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.