The inclusion complex formed between β-cyclodextrin (β-CD) and 3-(5,6-dihydro- [1, 3]dithiolo[4,5-b] [1, 4]dithiin-2-yl)-4-hydroxy-5-methoxybenzaldehyde (DTMB) was investigated using a combined semi-empirical and density functional theory (DFT) approach. Two possible inclusion orientations of the guest molecule within the β-CD cavity were examined in both gas phase and aqueous medium. Initial geometry optimizations were performed using the PM3 method, followed by full optimizations at the MN15L/6-311G(2d, p) level of theory. Complexation, interaction, and deformation energies, as well as thermodynamic parameters, were calculated to assess the stability of the inclusion complexes. The results indicate that orientation B, in which the aromatic moiety of DTMB is oriented toward the primary hydroxyl rim of β-CD, is energetically more favorable in both phases. Frontier molecular orbital analysis and global reactivity descriptors further support the higher stability of this orientation. Natural bond orbital (NBO) and noncovalent interaction (NCI) analyses reveal that the complexation process is mainly governed by van der Waals interactions and hydrogen bonding. In addition, 1H NMR chemical shifts were computed using the GIAO method and show good agreement with the experimental data, providing further validation of the proposed inclusion modes. Overall, this study offers detailed insights into the structural features, energetics, and interaction mechanisms of DTMB/β-CD inclusion complexes and contributes to a better understanding of host–guest systems involving sulfur-rich aromatic compounds.
