On the conformation of 8-membered ring heterocycles - Dynamic and static conformational analysis of acylated hexahydrobenzazocines

A high-field NMR analysis of several acylated hexahydrobenzazocines indicates that, surprisingly, ring methylene groups are typically diastereotopic at room temperature, as the barriers for the process of enantiomerization of the eight - membered ring are much higher than expected. It is shown that ring inversion is correlated (but not concerted) with rotation of the amide moiety, as the carbonyl is forced out of conjugation with the nitrogen in the transition state. A detailed analysis of vicinal proton-proton coupling constants, supported by molecular mechanics calculations, indicates that these compounds exist at room temperature as a mixture of fast-interconverting conformers of the octacycle. This is proved by the observation of two species in the ¹³C NMR spectrum of the parent compound, at temperatures below -90°C.