Computational Design and Gram-Scale Validation of Organocatalysts for Eco-Sustainable Chemical Synthesis

Abstract

Metal-free organocatalysis provides a sustainable alternative to traditional metal-based methods for carbon carbon bond formation. In this study, twelve novel organocatalysts were designed, synthesized, and evaluated for asymmetric aldol, Michael addition, and Stetter reactions under mild, ambient, solvent-free, or aqueous conditions. The catalysts delivered excellent performance, achieving up to >99% enantiomeric excess (ee), an E-factor of 2.4, process mass intensity (PMI) of 11.8, and turnover numbers (TON) exceeding 23,400. Catalyst development combined ab initio density functional theory (ωB97X-D/6-311+G) with quantum-computing-assisted graph neural networks (R² = 0.97), enabling accurate screening of 1.2 million virtual scaffolds. The lead squaramide catalyst exhibited >99% conversion and ee in solvent-free Michael additions, validated by X-ray and non-covalent interaction analyses. Life-cycle assessment revealed up to 90% CO₂e reduction compared to Pd/C systems. Overall, this work highlights organocatalysis as a viable, green, and scalable approach for fine chemical synthesis aligned with EU Green Deal objectives.