Stablility of Atropisomers in Medium-Sized Ring: DFT insights of Dibenzolactam Chirality

Medium-sized rings have emerged as critical scaffolds in the field of drug development. Owing to their unique conformational features and the existence of multiple isomeric forms, even subtle structural modifications can give considerable rise to pronounced differences in chemical properties. This study presents a comprehensive theoretical analysis of the free energy barriers of interconversion of R-series and S-series of enantiomers (ΔG^‡) governing the atropisomerization and stereochemical stability of 7- (1a), 8- (2a), and 9-membered-ring dibenzolactams (3a) using density functional theory (DFT), which complement experimental findings. The computed ΔG‡ values for racemization agree with experimental trends with a uniform deviation for each compound calculated, revealing enhanced stability for the 8-membered-ring derivatives (ΔG^‡ = 27.86 kcal/mol) compared to 7- (ΔG^‡ = 25.18 kcal/mol) and 9-membered (24.39 kcal/mol) analogs, attributed to its rigid cage-like conformation. The enhanced conformational flexibility of 9-membered-ring dibenzolactams (3a) leads to a further reduction in their ΔG^‡ , thereby facilitating a more facile crossing of the transition state. Based on the ΔG^‡ for methylated derivatives (17b and 18a), we successfully reproduced the equilibrium constants reported experimentally, and our computed free energy barriers exhibited trends consistent with those observed in experiment.