Diagnosing conformational preferences of lower-rim-functionalized thiophene resorcin[4]arenes and pyrogallol[4]arenes...

Conformational preferences and interconversion events between different conformers can hinder the prediction and control of the supramolecular interactions that occur between molecular building blocks and the frameworks they form. Although experimental and computational methods can aid in our understanding of conformational trends and thermodynamic analysis for specific systems, low interconversion barriers between conformers, multiple configurations existing in equilibrium, and solvent preferences pose significant challenges, and a priori assessment of these properties is limited by the scope of methods like density-functional theory. In this endeavor, the discovery of different conformers of a novel aromatic derivative of resorcin[4]arene-as a result of two distinct synthetic methodologies-led to a deeper investigation of the molecular interactions governing this outcome. Herein, we present a computational approach that quantifies conformer stability via molecular dynamics (MD) simulations. Using C-thiophene-substituted resorcin[4]arene (Rs[4]Thio) as a model system, we evaluated the relative stabilities of the three primary conformers-boat, cone, and chair-in dimethyl sulfoxide (DMSO). By analyzing geometric parameters such as upper-rim phenol carbon distances and solute-solvent interactions, we established the observed stability of the boat conformer, alongside the conformational preferences and conformerism of Rs[4]Thio. This methodology was then extended to C-thiophene-pyrogallol[4]arene (Pg[4]Thio) in DMSO as well. For Pg[4]Thio, the chair conformer was found to be the most stable structure and was observed as a part of the asymmetric unit cell in a reported single-crystal X-ray structure, further supporting the reliability of our approach as a predictive tool. The ability to corroborate experimentally demonstrated conformer preferences using our computational approach provides a robust framework for modeling and predicting the formation of key supramolecular interactions and their subsequent architectures.