Lone-Pair-Induced Topicity Observed in Macrobicyclic Tetra-thia Lactams and Cryptands: Synthesis, Spectral Identification, and Computational Assessment

The
synthesis of a rigid macrobicyclic N,S lactam L1 and
a topologically favored in/in N,S cryptand L2 are reported
with X-ray structure analysis, dynamic correlation NMR spectroscopy,
and computational analysis. Lactam L1 exhibits two distinct
rotameric conformations (plus their enantiomeric counterparts) at
25 °C, as confirmed via NMR spectroscopy and computational analysis.
Coalescence of the resonances of L1 was observed at 115
°C, allowing for complete nuclei to frequency correlation. Combining
computational investigations with experimental data, topological equilibria
and relative energies/strain relating to the perturbation of the pore
were determined. Due to the increased conformational strain of the
N2S2 template, the nitrogen lone pairs in L2 elicit a unique transannular interaction, resulting in
a thermodynamically favored in/in nephroidal racemate. The combination
of preferred topology, steric relief, and electronic localization
of L2 induces a chiral environment imparted through the
amine with a computed inversion barrier of 10.3 kcal mol–1.