The full catalytic cycle of the proline-catalyzed intermolecular aldol reaction of acetone and p-nitrobenzaldehyde in acetone solvent has been investigated by quantum chemistry at the G3(MP2,CC)//M062X/6–31+G(d)/SMD level of theory, and the results used to develop an ab initio kinetic model. Proline catalyzes the aldol reaction according to the enamine mechanism. The initial reaction between proline and acetone was reinvestigated, and a revised mechanism for enamine formation is proposed in which a second proline assists the process contributing to the enamine formation. Using various initial concentrations of proline while keeping the experimental ratio of water, aldehyde and acetone constant, we find that the enamine formation from the first-order to proline pathway dominates when the concentration of proline is low (<0.005 M); while the second-order enamine formation pathways contribute and then dominate as the proline concentration is increased. The relative rates of formation of the syn and anti-enamine are not important, as these interconvert via C–N bond rotation and equilibrate faster than their subsequent reaction, which follows the standard Houk/List mechanism. While the stereochemistry can be predicted from an analysis of the alternative C–C bond formation pathways, their relative contributions to the major and minor product yields are influenced by their subsequent rates of hydrolysis. Indeed, while C–C bond formation is normally considered rate determining, our kinetic simulations show that the kinetic model is more complicated than this and under typically used concentrations, the process of initial enamine formation, C–C bond formation and the initial stages of product release all contribute to the overall reaction rate. Using our kinetic model, we predict that yield and %ee are optimal for concentrations of [proline]=0.005 M, [acetone]=2.25 M, [aldehyde]=0.1 M, and [water]=0.6 M. Using excess acetone (up to 2.6 M) increases both conversion and %ee. Excess aldehyde increases %ee but decreases conversion, and excess catalyst increases the conversion but decreases %ee. Aside from the indirect effect of increasing the solubility of the proline catalyst, water increases both conversion and %ee up to a point, but at large concentrations (>1.0 M) excess water is expected to decrease %ee. Side reactivity, including aldol condensation, acetone self-aldolization, oxazolidinone formation and azomethine and 1-oxapyrrolizidine formation were all considered in our kinetic model but shown to have a negligible effect (<2%) on the yield and %ee over the full range of reaction conditions investigated.
- Kinetic modelling
- Proline-catalysed aldol reaction
- Quantum chemistry