Regioselectivity radical bromination

A secondary alkyl radical is more stable than a primary radical Bromine therefore adds to C 1 of 1 butene faster than it adds to C 2 Once the bromine atom has added to the double bond the regioselectivity of addition is set The alkyl radical then abstracts a hydrogen atom from hydrogen bromide to give the alkyl bromide product as shown m... 

Radical bromination with NBS can result in the replacement of a sugar ring hydrogen by bromine.18 These reactions can be highly regioselective... 

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. 

Let us go back to radical brominations (cf. Section 1.7.3). The bromination of alkyl aromatics takes place completely regioselectively only the benzylic position is brominated. The intermediates are the most stable radicals that are available from alkyl aromatics, namely, benzylic radicals. Refluxing ortho-xylene reacts with 2 equiv. of bromine to give one monosubstitution... 

The methyl group at position 6 is more reactive for radical bromination than the 2-methyl group of 2,6-dimethylquinazolin-4 3//)-one ° or 2,6-dimethyl-4-methylsulfanylquinazo-line. Regioselective bromination with N-bromosuccininiide (NBS) or 1,3-dibromo-5,5-dimethylhydantoin (DDH) using benzoyl peroxide as a catalyst gives the respective benzyl bromides in good yields. 

Thus, research efforts in different industrial laboratories have been directed toward the preparation of 1-bro-moalkyl alkyl carbonates assumed to be more stable than the 1-iodo derivatives, and more reactive than the parent chloro compounds. For example, 1-bromoethyl ethyl carbonate was made by the halide exchange of 1-chloroethyl ethyl carbonate with LiBr or NaBr, or by a radical type bro-mination of diethyl carbonate (Ref. 82). However, in the case of halide exchange, the conversion is low and a mixture results. Even with a large excess of bromide salt, this problem remains. Radical bromination was found to give unsatisfactory results for the same reasons than the chlorination, and failed in the case of unsymmetrical dialkyl carbonates because of its non-regioselectivity. 

In Chapter 24 we introduced the fact that bromine radicals react regioselectively with alk-enes. Let us remind you of one reaction you met then radical addition to an alkene. The product is an alkyl bromide, and is a different alkyl bromide from the one formed when HBr adds to an alkene in an ionic manner. 

The regioselectivity of addition of HBr to alkenes under normal (electrophilic addi tion) conditions is controlled by the tendency of a proton to add to the double bond so as to produce the more stable carbocatwn Under free radical conditions the regioselec tivity IS governed by addition of a bromine atom to give the more stable alkyl radical Free radical addition of hydrogen bromide to the double bond can also be initiated photochemically either with or without added peroxides... 

Because the bromine adds to the less substituted carbon atom of the double bond, generating the more stable radical intermediate, the regioselectivity of radical-chain hydrobromination is opposite to that of ionic addition. The early work on the radical mechanism of addition of hydrogen bromide was undertaken to understand why Maikow-nikofF s rule was violated under certain circumstances. The cause was found to be conditions that initiated the radical-chain process, such as peroxide impurities or light. 

N2, and bromine trifluoride at 25-35°C " are also highly regioselective for tertiary positions. These reactions probably have electrophilic, not free-radical mechanisms. In fact, the success of the F2 reactions depends on the suppression of free-radical pathways, by dilution with an inert gas, by working at low temperatures, and/or by the use of radical scavengers. 

Some time ago, Holliman and co-workers illustrated a method for synthesizing polysubstituted phenazines by reductive cyclization of o-nitrodiphenylamine. However, the yield was poor when competitive cyclizations occurred <70CC1423>. Recently, Kamikawa and co-workers reported a more efficient method to synthesize phenazines using sequential aniline arylation, which was first introduced by Buchwald <97JOC1264>. Regioselective bromination of o-nitrodiphenylamine 226 with bromine in the presence of sodium bicarbonate yielded 227 which was subjected to the Buchwald conditions to provide the desired phenazine 228 and the eliminated product 229 <00TL355>. The former compound is a proposed intermediate for the synthesis of the radical scavenger benthocyanin A. 

Analogously, 5-tributylstannylimidazole 29 was easily obtained from the regioselective deprotonation of 1,2-disubstituted imidazole 28 at C(5) followed by treatment with tributyltin chloride [24]. In the presence of 2.6 equivalents of LiCl, the Stille reaction of 29 with aryl triflate 30 afforded the desired 1,2,5-trisubstituted imidazole 31 with 2,6-di-tert-butyl-4-methylphenol (BHT) as a radical scavenger. Reversal of the nucleophile and electrophile of the Stille reaction also provided satisfactory results. For example, the coupling reaction of 5-bromoimidazole 33, derived from imidazole 32 via a regioselective bromination at C(5), and vinylstannane 34 produced adduct 35 [24],... 

Addition of the dicyanomethyl radical to propadiene (la) occurs exclusively at Q (not shown in Scheme 11.8) [60]. On the other hand, methyl-substituted allenes, e.g. Id, undergo /3-selective reactions with 2-bromomalodinitrile (15). The significant /3-selectivity has been associated with the steric demand of the incoming radical 16, which favors addition to the sterically least hindered site at the diene Id to provide allylic radical 17. However, it seems likely that a stabilization of an intermediate allylic radical, e.g. 17, by methyl substituents contributes significantly to the observed regioselectivity of product formation. Trapping of intermediate 17 with bromine atom donor 15 proceeds at the least substituted carbon to afford allylic bromide 18. 

Radical addition of dibromodifluoromethane to alkenes followed by sodium borohydride reduction is a convenient two-step method for the introduction of the difluoromethyl group.5 Either one or both carbon-bromine bonds in the intermediate dibromides may be reduced, depending on the reaction conditions. In the case of acyclic dibromodifluoromethane-alkene adducts, the reduction occurs regioselectively to yield the relatively inaccessible bromodifluoromethyl-substituted alkanes. The latter are potential building blocks for other fluorinated compounds. For example, they may be dehydrohalogenated to 1,1-difluoroalkenes an example of this methodology is illustrated in this synthesis of (3,3-difluoroallyl)trimethylsilane. 

Iodocarbonyls are excellent substrates for atom transfer cyclization, as shown by examples from our recent work in Scheme 29.19-129 When two carbonyl (or cyano) groups are present, bromides can also serve as radical precursors. Photolysis with 10% ditin usually provides excellent yields of kinetic products at high concentration, and alkene substituents often dictate the regioselectivity. The y-iodo ester products are particularly versatile for subsequent transformations, which can often be conducted in situ. Although tertiary iodine products sometimes go on to give lactones or alkenes, primary and secondary iodides can often be isolated if desired. The last example is particularly noteworthy the kinetic product from the cyclization presented in Scheme 27 is trapped, because bromine atom transfer is much more rapid that reverse cyclization. 

In contrast to the large body of data pertaining the 5-exo and 6-exo cyclization modes, the 6-endo-trig mode has limited applications. This is simply because the 5-exo-trig cyclization is kinetically favored for S-hexenyl radical intermediates. Nevertheless, when the usually favored 5-exo-trig regioselectivity is surpressed by a substituent (e.g. bromine or ethyl) at the 5-position, the 6-endo-trig cyclization mode prevails. 

All these transformations are obtained in good yields and 5-bromo derivatives are often crystalline and easy to separate. By-products can be bromides or dibromides with halogen substituent at C-l and C-5, but the regioselectivity of photobromination at C-5 results from the easier formation of tertiary radicals. The a-bromination confirms the stereoselectivity of the substitution reaction with the preferential abstraction of axial H-5. 

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