5-hexenyl radicals substituent effects

Effects of substituent on the regiochemistry of the 5-hexenyl radical cyclization... 

Another major influence on the direction of cyclization is the presence of substituents. Attack at a less hindered position is favored by both steric effects and the stabilizing effect that most substituents have on a radical center. These have been examined by DFT (UB3LYP/6-31+G ) calculations, and the results for 5-hexenyl radicals are shown in Figure 10.14. For the unsubstituted system, the 5-exo chair TS is favored over the 6-endo chair by 2.7kcal/mol. A 5-methyl substituent disfavors the 5-exo relative to the 6-endo mode by 0.7kcal/mol, whereas a 6-methyl substituent increases the preference for the 5-exo TS to 3.3 kcal/mol.322... 

The cyclization of a range of fluorinated radicals has attracted interest. - The rate constants for the 5-exo cyclization of a range of fluorinated 5-hexenyl radicals have been studied as a function of the position and number of fluorine substiments. For fluorine substituents at or close to the alkene there is little effect on the rate, whereas... 

The reaction (equation 76) of the hexenyl radical 47 forming cyclopentyl-methyl radical was discovered independently in several laboratories and has been of pervasive utility in both synthetic and mechanistic studyThe competition between formation of cyclopentylcarbinyl and cyclohexyl radicals favors the former even though the latter is more stable, and this kinetic preference is explained by more favourable transition state interaction. The effects of substituents on the double bond, heteroatoms in the chain, and many other factors on the partitioning between these two paths have been examined. In the gas phase above 300°C, methylcyclopentane has been observed to form cyclohexane via isomerization of cyclopentylmethyl radicals into the more stable cyclohexyl radicals. ... 

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. 

A single fluorine substituent at C-5 (as in radical 13) leads to a significant, 11-fold decrease in rate constant. This decrease no doubt derives largely from the steric effect which would be expected from any substituent at the 5-position. A methyl substituent, for example, gives rise to a 45-fold decrease in cyclization rate [164]. Interestingly, whereas the presence of a 5-methyl substituent causes endo-cyclization to become preferred (63%), the cyclization of 5-fluoro-5-hexenyl radical remains exo-specific within our NMR analytical methodology ( 4%). 

This radical can be quenched by tin hydride, but still is able to undergo tandem C-C bond-forming reactions if a rationally designed system follows. However, as summarized in Scheme 6, tandem sequences have to overcome the problem of isomerization to the thermodynamically more stable six-membered radical [26], Table 2 lists several examples of cyclopentanone synthesis based on a 4+1 radical annu-lation process. The first example shown in Table 2 demonstrates that the 4-hexenyl radical/CO system faces this isomerization problem, which is difficult to suppress [27, 26a]. Of course, some substituents, such as phenyl and alkoxycarbonyl groups, are effective in hindering such an isomerization process from 5 to 6 (runs 2, 3, 4) [27]. 

Thus far we have been mainly concerned with unsubstituted double bonds. It may be expected that alkyl substituent effects (discussed in Section IV) will also produce a change in the cyclic products ratio in these cases and this has been observed recently by Butler in the Cy5/Cy6 case (Scheme 24). By working at different temperatures, he found what had been observed in the 5-hexenyl radical, namely, a decrease in the Cy5/Cy6 ratio with increasing temperature (43 1 at 40°C and 24 1 at 125°C for R3 = CH3), and though the dramatic effect on the Cy5/Cy6 ratio of an R3 = Me substituent on the internal terminus of the double bond observed with the 5-hexenyl radical (Section IV) is... 

Some of these conclusions are helpful in understanding the behavior of unsaturated radicals other than the 5-hexenyl ones. It should be emphasized that only modification by alkyl substituents has been discussed in this section. It will be seen in Sections VI and VII that inductive or other effects derived from heteroatoms, for instance, may have a profound influence on the cycliza-tion process. 

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