Theoretical Study On The Mechanisms In Proline-Catalyzed Mannich Reaction Of Acetaldehyde Or Ketones

In the present paper, the density functional theory (DFT) is employed to study the reaction mechanisms in proline-catalyzed Mannich reaction of acetaldehyde or ketones. The mechanisms of the single and double Mannich reactions between acetaldehyde and N-Boc imines are clarified. Meanwhile, we performed a systemic density functional theory study on the transformations and the tautomeric equilibrium among different intermediates in the proline-catalyzed reactions of aldehydes or ketones. The effects of hydrogen-bond, steric hindrance and solvent on the reactions are examined. The present theoretical calculation results are expected to help us further understand the essence of proline-catalyzed Mannich reactions and design new catalyst.1. Theoretical study on the mechanisms of proline-catalyzed Mannich reaction between acetaldehyde and N-Boc iminesBy means of the density functional theory (DFT) combined with the polarized continuum model (PCM), the mechanisms of the single and double Mannich addition reactions between acetaldehyde and N-Boc imines were investigated. The transition states in the Mannich reactions of the enamine with the N-Boc imines were located at the Becke, Three-Parameter, Lee-Yang-Parr (B3LYP)/6-31G*level. For single addition of Mannich reaction, the energy difference between the transition states of different configurations correspond an enantiomeric excess value of90.58%(with out solvent) and98.46%(in acetonitrile) in favor of (S)-configuration product. For bis-addition of Mannich reaction, the calculated enantiomeric excess value is95.02%(without solvent) and98.57%(in acetonitrile) in favor of (S, S)-configuration product. These calculated results are in good agreement with the experimental results. The calculations clearly demonstrate that the hydrogen-bonding determines the stereochemistry of the reactions.2. The transformations and the tautomeric equilibrium among different intermediates in the proline-catalyzed reactions of aldehydes or ketonesThe enamines, iminium ions and oxazolidinones are thought to be the key intermediates in the proline-catalyzed reactions of aldehydes or ketones, but there is an extensive controversy about their roles. Here, the corresponding transition states connecting any two of the three kinds of species were located at the ωB97XD/6-311++G**level of theory. The calculations demonstrate that the oxazolidinones are the predominant species in both the gas phase and solvents; there exist tautomeric equilibrium among these species and the equilibriums are controlled by the employed solvents in the reaction. A new reaction pathway is present herein for the transformation between iminium ions and oxazolidinones through iminium ion-water complex and oxazolidinone-water complex. The calculations demonstrate that the rate-limiting step in proline-catalyzed Mannich reaction between acetaldehyde or keteones and N-Boc imines is the formation of the C-C bond rather than the intermediates tautomerization. These calculations rationalize the available experimental observations and can be valuable in optimizing the experimental conditions of asymmetric organic-catalyzed reactions of aldehydes or ketones.