Why Is Ring Strain Alone Unable to Fully Explain the Rate Accelerations of Oxirane and Thiirane in Nucleophilic Substitution; Conference paper

摘要

Nucleophilic substitution has long been recognized as one of the most important reactions in synthetic organic chemistry. Because of their predictable regio- and stereochemistry, reactions proceeding through the SN2 mechanism have received considerable attention. The ease of displacement of the leaving group plays a significant role in determining the reactivity of a given substrate; however, even compounds that contain extremely poor leaving groups such as ethers, amines or thioethers are reactive and synthetically useful if these functional groups are structured in such a manner that the heteroatom is incorporated into a three- or four-membered ring. Relief of ring strain in the transition state is typically cited as the sole source of the increased reactivity of heterocycles with nucleophiles relative to acyclic analogs. Over a decade ago, however, it was noted that ring strain alone is insufficient to account entirely for rate increases in SN2 reactions relative to suitably chosen acyclic model compounds. Lillocci found the rate of the cleavage reaction of an aziridinium triflate with acetonitrile in the presence of N- ethyldiisopropylamine to be at least 103 times faster than that of the corresponding azetidinium salt in spite of similar ring strain energies. This phenomenon has also been observed in nucleophilic cleavage of these ions by sodium methoxide. In a related reaction, Stirling observed that the rate of ring cleavage of cyclopropanols under basic conditions was considerably faster than that of cyclobutanols. Recently, Hoz recognized that an additional factor, as yet uncharacterized, must be included to explain the high computed reactivity of anionic nucleophiles with 3-membered relative to 4-membered heterocycles.