A comparative study of inter- and intramolecular C-H aminations: Mechanism and site selectivity

Abstract

The mechanism and site selectivity of inter-and intramolecular C-H bond aminations have been studied using the M06L method. The similarities and differences between inter- and intramolecular aminations are discussed in detail, with an emphasis on the correlation between reaction pathway and site selectivity. Our calculations show that, for both inter- and intramolecular aminations, the triplet stepwise pathway is of H-atom transfer character, while the singlet concerted pathway is of hydride-transfer character. More importantly, for intermolecular C-H bond amination, the triplet stepwise pathway is favored over the singlet one. Conversely, in the intramolecular case, the singlet concerted pathway is dominant. This inverse preference for the singlet-triplet pathway for inter- and intramolecular aminations is an important contributing factor to their inverse site selectivity. The calculated benzylic-to-tertiary (B:T) C-H amination ratios for the inter- and intramolecular aminations are 13:1 and 1:17, respectively, which are in agreement with experimental results of 7:1 and 1:7. Specifically, intermolecular amination favors oxidation of the secondary benzylic C-H bond over the tertiary C-H bond, whereas the intramolecular case shows a preference for tertiary C-H amination. This inverse site selectivity can be mainly attributed to the fact that inter- and intramolecular aminations proceed according to the different state pathways mentioned previously, where the enthalpic and entropic contribution to free energy differ. In addition, there is a higher energy barrier for the cleavage of the C-H bond in the intermolecular amination than in the intramolecular case, due to a much larger negative entropy of activation for the former. These results provide some valuable information for the design and deconstruction of highly selective and highly efficient C-H amination systems.