Examples of Radical Clocks

There are numerous other examples of radical clock reactions in the literature used both for simple rate determinations to facilitate the quest for selectivity in synthesis and for more detailed probing of mechanistic pathways. 

Figure 6.6. Examples of radical clock probes of the cytochrome P450 mechanism, including the radical rearrangements typical of norcarane and bieyclo[2.I.O] pentane.

Fig. 4.7 The radical clock principle (a) and examples of radical clocks that have been utilized in cytochrome P450 studies (b)...

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. 

The pioneering work on the calibration of intramolecular cy-clization of the 5-hexenyl radical by Ingold and co-workers provided the basis for the development of a large number of radical clocks." These are now used both for the calibration of rate constants for intermolecular radical reactions and as mechanistic probes to test for the intermediacy of radical intermediates in a variety of processes. Furthermore, the ready availability of bimolecular rate constants from competitive product studies using free radical clocks without the use of time-resolved experiments has greatly enhanced the synthetic utility of free radical chemistry. The same concept has recently been extended to radical ion chemistry. For example, rate constants for carbon—carbon bond cleavage reactions of a variety of radical cations and anions derived from substituted diarylethanes have been measured by direct time-resolved techniques. " ... 

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. 

The kinetic data reported in this chapter have been determined either by direct measurements, using for example kinetic EPR spectroscopy and laser flash photolysis techniques or by competitive kinetics like the radical clock methodology (see below). The method for each given rate constant will be indicated as well as the solvent used. An extensive compilation of the kinetics of reaction of Group 14 hydrides (RsSiH, RsGeH and RsSnH) with radicals is available [1]. 

An elegant example of the radical clock principle is illustrated in the investigations of Rychnovsky where a conformational radical clock is used [15]. This approach relies upon knowing the rate of racemisation of a radical formed at a centre which is originally configurationally pure and using this process as the clock . The enantiomeric purity of the product from the reaction is, therefore, directly related to the lifetime of the radical. 

Hexenyl radicals were used as radical clocks for the indirect measurement of the rate of reduction of radicals to anions using SmI2-HMPA. For example, reduction of primary iodide 4 using SmI2-HMPA resulted in the isolation of coupled product 9 in 20% yield and cyclised-coupled product 7 in 80% yield. As the rate of cyclisation of the intermediate primary hexenyl radical 6 was known, a rate constant of k= 106 M 1 s 1 could be estimated for the reduction... 

Formation of a protein radical, for example Cys 151, RS, which promotes the synchronous insertion of oxygen atoms across the substrate C-H bond (Waller and Limscomb, 1996, Shilov, 1997). The absence of rearranged products of the radical clock substrates for MMOH isolated from M. capsulatus raises the possibility in principle, of such a mechanism. 

Clearly, there are many benefits to investigating radical processes in bulk polymers because the media constitute a viscous space in which the processes suffered by radicals (and, especially, pairs of radicals) are slowed significantly, allowing them to be observed more easily. We have provided an example in which decarbonylation can be used as a clock over time domains that are appropriate in polymeric media, but would be too slow in many fluid solvents. A great deal of basic scientific information about the dynamics of polymeric radicals can be derived as well. 

Another important feature of mass transfer processes is related to the very physical nature of the phenomenon. As such it is easily quantifiable and predictable. Thus the rate of mass transfer to and from an electrode may be determined a priori for a given electrochemical system. As a result this rate may be used as natural built-in clock by which the rate of other electrochemical processes may be measured. Such a property was apparent in our earlier discussions related to electrode kinetics (electron transfer and coupled chemical reactions). Basically it proceeds from the same idea as that frequently used in organic chemistry for relative rate constant determinations, when opposing a chemical reaction of known (or taken as the reference in a series of experiments) rate constant against a chemical reaction whose rate constant (or relative rate constant) is to be determined. Many such examples exist in the organic literature, among which are the famous radical-clocks ... 

As already mentioned, the second system to be studied [116] was the 5-norbornenyl system. The radical clock-5-norbornenyl 149 [118] is known to rearrange to the 3-nortricyclenyl radical with a rate constant, determined by EPR, on the order of 6 x 10 sec at -30 C and 10 -10 see" at 25 C [123, 124]. It has been firmly established from numerous examples of free radical reductions involving this system that the equilibrium in solution is in favor of radical 150. For example, a report by Davies [125] demonstrated that whether one started from 5-bromo-2-norbornene 148 Br or from 3-bromonortricyclene 153 Br when carrying out a cobaltous chloride-catalyzed reaction with methylmagnesium bromide, one obtains a mixture of 30% 2-norbornene 151 and 70% norticyclene 152 (Scheme 45a). 

