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

Abstract 5 N ‐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 (a R /a S ) due to the Ar−N(CO) (sp 2 ‐sp 2 ) axis were isolated using chiral HPLC, and the rotational barrier (Δ G ≠ ) in thermal isomerization was measured. The rotation barrier about the Ar−N(CO) axis was affected by both the substituents at the C 6‐position and the p ‐substituents on the benzoyl group. The substituents at C 6 (R 1 ) caused both steric and electronic effects. On the other hand, the p ‐substituents (R 2 ) on the benzoyl group caused electronic effects: the electron‐donating group (EDG) lowered the Δ G ≠ value, whereas the electron‐withdrawing group (EWG) raised it. The Δ G ≠ values were linearly correlated with the magnitude of the electronic effect (Hammett σ constants) of functional groups (R 2 ). 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 Δ G ≠ value.