Application of Density Functional Theory to Study the Mechanism of Alkali Metal Enolate Oxidation by N-sulfonyloxaziridines, Umpolung Amide Synthesis from Halo-Amino-Nitro Alkanes, Alkali-Metal Catalyzed Transfer Hydrogenation of Ketones, and Asymmetric Catalyzed Aza-Henry Reactions
Density functional theory (DFT) and other computational methods are useful tools for determining reaction mechanisms and the factors governing stereoselectivity. To illustrate the versatility of DFT methods, the following reactions were studied: (1) Li+, Na+, and K+ enolate addition to chiral N-sulfonyloxaziridines, stereoselectivity was found to be controlled by enolate, sulfonyl, and oxaziridine oxygen-cation chelation and steric contacts. From this study it was found that the mechanism proceeded in a SN¬1 rather than SN¬2 like fashion. (2) umpolung amide synthesis working from 1,1,1,1-halo-amino-nitro-alkanes leading to the finding that the amide oxygen originates from the nitro group but also from explicitly interacting water molecules in competing pathways. (3) alkali (Li+, Na+, and K+) metal-catalyzed transfer hydrogenation of acetophenone, the mechanism of which was found to proceed via a six-membered transition state affording direct hydrogen transfer to acetophenone generating the product phenylethanol. The TMEDA ligand had a profound effect in stabilizing the transition state which in turn, lowered the activation energy in comparison to the use of isopropanol ligands. Lastly, (4) asymmetric catalyzed Aza-Henry reactions. Controlling the stereoselectivity of such reactions catalyzed by HMeOQuin((Anth)Pyr)-BAM was an H-bonding manifold of specific hetero- and homonuclear hydrogen bonding motifs (N-H-O and N-H-N respectively) observed in the favored transition state structure (syn-(2S,3R)-TS(eq)). There was a central theme of sterics and other non-covalent interactions, such as - stacking or CH/ interactions, which also played significant roles in determining the stereoselectivity in the investigated reactions.