5-Hexenyl radical cyclization alkyl substituted

Substituent effects on cyclizations of simple nucleophilic hexenyl radicals have been well studied, and much quantitative rate data is available.12 The trends that emerge from this data can often be translated to qualitative predictions in more complex settings. Once the large preference for S-exo cyclization is understood, other substituent effects can often be interpreted in the same terms as for addition reactions. For example, electronegative substituents activate the alkene towards attack, and alkyl substituents retard attack at the carbon that bears them. The simple hexenyl radical provides a useful dividing point = 2 x 10s s-1. More rapid cyclizations are easily conducted by many methods, but slower cyclizations may cause difficulties. Like the hexenyl radical, most substituted analogs undergo irreversible S-exo closure as the predominate path. However, important examples of kinetic 6-endo closure and reversible cyclization will be presented. 

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. 

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 influence of substituents on the double bond, on the aliphatic chain, and on the carbon radical has been extensively studied in the case of irreversible cyclization processes. In this section, the results obtained by Walling, Beckwith, Julia, and their coworkers using alkyl-substituted 5-hexenyl radicals are described. The influence of heteroatoms and of stabilizing groups is discussed in another section. 

It must be also noted that 1,5-ring closures of 2-, 3-, or 4-alkyl-substituted 5-hexenyl radicals are also stereoselective 2- and 4-alkyl-substituted radicals afford mainly rrans-disubstituted (Cy5) products, while 3-substituted radicals (Section XI.4.A, Scheme 149) afford mainly the cis CyS products with ratios of up to 4 1. This observation has been generalized to the Cy5/Cy6 cyclization of peroxyl radicals. These results have been ascribed to a chair-like conformation of the transition state for the cyclizing (A ) radical with substituents preferentially occupying psewdo-equatorial positions. ... 

A5-hexenyl substituent, extensive cyclization occurs to yield the cyclopentylcarbinyl product from the yields of uncyclized and cyclized products for A5-hexenylmercury chloride, the rate constants for equation 50 have been estimated (vide supra). The SH2 reaction 49 has also been invoked to be the key step in the alkylation of -substituted styrenes by a free-radical addition-elimination sequence, namely96... 

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