Crystal Engineering of Quinazoline Derivatives: Impact of Chalcogen Substitution and Substituent Bulk on 3D Architecture and Intermolecular Interactions

The design of crystalline materials with tailored properties requires a profound understanding of molecular self-assembly principles. Quinazoline derivatives are essential pharmacophores [1]; however, the influence of specific substituents on their solid-state packing remains insufficiently explored. This study investigates the "chalcogen-switch" strategy, examining how substituting sulfur with oxygen and modifying the hydrocarbon radical volume serves as a directional mechanism for controlling supramolecular architecture. Three quinazoline derivatives—benzylthio-, methylthio- and ethoxy-substituted—were characterized via single-crystal X-ray diffraction. Structural refinement was performed using the Olex2 software package [2]. To visualize and quantify the competition between π∙∙∙π stacking of the quinazoline cores and directional chalcogen-mediated contacts, Hirshfeld surface analysis and 2D fingerprint plots were generated using CrystalExplorer [3] . The compounds crystallize in the monoclinic system (P21 and P21/c) with very good quality (R1: 2.09%–3.96%). Hirshfeld surface analysis (dnorm) revealed that while H∙∙∙H contacts dominate (45–55%), chalcogen-mediated interactions primarily dictate the crystal growth direction. Thio-derivatives exhibit diffuse yet numerous S∙∙∙H contacts, promoting flexible packing. In the ethoxy-derivative, the presence of the rigid, highly electronegative oxygen atom leads to shorter and more directional O∙∙∙H contacts, significantly altering the fingerprint plot landscape by shifting the "spikes" toward lower di/de regions. Our study demonstrates that subtle structural modulation, such as replacing sulfur with oxygen or increasing substituent bulk from methyl to benzyl, can fundamentally redirect the supramolecular landscape of quinazolines. These findings establish a predictive framework for using selective chalcogen substitution as a crystal engineering tool to design heterocyclic materials with controlled physicochemical properties.

1. Kalakwade, A. et all. Results in Chemistry, 2026, 19, 102932.
2. Dolomanov, O.V. et all. Journal of Applied Crystallography, 2009, 42, 339-341.
3. Spackman, M.A. and Jayatilaka D. . CrystEngComm, 2009, 11,19-32.