Hierarchical Porous Silica Aerogel Monoliths for High-Flow Rate Continuous-Flow Enzyme Catalysis

The use of immobilized enzymes in the continuous-flow synthesis of fine chemicals enables the development of a sustainable chemical industry. However, biocatalysis with immobilized enzymes in packed bed reactors is limited by the trade-off between activity and stability, diffusion limitation, and pressure drop. Here, a hierarchical porous silica aerogel monolith (HPSAM) microreactor encapsulating two coupled oxidoreductases was designed and prepared by the sol-gel method combined with an ice templating and freeze-drying technology. The HPSAM has a uniform and open porous structure characterized by 10-20 μm flow-through macropores, and the kinetic analysis of the immobilized enzyme indicates that the reaction is not diffusion limited. The HPSAM microreactor can be operated at flow rates up to 20 mL/min (1.06 × 10^-3 m/s) for a single reactor. As exemplified by the synthesis of chiral lactones, 30 mM (R)-γ-decactone (3c) was obtained in 13 s with 82% conversion and 99% ee, affording a high space-time yield (STY, 27,184 g L^-1 day^-1) that was 23 times higher than the maximum STY reported for batch reactions. The microreactor maintained consistent performance throughout 2 weeks of continuous operation, with the total turnover number (TTN) of SmCR_V4 reaching 1.05 × 10⁵ during this period. Five chiral lactones were successfully synthesized by using this approach via flow asymmetric reduction. The HPSAM microreactors stored at 4 and 25 °C maintained excellent catalytic performance for at least 4 weeks.