Substituent effects free radicals

L.P. Candeias, L.K. Folkes, M. Porssa, J. Patrick and P. Wardman, Enhancement of lipid peroxidation by indole-3-acetic acid and derivatives substituent effects. Free Radical Res., 23 (1995) 403. 

M. Birkhofer, H.-D. Beckhaus, and C. Ruchardt, Substituent Effects in Radical Chemistry, Reidel, Boston, 1986. J. Fossey, D. Lefort, and J. Sorba, Free Radicab in Organic Chemistry, John Wiley Sons, Chichester, U.K., 1995. 

The effect of sulfur-containing substituents on free radicals appears to be a topic of current interest, so we will discuss it briefly insofar as it concerns sulfinyl and sulfonyl groups. Our discussion will refer mainly to a few recent papers, which usually contain copious references to earlier work see also Block247. 

The absence of substituents with free radical scavenging properties in most of the (3-blockers makes doubtful their efficacy as powerful antioxidants. Arouma et al. [293] tested the antioxidative properties of several 3-blockers in reactions with superoxide, hydroxyl radicals, hydrogen peroxide, and hypochlorous acid. It was demonstrated that most of the compounds tested were inactive in these experiments. Nonetheless, propranolol, verapamil, and flunarizine effectively inhibited iron ascorbate-stimulated microsomal lipid peroxidation and all drugs (excluding flunarizine) were effective scavengers of hydroxyl radicals. Contrary to Janero et al. [292], these authors did not find the inhibition of xanthine oxidase by propranolol. It was concluded that 3-blockers are not the effective in vivo antioxidants. 

The Kochi reaction has also been used to demonstrate polar effects of remote substituents upon free-radical stereoselectivities in chlorine atom transfer. ... 

The quantification of electronic substituent effects is made possible by linear free-energy relationships (e.g., the Hammett equation) [50,51] however, for radical reactions, this is considerably more cumbersome since such effects are orders of magnitude smaller than in their corresponding ionic counterparts [52], Thus, it should be evident that a number of criteria are important in choosing a suitable chemical model system for evaluating substituent effects on radical species [53], Some of the more significant ones are ... 

The influence of the substituents on free-radical reactivity has been—and still is—an intensively studied subjeet. The IFRs are therefore facilitating systematic general studies of the reciprocal effect the influence of free-radical... 

For most vinyl polymers, head-to-tail addition is the dominant mode of addition. Variations from this generalization become more common for polymerizations which are carried out at higher temperatures. Head-to-head addition is also somewhat more abundant in the case of halogenated monomers such as vinyl chloride. The preponderance of head-to-tail additions is understood to arise from a combination of resonance and steric effects. In many cases the ionic or free-radical reaction center occurs at the substituted carbon due to the possibility of resonance stabilization or electron delocalization through the substituent group. Head-to-tail attachment is also sterically favored, since the substituent groups on successive repeat units are separated by a methylene... 

The nature of the secondary reactions is uncertain. Some beheve that the primary tar components are broken down to small free radicals that recombine as they travel toward the retort exit others suggest that some components remain relatively intact except for the removal of peripheral substituent groups and that the higher molecular weight components of coal tar are, in effect, slightly altered fragments of the original coal stmcture. 

Despite some recent discoveries, free radical reactions are still very much less common in azole chemistry than those involving electrophilic or nucleophilic reagents. In some reactions involving free radicals, substituents have little orienting effect however, rather selective radical reactions are now known. 

Nevertheless, many free-radical processes respond to introduction of polar substituents, just as do heterolytic processes that involve polar or ionic intermediates. The substituent effects on toluene bromination, for example, are correlated by the Hammett equation, which gives a p value of — 1.4, indicating that the benzene ring acts as an electron donor in the transition state. Other radicals, for example the t-butyl radical, show a positive p for hydrogen abstraction reactions involving toluene. ... 

Radical chlorination reactions show a substantial polar effect. Positions substituted by electron-withdrawing groups are relatively unreactive toward chlorination, even though the substituents may be potentially capable of stabilizing the free-radical intermediate " ... 

The trend in relative effectiveness of RAFT agents with varying Z is rationalized in terms of interaction of Z with the C=S double bond to activate or deactivate that group towards free radical addition. Substituents that facilitate addition generally retard fragmentation. O-Alkyl xanthates (Z=0-alkyl, Table... 

Free radical substituent effects have also been probed through the kinetics of rearrangement of 3-aryl-2,2-dimethylmethylenecyclopropanes 40 to 41252. The reaction... 

When free radicals are added to 1,5- or 1,6-dienes, the initially formed radical (9) can add intramolecularly to the other bond, leading to a cyclic product (10). When the radical is generated from an precursor that gives vinyl radical 11, however, cyclization leads to 12, which is in equilibrium with cyclopropylcarbinyl radical 13 via a 5-exo-trig reaction. A 6-endo-trig reaction leads to 14, but unless there are perturbing substituent effects, however, cyclopropanation should be the major process. 

By studying the effect of various a-substituents, it has been shown that the bond to the most highly substituted a carbon is preferentially cleaved and that the more nucleophilic alkyl carbon migrates to the relatively electron-poor free radical to form the carbene intermediate,... 

The first step of a free radical aromatic substitution, the formation of the a-com-plex, is also an addition step. The o,m,p-product ratio therefore also responds to steric effects. This is shown for the free radical phenylation and dimethylamination of toluene and r.-butylbenzene in Table 8. The larger the substituent on the aromatic system and the bulkier the attacking radical, the more p-substitution product is obtained at the expense of o-substitution. In the phenylation reaction the yield of m-product also increases in contrast to the dimethylamination reaction. The substitution pattern of this latter reaction is, in addition to the steric effect, governed heavily by polar effects because a radical cation is the attacking species113. ... 

Table 8. Steric substituent effects in free radical aromatic substitutions...

Additionally, it has been noted that Tetralin operates via hydride transfer, at least in its reduction of quinones. Thus it has been shown that Tetralin readily donates hydrogen to electron-poor systems, such as quinones at 50°-160°C. The reaction is accelerated by electron-withdrawing substituents on the H-acceptor and polar solvents, and is unaffected by free radical initiators (6). These observations are consistent with hydride transfer, as is the more recent finding of a tritium isotope effect for the reaction (7). 

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