Benzylic bromination reactivity

The difference in the reactivity of benzylic versus aromatic halogens makes it possible to reduce the former ones preferentially. Lithium aluminum hydride replaced only the benzylic bromine by hydrogen in 2-bromomethyl-3-chloro-naphthalene (yield 75%) [540]. Sodium borohydride in diglyme reduces, as a rule, benzylic halides but not aromatic halides (except for some iodo derivatives) [505, 541]. Lithium aluminum hydride hydrogenolyzes benzyl halides and aryl bromides and iodides. Aryl chlorides and especially fluorides are quite resistant [540,542], However, in polyfluorinated aromatics, because of the very low electron density of the ring, even fluorine was replaced by hydrogen using lithium aluminum hydride [543]. 

Few ring substitution reactions have been reported and these are predominantly benzylic brominations such as that indicated in Eq. (71) for the generation of benzosilepin systems. Multibromination of benz-silacyclopentane has been effected, but attempts to hydrolyze the tetrabromo derivative to the diketone resulted in the expulsion of the silicon heteroatom, in contrast to the reactivity of the six-membered ring [Eq. (69)]. 

Polymerization of styrene with n-butyllithium using vacuumline techniques, followed by addition of excess Br2 or xylylene dibromide, produced reactive Br-terminated polystyrenes VI and VII (24,25). Both contain benzylic bromine atoms, which are readily... 

Reagents with the six electrones are good electrophiles but rather complex and require controlled reaction conditions (Scheme 5.23). Thiirane in TM 5.11 is therefore conveniently interconverted by one-bond disconnection and regioselective ring opening, and then proper FGI affords styrene as the starting material. Formation of the thiirane ring in TM 5.11 needs more synthetic steps from styrene, bromination, substitution of more reactive benzylic bromine by sulfide anions and cyclization in the last step. 

Brominated copolymer of isobutylene and para-methylstyrene (DIMS) is the latest new class of synthetic rubber that has been developed for the rubber industry. The sole producer of this new class of elastomer is ExxonMobil, which commercialized it successfully under the trade name Exxpro in the first decade of this new century. The advantage of this new polymer class vs. bromobutyl rubber is that this new elastomer possesses a completely saturated backbone and possesses more reactive benzylic bromine functionality than the bromine sites on the conventional bromobutyl backbone. This means that DIMS reportedly gives superior performance in service vs. BUR. This superiority is shown as better high-temperature resistance, better aging stability than either BUR or EPDM, better weathering resistance, and better ozone resistance. Also, BIMS provides the potential of imparting superior air permeability resistance. 

These reactions occur on the benzylic hydrogens because these hydrogens are much more reactive. Competition experiments show, for example, that at 40°C a benzylic hydrogen of toluene is 3.3 times as reactive toward bromine atoms as the tertiary hydrogen of an alkane and nearly 100 million times as reactive as a hydrogen of methane. 

Important differences are seen when the reactions of the other halogens are compared to bromination. In the case of chlorination, although the same chain mechanism is operative as for bromination, there is a key difference in the greatly diminished selectivity of the chlorination. For example, the pri sec selectivity in 2,3-dimethylbutane for chlorination is 1 3.6 in typical solvents. Because of the greater reactivity of the chlorine atom, abstractions of primary, secondary, and tertiary hydrogens are all exothermic. As a result of this exothermicity, the stability of the product radical has less influence on the activation energy. In terms of Hammond s postulate (Section 4.4.2), the transition state would be expected to be more reactant-like. As an example of the low selectivity, ethylbenzene is chlorinated at both the methyl and the methylene positions, despite the much greater stability of the benzyl radical ... 

The benzylic position of an alkylbcnzene can be brominated by reaction with jV-bromosuccinimide, and the entire side chain can be degraded to a carboxyl group by oxidation with aqueous KMnCfy Although aromatic rings are less reactive than isolated alkene double bonds, they can be reduced to cyclohexanes by hydrogenation over a platinum or rhodium catalyst. In addition, aryl alkyl ketones are reduced to alkylbenzenes by hydrogenation over a platinum catalyst. 

The very small p- and m-values observed for the fast bromination of a-methoxystyrenes deserve comment since they are the smallest found for this electrophilic addition. The rates, almost but not quite diffusion-controlled, are amongst the highest. The sensitivity to polar effects of ring substituents is very attenuated but still significant that to resonance is nil. These unusually low p-values for a reaction leading to a benzylic carbocation are accompanied by a very small sensitivity to the solvent. All these data support a very early transition state for this olefin series. Accordingly, for the still more reactive acetophenone enols, the bromination of which is diffusion-controlled, the usual sensitivity to substituents is annulled. 

