Unrevealing the Nitrogen Elusive Chirality of 3‐Sulfanyl and 3‐Sulfinyl N‐Tosyl Isoindolinones by ECD Spectra: An Experimental and Theoretical Investigation

The nitrogen–hybridization/pyramidalization of two solvated N‐tosylisoindolinone derivatives having chiral residues in adjacent (I) or adjacent and distal (II) position has been investigated by a theoretical‐computational procedure based on Molecular Dynamics simulations and Quantum–Chemical calculations. After validation of our methodology in providing a reliable repertory of conformations by modeling the electronic circular dichroism (EDC) spectra, the electronic features associated with N‐pyramidalization were further characterized through Natural Bond Order (NBO) analysis. Comparing against the N‐geometry observed in crystal structures as a reference, our findings reveal that the presence of neighbouring chiral centers induces a more pronounced N‐pyramidalization in solution than in the solid state, both in I and II. Furthermore, NBO analysis confirms that the N‐lactam mostly retains the sp2 character but exhibits slight configurational distortion (ξI=13°; ξII=21°), which significantly influences the chiroptical activities observed in ECD spectra of I and II. This substantiates the N‐lactams as configurationally stable chiral centers. A combined theoretical–experimental strategy revealed the chiral, configurationally stable nature of solvated tricoordinate N‐lactams of the title compounds, offering reliable insights into their chiroptical properties.