Mechanistic Analysis of the C–H Amination Reaction of Menthol by CuBr2 and Selectfluor

The mechanism of the Ritter-type C–H amination reaction of menthol with acetonitrile using CuBr2, Selectfluor, and Zn(OTf)2, first disclosed by Baran and coworkers in 2012, was studied using a combination of online electrospray ionization mass spectrometry, continuous UV/vis spectrometric monitoring, and density functional theory calculations. In addition to corroborating Baran's original mechanistic proposal, these studies uncovered a second pathway to product formation, which likely only occurs in microdroplets. DFT calculations show that neither pathway has a barrier that is greater than 6.8 kcal/mol, suggesting that both mechanisms are potentially operative under ambient conditions.