Nucleophilic substitution with inversion of configuration at the nucleophile

Clayton H. Heathcock, Thomas W. Von Geldern, Carlito B. Lebrilla, Wilhelm F. Maier

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19 Scopus citations


Treatment of the tricyclic amino alcohol methanesulfonate 1 with lithium chloride in dimethylformamide gives only the tricyclic chloro amine 2, while similar treatment of 1 with sodium thiophenoxide in DMF produces solely the rearranged skeleton 3. Analogous skeletal rearrangement is seen in the reaction of alcohol 4 with phosphorus oxychloride and in the pyrolysis of the (thiocarbonyl)imidazolide 6. It is proposed that all of these reactions proceed through a tetracyclic azetidinium ion, B, and that thioether 3, chloride 5, and compound 7 are products of kinetic control, while chloride 2 is the product of thermodynamic control (Schemes I and II). It is unusual that chloro amine 5, which is forced to undergo SN2 reaction with net inversion of configuration at nitrogen, is substantially more reactive than its isomer 2, in which the substitution occurs with retention of configuration at the nucleophilic center. Several theoretical calculations have been carried out in order to assess the importance of possible stereoelectronic and steric effects. The marked preference of azetidinium ion B to react at C-4 rather than at C-2 can be nicely explained by steric effects; there is no indication of stereoelectronic control in the reactions of B.

Original languageEnglish (US)
Pages (from-to)968-972
Number of pages5
JournalJournal of Organic Chemistry
Issue number7
StatePublished - 1985

ASJC Scopus subject areas

  • Organic Chemistry


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