Atropisomeric Properties of 5N‐Benzoyl‐1,5‐benzodiazepin‐2‐ones: Substituent Effects on Rotation around the Ar−N(CO) Axis

Abstract

Abstract5N‐Benzoyl‐1,5‐benzodiazepin‐2‐ones with various substituents were synthesized and their atropisomeric properties were analyzed. For the rotational isomers (E/Z) based on the amide bond [N−C(=O)], the E‐isomers were preferentially formed regardless of the substituents. Atropisomers (aR/aS) due to the Ar−N(CO) (sp2‐sp2) axis were isolated using chiral HPLC, and the rotational barrier (ΔG≠) in thermal isomerization was measured. The rotation barrier about the Ar−N(CO) axis was affected by both the substituents at the C6‐position and the p‐substituents on the benzoyl group. The substituents at C6 (R1) caused both steric and electronic effects. On the other hand, the p‐substituents (R2) on the benzoyl group caused electronic effects: the electron‐donating group (EDG) lowered the ΔG≠ value, whereas the electron‐withdrawing group (EWG) raised it. The ΔG≠ values were linearly correlated with the magnitude of the electronic effect (Hammett σ constants) of functional groups (R2). The EDG causes an increase in the electron density on the carbonyl moiety in the amide, which may disturb the planarity of the amide bond, resulting in a decrease in the ΔG≠ value.