Radical-rebound mechanism

The KIE of 50nl00 far exceeds the classical limits derived from the zero point energy difference between protium and deuterium the maximum expected kjj/ko is 6n7 (Bell, 1973). Larger isotope effects can be accounted for by mechanisms that involve branched reaction pathways. 

FIGURE 15. Effect of substt ate deuteration on the rate of methane reaction with Q. The solid line is the expected relationship if the isotope effect is predominantly primary. The dotted and dashed lines show die ejqiected relationship of die rate constants if there were a secondary isotope effect of 1.2 or 2, respectively. (From Nesheim and Lipscomb, 1996). 

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These results are inconsistent with a radical rebound mechanism because this mechanism is a two-step process that requires the involvement of intermediates. Instead the results suggest that the hydroxylation is a concerted process, much like a singlet carbene reaction, which does not involve intermediates. However, this conclusion is in conflict with the properties of singlet carbene reactions discussed above. Subsequent studies on a number of substituted methylcyclopropanes and other stained hydrocarbon systems established that these findings were not anomalous. 

He, X. and Ortiz de Montellano, P.R. (2004) Radical rebound mechanism in cytochrome P-450 catalyzed hydroxylation of multifaceted radical clocks a-and p-thujone. The Journal of Biological Chemistry, 279, 39479-39484. 

The radical rebound mechanism has been proposed and proved in several cases in reaction of hydroxylation catalyzed by cytochrome 450 and methane monooxigenase (Section 3.2)... 

The masked radical rebound mechanism (Likhtenshtein, 1979 a, 1988 a) involves the reaction of a superoxide-like radical structure formed in the heme coordination sphere with the hydrocarbon followed by fast radical recombination ... 

Thus, it is becoming increasingly evident that the rebound mechanism is the most probable mechanism of the hydroxylation. Nevertheless, direct proof of occurrence of the ferryl active intermediate is as yet incomplete. Above mentioned the masked radical rebound mechanism can not be excluded. 

FIGURE 3. Generic radical rebound mechanism of monooxygenases such as MMO and P450. X is a species that can provide one electron to stabilize the high valent oxo intermediate such as a second iron in the case of MMO or a porphyrin macrocycle in the case of P450. 

The observation of a substantial decrease in the chirality of chiral ethane both strongly supports the existence of a substrate radical and brings into question the pure P450-like radical rebound mechanism for MMO. The extent of racemization from the chiral ethane experiments indicates that the rebound of the ethyl radical and hydroxy radical would have to occur at a rate of about 5 10 s, similar to that computed for some of radical... 

Additional studies demonstrated that replacement ofthe ligand ethylene by CO or PPh j did not influence the enantioselectivity of the reaction, suggesting that the ancillary ligand dissociates before the C H insertion. A bisimido ruthenium(VI) complex SO operating through an H abstraction/radical rebound mechanism, established in ruthenium porphyrin systems by Che, is proposed to account for the observed stereochemistry (Figure 12.2). 

C-H functionahzations can generally proceed through three types of mechanisms [5, 8] (i) radical rebound mechanisms, which proceed through radical intermediates (ii) direct insertions into C-H bonds and (iii) mechanisms through an organometaUic intermediate with a metal-carbon bond. These three different pathways are outlined in Scheme 23.2. 

On the other hand, participation of free radicals should be considered in most cases of oxygenations. Both of carbon and oxygen centered radicals can take part in the oxygenation processes. Apart from the apparent autoxidation process, it is not easy to differentiate explicitly metal-based mechanisms from free radical mechanisms. Different types of the radical-clock reagents have been developed for detection of radicals of different lifetime, especially in the discussions on the radical-rebound mechanisms. 

Kodera et al. synthesized a rigid (Tf-oxo-di T(-acctalo)diiron(III) complex with l,2-bis[2-di(pyridyl)methyl-6-pyridyl]ethane that is a dinucleating hexa-pyridine ligand. " The complex monooxygenates alkanes (cyclohexane, methylcyclohexane, adamantane) in the presence of m-CPBA with a large turnover frequency and number Radical-rebound mechanism was suggested based... 

Scheme 8.4 Observations that support a stepwise C-H abstraction/radical-rebound mechanism in Ruj catalyzed aminations.

The oxygenation of tertiary and benzylic C-H bonds of substrates bearing a number of common polar functional groups by CAN in aqueous solution is catalysed by 1,4,7-trimethyl-1,4,7-triaza cyclo-nonane-RuCl3 complex (62). A stepwise radical-rebound mechanism, based on chemoselectivity trends and kinetic isotope effect, is proposed. ... 

As indicated in the sections above, C—H bond activations can proceed through mechanistically distinct manifolds (i) H-atom abstraction followed by radical functionalization (radical rebound mechanism), (ii) direct insertion into the C—H bond, and (iii) organometallic C—H activation proceeding throngh an intermediate with an M—C bond. The different mechanisms determine the types of C—H bonds that can be broken and can thus be used to achieve selectivity. 

Radical rebound mechanisms are frequently invoked for reactions of metal-oxo catalysts," " bnt also for some functionalizations proceeding throngh metal nitrenoids." Since the formation of radical intermediates (11) is involved, selectivity for the functionalization of weak C—H bonds is typical in such protocols. Stereoselective C—H functionalizations are often difficult to achieve with this mechanistic manifold due to the stereochemical liability of 11," but can be overcome if radical recombination is fast (e.g., in enzymes)." ... 

On the basis of the similarity in the reactivity of sMMO to that of cytochrome P-450, the alkane hydroxylation catalyzed by sMMO is assumed to proceed through a radical-rebound mechanism [73]] as shown in Scheme 2. 

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