Interplay of Nitrogen-Atom Inversion and Conformational Inversion in Enantiomerization of 1H-1-Benzazepines

Abstract

A series of 2,4-disubstituted 1H-1-benzazepines, 2a-d, 4, and 6, were studied, varying both the substituents at C2 and C4 and at the nitrogen atom. The conformational inversion (ring-flip) and nitrogen-atom inversion (N-inversion) energetics were studied by variable-temperature NMR spectroscopy and computations. The steric bulk of the nitrogen-atom substituent was found to affect both the conformation of the azepine ring and the geometry around the nitrogen atom. Also affected were the Gibbs free energy barriers for the ring-flip and the N-inversion. When the nitrogen-atom substituent was alkyl, as in 2a-c, the geometry of the nitrogen atom was nearly planar and the azepine ring was highly puckered; the result was a relatively high-energy barrier to ring-flip and a low barrier to N-inversion. Conversely, when the nitrogen-atom substituent was a hydrogen atom, as in 2d, 4, and 6, the nitrogen atom was significantly pyramidalized and the azepine ring was less puckered; the result here was a relatively high energy barrier to N-inversion and a low barrier to ring-flip. In these N-unsubstituted compounds, it was found computationally that the lowest-energy stereodynamic process was ring-flip coupled with N-inversion, as N-inversion alone had a much higher energy barrier.

The Synthesis and Base-Induced Breakdown of Triaryl 1,4-Oxathiins—An Experimental and DFT Study

“…To minimize computational cost, explicit solvation was excluded from the calculations due to the computational intensity of the optimizations induced by the size of the molecular system. Transition state structures possessed a single imaginary frequency and were further validated by intrinsic reaction coordinate (IRC) calculations and/or analysis of the displacement vectors [47]. The vibrational mode for that imaginary frequency was fully consistent with the atomic motion anticipated for the reaction under analysis.…”

Stereochemical Stability of Planar-Chiral Benzazepine Tricyclics: Inversion Energies of P- and S-Alkene Ligands

“…The ring flip involves a gross steric interaction between the N-substituent and the abutting aromatic ipso -H atoms. Consequently, the transition state geometries of compounds 2 – 7 show large torsion angles, φ, measured along the C···C vector connecting the ipso -C–H units (see Table ), which is a common phenomenon for seven-membered heterocycles. , Moreover, structural factors facilitating or hindering the opening of the angle θ, spanned by C–N–C (or the corresponding angle in tropylidenes), will affect the inversion barrier. Among P- and S-alkene compounds, molecules with a large mean value of the angle θ in the ground and transition states have low inversion barriers because steric repulsion is relieved upon opening of the angle θ (Figure ).…”

Construction of 5H‐Dibenzo[c,e]azepine Framework from Dibenzothiophene Dioxides andN‐Benzylimines through SNAr Reactions

“…344.1560). Atropisomerism of rigid seven-membered rings including benzazepines [4,31,32] and dibenzocycloheptanes [33][34][35] were reported in the literature. We also investigated the atropisomerism of 3aa and 4 computationally, which is described in Supporting Information.…”