus. 

Free-radical bromination of toluene is selective for the benzylic position. Benzyl bromide cannot undergo elimination, and so nucleophilic substitution of bromide by hydroxide will work well. 

Also, according to Equation 1.9, the overall reaction radical chlorination takes place on a given substrate considerably faster than the overall reaction radical bromination. If we consider this and the observation from Section 1.7.3, which states that radical chlorinations on a given substrate proceed with considerably lower regioselectivity than radical brominations, we have a good example of the so-called reactivity/selectivity principle. This states that more reactive reagents and reactants are less selective than less reactive ones. So selectivity becomes a measure of reactivity and vice versa. However, the selectivity-determining step of radical chlorination reactions of hydrocarbons takes place near the diffusion-controlled limit. Bromination is considerably slower. Read on. 

Because of the greater selectivity of the bromine atom, radical brominations can be useful in synthesis as long as the compound to be brominated has one hydrogen that is considerably more reactive than the others. The reaction of 2-methylpentane with bromine, shown previously, gives predominantly a single product because there is only one tertiary hydrogen. Because allylic and benzylic radicals are stabilized by resonance, bromination at these positions can also be successfully accomplished. An example is provided by the following equation ... 

Free-radical bromination is highly selective, chlorination is moderately selective, and fluorination is nearly nonselective. 

For each compound, predict the major product of free-radical bromination. Remember that bromination is highly selective, and only the most stable radical will be formed. 

All the hydrogen atoms in cyclohexane are equivalent, and free-radical chlorination gives a usable yield of chlorocyclohexane. Formation of dichlorides and trichlorides is possible, but these side reactions are controlled by using only a small amount of chlorine and an excess of cyclohexane. Free-radical bromination is highly selective (Section 4-14), and it gives good yields of products that have one type of hydrogen atom... 

Although free-radical halogenation is a poor synthetic method in most cases, free-radical bromination of alkenes can be carried out in a highly selective manner. An allylic position is a carbon atom next to a carbon-carbon double bond. Allylic intermediates (cations, radicals, and anions) are stabilized by resonance with the double bond, allowing the charge or radical to be delocalized. The following bond dissociation enthalpies show that less energy is required to form a resonance-stabilized primary allylic radical than a typical secondary radical. 

Because radical brominations are so selective, they can be used successfully in the lab to make alkyl bromides. There are relatively few ways of functionalizing an unfunctionalized centre, but radical allylic bromination is one of these. Just as tertiary radicals are more stable than primary ones, so allylic radicals are even more stable than tertiary ones (see the table on p. 1026). In the presence of a suitable initiator, bromine will therefore selectively abstract an allylic hydrogen atom to give an allylic radical that can then be trapped by a molecule of bromine to regenerate a bromine radical (chain propagation) and produce the allylic bromide, initiation Br2 ----------- 2 x Br ... 

Selective radical bromination of the p-methyl group by elemental bromine is performed in solution either thermally, photolytically, or in the presence of radical initiators. The reaction does not lead to any change in molar mass or distribution, and the only potential side reaction, which has to be controlled by adjusting the reaction conditions, is debromination between two p-bromobenzyl moieties. Under similar conditions radical chlorination leads to substitution on the benzylic site as well as on the methylene and methyl groups of isobutene units, with changes in molar mass. 

As a result, an alkyl benzene undergoes selective bromination at the weak benzylic C—H bond under radical conditions to form a benzylic halide. For example, radical bromination of ethylbenzene using either Br2 (in the presence of light or heat) or A/-bromosuccinimide (NBS, in the presence of light or peroxides) forms a benzylic bromide as the sole product. 

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