Stability of free radicals

It is useful to be able to look at the structure of a drug molecule and be able to predict which sites, if any, in the molecule are susceptible to oxidative deterioration. To do this we must have an understanding of the ease of formation and the stability of free radical species. 

Oxygen-hydrogen and nitrogen-hydrogen bond cleavage. 

In the case of oxidation of phenols, the reaction can very quickly give a complex mixture of products. This is because the phenoxy radical formed on abstraction of the hydrogen radical, H can give rise to carbon-carbon, carbon-oxygen and oxygen-oxygen coupling reactions. 

A number of steps can be taken to minimise oxidative decomposition in drugs and medicines. These can be summarised as follows. 

This is pretty obvious if oxygen in the air is causing the oxidation, then exclusion of oxygen from the formulation will minimise oxidative 

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With resonance possibilities, the stability of free radicals increases some can... 

It has been postulated that the stability of free radicals is enhanced by the presence at the radical center of both an electron-donating and an electron-with-drawing group.This is called the push-pull or captodative effect (see also pp. 159). The effect arises from increased resonance, for example ... 

Dissociation energies D values) of R—H bonds provide a measure of the relative inherent stability of free radicals Table 5.4 lists such values. The higher the D value, the less stable the radical. Bond dissociation energies have also been reported for the C—H bond of alkenes and dienes and for the C—H bond in radical precursors XYC—H, where X,Y can be H, alkyl, COOR, COR, SR, CN, NO2, and so... 

See Shoppee, "Christopher Kelk Ingold," 355, discussing C. K. Ingold and H. Burton, "The Existence and Stability of Free Radicals," Proceedings of the Leeds Philosophical Society, Science Section, 1 (1929) 421 ff. also, Ingold, Structure andMechanism on Organic Chemistry, 8384. 

The study of substituted allyl radicals (Sustmann and Brandes, 1976 Sustmann and Trill, 1974 Sustmann et al., 1972, 1977), where pronounced substituent effects were found as compared to the barrier in the parent system (Korth et al., 1981), initiated a study of the rotational barrier in a captodative-substituted allyl radical [32]/[33] (Korth et al., 1984). The concept behind these studies is derived from the stabilization of free radicals by delocalization of the unpaired spin (see, for instance, Walton, 1984). The... 

The results given in this paper show that aliphatic amines do not catalyze the decomposition of peroxides, and compared with their effect at the start of reaction, they have much less effect on the later stages of oxidation, although they appear to retard the decomposition of peracetic acid. The reactions of radicals with aliphatic amines indicate that an important mode of inhibition is most probably by stabilization of free radicals by amine molecules early in the chain mechanism, possibly radicals formed from the initiation reaction between the fuel and oxygen. For inhibition to be effective, the amine radical must not take any further part in the chain reaction set up in the fuel-oxygen system. The fate of the inhibitor molecules is being elucidated at present. 

Discuss stabilization of free radicals by the captodative effect. [See, e.g., (a) Kosower,... 

With resonance possibilities, the stability of free radicals increases 149 some can be kept indefinitely.150 Benzylic and allylic151 radicals for which canonical forms can be drawn similar to those shown for the corresponding cations (pp. 168, 169) and anions (p. 177) are more stable than simple alkyl radicals but still have only a transient existence under ordinary conditions. However, the triphenylmethyl and similar radicals152 are stable enough to exist in solution at room temperature, though in equilibrium with a dimeric form. The concen-... 

Dissociation energies (D values) of R—H bonds provide a measure of the relative inherent stability of free radicals R.172 Table 5.3 lists such values.173 The higher the D value, the less stable the radical. 

It has been found63 that the stability of free radicals of the type A... 

The stability of free radicals is reflected in their ease of formation. Toluene, which forms a benzyl radical, reacts with bromine 64,000 times faster than does ethane, which forms a primary alkyl radical. Ethylbenzene, which forms a secondary benzylic radical, reacts 1 million times faster than ethane. 

Effect of Reaction Conditions on Development and Stability of Free Radicals (2)... 

Based on these results we used electron spin resonance (ESR) spectroscopy to study the formation and stability of free radicals in paper samples after irradiation. Free radicals formed during irradiation but disappeared during storage. Figure 5 shows the... 

What is still not well understood is the remarkable stabilization of free radicals that these enzymes are able to achieve. The bond dissoeiation energy of the AdoCbl CooC bond is ca. 30kcal/mol, and in many eases, at saturating substrate concentrations, organic radical species accumulate to comprise 20n50% of the enzyme concentration under steady state conditions. This would seem to imply that the enzyme is able to destabilize the CooC covalent bond by about 30 kcal/mol. Put another way, the equilibrium constant for homolysis is shifted by a factor of 10 in going from free solution to the enzyme active site, a truly impressive feat even for an enzyme This, however, is an overestimation of the enzymeis prowess... 

Dipole moment offree radicals— It has already been pointed out in Chapter 5 that in the stabilization of free radicals containing oxygen and nitrogen atoms, the superposition of ionic states plays a significant part. This view is supported by the values of the dipole moments of a,a -diphenyl j3-picrylhydrazine, /, /i, — 4-92 D... 

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