Examining Kinetics and Product Inhibition in the Catalytic Intramolecular Schmidt Reaction

In the intramolecular Schmidt reaction of alkyl azides and ketones, stoichiometric acid loading has often been necessary to overcome product inhibition, where the product amide irreversibly binds to the acid and forms a catalytically inactive complex. This limitation has been circumvented by the use of catalytic TiCl4 or AcCl in HFIP. Despite this advance, several issues and details of product inhibition in the intramolecular Schmidt reaction remain unexplored. Here, we report kinetic studies and a variable time normalization analysis to experimentally determine the rate law and demonstrate the influence of product inhibition on the kinetics of the intramolecular Schmidt reaction. In addition, computational chemistry, basicity parameters, and additive studies were used to establish the relationship between basicity and the reaction rate. The structures of HCl adducts of product lactams were also determined using X-ray crystallography. Overall, this work establishes a more precise theoretical and experimental understanding of the mechanism of product inhibition and its role in the kinetics of the intramolecular Schmidt reaction.