S_N2 On A Tertiary Carbon

Here’s another tenet of organic chemistry that can be crossed out of the textbooks: Tertiary carbons can’t undergo bimolecular nucleophilic substitutions, also known as S_N2 reactions. Mark Mascal, Nema Hafezi, and Michael D. Toney of the University of California, Davis, have demonstrated that the tertiary carbons of the oxonium salt 1,4,7-trimethyloxatriquinane are susceptible to S_N2 attack by the azide anion (shown in scheme below) (J. Am. Chem. Soc., DOI: 10.1021/ja103880c). Granted, the tertiary alkyl oxonium salt isn’t your typical electrophile. It withstands classic solvolysis conditions, resisting any reaction after several hours in refluxing ethanol. And reaction with basic nucleophiles, such as methoxide, cyanide, and acetate, leads only to elimination reactions. The researchers conclude that because an S_N1 reaction route is excluded, the only reasonable mechanistic interpretation for the reaction is the S_N2 pathway, even though the substitution occurs at a tertiary carbon. To back up its conclusion, the team studied the reaction’s dynamics and found second-order kinetics. “With the exception of unusual cases in which carbocation formation is electronically disfavored, there are no previous examples to our knowledge of substitution reactions at tertiary alkyl centers that proceed exclusively with second-order kinetics,” the researchers note.