Active centre radical

Chain reactions do not continue indefinitely, but in the nature of the reactivity of the free radical or ionic centre they are likely to react readily in ways that will destroy the reactivity. For example, in radical polymerisations two growing molecules may combine to extinguish both radical centres with formation of a chemical bond. Alternatively they may react in a disproportionation reaction to generate end groups in two molecules, one of which is unsaturated. Lastly, active centres may find other molecules to react with, such as solvent or impurity, and in this way the active centre is destroyed and the polymer molecule ceases to grow. 

These three types, radicals, carbocations and carbanions, by no means exhaust the possibilities of transient intermediates in which carbon is the active centre others include the electron-deficient species carbenes, R2C (p. 266), nitrenes, RN (p. 122) and also arynes (p. 174). 

The importance of carbon-centred radical cyclizations in organic chemistry has been documented in the large number of papers published each year and numerous reviews and books dealing with this subject. In Chapter 7 the reader can find a collection of such processes mediated by organosilanes. The silicon-centred radical cyclizations have instead received very little attention, although there has been a growing interest in silicon-containing compounds from a synthetic point of view, due to their versatility and applicability to material science. As we shall see, this area of research is very active and some recent examples show the potentiality of silyl radical cyclization in the construction of complex molecules. 

Posner and Oh, and later Jefford and coworkers led the earliest investigations by synthetic chemists into the mechanism of action of 1,2,4-trioxane antimalarials. Both proposed that formation of a C-centred radical was essential for activity but the nature of the radical (primary or secondary) and the mechanistic pathways put forward were not identical. The iron degradation studies of Posner and coworkers implicated a role for the... 

II. The alternative pathway involves association of 02 with ferrous iron—the resulting O-centred radical can abstract, via a 1,5-H shift, an a-hydrogen on the carbocylic ring to produce a secondary carbon-centred radical 12. This pathway will be referred to as the 02 route and it was proposed that this pathway may be more important for expression of high levels of antimalarial activity. 

In the presence of 1,4-cyclohexadiene (CHD) the C4-centred radical pathway was diverted from formation of artennuin D, 13, to afford significantly more deoxyartemisinin 3 (by the secondary C4 radical abstracting a H-atom from CHD) while the proportion of 21 remained the same. The authors proposed that the 02 pathway (Scheme 3) contributed most to the activity and that the C4 secondary radical intermediate (generated by... 

Posner and coworkers concluded that the low activity of the stannyl-substituted tri-oxanes indicated that the killing species must be an intermediate somewhere along the route after the 1,5-H shift has generated a C4-centred radical. 

O Neill and coworkers were also able to spin-trap the previously proposed C-centred radical 63b with sodium 3,5-dibromo-4-nitrosobenzenesulphonate (DBNBS) and the EPR of the adduct 64b was characteristic of a secondary radical (Scheme 19B). It was suggested that the parasiticidal action of arteflene stems from the alkylating properties of the radical intermediate or possibly from the enone 63a, which may be able to react with intracellular nucleophiles by a Michael addition. The enone itself did not exhibit antimalarial activity, possibly due to extracellular detoxification by glntathione before reaching its intraparasitic site of action. 

It should be emphasized that virmaUy all of the above discussion is based on biomimetic chemistry, where the Fe(II) source varies from salts such FeS04 to the more reactive FeCla-THaO as well as heme mimetics (TPP) and ester hematin variants. When heme models are used, since porphyrin alkylation is a favoured process, end-product distributions of products can be very different from when a free ferrous ion source is employed. Furthermore, solvent has been shown to have a profound effect on the rate of reaction and product distributions obtained in iron-mediated endoperoxide degradation. Thus all of these studies are truly only approximate models of the actual events within the malaria parasites. Future work is needed to correlate the results of biomimetic chemistry with the actual situation within the parasite. In general, most workers do accept the role of carbon-centred radicals in mediating the antimalarial activity of the endoperoxides, but the key information defining (a) the chemical mechanism by which these species alkylate proteins and (b) the basis for the high parasite selectivity remains to be unequivocally established. 

In effect, antimalarial trojan horse drugs of this type should deliver a double blow to the parasite by exploiting the presence of high concentrations of ferrous ion present in the parasite food vacuole as the trigger for protease inhibitor release. In model studies with prototype 81d, in the presence of ferrous ions, these systems readily degrade to produce the desired chalcone (82b, R = H, in 45% yield from 81d), in tandem with secondary carbon-centred radical 82a (Scheme 29). Furthermore, analogues 81d-f have superior in vitro antimalarial activity to that of arteflene (<25 nM in vitro versus Plasmodium falciparum, arteflene >50 nM). The other product obtained is the diol (82c), a product of two-electron reduction of the endoperoxide bridge. 

Phenylbutazone. - This anti-inflammatory drug inhibits prostaglandin H synthase. Earlier spin-trapping studies established that PB is oxidised to a carbon-centred radical by the peroxidase activity of the enzyme.175 The radical has since been trapped with MNP upon incubation of the drug with HRP. The intensity of the signal from the adduct was reduced by GSH, suggesting chemical repair of the radical by the thiol. The PB/HRP system induced lipid peroxidation in microsomes, which was suppressed by GSH.176... 

This formulation discloses the algebraic structure of what the chemist calls the mechanism of a reaction or set of reactions. To explain the reaction system the chemist will introduce further elements , such as catalysts, active centres or even the wall of the reaction vessel. He will introduce further species into the reaction mixture such as adsorbed or activated molecules, atoms or free radicals, and he will consider a set of proper reactions in this augmented mixture. Let t be the number of extra elements introduced, s the number of new species and r the number of new reactions. Then the (T + T) elements form an augmented module +,the (s + s) species an 9ft+ and the (r + r) reactions an SR Since the set of reactions considered in the mechanism must be proper for the augmented reaction mixture there are morphisms /3+ (5+ - 9ft+ and a+ 9ft+ —> R+ such that... 

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