Conformational Landscape of 1,3-Bis[oxo/thioxo-thiazolinyl] Aromatic Compounds with Two C-N Chiral Axes: A ¹⁵N NMR...

DFT calculations have been used to investigate the conformational landscape of a library of 1,3-bis[oxo/thioxo-thiazolinyl] aromatic compounds with two stereogenic C_sp2-N_sp2 axes (63 compounds). The good correlation between the experimental and DFT-calculated rotational barriers for five of these compounds allowed the use of DFT as a predictive tool for the entire library. The library was generated by systematically varying the position and number of methyl substituents on the central aromatic ring and on the two oxo/thioxo-thiazoline rings. The predicted rotational barriers span from 3 to 58 kcal/mol at 298.15 K, placing these structures across all three categories defined by LaPlante's classification of rotational stereoisomers. DFT calculations unveiled the preferred rotational pathways, highlighting the main factors influencing the energetic cost of the rotation: intramolecular donor-acceptor interactions, ring distortions, and the nature of the exocyclic heteroatom of the thiazoline rings. The structure-rotational barrier relationship obtained for these molecules with two C-N stereogenic axes represents reference values for the design of atropisomers with aryl-thiazoline scaffolds for various applications, such as chiral bioactive compounds. Also, ¹⁵N NMR data are reported for some of the synthesized compounds.