Radicals clock

A concerted [2 + 2] cycloaddition pathway in which an oxametallocycle intermediate is generated upon reaction of the substrate olefin with the Mn(V)oxo salen complex 8 has also been proposed (Scheme 1.4.5). Indeed, early computational calculations coupled with initial results from radical clock experiments supported the notion.More recently, however, experimental and computational evidence dismissing the oxametallocycle as a viable intermediate have emerged. In addition, epoxidation of highly substituted olefins in the presence of an axial ligand would require a seven-coordinate Mn(salen) intermediate, which, in turn, would incur severe steric interactions. " The presence of an oxametallocycle intermediate would also require an extra bond breaking and bond making step to rationalize the observation of trans-epoxides from dy-olefms (Scheme 1.4.5). 

The radicals formed by imimolecular rearrangement or fragmentation of the primary radicals arc often termed secondary radicals. Often the absolute rate constants for secondary radical formation are known or can be accurately determined. These reactions may then be used as radical clocks",R2° lo calibrate the absolute rate constants for the bimolecular reactions of the primary radicals (e.g. addition to monomers - see 3.4). However, care must be taken since the rate constants of some clock reactions (e.g. f-butoxy [3-scission21) are medium dependent (see 3.4.2.1.1). 

Here we plan to devote further attention to reaction intermediates. The methods used to verify the intervention of an intermediate include trapping. That is, the intermediate can be diverted from its normal course by a substance deliberately added. A new product may be isolated as a result, which may aid in the identification of the intermediate. One can also apply competition kinetics to construct a scale of relative reactivity, wherein a particular intermediate reacts with a set of substrates. Certain calibration reactions, such as free radical clocks, can be used as well to provide absolute reactivities. 

A better-known example of a free radical clock is the 5-hexenyl radical. Timing is provided by the rearrangement reaction... 

The radical rearrangement reaction, serving as a timing device, has been called a free radical clock 2 It provides a means of evaluating the rate constant for reactions of this radical with other substrates. The example shows how the radical-chromium(II) rate constant can be determined. A number of other instances have been summarized.13... 

More than two dozen radical clocks are now known. They span a range of lifetimes from 10 to 10"7 s.12 The investigator must be aware of the possibility that the clock rearrangement is due to a side reaction or that the radical induced an efficient chain mechanism (Chapter 8). Also, radicals are not the only entities that can rearrange in this fashion. Carbanions, for example, have been shown to rearrange under certain conditions. 

Radical chain processes 772, 1063 Radical clock 1059 Radical reactions radical-molecule 1102-1111 radical-radical 1099-1102 unimolecular 1098, 1099 Radicals, formation during radiolysis 891-922... 

By using an identical radical clock substrate probe which did not rearrange upon hydroxylation with M. capsulatus (Bath), rearranged product was detected with MMO from AT. trichosporium 0B3b (59). From the ratio of unrearranged to rearranged products, a rebound rate constant was calculated to be 6 x 1012 s-1 at 30°C for this system. A separate study with another radical clock substrate probe with MMO from M. trichosporium 0B3b reported products consistent with both radical and cationic substrate intermediates (88). 

Allylic rearrangements with 3,3,6,6-dj-cyclohexene occurred in 20% of the MMO hydroxylation products compared to 33% for cytochrome P-450. These two experiments suggest that, with M. trichospor-ium OB3b, a rebound reaction must occur with a greater rate constant than with cytochrome P-450, in accord with the radical clock substrate work. 

Since work with the radical clock substrate probes indicated important differences in the hydroxylation mechanisms for M. capsulatus (Bath) and M. trickosporium OB3b, work with (R) and (S)-[1-2H,1-3H]ethane with both enzymes was carried out (93, 94). With M. tri-chosporium OB3b, approximately 65% of the product displays retention of stereochemistry (93). A rebound rate constant of 2 - 6 x 1012 s-1 was calculated, assuming a free energy change of 0.5 kcal mole-1 for rotation about the C-C bond (94). This estimate approaches the value obtained from the radical clock substrate probe analysis (59). 

In summary, mechanistic studies have revealed intriguing differences between MMO from M. capsulatus (Bath) and MMO from M. triehosporium OB3b. With M. capsulatus (Bath), radical clock substrate probes indicated either that a substrate radical is not produced or that it reacts with a rate constant > 1013 s-1. With MMO from M. triehosporium OB3b, radical involvement was suggested from several experiments, and a rebound rate constant of 6 x 1012 s"1 was calculated for this system. 

