The innovative PABSA-Pr-PMO catalyst represents a significant advancement in nanomaterial design for sustainable catalysis. By combining periodic mesoporous organosilica (PMO) with p-aminobenzenesulfonic acid (PABSA) via a co-condensation process followed by sequential integration, the material achieves a hierarchical structure with exceptional thermal stability, a high surface area, and uniform mesopores. These features create abundant, accessible active sites while ensuring robustness for repeated use. The precise engineering of Brønsted acidic sites from PABSA enhances proton-transfer efficiency, critical for activating C–H acids in multicomponent reactions. In the Traube–Schwarz reaction, PABSA-Pr-PMO catalyzes the synthesis of imidazopyrimidine derivatives—compounds with pharmaceutical relevance, including anticancer and antimicrobial properties—by efficiently coupling 2-aminobenzoimidazole, C–H acids, and aromatic aldehydes under mild conditions. The catalyst’s performance excels with ultralow loading , driving reactions to completion within 5 –15 minutes versus hours with conventional acids. Yields reach 90–99%, emphasizing precision in product formation.Its recyclability, maintaining >90% activity after five cycles, underscores economic and environmental benefits, aligning with green chemistry principles. The absence of toxic solvents or excessive energy input further reduces the process footprint. This protocol not only streamlines synthesis but also demonstrates scalable potential for industrial applications, offering a reusable, efficient alternative to homogeneous catalysts. By merging advanced nanomaterial design with sustainable reaction engineering, PABSA-Pr-PMO exemplifies a transformative approach to green chemical manufacturing, bridging molecular innovation with practical scalability.