Abstract
Cyclodextrin-enhanced cinchona organocatalysis in a coiled tube continuous–flow reactor coupled with a nanofiltration recycle unit for asymmetric synthesis.
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•Cinchona-squaramide and -thiourea organocatalysts were anchored to cyclodextrins.•Cyclodextrin-anchored organocatalysts were in situ recovered via organic solvent nanofiltration.•Quantum chemical studies of the cyclodextrin–catalyst–reagents complex system.•Correlation between the enantiomeric excess and the Kamlet–Taft parameters.•Continuous catalysis–separation using coiled tube plug flow reactor coupled with nanofiltration.
This work presents a cyclodextrin-enhanced organocatalytic method from molecular to process design. Cinchona-thiourea and -squaramide catalysts were covalently anchored to inherently large, stable and well-defined permethyl-β-cyclodextrins. The asymmetric catalysis was successfully demonstrated on the Michael reaction of 1,3-diketones and trans-β-nitrostyrene. Both emerging green and conventional solvents were screened for the asymmetric addition (up to 99% ee), and the Kamlet–Taft solvent parameters were correlated to the enantioselectivity. Quantum chemical modelling revealed that the catalyst anchoring resulted in favorable structural changes, and stronger intermolecular interactions between the catalyst and the reagents. Continuous organocatalysis was performed in coiled tube flow reactor coupled with a membrane separation unit, which allowed complete recovery of the catalyst and 50% solvent (2-MeTHF) recycling. The 100% conversion, 98% purity, 99% ee, 100% in-line catalyst recovery, and 80 g L−1 h−1 productivity makes it an attractive catalytic platform.