How is the course of halogen substitution in the benzene nucleus to be explained It is not at all probable that direct replacement of hydrogen occurs, such as we must assume in the formation of benzyl chloride and in the reaction between methane and chlorine, since the hydrogen attached to the doubly bound carbon atom of olefines exhibits no special reactivity. However, various facts which will be considered later (p. 164) indicate that benzene reacts with halogen in fundamentally the same way as does ethylene. The behaviour of ethylene towards bromine is the subject of the next preparation. 

When chlorination or bromination of alkenes is carried out in the gas phase at high temperature, addition to the double bond becomes less significant and substitution at the allylic position becomes the dominant reaction.153-155 In chlorination studied more thoroughly a small amount of oxygen and a liquid film enhance substitution, which is a radical process in the transformation of linear alkenes. Branched alkenes such as isobutylene behave exceptionally, since they yield allyl-substituted product even at low temperature. This reaction, however, is an ionic reaction.156 Despite the possibility of significant resonance stabilization of the allylic radical, the reactivity of different hydrogens in alkenes in allylic chlorination is very similar to that of alkanes. This is in accordance with the reactivity of benzylic hydrogens in chlorination. 

The unique chemical behavior of K02 is a result of its dual character as a radical anion and a strong oxidizing agent (68). The reactivity and solubility of K02 is gready enhanced by a crown ether (69). Its usefiilness in furnishing oxygen anions is demonstrated by its applications in SN2-type reactions to displace methanesulfonate and bromine groups (70,71), the oxidation of benzylic methylene compounds to ketones (72), and the syntheses of a-hydroxyketones from ketones (73). 

The rates of bromine atom abstraction by tris(trimethylsilyl)silyl radicals from a range of /Jara-substitutcd benzyl bromides has indicated that the silyl radical is nucleophilic. In addition both the polar and spin-delocalization effects of the substituents play a role in the abstraction reaction with the latter effect greater than for H-atom abstractions.166 The perfluoroalkylation of aromatics and alkenes has been investigated using C4F9I as the source of C,. Measurement of rate constants indicated that perfluoroalkyl radicals were 2-3 orders of magnitude more reactive than the corresponding alkyl radicals. This was attributed primarily to the reaction enthalpy and far less to the electrophilic nature of the radicals.167... 

Direct introduction of a vinyl substituent onto an aromatic ring is not a feasible reaction. p-Methoxystyrene must be prepared in an indirect way by adding an ethyl side chain and then taking advantage of the reactivity of the benzylic position by bromination (e.g., with N-bromosuccinimide) and dehydrohalogenation. 

V-Bromosuccinimide (NBS) is a reagent used to substitute benzylic and allylic hydrogens with bromine. The benzylic bromide undergoes SN2 substitution with the nucleophile, methanethiolate. As in part (e), the alkyl halide is more reactive toward substitution than the aryl halide. 

Checking for chemoselectivity problems, we might suspect that the amine could be alkylated twice by the very reactive a-bromoketone 74 so it might be better to protect the nitrogen atom with a benzyl group. This can be removed by catalytic hydrogenation. In the laboratory, it proved better to brominate 73 in neutral rather than acidic solution so the final scheme becomes ... 

Polyhalide salts are prepared in situ in the bromination of less reactive aromatic substrates. Thus, tetra- -butylammonium bromide(TBAB) functions as a catalyst in the bromination of benzene, toluene and even benzyl bromides and a-bromoethylbenzene537 (both tend to polymerize in presence of normal Friedel-Crafts catalysts). Tetra-ethylammonium chloride in CH2Cl2/methanol catalyzes the bromination of anilines538. Improved selectivity is found in the chlorination of toluene catalyzed by onium chloride salts alone or combined with SnCl4539. 

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 ... 

Bromine radicals are not as reactive as chlorine radicals, so bromination is more selective than chlorination (Section 4-13C). Bromine reacts exclusively at the benzylic position. 

The amide N-H may also be halogenated, oxidized and nitrosated. A -Bromosuccinimide (NBS), like a number of other iV-halo compounds, readily undergoes a radical fission to give a bromine radical. This provides a useful reagent for radical bromination at, for example, allylic or benzylic positions. In the presence of acid, NBS is also a mild source of the halonium ion, which is used for the addition of hypobromous acid (Scheme 3.74) to alkenes or for the bromination of reactive aromatic rings. 

When the unusual bromine cleavage of oxytocin and vasopressin, reported by du Vigneaud and his associates, was repeated with a simplified tripeptide model, N-carbobenzyloxy-(S-benzyl-L-cysteinyl-L-tyrosyl-L-iso-leucine (CXV) (Ressler and du Vigneaud, 1957), bromine or NBS liberated a ninhydrin-reactive material in 40% yield. Paper chromatography proved isoleucine to be the sole ninhydrin-reactive substance present. The ultraviolet spectrum of the reaction mixture showed the characteristic 260 mM absorption for a dienone (CXVI). 

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