Biaryl moieties remain one of the most captivating structural motifs. They are frequently encountered in both pharmacologically active natural products and synthetic drugs. Axial chirality of biaryl systems has been widely employed in synthetic organic chemistry where they are used as chiral auxiliaries and catalysts to transfer chirality. When biaryls have bulky substituents in ortho positions they are prone to atropisomerism, a property of stereoisomerism defined by the high (&gt;25 kcal/mol) barrier of rotation. Despite considerable experimental data on cyclic biaryl atropisomers, there is only very limited research published on a mechanism of their atropisomerization. Detailed experimental and theoretical quantum mechanical analysis of the atropisomerization mechanism of an 8-membered dibenzolactam will be presented. Experimental Gibbs free activation energy, activation enthalpy, and activation entropy were established by temperature-dependent kinetic NMR experiments. Twelve energy minima and seventeen transition states associated with five different atropisomer interconversion pathways were determined by DFT calculations. Among the five possible atropisomerization pathways the lowest DFT-predicted Gibbs free activation energy 25.8 kcal/mol was in close agreement with the experimentally determined value of 26.8 kcal/mol. Theoretical activation entropies and enthalpies were also consistent with experimental data. The mechanism of atropisomer interconversion as a rotation of the eclipsed endocyclic coordinate in a clockwise or counterclockwise direction along the ring was proposed.

Atropisomerization of 8-membered dibenzolactam: Experimental NMR and theoretical DFT study

253rd National Meeting (2017)

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