Understanding chiral proton organocatalysis using cinchonium derivatives

05 May 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


This work presents a detailed mechanistic study of a quininium-catalyzed aza-Michael reaction, providing essential infor-mation for the development of reactions in chiral proton organocatalysis (CPO). The use of cinchona derivatives as chiral proton catalysts demonstrates their potential beyond their conventional roles as base-promoted and phase-transfer cata-lysts. Competitive reaction pathways are studied using density functional theory (DFT), wavefunction theory, and microki-netic simulations. Additionally, theoretical studies are complemented with experimental titration and kinetic techniques to verify the intrinsic details of the reaction. The mechanistic study reveals a complex hydrogen bond network formed in the rate- and selectivity-determining step (hydrazide addition), involving four noncovalently attached components that favor a more efficient substrate docking in the R transition state. Notably, while counteranions are often considered innocent reac-tion components, carboxylic anions are crucial in understanding reaction yield and enantioselectivity, as they act as nucleo-phile-activating bases. Overall, this study introduces cinchonium derivatives as new options for CPO and provides a thor-ough mechanistic analysis that may be critical in expanding this underdeveloped type of catalysis.


chiral proton organocatalysis
cinchonium derivatives
computational chemistry
mechanistic studies
aza-Michael addition


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