Abstract
The Michael addition of nitromethane to cinnamaldehyde has been computationally studied in the absence of a catalyst and the presence of a biotinylated secondary amine by a combined computational and experimental approach. The calculations were performed at the density functional theory (DFT) level with the M06-2X hybrid functional, and a polarizable continuum model has been employed to mimic the effect of two different solvents: dichloromethane (DCM) and water. Contrary to common assumption, the product-derived iminium intermediate was absent in both of the solvents tested. Instead, hydrating the C1–C2 double bond in the enamine intermediate directly yields the tetrahedral intermediate, which is key for forming the product and regenerating the catalyst. Enamine hydration is concerted and found to be rate-limiting in DCM but segregated into two non-rate-limiting steps when the solvent is replaced with water. However, further analysis revealed that the use of water as solvent also raises the energy barriers for other chemical steps, particularly the critical step of C–C bond formation between the iminium intermediate and nucleophile; this consequently lowers both the reaction yield and enantioselectivity of this LUMO-lowering reaction, as experimentally detected. These findings provide a logical explanation to why water often enhances organocatalysis when used as an additive but hampers the reaction progress when employed as a solvent.
Highlights
Secondary amine organocatalysts have been widely used in organic synthesis as they are known to be multifunctional and able to mediate a plethora of chemical transformations.[1−3] Because they drive the progress of a reaction by inducing covalent intermediate formation, performing acid/base reaction, and controlling stereoselectivity via hydrogen bonding and steric effects, secondary amine organocatalysts are often referred to as the minimalist versions of enzymes.[3]
The Michael addition of nitromethane to α,β-unsaturated aldehyde catalyzed by a pyrrolidine-derived organocatalyst has been investigated at the density functional theory (DFT) level with a polarizable continuum model to mimic the effect of dichloromethane (DCM) and aqueous solution (Scheme 1)
The hydroxyl group of the newly generated tetrahedral species INT-A abstracts a proton from nitromethane, generating a water molecule and an ion pair that contains the iminium intermediate INT-B
Summary
Secondary amine organocatalysts have been widely used in organic synthesis as they are known to be multifunctional and able to mediate a plethora of chemical transformations.[1−3] Because they drive the progress of a reaction by inducing covalent intermediate formation, performing acid/base reaction, and controlling stereoselectivity via hydrogen bonding and steric effects, secondary amine organocatalysts are often referred to as the minimalist versions of enzymes.[3] unlike enzyme catalysis, many organocatalytic reactions cannot tolerate a reaction medium that contains a large degree of aqueous solvent.[1−3] This has affected the development of many potential applications. In the case where proline was used as the catalyst, the corresponding iminium intermediate can lead to the formation of an off-target parasitic
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
