Substrate derived radical

In a second type of experiment, oxidative quenching is achieved by use of [Co(NH3)5C1]2+ as the quencher. In the one example reported the ethyl-phenyl derivative of the substrate was used, and the Rum so generated oxidized the heme with k = 6x 103 s l. Prom spectroscopic studies it is believed that the heme is oxidized to a porphyrin n-cation radical and has an axial water ligand. One might anticipate the generation of other oxidized states with the use of other substrate derivatives. 

The concentration of the spin trap is usually not critical, although care must be exercised in quantitative studies (next Section). When reactive radicals are being trapped in competition with attack on substrate, the scavenger concentration may have to be adjusted in order to detect substrate-derived radicals. In these experiments the variation of the scavenger concentrations can give useful information, as in the example of alcohol oxidation discussed earlier. 

The first intermediate to be generated from a conjugated system by electron transfer is the radical-cation by oxidation or the radical-anion by reduction. Spectroscopic techniques have been extensively employed to demonstrate the existance of these often short-lived intermediates. The life-times of these intermediates are longer in aprotic solvents and in the absence of nucleophiles and electrophiles. Electron spin resonance spectroscopy is useful for characterization of the free electron distribution in the radical-ion [53]. The electrochemical cell is placed within the resonance cavity of an esr spectrometer. This cell must be thin in order to decrease the loss of power due to absorption by the solvent and electrolyte. A steady state concentration of the radical-ion species is generated by application of a suitable working electrode potential so that this unpaired electron species can be characterised. The properties of radical-ions derived from different classes of conjugated substrates are discussed in appropriate chapters. 

Methods for detecting whether peroxy compound have been used for cross-linking elastomers have been reviewed. An important application of dialkyl peroxides is as initiators of cross-linking and graft polymerization processes. The success of both processes depends on the ability of the peroxide to produce free radicals and the ability of the free radicals for H-abstraction from a relevant donor substrate. A method for evaluating this ability consists of inducing thermal decomposition of the peroxide dissolved in a mixture of cyclohexane and MSD (225). The free radical X" derived from the... 

Radical cations of n donors are derived typically from substrates containing one or more N, O, or S atoms they are substituted frequently with alkene or arene moieties. Among these systems, we mention only a few examples, including two radical ions derived from l,4-diazabicyclo[2.2.2]octane (2) and the tricyclic tetraaza compound (3). For both ions, ESR as well as OS/PES data were measured. The bicyclic system (an = 1-696 mT, 2N ah = 0-734 mT, 12H) ° shows... 

P-450-catalyzed hydroxylations of aliphatic C—H bonds most often involve a nonconcerted mechanism (Figure 8), which occurs in two steps (1) an abstraction of the hydrogen atom by the P-450 active oxygen complex, which exhibits a free radical-like reactivity, and (2) an oxidation of the substrate-derived free radical formed in this step by the Fe(IV)—OH intermediate [34,37,38],... 

There may be common themes in the role of protein-coenzyme contacts in these B -dependent enzymatic processes. In particular, these contacts could alter the relative stability of the Co(III)—R, Co(II), and Co(I) states to enhance reactivity. For coenzyme B 12-dependent enzymes, the deoxyadenosyl radical generates a substrate-derived radical, either directly or via a radical chain mechanism through the intermediacy of a protein-side-chain-based radical, such as S of cysteine or O of tyrosine. This protein-bound substrate-derived radical then undergoes rearrangement, possibly assisted by protein contacts. Thus, cofactor-protein contacts are probably very important in the activation of the Co—C bond, in altering the Co redox potentials, and in assisting in the rearrangements. 

On the other hand, five other possibilities exist (b) the rearrangement is influenced by the Co through a loose electronic influence in the radical pair (c) there is an electron transfer from the radical to Co(II) to produce Co(I) and a carbonium ion and (d) there is an electron transfer from the Co(II) to the radical to produce Co(III) and a carbanion. In cases (c) and (d), the ionic substrate derivative would rearrange (e) the Co(II) binds to the substrate radical to form a o-bonded species, and then this new organocobalt species rearranges or generates... 

Figure 4 Possible pathways (a-e) for the conversion of the substrate-derived radical, S , into the rearranged product radical, PV...

Little effort has been devoted to ascertain how the coenzyme is re-formed (the termination step). In the radical initiation step (ii, Figure 3), deoxyadenosine is formed. To re-form the Co-C bond to the 5 position of the nucleoside, a methyl group in the 5 -deoxy adenosine must be activated. Such activation requires either H atom abstraction, perhaps by the amino acid side chain radical or by a rearranged radical intermediate derived from the substrate (iv, Figure 3). This step is still not well understood. In the first edition of this volume [75], I expressed the hope that the steps that regenerate the coenzyme would become obvious once the rearrangement process was understood. Recent studies [67] to be described... 

For cyclopropane, substituents at a single carbon might most effectively stabilize the antisymmetrical HOMO, whereas substitution at two carbons is expected to stabilize the symmetrical orbital. Since there is ample evidence for radical ions derived from the prototype of 2At symmetry (vide supra), cyclopropane radical cations with the alternative, antisymmetrical singly occupied (SO) MO appeared be of particular interest. We have identified two substrates, benzonorcaradiene (105) [229] and spiro[cyclopropane-l,9 -fluorene] (106), whose radical cations belong to this category [299, 300]. Interestingly, there is, as yet, no theoretical support for such species. 

