Radicals clock studies

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. 

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,...

Scheme 17.7 Radical clock study of metallo-nitrene C-H insertion.

This chapter contains a brief description of the background and methods of radical clock studies and examples of clocks. A wide range of calibrated clock reactions exists for many types of radicals, and the examples are only representative. 

Scheme 1. Competing processes in a typical radical clock study...

Figure 2 shows an idealized set of data for a radical clock study in which the clock reaction is reversible. The positive intercept is the indication of reversibility in the clock reaction. In this case, the rate constant for the forward reaction ( r) is twice as great as that for the reverse reaction (k R). The slope of the line from multiple experiments, shown as a solid line, will give an accurate ratio of rate constants (kTi/ka) = 5 M in this example. If a single experiment had been conducted at 0.2 M concentration of trapping agent, however, a line with an assumed intercept of zero would result in a considerable kinetic error. The result, shown as a dashed line in Fig. 2, gives an apparent value of (kn/kR) = 7.5 M . ... 

The most convenient radical clock studies are based on radical chain reactions because these processes usually have high conversions with small amounts of initiation. Two general types of radical chain processes have been extensively employed in clock studies, the tin hydride method and the PTOC-thiol method. 

If one of the reactions in a radical chain sequence is too slow to compete effectively with radical-radical reactions, the chain will collapse. Slow reactions of simple silanes such as Et3SiH with alkyl radicals precludes their use in the tin hydride method. Although quite reactive with alkyl radicals, thiols and selenols fail in the tin hydride method because the thiyl and selenyl radicals do not react rapidly with organic halide precursors. Nonetheless, it is possible to use thiols and selenols in tin hydride sequences when a Group 14 hydride is used as a sacrificial reducing agent. The thiyl or selenyl radical reacts with the silane or stannane rapidly, and the silicon- or tin-centered radical thus formed reacts rapidly with the organic halide [8], In practice, benzeneselenol in catalytic amounts has been used in radical clock studies where BusSnH served as the sacrificial reductant [9]. 

Strength) [24, 25]. There is a smaller rate difference between Cp/Cp with the more reactive 5-hexenyl radical radical clock methods have shown that the rate constant for H" transfer decreases by a factor of two from Cp(CO)3MoH to Cp (CO)3MoH at 298 K [30]. The considerable primary secondary tertiary selectivity of Cp (CO)3MoH in these radical clock studies (26 7 1) arises from steric interactions with the radical substituents [30]. 

With P-450 from rat liver,this substrate (X = H) gave predominantly unrearranged product with hydroxylation at the methyl group and similar amounts of Ph-hydroxylation products. The remaining product (5-15%) is derived from the cationic pathway. It was suggested that the latter may be the source of rearranged product in previous radical clock studies. More recently, using different probes and enzyme sources,... 

Radical clock studies by Hartshorn and Telfer, as shown in Scheme 7.4, suggest that the mechanism may not involve radicals. Sciano and co-workers have shown that the photodecarboxylation of ketoprofen derivatives in water proceeds via a carbanion intermediate, as shown in the following reaction ... 

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). 

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. 

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. 

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... 

Radical clock competition kinetic studies of reactions of Bu3SnH with acyl radicals have been reported. Relative rate constants for reactions of... 

Cyclizations of amidyl radicals have been studied both synthetically and kinetically. A detailed study on the rates of a variety of amidyl radical reactions was determined by both LFP and indirect competition methods (Table l) In addition, the rate constants for reactions with BusSnH and PhSH were also reported (thus giving a range of simple amidyl radical clocks). The results obtained will be useful in synthetic sequenceplanning involving amidyl radicals. 

The kinetic data for the reaction of primary alkyl radicals (RCH2 ) with a variety of silanes are numerous and were obtained by applying the free-radical clock methodology. The term free-radical clock or timing device is used to describe a unimolecular radical reaction in a competitive study [2-4]. Three types of unimolecular reactions are used as clocks for the determination of rate constants for this class of reactions. The neophyl radical rearrangement (Reaction 3.1) has been used for the majority of the kinetic data, but the ring expansion rearrangement (Reaction 3.2) and the cyclization of 5-hexenyl radical (Reaction 3.3) have also been employed. 

The biradical benzo-l,2 4,5-bis(l,3,2-dithiazolyl) (BBDTA) is known in the literature but characterization is incomplete. A new study reports the electronic, molecular, and solid-state structure of BBDTA.224 The lifetime of an alkyl phenylglyoxalate-derived 1,4-biradical has been estimated, using the cyclopropylmethyl radical clock , to be in the range 35—40 ns.225 The indanols (88) and their C(3) methyl and trideuteromethyl analogues have been prepared from phenyl benzyl ketone via photo-cyclization of an intermediate 1,5-biradical species.226,227 Selectivity for these products over their C(l) epimers is high but is profoundly effected by substitution in the benzyl ring or the alkyl side-chain. The findings are rationalized in terms of the conformational preference of the intermediate 1,5-biradicals. 

In addition to their use for the calibration of rates for radical reactions, radical clocks can be employed to distinguish between ionic and radical pathways. In the simplest embodiment of this idea, a suitable clock reaction that undergoes a known fast rearrangement with easily identifiable products is incorporated into the reaction system to be studied. This approach has been exploited in the pioneering work of Newcomb and co-workers in studies of the mechanism of cytochrome P450 oxidation reactions [13]. Newcomb has developed a range of ultrafast radical clocks able to detect radical species with lifetimes of 80-200 fs. 

In another use of the radical clock principle with the clock reaction incorporated within the substrate to be studied, Beckwith and Storey determined the rate constant for 5-exo-cyclisation of an aryl radical onto an acryloyl double bond, as depicted in Scheme 10.16 [ 14]. Since the rate constant for cyclisation onto the O-allyl double bond to give 9 is known (ko-aiiyi = 5 x 108 s 1 at 25°C, see Scheme 10.3), the unknown rate constant, kacryioyi> can be determined by Equation 10.13 simply by determining the ratio of the products 9 and 10 ... 

---