Cyclization of the 5-hexenyl radical

Activation parameters. Calculate AW and AS for the cyclization of the 5-hexenyl radical, whose rate is given in Eq. (5-39). 

Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C=C ir bond) have emerged as one of the most interesting and widespread applications of free-radical chemistry to organic synthesis. Free-radical cyclizations are useful because they are so fast. The cyclization of the 5-hexenyl radical to the cyclopentylmethyl radical is very fast, occurring at a rate of about 1.0 X 105 s-1. In fact, the rate of formation of the cyclopentylmethyl radical is much faster than the rate of cyclization to the lower energy cyclohexyl radical. This stereoelectronic effect is derived from the fact that the overlap between the p orbital of the radical and the rr MO of the double bond is much better when Cl attacks C5 than when it attacks C6. The relative rates of 5-exo and 6-endo ring closures are strongly dependent on the nature of the substrate and especially on the amount of substitution on the ir bond. Cyclization of the 6-heptenyl radical in the 6-exo mode is also very favorable. 

The data of Table 5 indicate that the conversion of the anion 145 into 146 is very much slower (by a factor of 108-1010) than the cyclization of the 5-hexenyl radical 131. However, nonnegligible quantities of product containing the cyclopentylmethyl group may still arise from cyclization of the anion 145 since the half-life for this process at temperatures above 0 °C (t1/2 = 23 min at 0 °C 5.5 min at 23 °C) is short relative to the time scale of many experiments that seek radical intermediates 103). A differentiation between radical and anion cyclization, as in the case of 134 and 138, is not available with 131 and 145. The cyclization of the anion 145 is, however, very slow at lower temperatures like —78 °C. 

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. 

The cyclization of the 5-hexenyl radical to cyclopentylmethyl (Entry 33) is a commonly observed reaction. The is 6 kcal/mol. The cyclization shows a preference for exo cyclization to a five-membered ring over endo cyclization to a six-membered ring/ even though it results in formation of a less stable primary radical. The cause for this preference has been traced to stereoelectronic effects. In order for a bonding interaction to occur, the radical center must interact with the it orbital of the alkene. According to MO calculations, the preferred direction of attack is from an angle of about 70° with respect to the plane of the double bond. ° ... 

Several computational studies have explored the cyclization of the 5-hexenyl radical. CBS-RAD(B3LYP) calculations provided thermochemical and kinetic parameters that are in good agreement with experiment. Similar results were obtained with UB3LYP/6-31G(i) calculations." ... 

The solutions for (he concentration profiles are complex (sec the Appendix). We illustrate them with the parameter values used above for the T case plus 4/ = 4.4 x 10 s, the value for the cyclization of the. 5-hexenyl radical. Thus, the calculations presented here for the R ease are D-model predictions for the Grignard reaction of 5-hexenyi bromide in DEE at 40 C. 

The most important process (which accounts for most of the uses of radical cychzations in synthesis) is the selective 5-exo-cyclization of the 5-hexenyl radical to give the cyclopentyl methyl radical. This occurs even though the alternative - a 6-endo cyclization to give a more stable, cyclohexyl radical - is thermodynamically more favorable. Thus, the 5-ex o-cycHzation proceeds under kinetic control. The preference for 5-ex o-cyclization is explained by an early transition state with little product character. The transition state is a strain-free chair-like arrangement, which nicely accommodates the stereoelectronically required attack angle on the alkene. This model also nicely explains the stereochemical outcome of the cycHzation reaction. Assuming that substituents prefer to adopt pseudo-equatorial positions in the chair-Uke transition state, we see why ... 

R2 = -Bu) (Scheme 33), where a competitive Barton reaction could be anticipated, gives only the corresponding oxime (62) and no product resulting from the Barton reaction. Gilbert and Norman have recently been able to provide indirect quantitative confirmation that the cyclization of the 4-pentenyl-1-oxy radical in aqueous solution is very selective toward formation of the (Cy 5) radical, and is even faster (>10 liter mol sec ) than the cyclization of the 5-hexenyl radical. 

Some years later, Kochi investigated extensively by esr the structure of alkyl radicals in nonaqueous solution. He showed that by this technique it was possible to observe the low-temperature cyclization of the 5-hexenyl radical and the opening of the cyclopropylcarbinyl radical. This led Ingold to use the esr technique in order to obtain accurate kinetic data for free radical intramolecular reactions. In this way the room temperature cyclization rate of the 5-hexenyl radical was confirmed and its temperature dependence was determined ... 

In many cases, particularly for the study of fast reactions (ky> key in Scheme 164), the opening of the cyclopropylmethyl radical to the isomeric allyl-carbinyl radical, one thousand times faster than the cyclization of the 5-hexenyl radical, is a useful complementary tool. It has been used mainly by Kochi for the study of cage reactions of alkyl radicals in solution as well for the study of ligand and electron transfer oxidations of alkyl radicals. Furthermore, in the last three studies the knowledge of the fate of the isomeric cyclobutyl intermediate was very useful in distinguishing between a homolytic (no rearrangement of the cyclobutyl radical) and a heterolytic pathway (fast... 

In the foregoing we have seen how kinetic E.S.R. spectroscopy has been used to solve a long-standing problem in reaction mechanism. I now want to turn to a different radical rearrangement reaction, the cyclization of the 5-hexenyl radical, JU, to the cyclopentylmethyl radical, TR ... 

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