The second, more selective oxidant noted above is expected to be substrate-derived alkoxyl radicals, generated via metal-dependent decomposition of the intermediate alkylhydroperoxide. Indeed, 1-AdOOH has been shown [1] to support Gif-type oxygenation of adamantane with tert/sec selectivity ( 9) consistent with that expected for 1-AdO radicals. Most interestingly, 2-AdOOH was found not to support oxygenation of adamantane, but merely undergoes decomposition to afford largely... 

Hydroxyl and substrate-derived alkoxyl radicals, produced via Eq. (3), are the two main oxidants in Gif chemistry which are capable of effecting H-atom abstraction from unfunctionalized alkanes (Eq. 5). In contrast, Eq. (4) serves as a provider of Fe(II) ions and peroxyl radicals, the latter being responsible for the increased amounts of dioxygen observed with Fe(III) reagents by virtue of disproportionation paths. 

As an analogy of an electrochemical process at the cathode, consider a solution of an anion radical (NT) salt in an inert solvent in the presence of an excess of the substrate (M) from which the anion radical is derived. The following primary reactions are then possible ... 

A particularly stable ketyl radical is derived from benzophenone (cf. Figure 17.52). This is why additions of the Grignard reagents R2Mg2Hal2 to this substrate proceed more frequently via radicals as intermediates than others. An example in which the occurrence of such a radical intermediate is documented by the typical radical cyclization 5-hexenyl —> cyclopentyl-carbinyl (cf. Section 1.10.2) is the following ... 

The common overall reaction of the peroxidases can be written as in the following equation, where RH is a suitable peroxidase substrate and R is a free-radical product derived from it ... 

Reactions of this type have been referred to in connection with intramolecular cyclizations of acyclic diones. They are exceedingly common with all types of diketones (excepting cyclobutane derivatives and bridged cyclohexenediones) since almost any C—H bond is susceptible to attack by triplet diketone. The products are semidione radical 164) and substrate derived radical. 

The vast majority of flavoenzymes catalyze oxidation-reduction reactions in which one substrate becomes oxidized and a second substrate becomes reduced and the isoalloxazine ring of the flavin prosthetic group (Figure 1) serves as a temporary repository for the substrate-derived electrons. The catalytic reaction can be broken conveniently into two steps, a reductive half reaction (from the viewpoint of the flavin) and an oxidative half reaction. The flavin ring has great utility as a redox cofactor since it has the ability to exist as a stable semiquinone radical. Thus, a flavoenzyme can oxidize an organic substrate such as lactate by removal of two electrons and transfer them as a pair to a 2-electron acceptor such as molecular oxygen, or individually to a 1-electron acceptor such as a cytochrome. 

Scheme 4 Proposed catalytic mechanism of PHM and D/3M showing the reactive ternary complex. Proposed structure of the intermediate formed after reaction of Cub(H)-02 with substrate to form a substrate-derived free radical and Cub(11)-OOH. This illustrates a possible pathway for electron transfer from QiaCI) to Cub(H)-OOH throngh the solvent-filled cleft and the changes in copper ligation that accompany oxidation. With the exception of reactive intermediates, the water molecules complexed to the copper sites have been omitted. (Ref 27, Reproduced by permission of American Society for Biochemistry and Molecular Biology)...

In the photoaddition of acetone and other ketones to 1-, 2- and 1,2-di-methylimidazoles the products sire a-hydroxyalkylimidazoles (153) which are derived from the selective attack of excited carbonyl oxygen at C-5. In the case of 2-methylimidazole the products are the 4-mono- (8%) and 4,5-di- (14.5%) substituted compounds, but imidazole itself does not react. The suggestion that it is not a sufficiently electron-rich substrate is not particularly convincing. The reaction mechanism (Scheme 72) may reflect the greater radicd reactivity at C-5, and the comparative stabilities of the radical intermediates derived from carbonyl attack at this position. Hiickel calculations of radical reactivity indices show that, indeed, C-5 is more reactive, and the radical intermediate at C-5 is more stable than that at C-4, but a concerted cycloaddition could also give rise to the oxetane (152). Such an oxetane can be isolated in the photochemical addition of benzophenone to 1-acetylimidazole. 

This enzyme s role in humans is to assist the detoxification of propionate derived from the degradation of the amino acids methionine, threonine, valine, and isoleucine. Propionyl-CoA is carboxylated to (5 )-methylmalonyl-CoA, which is epimerized to the (i )-isomer. Coenzyme Bi2-dependent methylmalonyl-CoA mutase isomerizes the latter to succinyl-CoA (Fig. 2), which enters the Krebs cycle. Methylmalonyl-CoA mutase was the first coenzyme B -dependent enzyme to be characterized crystallographically (by Philip Evans and Peter Leadlay). A mechanism for the catalytic reaction based on ab initio molecular orbital calculations invoked a partial protonation of the oxygen atom of the substrate thioester carbonyl group that facilitated formation of an oxycyclopropyl intermediate, which connects the substrate-derived and product-related radicals (14). The partial protonation was supposed to be provided by the hydrogen bonding of this carbonyl to His 244, which was inferred from the crystal structure of the protein. The ability of the substrate and product radicals to interconvert even in the absence of the enzyme was demonstrated by model studies (15). 

The hydrogen atom transfer is proposed to result in a substrate derived ketyl radical (3), which then would be oxidized through electron transfer to the copper center, yielding Cu(I) and the aldehyde product (4). As mentioned above, these two steps have been proposed by Branchaud and co-workers to occur in a concerted manner [21]. 

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