Reaction Mechanism of Organocatalytic Michael Addition of Nitromethane to Cinnamaldehyde: A Case Study on Catalyst Regeneration and Solvent Effects

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.

Scheme 1. Organocatalytic Michael Addition of Nitromethane to Cinnamaldehyde

Figure 1

Schematic representation of the reactants complex (RC), products complex (PC), and intermediate states located along the catalyzed Michael addition of nitromethane to cinnamaldehyde in DCM. R = NH-biotin. The direct noncatalyzed reaction from RC to PC is indicated in the dashed rectangle. Labels of key atoms are shown in the RC panel.

Figure 2

M06-2X/6-31+G(d,p) free energy profiles for the catalyzed Michael addition of nitromethane to cinnamaldehyde obtained in DCM (orange line) and in aqueous solution (blue line).

Figure 3

Representation of the TS structures obtained along the reaction coordinate of the catalyzed Michael addition of nitromethane to cinnamaldehyde in DCM and in water. Key interatomic distances are reported in Å, while imaginary frequencies are reported in cm^–1.

Figure 4

Schematic representation of the reaction mechanism of the noncatalyzed Michael addition of nitromethane to cinnamaldehyde in DCM.

Figure 5

Free energy profile for the uncatalyzed Michael addition of nitromethane to cinnamaldehyde obtained in DCM (orange line) and in aqueous solution (blue line).

Figure 6

Representation of the TS structures obtained along the reaction coordinate of the uncatalyzed Michael addition of nitromethane to cinnamaldehyde in DCM and in water. Key interatomic distances are reported in Å, while imaginary frequencies are reported in cm^–1.

Figure 7

Frontier orbital representation of isolated cinnamaldehyde (left) and the iminium intermediate, INT-B (right). Results computed with TDDFT at the M06-2X/6-31G(d,p) level in DCM and in water.