To create a potential heterogeneous catalyst for the Domino Knoevenagel cyclo-condensation that produces tetrahydropyran derivatives in aqueous media, amorphous silica derived from rice husk ash (RHA) and cotton ball ash (CBA), were modified with 3-(chloropropyl)triethoxysilane, metformin, and copper acetate. Fourier transform infrared spectroscopy, thermal gravimetric, field emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray fluorescence, and Brunauer–Emmett–Teller were utilized to characterize the produced catalysts' structure. Based on the characterization results, extracted nano-silica exhibits higher surface area and catalytic activity than commercial nano-silica. These solid acid catalysts demonstrated outstanding catalytic activity for carbonyl group activation to react with malononitrile and 1,3 dicarbonyl compounds to give a high to excellent yield of the desired substances (80–97%). Without losing their catalytic activity and leaching, the catalysts can be recovered, separated by filtration or centrifugation, and reused for several cycles. This research indicates that the desired catalysts are stable and may be effectively exploited in organic synthesis. The high rate of reaction, mild reaction conditions, high product yield, low production cost, availability, and reusability are advantages of these catalysts that make them attractive for organic transformations. A comparison was also made between the catalytic behavior of the prepared natural catalysts and that derived from commercial-grade nano-silica. Based on analyses, the rice husk-derived nano-catalyst is described as a mesoporous catalyst with a higher specific surface area (143 m2 g−1) and narrower pore diameter (4.3 nm), showing excellent catalytic activity compared to cotton ball-based nanocatalyst and the catalyst prepared from commercial-grade nano-silica regarding reaction rate and yield.
