Over the course of millions of years, nature has perfected the art of catalysis to an extent that only recently researchers are beginning to fully understand and emulate. The efficiency with which enzymes promote biologically relevant reactions has been known for a few decades, but it is only in the past several years that species that utilize similar catalytic mechanisms have been investigated. A class of catalytic materials that has received growing attention lately for its ability to carry out aldol and aldol-type reactions, similar to their biological counterparts, is organocatalysts. These species promote reactions that are fundamental for the creation of carbon-carbon, carbon-nitrogen, and carbon-oxygen bonds and are thus crucial for the formation of complex molecules from smaller hydrocarbons. L-proline, an amino acid, has been demonstrated to catalyze the direct aldol-type reactions without the need for modification of the carbonyl compounds. Additionally, the strength of L-proline as a catalyst lies in the fact that it is inexpensive, operates at low temperatures, and has been shown to function when attached to a heterogeneous support. Nevertheless, there exists a practical limitation to the use of L-proline as a catalyst. Most proline-assisted aldol reactions require long reaction times with low turnover number.

As a first step towards realizing the promise of organocatalysts, we are investigating the kinetics of the L-proline catalyzed a-aminoxylation between propionaldehyde and nitrosobenzene at the molecular level. Unlike the L-proline assisted aldol reactions, a-aminoxylation has been shown to exhibit much higher yields and turnover frequencies. This may be due to an observed auto-acceleration phenomenon that is suspected to arise from the formation of a product-catalyst hydrogen-bond complex, which alters the reaction pathway and lowers the activation barrier of the rate-limiting step.

There are currently reports in the literature that investigate the origins of selectivities in proline-catalyzed a-aminoxylations. However, the complete reaction pathway is still unknown. We are studying the mechanism for the reaction between propionaldehyde and nitrosobenzene which is believed to proceed through the creation of an enamine intermediate similar to what is involved in the aldol processes aided by Type I aldolase and catalytic antibodies. In the proposed system, all intermediates and transition states were located using density functional theory with the B3LYP functional and the 6-31+G(d,p) basis set. In order to locate the geometry of all intermediate species with the lowest electronic energy, relaxed potential energy scans were performed. As most aldol reactions, a-aminoxylation occurs in the presence of a solvent such as DMSO, CHCl3, etc. To capture these effects, the conductor-like polarizable continuum solvation model (C-PCM) as implemented in the Gaussian 03 computational chemistry software and DMSO with a dielectric constant of 46.7 as the solvent were used. All transition states were verified by the presence of a single imaginary frequency and the internal reaction coordinate (IRC) was followed in both directions to the respective intermediates.

In the course of the reaction, certain chiral centers and double bonds are created and/or destroyed. Therefore, multiple reaction channels from the reactants to the final product were considered. Additionally, reaction rate parameters were calculated using transition state theory, and microkinetic modeling was carried out. Finally, the experimental and theoretical results are compared to assess the validity of the proposed mechanism.