Cyclization, radicals steric effects

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 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. 

Scheme 19)." Homoallyloxysilanes gave a mixture of five- and six-membered rings, but the intermediate silyl radical underwent predominantly 6-endo cyclization. Pentenyloxysilane gave the 1-endo product only. The stereochemistry of these reactions was found to be determined by steric effects, even in the presence of chiral thiol catalysts. The structures of the radical intermediates were studied by EPR. 

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%). 

In the case of 6-trimethylsilyl-6-hepten-2-one, the 6-c /n-cyclization product was obtained exclusively, probably due to steric inhibition of 5-cxn-cyclization and electronic effects favoring radical formation in the 6-cwr/o-cyclization [Eq. (43)] [180]. 

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. 

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