Benzyl radicals, reaction

McCarthy RL, MacLachlan A. (1960) Transient benzyl radical reactions produced by high-energy radiation. Trans Faraday Soc 56 1187-1200. 

As is broadly true for aromatic compounds, the a- or benzylic position of alkyl substituents exhibits special reactivity. This includes susceptibility to radical reactions, because of the. stabilization provided the radical intermediates. In indole derivatives, the reactivity of a-substituents towards nucleophilic substitution is greatly enhanced by participation of the indole nitrogen. This effect is strongest at C3, but is also present at C2 and to some extent in the carbocyclic ring. The effect is enhanced by N-deprotonation. 

A similar reaction of benzyl radicals is observed in the thermolysis at 200 C and in the presence of powdered copper of N-benzylthiazolium... 

Reactions involving benzylic cations benzylic radicals and aUcenylbenzenes will be dis cussed m Sections 11 12 through 11 17... 

Section 11 10 Chemical reactions of arenes can take place on the ring itself or on a side chain Reactions that take place on the side chain are strongly influ enced by the stability of benzylic radicals and benzylic carbocations... 

Substitution Reactions on the Methyl Group. The reactions that give substitution on the methyl group are generally high temperature and free-radical reactions. Thus, chlorination at ca 100°C, or in the presence of ultraviolet light and other free-radical initiators, successively gives benzyl chloride, benzal chloride, and benzotrichloride. 

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 absolute rate of dissociation of the radical anion of /i-nitrobenzyl chloride has been measured as 4 x 10 s . The w-nitro isomer does not undergo a corresponding reaction. This is because the meta nitro group provides no resonance stabilization of the benzylic radical. 

The results are consistent with the rate-determining step being addition of the aryl radical to the aromatic ring, Eq. (9). Support for this mechanism is derived from the results of three other studies (a) When A -nitrosoacetanilide is decomposed in pyridine, the benzene formed by abstraction of hydrogen from pyridine by phenyl radical accounts for only 1 part in 120 of the reaction leading to phenyl-pyridines. (b) 9,9, 10,lCK-Tetrahydro-10,10 -diphenyl-9,9 -bianthryl is formed in the reaction between phenyl radicals and anthracene, probably by the addition mechanism in Eq. (11). Adducts are also formed in the reactions of benzyl radicals with anthracene- and acridine. ... 

Alkyl radicals can be obtained by abstraction of a hydrogen atom from an alkyl group by another radical. This method was utilized for the generation of benzyl radicals from toluene with iert-butoxy radical obtained on heating di- er -butyl peroxide. BenzoyP and carboxymethyP radicals have also been obtained by this method. The reaction gives rise to a complex mixture of products and therefore is of rather limited use. 

The first reaction probably involving attack by benzyl radicals on a heterocyclic system was reported by Hickinbottom. - He found that, when benzyl phenyl ether is heated in quinoline to about 250 C, benzylquinoline and hydroxyphenylquinolines are the main products. 

The reaction of benzyl radicals wdth several heterocyclic compounds W as more extensively studied by Waters and Watson, " - who generated benzyl radicals by decomposing di-tert-butyl peroxide in boiling toluene. The products of the reaction with acridine, 5-phenyl-acridine, 1 2- and 3 4-benzacridine, and phenazine were studied. Acridine gives a mixture of 9-benzylacridine (17%) (28) and 5,10-dibenzylacridan (18%) (29) but ho biacridan, w hereas anthracene gives a mixture of 9,10-dibenzyl-9,10-dihydroanthracene and 9,9 -dibenzyl-9,9, 10,10 -tetrahydrobianthryl. This indicates that initial addition must occur at the meso-carbon and not at the nitrogen atom. (Similar conclusions were reached on the basis of methylations discussed in Section III,C.) That this is the position of attack is further supported by the fact that the reaction of benzyl radicals with 5-... 

The reaction of benzyl radicals with phenazine gives 5,10-dibenzyl-5,10-dihydrophenazine (39) and 1-benzylphenazine (40) in the approximate ratio of 1 3. " ... 

Only about 1% of bibenzyl is formed during the reaction and it was suggested that this reflects the high reactivity of phenazine toward benzyl radicals. Evidently direct attack on the nitrogen atom occurs with relative ease in this case. 

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. 

The chlorination of toluene by substituting the methyl hydrogens is a free radical reaction. A mixture of three chlorides (benzyl chloride, ben-zal chloride and benzotrichloride) results. 

Draw resonance structures for the benzyl radical, C6H5CH2-, the intermediate produced in the NBS bromination reaction of toluene (Problem 10.27). 

Analogous side-chain oxidations occur in various biosynthetic pathways. The neurotransmitter norepinephrine, for instance, is biosynthesized from dopamine by a benzylic hydroxylation reaction. The process is catalyzed by the copper-containing enzyme dopamine /3-monooxygenase and occurs by a radical mechanism. A copper-oxygen species in the enzyme first abstracts the pro-R benzylic hydrogen to give a radical, and a hydroxyl is then transferred from copper to carbon. 

The mechanism of benzylic bromination is similar to that discussed in Section 10.4 for allylic bromination of alkenes. Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical, which reacts with Br2 to yield product and a Br- radical that cycles back into the reaction to carry on the chain. The Br2 necessary for reaction with the benzylic radical is produced by a concurrent reaction of HBr with NBS. 

Reaction occurs exclusively at the benzylic position because the benzylic radical intermediate is stabilized by resonance. Figure 16.20 shows how the benzyl radical is stabilized by overlap of its p orbital with the ring 77 electron system. 

Sjsj2 reaction and, 377-378 Benzylic radical, resonance in, 578 spin-density surface of, 578 Benzylpenicillin, discovery of, 824 structure of, 1 Benzyne, 575... 

The reaction between nitroxides and carbon-centered radicals occurs at near (but not at) diffusion controlled rates. Rate constants and Arrhenius parameters for coupling of nitroxides and various carbon-centered radicals have been determined.508 311 The rate constants (20 °C) for the reaction of TEMPO with primary, secondary and tertiary alkyl and benzyl radicals are 1.2, 1.0, 0.8 and 0.5x109 M 1 s 1 respectively. The corresponding rate constants for reaction of 115 are slightly higher. If due allowance is made for the afore-mentioned sensitivity to radical structure510 and some dependence on reaction conditions,511 the reaction can be applied as a clock reaction to estimate rate constants for reactions between carbon-centered radicals and monomers504 506"07312 or other substrates.20... 

In the anodic decarboxylation of phenylacetic acid benzaldehyde is the major product (80%) at low current density (< 3.2mA/cm ). Its formation is supposed to occur by reaction of the intermediate benzyl radical with oxygen, which is possibly simultaneously generated at the anode [31]. 

Partenheimer showed (ref. 15) that when toluene was subjected to dioxygen in acetic acid no reaction occurred, even at 205 °C and 27 bar. He also showed that when a solution of cobalt(II) acetate in acetic acid at 113 °C was treated with dioxygen ca. 1 % of the cobalt was converted to the trivalent state. In the presence of a substituted toluene two reactions are possible formation of a benzyl radical via one-electron oxidation of the substrate or decarboxylation of the acetate ligand (Fig. 9). Unfortunately, at the temperatures required for a reasonable rate of ArCH3 oxidation (> 130 °C) competing decarboxylation predominates. As noted earlier, two methods have been devised to circumvent this undesirable... 

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