This approach has been used, for example, to find whether the intramolecular photocycloaddition reaction of the triplet excited cyclopropyl-substituted 4-(buteny-loxy)acetophenone 220 proceeds via the 1,4-biradical 221 (Scheme 6.87).827 This presumption was confirmed by identifying the three rearrangement cyclization products 222 224. Because the rate constant of the cyclopropylcarbinyl radical opening to the allylcarbinyl radical is known to be 7 x 107 s 1,828 it was suggested that the rate constant for the formation of the (not observed) or// o-photocycloaddition adduct (225) must be less than 3 x 106s This technique comparing the rate constants of two parallel processes, of which one is known is often referred to as a kinetic (or radical) clock 29... 

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 . ... 

Figure 3 shows the simple case of a clock reaction competing with hydrogen atom transfer from tin hydride. If one wished to determine, for example, the rate of addition of a primary alkyl radical to an activated alkene such as an acrylate, then the reaction could be run at low concentrations of tin hydride such that both the radical clock and its rearrangement product reacted predominantly with the alkene. The products of the acrylate addition reaction are deactivated with respect to addition to another acrylate molecule, and one could control concentrations such that these adducts reacted primarily with the tin hydride (Scheme 3). In this case, then, one would analyze for the acrylate addition products of the unrearranged and rearranged radicals.

The assumption that one radical is an appropriate model for another is most sound when one is using a clock to calibrate a bimolecular reaction and the local environment of the clock is similar to that of the radical of interest. For example, the rate constant found for reaction of the 5-hexenyl radical with a specific trapping agent should be a good approximation of the rate constant for reaction of another primary alkyl radical, especially one without substituents at C2. For most synthetic applications, the small errors in rate constants from this assumption will be unimportant. 

Some primary alkyl radical clocks are collected in Table 1. These examples demonstrate the wide range of kinetics that can be studied with radical clocks, but other classes of clocks are not nearly as well developed. Radical 1-1 was calibrated by kinetic ESR methods [2], and radical 1-9 was calibrated direetly by LFP [3]. All of the others [3, 17, 20-28] were calibrated by indirect methods. 

Limited examples of substituted alkyl radical clocks are available. Fortunately, some calibrated clocks that are available have rate constants in the middle ranges for radical reactions and should be useful in a number of applications. Examples of clocks based on the 5-exo cyclization of the 5-hexenyl radical are shown in Table 2. The data for the series of radicals 2-1 and 2-2 [17, 32, 34, 35] are from indirect studies, whereas the data for radicals 2-3 and 2-4 [3, 35-38] are from direct LFP studies. The striking feature in these values is the apparent absence of electronic effects on the kinetics as deduced from the consistent values found for secondary radicals in the series 2-1 and 2-3. The dramatic reduction in rate constants for the tertiary radical counterparts that contain the conjugating ester, amide and nitrile groups must, therefore, be due to steric effects. It is likely that these groups enforce planarity at the radical center, and the radicals suffer a considerable energy penalty for pyramidalization that would relieve steric compression in the transition states for cyclization. 

Several acyl radical clocks have been calibrated, and these are collected in a recent excellent review of the general subject [44]. Examples of the two types of unim-olecular clock reactions, decarbonylations and cyclizations, are shown in Fig. 7, with rate constants for reactions at ambient temperature. Decarbonylations of acyl radicals, as shown for radical 16 [45], and the related decarboxylations of alkox-ycarbonyl radicals such as 17 [2] have log A terms of about 13 for cases where alkyl radical products are formed [46, 47]. The decarbonylation reactions involve a reduction in charge separation in the transition states, and the kinetics are sensitive to solvent polarity with decreases in rates as polarity increases [45]. Cyclization reactions, such as that shown for radical 18, are complicated. The 5-exo products shown are the predominant first-formed products, but they further rearrange to the thermodynamically favored 6-endo products by addition of the radical center to the carbonyl group to give a cyclopropyloxyl radical followed by ring opening [48]. 

This brief overview was intended to introduce the concepts of the radical clock method with a relatively limited number of examples. Extensive tables of radical kinetics exist, and many reactions can be used as clocks. In regard to the kinetic values available, however, one should appreciate that determinations of radical kinetics tend to involve a series of increasingly precise and accurate approximations. For that reason, more recently determined rate constants usually were selected for this overview. When using radical clocks, one is well advised to search a reference in the forward direction for improved kinetic values, especially those involving recalibrations of absolute rate constants. 

The technique has been used to determine rate constants for a number of radical reactions in solution, notably ring closure and ring fission processes which serve as clock reactions in conventional radical kinetics [45]. As an example, the bimolecular reaction of the cyclohexadienyl radical with molecular iodine is shown in Figure 11. The straight line behavior demonstrates a pseudo-first order... 

---