Strain nucleophilic substitution, effect

Associative nucleophilic substitution at phosphorus contained in a six-membered ring is not a rapid process relative to the analogous reaction of acyclic compounds. Whereas associative reactions of five-mem bered sp>ecies are dominated by the influence of special strain effects, the same is not true for six-membered species. One must therefore bear in mind that other competitive processes may become significant in the reaction of six-membered ring phosphorus compounds with nucleophiles. For example, it has been suggested that the cAMP derivative [92] is hydrolysed by a dissociative Sf l mechanism (Scheme 32) (Bottka and Tomasz, 1985). 

The second nucleophilic substitution by alkoxide is unusual, inasmuch as it has to occur at a position meta to the carbonyl function. Therefore, the intermediate anion is not stabilized by resonance, but solely by inductive effects. The regioselectivity is controlled by strain The alkoxide cannot reach the more favorable carbon para to the carbonyl. 

This is one of the few examples where RO acts as a leaving group. The reason this reaction takes place is that it opens a highly strained three-membered ring. Note that in base the nucleophile reacts at the less substituted carbon. This is because the Sj 2 reaction is sensitive to steric effects. 

Photolysis of 1,4-diiodocubane (494) in nucleophilic solvents, such as methanol, was found to provide effectively the substitution product 495 (Scheme 6.241).1348 It was argued that the reaction proceeds via the formation of a caged radical pair and electron transfer to give iodide ion and a carbocation, which is trapped by the solvent (SN1 pathway). Hyperconjugative stabilization in cubyl cation cannot assist much from an extremely strained olefin cubene. However, the authors expected that photochemical fission of the C—I bond would still provide sufficient energy for production of the cation intermediate. 

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