Cyclization radical clock

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-... 

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. 

The reaction of bornyl and isobornyl bromides with the nucleophile (Scheme 18) is another case where the amount of inversion is small and the rate constant close to that observed with an aromatic anion radical of the same standard potential (Daasbjerg et al., 1989) it can therefore be rationalized along the same lines. Cyclizable radical-probe experiments carried out with the same nucleophile and 6-bromo-6-methyl-1-heptene, a radical clock presumably slower than the preceding one, showed no cyclized coupling product. It should be noted, on the other hand, that, unlike the case... 

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. 

When the basis reaction in the competition kinetic scheme is a calibrated first-order rearrangement, a cyclization, ring opening, or rearrangement reaction, then the radical is called a radical Calibrated alkyl radical clocks that cover... 

Free radical clocks are reactions with known rate constants such as the cyclization of 5-hexenyl radicals (equation 76) or the ring opening of cyclo-propylmethyl radicals 46 (equation 74). Competition reactions of these processes compared to other reactions permit the assignment of rate constants to... 

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. 

By incorporating a cyclopropylcarbinyl radical clock, Cheng and Wagner have confirmed the intermediacy of a 1,4-biradical 222, which cyclized very slowly [274] (Scheme 64). 

Another common scenario in competition kinetics utilizes unimolecular radical reactions as a clock against which other reactions can be timed. Among the most commonly used free radical clocks are the cyclization of 1 -hexenyl and other radicals with double or triple bonds in the chain,33 ring opening,34 and p-elimination from alkoxyl radicals.35... 

Xenon difluoride reacted with various carboxylic acids, and the type of transformation depends on the structure of the organic molecules35-39. The reaction with primary carboxylic acids involves free-radical intermediates. 6-Hexenoic acid was used as a free-radical clock device in which a A abs of 1.1 x 106 M-1s-1 at 25 °C was determined, while the alkyl radical was also spin-trapped to give an ESR signal37. The primary free radical was trapped by internal cyclization, and (fluoromethyl) cyclopentane in 25% yield was formed, while 6-fluoro-l-hexene could be formed from a radical or ionic intermediate, but 1-fluo-rocycloclohexane was not observed as a product (Scheme 42). 

Bergman cyclization 35 PTOC Esters 36 Chlorination 37 Radical clocks 37... 

Because of the rather fast cyclization 131 - 132 (kj = 1 10s s"1 at 25 °C)90) this reaction or the cyclization of the related l-methyl-5-hexenyl radical 134 91) and the o-(3-butenyl)phenyl radical 135 92> is often used as a radical clock in reactions possibly passing through radical intermediates 93... 

Intramolecular competition experiments using a radical clock have revealed that the 5- and 6-exo cyclizations of primary alkyl radicals bearing an acylsilane moiety are slightly faster than those of the 5- and 6-alkenyl radicals [600]. The rate of cyclization depends on the substituents on silicon - the presence of a phenyl group on silicon increases the rate, probably because of its electron-withdrawing nature. 

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... 

The probe is useful as a radical clock since it is us mentioned above possible lo measure the time spent between the HT and the radical recomhina (ion. Cyclizalion during the reaction is a proof of a radical mechanism (at least for the cyclized part), but that no cyclizalion lias taken place is mu a proof against a radical mechanism, but only tells that iI a free radical was produced, its lifetime wax signilicanlly less than ca. 10 s. 

Radical cyclizations usually comprise the central portions of radical clock scales. Cyclizations that produce low-strain five- and six-membered rings are exothermic, but the entropy demand in the transition states for these cyclizations results in reactions that are considerably slower than ring openings. Increasing the exo-... 

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. 

Phenyl-substituted radical clocks (Fig. 6) display definite enthalpy effects that one expects for strong radical-stabilizing groups. The result is that unimolecular clock reactions are orders of magnitude less rapid than their non-substituted counterparts as evidenced in the rate constants at ambient temperatures for 5-exo cyclization of radical 9 [39] and ring openings of radicals 10 [4, 40], 11 [4], and 12 [41]. Note that... 

A more recent determination of the rate constant for reaction of an aryl radical with Bu3SnH at ambient temperature is available, viz. ki = 7.8 x 10 M s [42], If one assumes that this kinetic value can be used for any aryl radical reacting with tin hydride, then the rate constants for cyclization of the aryl radical clocks shown below can be calculated from the reported relative Arrhenius functions [29]. Specifically, radicals 13 and 14 cyclize with rate constants of 5 x 10 s and... 

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]. 

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