Reactivity radical reactions

Tirapazamine is inactivated by two-electron reduction steps catalyzed by quinone reductase, yielding first the mono-N-oxide (reaction a and compound 18). In contrast, it is activated to a cytotoxic nitroxide (16) by a one-electron reduction catalyzed by NADPH-cytochrome P450 reductase (reaction b). This delocalized radical loses one molecule of water to yield a reactive radical (reaction c and compound 17). Radical 17 can then abstract one hydrogen radical from DNA (reaction d and compound 18), leading to DNA breaks and cytotoxicity. In summary, both inactivation and activation involve reduction reactions, but cytotoxicity will depend on the relative levels of quinone reductase and CYP reductase in hypoxic cells. 

Heterogeneous photochemical reactions fall in the general category of photochemistry—often specific adsorbate excited states are involved (see, e.g.. Ref. 318.) Photodissociation processes may lead to reactive radical or other species electronic excited states may be produced that have their own chemistry so that there is specificity of reaction. The term photocatalysis has been used but can be stigmatized as an oxymoron light cannot be a catalyst—it is not recovered unchanged. 

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. 

The BDE theory does not explain all observed experimental results. Addition reactions are not adequately handled at all, mosdy owing to steric and electronic effects in the transition state. Thus it is important to consider both the reactivities of the radical and the intended coreactant or environment in any attempt to predict the course of a radical reaction (18). AppHcation of frontier molecular orbital theory may be more appropriate to explain certain reactions (19). 

Free-radical reaction rates of maleic anhydride and its derivatives depend on polar and steric factors. Substituents added to maleic anhydride that decrease planarity of the transition state decrease the reaction rate. The reactivity decreases in the order maleic anhydride > fumarate ester > maleate ester. 

Vinyhdene chloride polymeri2es by both ionic and free-radical reactions. Processes based on the latter are far more common (23). Vinyhdene chloride is of average reactivity when compared with other unsaturated monomers. The chlorine substituents stabih2e radicals in the intermediate state of an addition reaction. Because they are also strongly electron-withdrawing, they polari2e the double bond, making it susceptible to anionic attack. For the same reason, a carbonium ion intermediate is not favored. 

Although reactivity ratios indicate that VP is the more reactive monomer, reaction conditions such as solvent polarity, initiator type, percent conversion, and molecular weight of the growing radical can alter these ratios (138). Therefore, depending on polymerization conditions, copolymers produced by one manufacturer may not be identical to those of another, especially if the end use appHcation of the resin is sensitive to monomer sequence distribution and MWD. 

Although the existence of the stable and persistent free radicals is of significance in establishing that free radicals can have extended lifetimes, most free-radical reactions involve highly reactive intermediates that have fleeting lifetimes and are present at very low concentrations. The techniques for study of radicals under these conditions are the subject of the next section. 

Structure-reactivity relationships can be probed by measurements of rates and equiUbria, as was diseussed in Chapter 4. Direct comparison of reaction rates is used relatively less often in the study of radical reactions than for heterolytic reactions. Instead, competition methods have frequently been used. The basis of competition methods lies in the rate expression for a reaction, and the results can be just as valid a comparison of relative reactivity as directly measured rates, provided the two competing processes are of the same kinetic order. Suppose that it is desired to compare the reactivity of two related compounds, B—X and B—Y, in a hypothetical sequence ... 

Similarly, carboxylic acid and ester groups tend to direct chlorination to the / and v positions, because attack at the a position is electronically disfavored. The polar effect is attributed to the fact that the chlorine atom is an electrophilic species, and the relatively electron-poor carbon atom adjacent to an electron-withdrawing group is avoided. The effect of an electron-withdrawing substituent is to decrease the electron density at the potential radical site. Because the chlorine atom is highly reactive, the reaction would be expected to have a very early transition state, and this electrostatic effect predominates over the stabilizing substituent effect on the intermediate. The substituent effect dominates the kinetic selectivity of the reaction, and the relative stability of the radical intermediate has relatively little influence. 

The reactivity of pyridine relative to that of benzene has been measured using the competitive technique developed by Ingold and his schoool for corresponding studies of electrophilic aromatic substitution. The validity of the method applied to free-radical reactions has been discussed. Three sources of the phenyl radical have been used the results obtained are set out in Table II. 

The same high reactivity of radicals that makes possible the alkene polymerization we saw in the previous section also makes it difficult to carry out controlled radical reactions on complex molecules. As a result, there are severe limitations on the usefulness of radical addition reactions in the laboratory. Tn contrast to an electrophilic addition, where reaction occurs once and the reactive cation intermediate is rapidly quenched in the presence of a nucleophile, the reactive intermediate in a radical reaction is not usually quenched, so it reacts again and again in a largely uncontrollable wav. 

The transfer of an electron from a photoexcited donor molecule (D) to an acceptor molecule (A) to generate a highly reactive radical ion pair is the most fundamental photochemical reaction, and it can be generally expressed as... 

Until the early 1970s, views of radical reactions were dominated by two seemingly contradictory beliefs (a) that radical reactions, in that they involve highly reactive species, should not be expected to show any particular selectivity,... 

The traditional means of assessment of the sensitivity of radical reactions to polar factors and establishing the electrophilicity or nucleophilieity of radicals is by way of a Hammett op correlation. Thus, the reactions of radicals with substituted styrene derivatives have been examined to demonstrate that simple alkyl radicals have nucleophilic character38,39 while haloalkyl radicals40 and oxygcn-ccntcrcd radicals " have electrophilic character (Tabic 1.4). It is anticipated that electron-withdrawing substituents (e.g. Cl, F, C02R, CN) will enhance overall reactivity towards nucleophilic radicals and reduce reactivity towards electrophilic radicals. Electron-donating substituents (alkyl) will have the opposite effect. 

The basic Hammett scheme often does not offer a perfect correlation and a number of variants on this scheme have been proposed to better explain reactivities in radical reactions.-0 However, none of these has achieved widespread acceptance. It should also be noted that linear free energy relationships are the basis of the Q-e and Patterns of Reactivity schemes for understanding reactivities of propagating species in chain transfer and copolymerization. 

The most popular methods are the Q-e (Section 7.3.4.1) and Patterns of Reactivity schemes (Section 7.3.4.2). Both methods may also be used to predict transfer constants (Section 6.2.1). For furtherdiscussionontheapplicationofthe.se and other methods to predict rate constants in radical reactions, see Section 2.3.7. 

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