Scheme 9.8 Radical clock-based mechanistic probe...

Atkinson JK, Hollenberg PF, Ingold KU, et al. Cytochrome P450-catalyzed hydroxylation of hydrocarbons kinetic deuterium isotope effects for the hydroxylation of an ultrafast radical clock. Biochemistry 1994 33(35) 10630-10637. 

Bowry VW, Ingold KU. A radical clock investigation of microsomal cytochrome-P-450 hydroxylation of hydrocarbons—rate of oxygen rebound. J Am Chem Soc 1991 113(15) 5699-5707. 

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. 

A major source of error in any indirect method is inaccuracy of the basis rate constants. Errors can result from determinations of rate constants by a sequence of several indirect studies or by an unanticipated solvent effect on the kinetics of a basis reaction. An error can also result in calibration of a radical clock if the requisite assumption that the clock radical will react with a rate constant equal to that of a simple model radical is not correct. Nevertheless, indirect methods in general, and radical clock studies in particular, have been the workhorse of radical kinetic determinations. 

LFP-Clock Method. In this method, rate constants for the radical clock reactions are measured directly by LFP, and the clocks are used in conventional competition kinetic studies for the determination of second-order rate constants. The advantages are that the clock can be calibrated with good accuracy and precision in the solvent of interest, and light-absorbing reagents can be studied in the competition reactions. The method is especially useful when limited kinetic information is available for a class of radicals. 

Table II. Most of the data was obtained from radical clock studies. The neophyl radical rearrangement24 [Eq. (2)] was used for the majority of the kinetic data in Table II, but the ring expansion rearrangement reactions25-27 of radicals 7 and 8, cyclizations of 5-hexenyl type radicals,...

The kinetic data for these reactions are numerous, as shown in Table VI. Most of values were obtained by radical clock methods. The ring expansion of radical 7 has been employed as the clock in a study that provided much of the data in Table VI.74 Cyclizations of 5-hexenyl-type radicals also have been used as clocks,75-77 and other competition reactions have been used.78 Hydrogen atom abstraction from n-Bu3GeH by primary alkyl radicals containing a trimethylsilyl group in the a-, >8-, or y-position were obtained by the indirect method in competition with alkyl radical recombi-... 

Table VIII contains rate constants for reactions of tin hydrides with carbon-centered radicals. A striking feature of Table VIII in comparison to other tables in this work is the high percentage of reactions for which Arrhenius parameters were determined by direct LFP or the LFP-clock method. These results are expected to be among the most accurate listed in this work. Scores of radical clocks have been studied with Bu3SnH, but the objectives of those studies were to determine rate constants for the clocks using tin hydride trapping as the calibrated basis reaction.

Rate constants for reactions of Bu3SnH with some a-substituted carbon-centered radicals have been determined. These values were obtained by initially calibrating a substituted radical clock on an absolute kinetic scale and then using the clock in competition kinetic studies with Bu3SnH. Radical clocks 24 and 25 were calibrated by kinetic ESR spectroscopy,88 whereas rate constants for clocks 26-31 were measured directly by LFP.19,89 90 For one case, reaction of Bu3SnH with radical 29, a rate constant was measured directly by LFP using the cyclization of 29 as the probe reaction.19... 

The rate constants for reaction of Bu3SnH with the primary a-alkoxy radical 24 and the secondary ce-alkoxy radical 29 are in reasonably good agreement. However, one would not expect the primary radical to react less rapidly than the secondary radical. The kinetic ESR method used to calibrate 24 involved a competition method wherein the cyclization reactions competed with diffusion-controlled radical termination reactions, and diffusional rate constants were determined to obtain the absolute rate constants for the clock reactions.88 The LFP calibrations of radical clocks... 

The tertiary a-ester (26) and a-cyano (27) radicals react about an order of magnitude less rapidly with Bu3SnH than do tertiary alkyl radicals. On the basis of the results with secondary radicals 28-31, the kinetic effect is unlikely to be due to electronics. The radical clocks 26 and 27 also cyclize considerably less rapidly than a secondary radical counterpart (26 with R = H) or their tertiary alkyl radical analogue (i.e., 26 with R = X = CH3), and the slow cyclization rates for 26 and 27 were ascribed to an enforced planarity in ester- and cyano-substituted radicals that, in the case of tertiary species, results in a steric interaction in the transition states for cyclization.89 It is possible that a steric effect due to an enforced planar tertiary radical center also is involved in the kinetic effect on the tin hydride reaction rate constants. 

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